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Muscle NMJ Nerve Spinal Ataxia Antibody & Biopsy Patient Information

CONGENITAL MYOPATHIES & WEAKNESS

CONGENITAL WEAKNESS Absent muscles Apoptosis Arthrogryposis Bethlem myopathy Broad A band Cap Carey-Fineman-Ziter Syndrome Central core Centronuclear (Myotubular) Congenital muscular dystrophies Cytoplasmic Body (Spheroid) Diarrhea & Deafness DOPA-responsive dystonia Excessive autophagy Fiber Type Size Disproportion Fingerprint body Focal FSH dystrophy Hyaline body (Myosin storage) IBM, Contractures & Ophthalmoplegia Mental retardation, X-linked Metabolic disorders Mitochondrial Multicore (Minicore) Myasthenic Syndromes Myotonic dystrophy Native American Myopathy Nemaline rod Neuropathic syndromes Ophthalmoplegias Perifascicular myopathy, neonatal Reducing body Sarcotubular (LGMD 2H) Skeletal disorders + Weakness Tel Hashomer camptodactyly Thin filaments: Excess Trilaminar myopathy Type 1 fiber smallness Williams-Beuren syndrome Woods-Black-Norbury syndrome Zebra body

CONGENITAL MUSCULAR DYSTROPHIES Adducted thumbs & Ophthalmoplegia Cerebellar atrophy CMD: 4p16 CMD + Cardiomyopathy: Titin; 2q24 CNS atrophy & absent large myelinated PN axons Desmin inclusions: SEPN1; 1p36 Fukuyama: Fukutin; 9q31 Integrin α-7: 12q13 Joint Hyperlaxity: 3p23 Junctional Epidermolysis Bullosa: Plectin; 8q24 Marinesco-Sjögren: SIL1; 5q31 Merosin (laminin α2-chain)   Deficient (MDC1A): 6q22   Normal: "Pure" form Mitochondrial structural changes Muscle-Eye-Brain Disorders Walker-Warburg: POMT1; 9q34 Muscle hypertrophy   Mental retardation   Respiratory failure (MDC1B): 1q42   Muscle hypertrophy (MDC1C): FKRP; 19q13   Severe retardation (MDC1D): LARGE; 22q12 Rigid spine with CMD   SEPN1: 1p35   Lamin A/C: 1q21   Other rigid spine syndromes Santavuori (Finnish): POMGnT1; 1p32 Ullrich   COL6A1; 21q22   COL6A2; 21q22   COL6A3; 2q37 Walker-Warburg: POMT1; 9q34 Walker-Warburg 2: POMT2; 14q24 General features   Other congenital weakness

ABSENT or WEAK MUSCLES Abdominal Brachial plexus Cardiofacial syndrome Depressor anguli oris Diaphragm Extraocular muscles   Blepharophimosis   Congenital fibrosis   Duane's syndrome   Möbius syndrome   Ptosis   Superior rectus Finger extensors Holt-Oram Palmaris longis Pectoral Peroneus tertius Poland syndrome Prune belly Psoas (CHILD) Thenar eminence Trapezius Batten

GENERAL

• Hypotonia: Clinical assessment
  • Traction response
    • Maneuver: Grasp child's hands; Pull to sitting position
    • Newborn: Head lags behind; Drops forward suddenly when upright posture is reached
    • Normal at 1 month: Minimal head lag; Flexion at the elbows, knees, and ankles
    • Premature infants < 33 weeks' gestation: Absent
  • Suspension: Vertical & Horizontal
  • Assessment of mother
    • History: Delayed walking or other motor functions; Skeletal or joint deformity
    • Strength
    • Myotonia
• CNS disease is the most common cause of congenital hypotonia
• Common features of presentation of Neuromuscular disorders in infants
  • Hypotonia
    • Posture with normal tone: Flexion at knees, hips, & elbows; Hips internally rotated
    • Posture with reduced tone: Head lag; Legs & arms extended
  • Weakness: Similar degrees in facial, appendicular, & axial muscles
  • Muscle mass: Reduced
  • Normal sensation
  • Skeletal disorders
    • Rigid spine syndromes
    • Contractures
• The best defined neuromuscular causes of congenital weakness include
  • Congenital Myopathies
    • Centronuclear (myotubular) myopathy
    • Nemaline rod myopathy
    • Central core disease
  • Congenital muscular dystrophies
  • Congenital presentations of adult dystrophies
    • Myotonic dystrophy
    • FSH dystrophy
  • Myasthenic syndromes
  • Neuropathic syndromes
• The diagnosis of syndromes with congenital weakness
  • Often based on morphological findings on muscle biopsy
  • Clinically distinctive congenital weakness syndromes
  • Centronuclear myopathy (X-linked)
    • EOM limitation
    • Respiratory failure
    • Mental changes
  • Nemaline myopathy (Severe infantile)
    • Facial & Axial weakness
    • High-arched narrow palate
  • Central core
    • Dominant inheritance: Often
    • History of malignant hyperthermia in family
    • Proximal weakness
  • Congenital muscular dystrophy
    • Severe weakness
    • Creatine kinase: High
    • Myopathy with early fibrosis
  • Spinal muscular atrophy
    • Proximal > Distal weakness
    • Tongue fasciculations
    • Respiratory dysfunction
    • DTR reduced
    • Face spared
  • Congenital hypomyelinating neuropathy
    • Distal > Proximal weakness
    • Sensory loss
    • DTR reduced
  • Cervical myelopathy
    • Quadriplegia, sparing face
    • Sphincter function abnormal

Central Core Disease ± Malignant Hyperthermia

• Genetic features¹¹
  • 251 mutations identified
  • Mutation types: Most missense; Few small deletions; Rare splice or insertion
  • Most central core families linked to Ryanodine receptor mutations
  • Some point mutations produce MH alone: Most in N-terminus region
    • Arg614Cys: Common (4% to 9%)
      • Also produces porcine MH
      • Higher thresholds & Smaller contractures compared to other mutations
    • Gly2433Arg: Common (4% to 7%)
    • Gly341Arg: 5% to 6% of British & Irish families
    • Arg2454Cys: Low trigger thresholds
    • Other: Gly248Arg; Arg552Trp; Arg614Leu; Val2168Met; Thr2206Met
  • Some mutations with Central core disease & MH
    • Arg163Cys; Ile403Met; Tyr522Ser; Arg2434His; Arg2454His
    • Severe & penetrant phenotype: Ile4898Thr
      • Mexican pedigree
      • C-terminal transmembrane/luminal region
      • Channel properties
        • Leaky
        • Activated by Ca⁺⁺ concentrations 4-fold lower than normal
  • Ryanodine receptor mutation with Central core disease, Rods & MH: Y4796C
  • Mutation hot spots
    • Cytosolic region of protein
      • Cytoplasmic N terminus: Malignant hyperthermia phenotype mutations in this region
      • Central cytoplasmic region: Gene segment 6400-6700
      • Mutations often occur at CpG dinucleotide sequences on coding or anti-sense DNA strand
    • 3' Transmembrane domain (Exons 93-105): 30% of cases
      • Malignant hyperthermia by IVCT
      • But no clinical complications with exposure to MH triggering agents
  • Mutations: Other
    • 2 different mutations in codons 614 (Same as pig 615), 2163, 2454 & 2458
    • 1 Mutation in C-terminus: Severe phenotype
• Ryanodine receptor protein
  • 560 kDa
  • Tetrameric structure
  • Associated proteins
    • Dihydropteridine receptor
    • FK506 binding protein
    • Calmodulin
    • Triadin
    • Calsequestrin
  • Skeletal muscle Ca⁺⁺ release channel
  • Allows release of Ca⁺⁺ from lumen of sarcoplasmic reticulum into sarcoplasm
  • C-terminal 20% of molecule forms transmembrane Ca⁺⁺ channel
  • N-terminal contains most ligand binding sites
  • Functions
    • Structural: Foot structure bridges gap between sarcoplasmic reticulum & t-tubule in skeletal muscle
    • Excitation-contraction coupling
• Mutation effects on protein function: More MHS + CCD with
  • Greater Sensitivity of mutant RYR protein to agonists caffeine & halothane
  • Higher resting Ca⁺⁺ in sarcoplasm
  • Lower endoplasmic reticulum Ca⁺⁺ stores
  • Reduced Size of releasable Ca⁺⁺ stores
• Clinical features: Several syndromes
  • Childhood or congenital onset
    • Genetics
      • Mutation hotspot: C-terminal exons 101–102
    • Developmental
      • Reduced Fetal movements
      • Breech presentation
    • Motor
      • Hypotonia
      • Proximal Weakness: Legs > Arms
      • Face: Mild weakness
      • Extraocular movements: Normal
    • Cramps
    • Skeletal: Congenital hip dislocation; Scoliosis; Foot deformities
    • Course: Non- or Slowly Progressive
  • Malignant Hyperthermia: Onset in teens
  • King-Denborough Syndrome
  • Limb-Girdle Syndrome: Onset in teens
    • Weakness: Proximal; Symmetric
    • Malignant Hyperthermia
    • Course: Slowly progressive
  • High serum CK: Asymptomatic
  • Ryanodine receptor mutation with Central core disease, Rods & Malignant Hyperthermia
    • Mutation: Y4796C
      • C-terminal channel forming domain
    • Epidemiology: French family
    • Clinical
      • Onset: Infantile
      • Weakness: Non-progressive; Hypotonia; Walk at 2.5 years
      • Contractures: Ankles
      • Course: Still walking in 3rd & 4th decades
    • Laboratory
      • Serum CK: Normal
      • Muscle biopsy: Central cores; Rods in areas without cores
      • In vitro contracture test: +
  • Central core disease with transient minicores³⁰
    • Genetics
      • Inheritance: Recessive
      • Homozygous missense mutation (P3527S)
    • Epidemiology: Algerian, Turkish & German families
    • Clinical
      • Onset: Infancy; Hypotonia
      • Weakness
        • Severity
          • Usually Moderate
          • Variable in families: Some patients with severe disability
        • Distribution
          • Axial muscles: Neck; Trunk flexors
          • Pelvic girdle
          • Hands: Moderate weakness; Wasting
          • Face: Some patients
        • Course: Stable or Slowly progressive
      • Joints
        • Hyperlaxity: Hand involvement; Other joints also involved; Patellar & Knee dislocations
        • Contractures: Some patients; Mild; Mainly at heels
    • Laboratory
      • Serum CK: Normal
      • Cardiac: Normal
      • MRI: Gluteus maximus & Quadriceps preferentially involved
    • Muscle biopsy
      • Childhood: Multiple minicores
      • Adult: Central cores; Muscle fiber loss
      • Type 1 muscle fiber predominance
  • Syndrome with Central core disease or Multicores
    • Genetics: Missense mutation Arg 4893Trp; Heterozygous
    • Dominant inheritance
  • Central core disease with fetal akinesia⁴⁵
    • Inheritance: Dominant or Recessive
    • Mutations
      • Recessive
        • R614C (Often associated with MH) & G215E
        • L4650P & K4724Q
      • Dominant: G4899E (Mother less severely affected)
    • Clinical
      • Pregnancy
        • Fetal akinesia
          • Differential Dx in NM disorders: Nemaline & Myotubular myopathies; Pena-Shokeir
        • Arthrogryposis: Multiple
        • Hydramnion
      • Post-natal
        • Hypotonia: Severe
        • Respiratory distress
        • Multiple malformations
      • Course
        • Death in some
        • Others with stable weakness after prolonged respiratory support
        • Ocular: Strabismus & Ptosis may develop
    • Muscle pathology
      • Central cores: Eccentric
      • Endomysial connective tissue: Increased
  • Central core disease: Mild phenotype & Recessive inheritance
    • RYR1 Genetics
      • Missense V4849I mutation
      • Same mutation also found in dominant malignant hyperthermia family
    • Disease pattern overlaps with mild phenotype of multicore disease
  • Congenital neuromuscular disease with uniform type 1 fibers (CNMDU1)⁶⁹
    • RYR1 genetics: Mutations
      • Heterozygous
      • Missense or Deletion
      • Location: C-terminal domain of RYR1; Pore forming segment
      • Mutations found in 40% of patients with CNMDU1
        • None in patients with mental retardation
    • Clinical: Congential myopathy
      • Onset: Congenital or early childhood
      • Weakness: Mild; Proximal; Face normal
      • Tendon reflexes: Reduced or Absent
      • CNS: No mental retardation
    • Laboratory
      • Serum CK: Normal
      • EMG: Myopathic
      • Muscle biopsy
        • All muscle fibers type 1 (> 99%)
        • No cores
        • Endomysial connective tissue: Normal or Mild increase
• Laboratory
  • CK
    • High in central core & MH patients
    • CK may be high in some asymptomatic carriers (G341R)
  • In vitro contracture test for malignant hyperthermia
    • Sensitivity: 97% to 99%
    • Specificity: 78% to 94%
• Muscle MRI⁵²
  • Features of muscle involvement
    • Muscle signal: Increased T1
    • Clinical correlation: Similar patterns with different clinical syndromes & RYR1 mutations
  • Thigh
    • Involvement: Vasti, Sartorius, Adductor magnus
    • Spared: Rectus, Gracilis, Adductor longus
  • Lower leg
    • Involvement: Soleus, Gastrocnemius, Peronei
    • Spared: Tibialis anterior
• Central core: Muscle pathology
  • Myopathy
    • Variable muscle fiber size
    • Increased endomysial connective tissue
    • Internal nuclei: Especially in older patients
  • Cores: Internal zone, "core", in muscle fiber
    • Altered Z-disk morphology
    • Reduced or absent in core
      • Oxidative enzyme activity
      • Mitochondria
      • Some cores also have loss of central myofibrillar structure
    • Cores run whole length of muscle fiber
    • Most prominent on NADH & mitochondrial stains
    • Immunoreactivity in cores³⁶
      • Myofibrillar proteins
        • αB-Crystallin; Desmin; Filamin C
        • Similar patterns of immunoreactivity seen in targets
      • Ca⁺⁺-related proteins
        • Depleted from the cores: RyR1
        • Accumulate in, or around, lesions
          • Other sarcoplasmic reticulum proteins: Calsequestrin, SERCA1/2 & Triadin
          • T-tubule protein: Dihydropyridine receptor-α1-subunit
        • SelN mutation-related minicores: Normal distribution of Ca⁺⁺-related proteins
  • Marked type I muscle fiber predominence
  • Clinical correlation
    • Well formed cores + Marked type 1 predominance
      • Myopathy syndrome: Often without MHS
      • RYR1 mutations: 90% with 60% in C-terminus
    • Variable cores + Less type 1 predominance + Internal nuclei
      • MHS syndrome: Usually normal strength
      • RYR1 mutations: 35%, Outside C-terminus
• Management: Avoid anesthesia-related malignant hyperthermia

• Clinical features
  • Familial hypertrophic cardiomyopathy
  • ? Normal strength
• Muscle biopsy
  • Central cores & type I muscle fiber predominance
  • Other familial hypertrophic cardiomyopathies have normal skeletal muscle histology

Nemaline (Rod) Myopathies

Clinical features: General Laboratory features: General Pathology Hereditary Types   α-Actin: 1q42   α-tropomyosin 3 (TPM3): 1q21   β-tropomyosin (TPM2): 9p13   Cofilin-2 (CFL2): 14q12   Nebulin: 2q21   Ryanodine receptor (Rods + Cores): 19q13   Troponin T1: 19q13   Myopathy + Slow movements & cores: 15q21   Rod myopathy, mild Sporadic disorders with rods   Infant onset myopathy   Adult onset myopathy   HIV rod myopathy   Target fibers (Acute Denervation)

Rod myopathy: Distal weakness & contractures From A Connolly

• Onset
  • Overall: Congenital (90%) to Adult
  • Severe: Congenital; α-Actin, Nebulin & Troponin T1 mutations
  • Mild: Childhood; α-Actin, Nebulin, α-tropomyosin 3 (TPM3), β-tropomyosin (TPM2) mutations
  • Adult onset: Mutations not known
• Inheritance: Dominant, Recessive & Sporadic
• Common mutation: Skeletal muscle α-Actin
• Early onset cases: Respiratory failure & Feeding difficulties common
• Clinical features
  • Motor: Weakness & Hypotonia
  • CNS: Cognitive involvement in younger onset patients
  • Cardiac: Rarely symptomatic after neonatal period
  • Arthrogryposis: Severe congenital cases
  • Paraspinous or posterior neck weakness: Adult onset patients
• Course
  • Morbidity from respiratory infections & feeding problems less with increasing age
  • Walking
    • Rare in congenital rod myopathy
    • Childhood onset usually remain ambulant
• Mortality
  • Deaths due to respiratory insufficiency
  • Early increased with: Respiratory insufficiency; Arthrogryposis; Failure to achieve early motor milestones
• Variable features from single genes
  • Dominant or Recessive inheritance: α-Actin; α-tropomyosin 3 (TPM3)
  • Lethal congenital or Late onset: α-Actin; α-tropomyosin 3 (TPM3)

• Mutant proteins: Usually structural member of thin filaments
• Muscle pathology: Thin filament disorders
  • Rods
    • Histochemical appearance: Dark red-blue structures only visible on Gomori trichrome stain
    • Fiber type distribution: Type I > II
    • Size: 1 to 7 μm in length
    • Composition: Contain α-actinin + Actin + Other Z-line proteins
    • Ultrastructure
      • Electron dense
      • Rod shaped
      • Emanate from Z-lines
        • Thickened Z-lines, or
        • Extend along long axis of thin filaments
    • Subcellular location: Originate from Z-disks
      • Myopathy: Tend to cluster under sarcolemma & around nuclei
      • Target fibers: Center of target
    • Underlying pathogenic process
      • Rod formation 2° to contractile dysfunction
      • Load-dependent processes probably involved
    • Often increase in number with age
    • Differential diagnosis
      • Sarcoglycanopathies
      • Target fibers (Denervation)
      • Tenotomy
      • Neostigmine myopathy²³
      • HIV myopathy²⁴
  • Type I muscle fibers: Small; Predominant
• CK: Normal (90%) or ± Elevated in adult-onset forms
• EMG: Myopathic or Neuropathic (Especially severe cases)
• Most common mutations: Nebulin; ACTA1

NEM1 Rod myopathy : α-tropomyosin 3 (TPM3)

• TPM3 protein
  • Muscle: Expressed in type I muscle fibers
  • 11 different forms: Expressed in many tissues including brain
  • See: Muscle fiber proteins
• Clinical-Genetic correlations
  • Infrequent cause of nemaline rod myopathy
  • Frequency: < 3%
  • Mildest syndrome: Missense mutation; Dominant inheritance
  • Severe syndrome: Stop codon; Recessive inheritance
• Dominant inheritance
  • Mutations: Met9Arg; Arg167His³⁸
  • Onset: 0 to 15 years
  • Clinical
    • Weakness
      • Development: Motor delay in some patients
      • Distribution
        • Symmetric
        • Distal Legs (Ankle dorsiflexors)
        • Arms
        • Respiratory failure
        ]
        • Proximal weakness: Later in disease course
      • Progression: Slow; Wheelchair often by 40 years
    • Tendon reflexes: Reduced
    • Achalasia: Involvement of smooth muscle
    • Morphology
      • Kyphoscoliosis
      • Slender build
      • Long face
  • Laboratory
    • Serum CK: Normal
    • Pathology
      • Type I fibers: Atrophy; Predominance
      • Rods: In Type I fibers; May be infrequent
• Recessive inheritance
  • Early onset, severe disease
    • Mutation: Homozygous; Stop at codon 31
    • Onset: Birth
    • Motor development: Extremely delayed and impaired
    • Cognitive: Appropriate for age
    • Death: 21 months
    • Pathology
      • Rods: Only in type 1 fibers
      • Type 1 muscle fiber smallness
      • Loss of α-tropomyosin 3 from muscle
  • Intermediate syndrome³⁵
    • Family history: Sporadic
    • Genetics
      • Compound heterozygote
      • Mutations: X285Ser; Splice site at skeletal muscle-specific translational stop signal
    • Mutated protein: contains 57 additional amino acids
    • Clinical
      • Onset: Birth; Hypotonia
      • Motor
        • Walking: 18 months
        • Wheelchair: 6 years
        • Weakness: Proximal
      • Face: Long & narrow; High arched palate
    • Muscle pathology
      • Rods: In type I muscle fibers
      • Endomysial connective tissue: Increased
      • Type I fiber predominance
      • Internal nuclei
      • Small fibers both types
      • Reduced β-tropomyosin in muscle fibers
• Variant syndrome: Congenital fiber type disproportion with TPM3 mutations ⁷⁰
  l Dominant or Sporadic
• General
  • Most common cause of CFTD: ~20% to 25%
  • Type 1 fibers: At least 50% smaller than type 2
  • Type 2 fibers: Normal or large sized
• Genetics
  • Mutations: Missense; Heterozygous
  • Locations: Leu100Met, Arg168Cys, Arg168Gly, Arg168His, Lys169Glu, Arg245Gly
  • Arg168Cys mutation: May be associated with CFTD & nemaline myopathy pathology in same family
• Clinical
  • Onset
    • Age
      • Usually < 1 year
      • Variable: Even within families
    • Hypotonia
    • Poor head control
  • Weakness
    • Proximal > Distal
    • Legs > Arms
    • Neck: Flexion & Extension
    • Ankle: Dorsiflexion
    • Trunk: Paraspinal; Abdominal
    • Facial: Mild
    • Ptosis: Mild; Unilateral or Bilateral
    • Respiratory
      • Frequency: 90%
      • Nocturnal noninvasive ventilation: Onset 3 to 55 years
      • Even in some ambulatory patients
    • Scapular winging: Mild; 40%
    • Quadriceps: Relatively preserved
    • Course
      • Improvement in strength & function over time
      • Patients often eventually walk or run
  • Other muscle
    • Amyotrophy: Generalized
    • Body habitus: Thin
    • Gait: Waddling; Foot drop
  • Skeletal
    • Young children: Hypotonic stance; Exaggerated lumbar lordosis & thoracic kyphosis
    • Late childhood or adulthood: Mild-to-severe kyphoscoliosis with neck extensor contractures
    • Other contractures: Uncommon
• Laboratory
  • EMG: Normal or Myopathic
  • NCV: Normal
  • Cardiac: Normal
  • Muscle pathology
    • Type 1 muscle fibers
      • Small
        • 60% of normal; Range 30% to 80%
        • 23% to 50% of Type 2 size
      • Predominance: > 55%
    • Type 2 muscle fibers
      • Size: Large; 160% of normal; Range 110% to 220%
      • Type 2B: Absent
      • Type 2C: None or Few
      • Internal nuclei: In older patients; Up to 25% of type 2 fibers
    • No rods
• Also see: Nemaline rod myopathy

NEM2 Rod myopathy: Nebulin

• Genetics
  • Mutations
    • Small insertions, deletions or point mutations
    • 3' end of gene: Exons 165 to 185; Z-disc part of nebulin
  • Allelic with: Distal nebulin myopathy
• Infantile onset: Mild to moderate
  • Onset: Birth; some movement present
  • Weakness: Trunk; Distal legs (Ankle dorsiflexors) & Facial
  • Respiratory difficulty
  • Dysmorphic features
    • HEENT: High arched palate; Micrognathia
    • Contractures: Fingers
    • Chest deformaties
    • Joint hypermobility
  • Progression: Slow or none; May improve after initial respirator dependance
  • Pathology: Nebulin still present
• Muscle MRI⁵³
  • Mild phenotype
    • Involvement: Tibialis anterior, Soleus
    • Sparing: Thigh muscles
  • Moderate phenotype involvement
    • Rectus femoris, Vastus lateralis, Hamstring, Anterior leg, Soleus

• Mutations
  • ~15 Missense mutations identified
  • Distributed in all 6 coding exons
  • Some involve known functional domains of actin
• Actin (ACTA1) protein
  • α-Skeletal muscle actin
    • Normal adults: Present in muscle but not heart
    • Development: Becomes predominant isoform in muscle at 3rd trimester of gestation
  • Dominant syndromes: Mutant ACTA1 exerts dominant negative effect
  • Aggregation may be caused by
    • Heat shock
    • Leptomycin B (a specific inhibitor of nuclear export mediated by leucine-rich nuclear export signals)
    • Mutation in leucine-rich nuclear export signals
• Clinical
  • Dominant inheritance
    • Onset: Variable within families
    • Clinical: Variable phenotypes
      • Mild
      • Mutations: Asn115Ser; Gly268Cys; Ile136Met
      • Onset: Age 12
      • Weakness: Trunk & Proximal; Mild facial
      • Respiratory failure: 5th decade
      • Progression: Slow over decades
      • Serum CK: Normal
      • MRI: Gluteal & Anterolateral thigh involvement
      • Muscle morphology
        • Rods, especially in small fibers; Core-like structures
        • Muscle fiber hypertrophy: Ile136Met
      • Severe
      • New dominant mutations: Ile357Leu; Arg183Gly
      • Phenotypes
        • Lethal; Congenital
        • Congenital weakness
      • Other mutations: Met132Val; Val163Met; Met269Arg
      • Cardiac function: Normal
    • Pathology
      • Abnormal fiber type differentiation
      • Glycogen accumulation
      • Rods
        • No relation between abundance & disease severity
        • More in small muscle fibers
        • Stain for α-actinin 2
        • Rods tend to be in type 1 muscle fibers
        • May be present in some muscles but not others
      • Myofibrillar disruption
      • Whorling of actin thin filaments
  • Recessive inheritance⁶⁶
    • Genetics
      • Truncation mutations identified; ? Missense
      • Truncation: Arg41X (French), Tyr364fsX (Spanish), Asp181fsX10 (British)
    • Course
      • Weakness
        • Severe in most: Diffuse; Hypotonia
        • Respiratory failure
        • Feeding difficulties
        • Death in 1st year: Most
        • Contractures (30%)
      • Serum CK: Mildly elevated or normal
      • Muscle
        • Morphology: Nemaline rods & Zebra bodies
        • Actin: Skeletal α-actin absent; Cardiac α-actin increased
        • Lipid: Increased
      • Survival through childhood in some
  • Sporadic patients: Often de novo mutations
  • Variant: Nemaline myopathy with intranuclear rods⁶²
    • All mutations involve ACTA1
    • Inheritance
      • Sporadic (Most) or Dominant
      • Marked phenotypic variation in family
    • Onset: Birth (Most) to 55 years
    • Clinical
      • Narrow face
      • Thin musculature
      • Hypotonia
      • Weakness: Diffuse
    • Laboratory
      • Serum CK: Normal or Mildly elevated
      • EMG: Myopathic
    • Course
      • Death in 1st year in 40% due to respiratory insufficiency
      • Similar to ACTA1 mutations without intranuclear rods
• Muscle MRI
  • Involved muscle signal: Increased T1
  • Involved muscles: Diffuse involvement of thigh and leg
  • Relative sparing: Gastrocnemius
• Also see
  • Congenital myopathy with excess of thin filaments
  • Congenital fiber type size disproportion: Actin mutations

NEM4 Rod myopathy : β-Tropomyosin (TPM2)

• Mutations
  • Missense Q147P & E117K
  • Mutations in TPM2 also cause
    • Distal arthrogryposis 1
    • Cap myopathy
• β-Tropomyosin protein
• Frequency: Rare
• Onset: Infancy to Childhood
• Clinical
  • Weakness: Proximal > Distal; Some with respiratory failure
  • Contractures: Few or None
  • Progression: Slow or None
• Variant: Escobar syndrome ⁷⁴
  • Epidemiology: Consanguenous Algerian family
  • Genetics
    • Inheritance: Recessive
    • Mutation
      • Homozygous
      • Gln210Stop: Exon 6b, specific for skeletal muscle β-TM isoform 1
  • TPM2 protein: Absent skeletal muscle isoform of β-tropomyosin
  • Clinical
    • Onset: Congenital
    • Motor: Hypotonia; Delayed milestones
    • Respiratory distress
    • Joints: Pterygia; Arthrogryposis
    • Cardiac: Bifascicular ventricular block with right bundle block & left anterior hemiblock
  • Muscle
    • Connective tissue: Abundant
    • Rods: More common in type I muscle fibers (60%)

NEM5 Rod myopathy : Troponin T1 (Skeletal, Slow; TNNT1)

• Mutation: Nonsense; E180X; Homozygous
• Epidemiology: Older Order Amish
• Clinical
  • Onset
    • 1st months of life
    • Tremors
      • Begin within few days of birth
      • Distribution: Jaw & Lower limbs
      • Resolve by 2 to 3 months
    • Hypotonia
    • Contractures: Shoulders & Hips; Mild
  • Progression
    • Proximal contractures: Increase
    • Weakness: Proximal > Distal
    • Pectus carinatum: Rigid chest wall; Develops with proximal contractures
    • Cardiac: No 1° involvement; Terminal right congestive failure
    • Death from respiratory insufficiency < 2 years
• Pathology
  • Type 1 fiber disproportion
  • Z-band streaming
  • Rods: Centrally placed
  • Myofibrillar disruption
  • Myofiber degeneration

• Genetics: No TPM1 mutations
• Onset: Childhood
• Clinical
  • Weakness: Mild; Proximal & Neck flexors
  • Movements: Slow; Unable to run; Poor rapid postural correction
  • Progression: Slow
  • Skeletal (Some patients): High Palate; Thorax deformities
• Laboratory
  • EMG: Myopathic
  • Muscle CT: Fatty infiltration of proximal limb & truncal muscles
  • Muscle biopsy
    • Type 1 predominance
    • Internal nuclei
    • Rods: Granular; Diffusely distributed; All fibers
    • Core-like structures
      • Less sharply defined than typical cores
      • Ultrastructure: Large regions of rods with loss of muscle structure

NEM7 Rod myopathy : Cofilin-2

• Epidemiology: 1 Middle Eastern family, 2 siblings
• Genetics
  • Mutation: Missense, Ala35Thr; Homozygous
  • Heterozygotes: Not affected
• Cofilin-2 protein
  • Member of AC (ADF/Cofilin) protein group
    • Regulate actin filament dynamics: Actin depolymerizing factors
    • Other group members: Cofilin-1 ; Destrin
  • Skeletal muscle specific isoform
  • Localized to thin filaments
  • Exerts effect on actin, in part, through interactions with tropomyosins
  • Binds G- and F-actin in 1:1 ratio
  • Major component of intranuclear & cytoplasmic actin rods
• Clinical
  • Onset: Hypotonia at birth
  • Early motor milestones: Delayed
  • Ambulation: Present for short distances; Frequent falls; Inability to run
  • No facial weakness or foot drop
• Muscle pathology
  • Nemaline rods: 1 of 2 patients
  • Minicores: Few fibers
  • Type I muscle fiber predominance
  • Fiber size variability
  • Concentric laminated bodies
  • Cofilin-2
    • Sarcomeric staining: Reduced
    • Phosphorylated forms: Absent
  • Phalloidin staining: 4% of myofibers contain actin filament accumulations

• Epidemiology: Swiss family
• Onset
  • Age: Neonatal
  • Hypotonia
• Clinical: Mild Course
  • Walking: Onset 18 to 24 months
  • Weakness: Axia; & Proximal
  • Difficulty running
  • Most with no limitation in normal ADLs
• Muscle biopsy
  • Type 1 muscle fiber predominance
  • Rods: 1% to 5% of muscle fibers; Increase with age

• Infantile onset types: Severe
  • Fetal akinesia sequence
    • Onset: 2nd trimester of pregnancy
    • Polyhydramnion; Joint contractures (Multiple); Lung hypoplasia
    • Not linked to α-actin, nebulin or α-tropomyosin 3
  • Birth
    • Diffuse Hypotonia, Weakness & Little spontaneous activity
    • Respiratory failure
    • Cardiomyopathy: Dilated
    • Arthrogryposis
    • Survival: Weeks to months
  • Pathology: Cytoplasmic & intranuclear rods
    • May need oil immersion lens to visualize
  
  
• Adult onset rod myopathy: Heterogeneous⁵⁹
  • Often no family history
  • Onset
    • 4th to 9th decade
    • Subacute
  • Clinical
    • Weakness
      • Proximal > Distal
      • Posterior neck weakness (50%)
      • Dysphagia (50%)
      • Respiratory failure (40%): Occasionally presenting feature
      • Asymmetry (30%)
      • No face weakness
    • Myalgia
    • Cardiomyopathy
    • Progression
      • High mortality in 40%: Death within 1 year
      • Slow progression over years in others
  • Laboratory
    • Muscle biopsy
      • Rods
        • Immunostain for α-actinin or myotilin
        • Rods may be best seen on trichrome in 3 μM sections
      • Rod bearing fibers also have
        • Large vesicular nuclei
        • Focal cytoplasmic basophilia
        • Small vacuoles
      • Inflammation (30%)
      • Necrotic muscle fibers: Occasional
      • Lobulated muscle fibers (50%)
      • Type I predominance (20%)
      • Ultrastructure: Rods < 1μM in length
    • M-protein (50%): ? Unfavorable outcome
    • Serum CK: Normal or Mildly elevated
    • EMG: Irritable myopathy
  • Rule out
    • Sarcoglycanopathies
    • HIV nemaline rod myopathy
    • Hereditary nemaline rod myopathy
  • Treatment: Uncertain; ? Prednisone
  
  
• Central core disease, Rods & Malignant Hyperthermia

Centronuclear (Myotubular) Myopathy

Types   Dominant     Dynamin 2: 19p13     MYF6: 12q21   Recessive     BIN1: 2q14   X-linked: Myotubularin; Xq27     Carriers Pathology

• Centronuclear myopathy: X-linked (MTM 1)
    l Myotubularin (MTM1) ; Chromosome Xq27.3-q28; Recessive
    
  • Epidemiology: 1 male in 50,000
  • Gene features
    • 15 exons: Translation start codon in exon 2
    • Gene expression
      • Ubiquitous
      • Smaller transcript selectively expressed in skeletal muscle & testis
    • Has characteristics of housekeeping function
      • High GC content of MTM1 promoter
      • No defined TATA-box or CAAT-box structure
  • Gene Mutations: Spread unevenly across whole gene
    • General
      • 151 different disease related mutations identified in 248 families¹⁰
      • Mutations widely distributed throughout the gene
      • Hotspots: 6 recurrent mutations
        • Codon 48 frameshift; P205L; R224X; R241C; 420insFIQ; R421X
        • Arg241 Cys: 2nd most frequent mutation; Causes mild (72%) or severe myopathy
      • Mutations in Males > Females
    • Mutation types
      • Point mutations: Missense (55) & Nonsense (40); Most between exons 8 & 12
      • Small insertions or deletions (50)
      • Large deletions (15)
      • Splice site mutations (38)
        • IVS11, A-G, -10: Most common mutation; Causes severe myopathy
      • Germline mosaicism identified in some families
    • Mutation locations
      • Most frequent in exons: 4 > 12 > 3 > 8 > 9 > 11
      • Highly conserved regions
      • ? Reflects importance of mutated gene regions to functional domains
    • Genotype-Phenotype Correlations
      • Truncating & splice site mutations
        • Usually associated with severe phenotype
          • Frequent death or ventilator dependent
          • Muscle fiber size: Smaller
        • Some mild phenotypes with very distal mutations
      • Missense & single amino acid deletion mutations
        • Higher prevalence of mild phenotypes (33%)
        • All in phosphatase active site or SID domain have severe phenotype
      • Protein alteration
        • Predicted severe: 99% with severe phenotype
        • Normal level of myotubularin: Missense mutation or Small deletion or insertion
      • Large chromosomal deletions: Associated abnormal genital development
      • Some symptomatic female carriers
    • Many mutations can be explained by
      • Methylation-mediated DNA repair of modified CpG dinucleotides, or
      • DNA polymerase slippage with short tandem-repeated sequences
  • MTM1 protein features
    • Tisssue localization: Ubiquitously expressed
    • Cell localization
      • Sarcolemma
      • I band, including triads
      • Associated with endosomes
      • ? Nuclear
    • MTM1 structure
      • Contains active site of protein tyrosine phosphatases (PTP)
      • Displays similarity to dual-specificity serine/tyrosine phosphatases (dsPTPases)
    • MTM1 functions
      • Enzyme action: Dephosphorylates phosphatidylinositol 3-phosphate
      • Associates with SET (Suvar3-9, Enhancer-of-zeste, Trithorax) domains
        • SET domains: In proteins contributing to epigenetic mechanisms of gene regulation
      • ? Roles: Muscle fiber maturation; Plasma membrane homeostasis
      • Overexpression
        • Induces the formation of filopodia-like projections
        • Affects protein trafficking from late endosome to lysosome
        • Muscle
          • Proliferation of membrane structures that contain myotubularin
          • Vacuoles labelled by markers of sarcolemma & T-tubules (caveolin-3, dystrophin, DHPR)
    • Myotubularin family & related disorders
      • Myotubularin-related protein-2: CMT 4B
      • SBF2 (MTMR13): CMT 4B2
      • Endosomal phosphoinositides: PIP5K3 ; François-Neetens Fleck Corneal Dystrophy
  • Clinical features
    • Onset: Infancy
    • Polyhydramnios: 50%
    • Skeletal: Large head (70%); Narrow face (80%); Long digits (60%)
    • Motor
      • Severe Hypotonia
      • Weakness: Proximal & Distal; Symmetric
      • Respiratory Insufficiency
    • Ophthalmoplegia & Ptosis
    • Prognosis
      • Early death: Mean = 5 months
      • ? Improvement after neonatal period
      • Weakness non-progressive
      • Survivors often respirator dependent (80%)
    • Systemic features in some survivors > 1 year
      • Pyloric stenosis
      • Spherocytosis
      • Gallstones
      • Renal: Stones or calcinosis
      • Bleeding diathesis: Vitamin K-responsive
      • Skeletal: Rapid linear growth; Advanced bone age
      • Hepatic dysfunction
  • Laboratory
    • CK: Normal or mildly elevated
    • EMG
      • Motor unit potentials: Small amplitude; Polyphasic
      • Spontaneous activity: Fibrillations; Positive sharp waves; Complex repetitive discharges
    • Muscle pathology⁶⁷
      • Single central nucleus
        • In some muscle fibers: Range = 4% to 40%
        • Frequency may increase with age
      • Type 1 muscle fiber predominance
      • Muscle fiber size
        • Average fiber size: Reduced
        • Increase in size with age: Reduced
        • Type 1 muscle fibers smaller than type 2: More prominent in older patients
        • Fiber size smaller in more severe disease
        • Fiber size smaller with truncation/deletion mutations than missense mutations
  • Myotubularin mutation: Carriers
    • Occasional: Mild facial weakness
    • More severe⁵⁶
      • Genetics
        • Mutations: R253X; c.1354–1G>A (Splice site)
        • Skewed X-inactivation: 1 family
        • ? Other mechanisms
        • Incomplete penetrance
      • Onset
        • 1st decade
        • Arm weakness
        • Gait disorder
        • Skeletal asymmetry
      • Weakness
        • Early: Arm
        • Proximal & Distal: With disease progression
        • Elevated hemidiaphragm
        • Progressive in 3rd to 5th decades
      • Skeletal
        • Asymmetry
        • Kyphoscoliosis
        • Pes equinovarus (Bilateral)
      • Serum CK: Normal
      • Muscle pathology
        • Varied fiber size: Both fiber types
        • Internal nuclei
        • NADH: Normal internal architecture
    • Neonatal onset³⁹
      • Mutation: 605delT
      • Non-familial case
      • Clinical
        • Hypotonia
        • Joint laxity
        • Waddling gait
        • Weakness: Limb-girdle; Facial
        • Tendon reflexes: Absent
  • Myotubularin knock-out mouse³⁷
    • Progressive weakness
    • Muscle fiber development
      • Initially normal with peripheral nuclei
      • Later: Degenerative changes & central nuclei
    • Pathology of muscle fibers
      • Variable among muscles: Most in biceps
      • In type I & II muscle fibers
      • Atrophy
      • Mis-localized mitochondria & nuclei
    • Serum CK: Mildly elevated
    • Tissues other than muscle: Spared
  
  
• Centronuclear myopathy: Autosomal Recessive
  • General
    • Onset
      • Infancy, Childhood, Adult < 30 years: ~1/3 each
      • Possible subgroups⁴⁹
        • Early onset with ophthalmoplegia
        • Early onset without ophthalmoplegia
        • Late onset without ophthalmoplegia
    • Clinical
      • Weakness: Proximal > Distal
      • Ophthalmoplegia: Early onset patients
      • Facial weakness
      • Usually survive past infancy
  
    l Amphiphysin 2 (Bridging integrator 1 (BIN1)) ; Chromosome 2q14; Recessive ⁶⁸
  • Epidemiology: 4 individuals from 3 consanguinous families; India & Iraq
  • Genetics: Mutations
    • Types: Missense & Stop; K35N, D151N, K575X
    • Effect: All elicit only a partial loss of function
    • Homozygous
  • BIN1 protein
    • Involved in membrane remodeling
    • Regulated by phosphoinositides
    • Role in organization of T tubules
    • Mutations
      • Loss of functional link to Dynamin 2
      • ? Disordered T tubule biogenesis
    • Malignant cells: Often reduced
  • Clinical
    • Onset
      • Age: Birth to Childhood (8 yrs (D151N mutation))
      • Pregnancy: Reduced or normal fetal movements
    • Weakness
      • Proximal
      • Mild
      • Ophthalmoparesis & Ptosis: Some patients
      • No respiratory failure
    • Contractures: Birth
    • Cardiac: Dilated in some patients
    • Course
      • Slowly progressive weakness
      • Survival through childhood: 60%
  • Pathology: Typical CNM muscle
    • Numerous fibers with central nuclei
    • NADH
      • Central nuclei surrounded by rim of densely stained material
      • Radial organization of sarcoplasmic reticulum not present
    • Caveolin 3: Immunoreactivity in centrally located vacuoles in some fibers
    • T tubule marker dihydropyridine receptor-a (DHPRa): Immunoreactivity around centrally located nuclei
  
  
• Centronuclear myopathy: Autosomal Dominant
    l MYF6 ; Chromosome 12q21; Dominant
  • Epidemiology: 1 patient
  • MYF6 gene mutation: Ala112Ser
  • MYF6 protein
    • Muscle determination factor
    • Helix--loop--helix domain: Common feature of myogenic factors
  • Clinical
    • Onset: Late Childhood - Adult
    • Weakness: Proximal > Distal
    • Leg cramps
    • ± Ophthalmoplegia, Facial, or Scapular weakness
    • MYF6 mutation in setting of Becker dystrophy: Converts disease to more severe phenotype
  • Laboratory
    • CK: Normal or Mildly elevated
    • Muscle biopsy: Myopathic; Ring fibers; Central nuclei
  
    l Dynamin 2 (DNM2) ; Chromosome 19p13.2; Dominant or Sporadic⁶⁰
  • Epidemiology: Multiple centronuclear myopathy families
  • Genetics
    • Point mutations: R465W; R369Q; R369W; E368K
    • Locations
      • Exons 8 & 11
      • Middle domain: Involved in self assembly & centrosomal location of protein
    • Allelic with
      • CMT, Dominant-intermediate Type B: Mutations in plecstrin domain
      • CMT 2 syndromes
  • DNM2 protein
    • Ubiquitously expressed
    • Associated with microtubules
    • Family: Large GTPases
    • Binds to BIN1 & SNX9
    • Implicated in endocytosis & cell motility
      • Regulates tubular invagination of plasma membrane
      • Part of cellular fusion-fission apparatus
  • Onset
    • Age
      • Early milestones: Normal
      • Usual ages: Adolescence & Adult
      • ? R465W mutation with earlier onset
    • Symptoms
      • Exercise-related muscle pain
      • Weakness: Difficulty walking & climbing stairs; Falls; Poor at sports
  • Clinical
    • Weakness
      • Distal > Proximal: Upper extremity all distal
      • Axial: Neck flexors; Abdomen
      • Ocular: Ptosis; Reduced upgaze (20%)
      • Face 40%
      • Respiratory: Normal
      • Progression: Slow; 1 patient in wheelchair in 6th decade
    • Contractures: Ankles (90%); Fingers
    • Other described changes in occasional patients
      • Retinopathy
      • Cardiomyopathy: In female carrier
  • Laboratory
    • Serum CK: Normal or Mildly high
    • NCV: Reduced CMAP; NCV some mildly slow
    • EMG: Myopathic; Some with spontaneous activity
    • MRI: Early involvement of distal, posterior leg
      • Involved: Lateral soleus, Gastrocnemius; Posterior thigh; Adductor longus; Biceps; Semimembranosus
      • Spared: Sartorius, gracilis & Rectus femoris
    • Muscle
      • Central nuclei: Some in chains
      • NADH: "Spoke-like" changes
      • Core-like lesions in more preserved proximal muscles
      • No multi-minicores
  • Variant: Severe neonatal⁷¹
    • Family history: Sporadic
    • Genetics: Mutations
      • Heterozygous
      • Exon 16: PH domain
      • Missense or In frame
      • Ala618Thr; Ser619Leu; Ser619Trp; V625del
    • Onset
      • Neonatal
      • Hypotonia
    • Clinical
      • Pregnancy: Normal
      • Hypotonia; Weak suck
      • Cranial nerve: Face; Ptosis; Ophthalmoparesis
      • Weakness: Generalized; Distal > Proximal
      • Respiratory: Restrictive syndrome in some patients
      • Cardiac function: Normal
      • Prognosis: Good; Slow improvement to mid-childhood
    • Laboratory
      • Serum CK: Normal to Slightly increased
      • EMG: Myopathic
      • Muscle
        • Type I predominance & smallness
        • Central nuclei (3% to 50%)
        • Radial sarcoplasmic strands: Some
  
    l Centronuclear myopathy: Genetically undefined phenotypes
  • Clinical subtype 1: Typical Dominant centronuclear myopathy⁴⁹
    • Epidemiology: 2 families
    • Onset age: Childhood to Adult
    • Clinical
      • Weakness
        • Severity: Mild
        • Distribution: Diffuse; Proximal & Distal; Occasional distal predominant
        • Progression: Slow
        • Disability: Mild; Most ambulatory to at least 6th decade
      • Ptosis: Most
      • Contractures: Occasional patient
      • Tremor: Postural; Some patients
    • Laboratory
      • Serum CK: Normal
      • EKG: Normal
      • Pulmonary function: Normal or Reduced
      • EMG: Myogenic
  • Clinical subtype 2: Typical Dominant centronuclear myopathy with muscle hypertrophy⁴⁹
    • Epidemiology: 1 family
    • Onset: Adolescence & Adult, Rare infant
    • Clinical
      • Muscle hypertrophy: Diffuse
      • Weakness
        • Slowly progressive
        • Distal arms
      • Ocular
        • Ptosis: Common
        • Ophthalmoplegia: Occasional patients
      • Skeletal
        • Rigid spine: Mild 40%
        • Ankle contractures: 30%
        • Finger contractures: 14%
    • Laboratory
      • Serum CK: High (2x to 4x) in some patients
      • EMG: Myopathic
      • FVC: May be reduced
  
  
  
• Centronuclear myopathy: Muscle Biopsy
  • Central nuclei
  • Central pallor on ATPase
    
  • Type 1 fibers predominant & small (50%)
  • NADH: Radial distribution of sarcoplasmic strands
  • 50% of carriers have central nuclei in muscle fibers
  • Endomysial fibrosis: More severe recessive cases
  
  
• Centronuclear myopathy: Dog⁵⁰
    l Canine chromosome 2
  

Congenital Muscular Dystrophies

CONGENITAL MUSCULAR DYSTROPHIES Adducted thumbs & Ophthalmoplegia Cerebellar atrophy CMD: 4p16 CNS atrophy & absent large myelinated PN axons Desmin inclusions Fukuyama: Fukutin; 9q31 Integrin α-7: 12q13 Junctional Epidermolysis Bullosa: 8q24 Marinesco-Sjögren: SIL1; 5q31 Merosin (laminin α2-chain)   Deficient (MDC1A): 6q22   Normal: "Pure" form Mitochondrial structural changes Muscle-Eye-Brain Disorders   Santavuori (Finnish): POMGnT1; 1p32   Walker-Warburg: POMT1; 9q34 Muscle hypertrophy   Mental retardation   Respiratory failure (MDC1B): 1q42   Normal CNS (MDC1C): FKRP; 19q13   Severe retardation (MDC1D): LARGE; 22q12 Epidermolysis bullosa: Plectin; 8q24 Rigid spine with CMD: SEPN1; 1p35 Ullrich   COL6A1; 21q22   COL6A2; 21q22   COL6A3; 2q37 General features

from A Kornberg MD

Congenital Muscular Dystrophy: Typical Features

• Inheritance: Autosomal recessive (AR)
• Frequency: Common cause of AR neuromuscular disorders
• Onset: Congenital or Infancy (< 1 year)
• Clinical features
  • Weakness: Diffuse
  • Contractures
  • CNS
    • Common in severe forms of CMD
    • May be subclinical
    • Disroders of myelin or neuronal migration
• Pathology of muscle
  • Myopathic
    • Varied fiber size
    • Increased endomysial connective tissue
    • Little muscle fiber degeneration after 4 years
  • Disorders of connective tissue molecules
    • Laminin α2: MDC1A
    • Collagen, type VI: Ullrich
    • Disorders of glycosylation⁴⁸
      • Marker molecule: α-Dystroglycan
      • Common O-mannosyl glycan structure: NeuAcα2-3Galα1-4GlcNAcα1-2Man-Ser/Thr
      • Specific disorders
        • Walker–Warburg syndrome (WWS): POMT1
        • Walker-Warburg 2: POMT2
        • Muscle–eye–brain disease (MEB): POMGnT1
        • Fukuyama congenital muscular dystrophy (FCMD): Fukutin
        • MDC1C: FKRP
        • MDC1D: LARGE

Fukuyama congenital muscular dystrophy

• Epidemiology
  • Common in Japan: Incidence is 40% of Duchenne MD
  • Rare in Western countries
• Genetics
  • Mutations
    • 80% of Japanese patients have similar haplotype
      • Retrotransposal insertion (3kb) of tandemly repeated sequences (Ancestral genotype)
      • Up to 100% of Japanese patients at least heterozygous for tandem-repeat insertion (Ancestral genotype)
    • Other mutations
      • Japanese patients: Stop codons; Point mutations & small deletions
      • Turkish patient: Homozygous 1 bp Insertion (nt504(insT)) in exon 5
    • Location: 3' untranslated end of fukutin gene
    • Effect of mutation: Reduced fukutin transcription
  • Genetic-Clinical Correlations
    • Milder phenotype: Homozygous for retrotransposon
    • Severe phenotype: Heterozygous for retrotransposon & point mutation
      • More ocular involvement
    • Homozygosity for point mutations
      • WWS-like syndrome reported
      • May be lethal
  • Allelic with
    • LGMD 2M
    • Cardiomyopathy
• Fukutin protein¹⁷
  • Brain mRNA
    • Expressed in similar levels in adult & fetal brain
    • Adult: Cortical neurons
    • Fetal: Neuronal precursor & Migrating cells
    • Cellular location: Neurons; Not astrocytes
  • Protein
    • ? More abundant in fetal brain
    • Possibly secreted
    • Skeletal muscle: Not detectable by immunocytochemistry
• Clinical
  • General
    • Brain: Milder involvement than Walker-Warburg or Muscle-Eye-Brain
    • Eye: Only occasionally severely affected
    • Clinical heterogeneity: Some patients walk & have longer survival
  • Clinical features: Severe cases
    • Motor deficits
      • Onset: Months to 1 year
      • Severe Hypotonia
      • Weakness & Wasting: Face & Limbs
      • Spasticity: Occasional
    • Face
      • Diplegia
      • Large cheeks
    • Skeletal
      • Contractures
      • Kyphoscoliosis
      • Skull: Microcephaly; Asymmetry
    • CNS
      • Seizures (50%)
      • Mental retardation: Severe; IQ 30 to 50
      • Hydrocephalus: Progressive
    • Ocular
      • Myopia
      • Retinal hypoplasia & detachment
      • Strabismus
      • Persistent primary vitreous body & hyaloid artery
      • Microphthalmos
      • Optic nerve atrophy
    • Course
      • Progressive disability
      • Death: Often < 11 years; Respiratory dysfunction
  • Clinical features: Milder or typical cases
    • Typical peak motor function: Unassisted sitting
    • Mildest cases: Walk unassisted
• Laboratory
  • CNS pathology
    • Cortex
      • Migrational defects
        • Altered radial & tangential neuronal migration
      • Micropolygyria (Type II lissencephaly)
      • Absence of lamination in gray matter
      • Breaks in glia limitans & basal lamina
      • Fukutin mRNA in Fukuyama CMD brain
        • Absent in regions of overmigrated dysplasia
        • Moderate expression in more normal areas
    • White matter
      • Hypomyelination
      • CT scan: Lucencies, especially Frontal, Occipital regions spared
    • Older patients
      • Cerebellar efferent pathway: Dentate nucleus, Superior cerebellar peduncle & Red nucleus
      • Lateral thalamic nucleus
  • Serum CK: Moderately high
  • EMG: Myopathic
  • Muscle pathology: Myopathic
    • Connective tissue: Increased
    • Muscle fiber size: Variable
    • Internal nuclei
    • Differential involvement of muscle fascicles
    • Basal lamina: Disrupted
    • Muscle proteins
      • α-dystroglycan: Greatly reduced in surface membrane & NMJs
      • Laminin α2: Reduced
    
    

Congenital muscular dystrophy: Merosin (laminin α2-chain) deficient

• Mutations in laminin α2-chain
  • Deletion, stop codon & occasional missense
  • Most common mutation (23%): 2 base pair deletion @ 2,096-2,097
  • Mild disease: Mutations
    • Internal in-frame deletion: Small protein (Missing N-terminal)
    • Mutations in conserved donor splicing consensus sequence of introns 37 and 63
  • Mutations uncommon: In globular or rod-like domain
  • Merosin expression
    • Severe: 300 kDa & 80kDa subunits abnormal
    • Mild or later onset: 300 kDa subunit often selectively reduced
  • Offspring of carriers: Heterozygotes more common than predicetd by chance
  • Defect in same gene in dy mouse
• Laminin α2 (Merosin) protein
  • Heterotrimeric glycoprotein
    • Heavy chain (400 kDa): α2-chain protein
    • Light chains (200 kDa): β1 & γ1
  • Location
    • Basement membrane
    • Muscle, Skin, CNS & Peripheral nerve (Schwann cells)
  • Binds to α-Dystroglycan in basal lamina
  • α2-laminin: 400 kD protein
    • Post-translationally cleaved into 300 kD & 80 kD subunits
    • Subunits remain associated by disulfide bonds
    • Globular domain attached to α-dystroglycan

  Pectoral folds (Arrow) with severe shoulder weakness

• Congenital muscular dystrophy: Clinical features
  • Weakness
    • Correlates with level of residual laminin α2 protein
    • Absent laminin α2 protein
      • Severe weakness
      • Distribution: Symmetric; Proximal + Distal; Face
      • Non-progressive
    • Reduced laminin α2: See variant syndromes
  • Muscle: Wasting & Hypotonia
  • Walking
    • Severe disease: Never
    • Mild disease: At 2-3 years
  • Contractures
    • Mild disease: Ankle tightness
    • Severe disease
      • Contractures at multiple joints
      • Hips; Knees; Ankles; Elbows; Neck extensor
      • Progressive with increasing age
  • CNS
    • Intelligence often normal
    • Perceptual-motor dysfunction in some
    • Seizures (20%)
  • Neuropathy: Mild; Occasional; ± Demyelination
  • Course
    • Progressively severe contractures
    • Severe disease: Death 15 to 30 years 2° Respiratory failure
• Laboratory
  • CK: Moderately high
  • MRI of CNS: White matter changes (Increased signal on T2); Cortex usually normal
• Laminin α2 disorders: Muscle pathology
  • Merosin (Laminin α2) staining
    • Usually absent: 95% with absent merosin have gene mutation
    • Partial merosin loss: Milder disability or later onset
      • Clinical: Milder disability or later onset; Late onset seizures
      • Muscle pathology: Myopathy; Rimmed vacuoles & inflammation in some
      • Especially reduced 300 kD subunit
      • Correlates with reduction of laminin β2 chain
      • Occasional 2° loss in other syndromes
        • CMD: MEB; Muscle hypertrophy
        • Myopathy with abnormal merosin: Not linked to merosin gene (6q22)
      • Normal visual evoked potentials
  • Pathology: Age-dependent
    • Childhood: Variable fiber size; Increased endomysial connective tissue
    • Neonatal: May be "predystrophic" with only a few degenerating & regenerating muscle fibers
    • Inflammation: Rare, except in biopsies from very young patients
    • Mild disease (Partial merosin loss)
      • Dystrophic: Variation in fiber size Increased endomysialconnective tissue
      • Other: Increased internal nuclei; Occasional split, hypercontracted & Whorled fibers
• Laminin α2 disorders: Variant syndromes
  • Reduced (Loss of 300 kD N-terminus) laminin α2
    • Genetics: Probably allelic with Laminin α2 disorders
    • Onset: Up to 12 years
    • Weakness
      • Mild weakness
      • Proximal ± Distal; Symmetric
    • Calf hypertrophy may occur
    • Course: ? Progressive
    • Leukoencephalopathy may occur
    • Muscle pathology
      • Myopathy
      • Rimmed vacuoles
      • Inflammation in some
      • Reduced laminin α2: Loss of 300 kD N-terminus
  • Hypermyelinating neuropathy; Mental retardation; Epilepsy³¹
    • Genetics: Probably allelic with Laminin α2 disorders
    • Onset: Childhood; Developmental delay
    • Clinical
      • Weakness: Distal; Feet > Hands
      • Mental retardation: Moderate
      • Refractory epilepsy: Absences ± eyelid myoclonus; Tonic & complex partial seizures
      • Tendon reflexes: Absent
      • No muscle wasting or joint contractures
    • Laboratory
      • Serum CK: High; 530
      • Nerve conduction velocities: Reduced
      • Brain MRI: Diffuse white matter involvement
      • Muscle biopsy
        • Myopathy
        • Neurogenic features
        • Laminin α2 mildly reduced
      • Nerve biopsy
        • Laminin α2 virtually absent
        • ‘Globular’ hypermyelination: Located at paranodal regions
        • Mild loss of myelinated axons
        • No demyelination-remyelination changes
  • LGMD 2I
    • Genetics: FKRP mutations with reduced Laminin α2 in muscle
• Mouse models
  • dy/dy
  • dy^2J/dy^2J: Milder phenotype; 300kD subunit selectively reduced

CMD: Normal merosin

Normal Merosin: "Pure" form of congenital MD

• Genes & Syndromes
  • CMD with Rigid spine
  • CMD + Respiratory failure & Muscle hypertrophy (CMD1B; MDC1B)
  • Ullrich: Collagen 6A2
  • CMD + Muscle hypertrophy
  • CMD 4p16
• Clinical features
  • Mild to Moderate Weakness
  • Non-progressive course; mild disability
  • Contractures
  • Normal intelligence
  • Rigid spine
• CK: Normal to moderately high
• MRI: Normal CNS
• Muscle
  • Some patients have absent α actinin-3 in muscle
  • No gene defects in actinin identified

Congenital MD with integrin α-7 mutations

• Epidemiology: 3 Japanese patients
• Gene change: 98 base pair deletion most common
• α7β1 Integrin protein
  • Subunit tissue specificity
    • α7: Muscle specific
    • β1: Expressed in many tissues
  • Abundance: α7β1 integrin is primary integrin in muscle
  • Functions
    • Laminin receptor
    • Transmembrane link: Cytoskeleton to Extracellular matrix
    • Myoblast migration
    • Formation of
      • Myotendinous junctions
      • Postsynaptic membrane
  • Changes in other myopathies
    • Increased in Duchenne & Becker MD
    • Reduced in Fukuyama & Laminin α2 deficient congenital MD
• Clinical
  • Motor
    • Hypotonia
    • Delayed milestones
    • Walk at 2 to 3 years
    • Proximal weakness
  • Mental retardation in 1 patient
• Lab
  • CK mildly elevated
  • MRI: Normal brain
• Pathology
  • Fiber size variation
  • Reduced staining for integrin α-7

Congenital MD with Joint Hyperlaxity⁶³

• Epidemiology: French-Canadian families from Southwestern Quebec
• Clinical: Similar to, but milder than, Ullrich CMD
  • Onset
    • Age: Birth
    • Hypotonia with Contractures
  • Weakness
    • Generalized
    • Walking (100%): 1 to 3 years
    • Progression
      • Slow
      • Wheelchair in 2nd to 4th decade
    • Respiratory
      • Vital capacity: Reduced; Mean 50%; Range 21% to 100%
      • No progression
      • No failure
  • Joints & Skeletal
    • Contractures: Ankle (71%), Knee (21%), Shoulder (21%)
    • Hyperlaxity
      • Distal + Other
      • Fingers (93%), Wrists (43%), Toes (43%), Elbows (43%), Cervical spine
    • Scoliosis: Variable; Mild to Severe
    • No protruding calcani
  • Intelligence: Normal
• Laboratory
  • Serum CK: Normal to 1000
  • Cardiac: Normal
• Muscle Pathology
  • Fiber size: Variation
    • Small fibers: Rounded or Angular
    • Hypertrophy
  • Central nuclei
  • Endomysial connective tissue: Increased
  • Type I muscle fiber predominance
  • Rimmed vacuoles: In scattered muscle fibers
  • Normal: α-dystroglycan; Collagen VI
• Heterozygotes: Joint hyperlaxity

Congenital MD with CNS atrophy & Absent large myelinated peripheral nerve axons

• Clinical
  • Onset: Neonatal
  • Arthrogryposis multiplex congenita
  • Psychomotor retardation: Severe and generalized
  • Motor
    • Hypotonia
    • Weakness: Face; Axial & limb
  • Dysmorphic features
  • Course: Respiratory failure & Death in 1st year in some
• Pathology
  • Ventriculomegaly
  • Atrophy: Severe of cerebrum and cerebellum

Congenital MD with cerebellar atrophy

• Clinical
  • Onset: Neonatal to 7 months
  • Hypotonia: Generalized; Delayed motor milestones
  • Weakness: Proximal > Distal
  • Cerebellar: Ataxia; Nystagmus; Dysarthria
  • Mental retardation
• Lab
  • CK: 900 to 5,000
  • Muscle
    • Fiber size variation
    • Connective tissue: Increased
    • Normal dystrophin & merosin
  • Cerebellum: Atrophy; Dandy-Walker variant
  • White matter: Normal
• Non-progressive

Muscle-Eye-Brain Disorders ¹⁹

• General CNS changes: "Cobblestone" cortex
  • Gyral absence or malformations
  • Disorganized cortex of variable thickness
  • Deficient neuronal migration
  
  
• Walker-Warburg Syndromes (WWS)
  
  • General
    • Clinical: Systems with anomalies
      • Brain
      • Muscle
      • Eye
    • Gene disorders
      • POMT1: 9q34
      • POMT2: 14q24
      • Fukutin: 9q31
      • FKRP: 19q13
      • 65% not identified
  
  l WWS: O-Mannosyltransferase 1 (POMT1) ; Chromosome 9q34.1; Recessive
  
  • Genetics: POMT1
    • Mutations
      • Misense: Gly76Arg
      • Stop & Frameshift: Gln303Stop; Gln385Stop; 2110InsG; 2167InsG
      • Transversion: 1283T to A,
    • Genetic heterogeneity
      • POMT1 mutations identified in 20% of Walker-Warburg families: Typical WW syndromes
    • Allelic with: LGMD with Mental retardation and reduced α-dystroglycan
  • O-Mannosyltransferase 1 (POMT1) protein
    • O-mannosyl-transferase
    • Different isoforms due to alternative splicing
    • Ubiquitously expressed
    • Peak levels: Adult testis; Skeletal & cardiac muscle; Fetal brain
    • Functions
      • Synthesizes O-mannose linked core of oligosaccharide with POMgnT1
      • POMT1 catalyses first step in O-mannosyl glycan synthesis
  • O-Mannosylated proteins
    • O-Mannosylated proteins in mammals: α-dystroglycan, N-CAM, tenascin-J1
      • O-glycans attached to α-dystroglycan play a role in molecular recognition of laminin-α2
    • O-Mannosyl glycan sequences share
      • Galβ1-4GlcNAcβ1-2Man-OSer/Thr
      • Sialated variant in both brain & muscle: Neu5Acα2-3Galβ1-4GlcNAcβ1-2Man-O-Ser/Thr
    • O-Mannose–linked glycosylation locations: Brain, Peripheral-nerve, Muscle glycoproteins
    • 30% of all O-linked sugar chains in brain are O-mannose based
    • Other disorders of glycosylation: POMGnT1, Fukuyama CMD & FKRP, LARGE
  • Epidemiology
    • World-wide distribution of WW syndrome
    • POMT1 mutations identified in Turkish & European families
  • Clinical
    • Most severe CMD with glycosylation disorder
    • Motor: Hypotonia
    • CNS
      • Seizures
      • Severe retardation
    • Eye: Multiple anterior & posterior anomalies; Congenital
      • Anterior
        • Cataract
        • Shallow anterior chamber
        • Microcornea & microphthalmia
        • Lens defects
      • Posterior
        • Retina: Detachment, Dysplasia & Undifferentiated neurons
        • Optic nerve & macula: Hypoplasia & atrophy
        • Coloboma
    • Other: Testicular defects in males
    • Course: Death in fetus or infancy
      • Usually < 1 year
      • Range 0.1 to 3 years
  • Laboratory
    • CK: Variable; POMT1 mutation patients > 1,500
    • Muscle pathology
      • Mild dystrophic changes
      • α-Dystroglycan in connective tissue: Reduced glycosylation
      • Normal merosin
  • CNS pathology
    • Cortex
      • Migrational defects
        • Pathology: Neuronal heterotopia
        • Pathophysiology
          • Defects in the pial glia limitans
          • Result in neural over-migration during neocortex lamination
      • Thin
      • Hydrocephalus: Dilated ventricles
      • Lissencephaly: Type 2; Not classic 4 layered cortex; Cobblestone
      • Occipital encephalocoele
    • White matter: Disorganized myelination; Absent or thin corpus callosum
    • Cerebellum: Afolia; Vermal or general hypoplasia
    • Brainstem: Small/Absent pyramids
    • Spinal cord: Small/Absent Lateral columns; Aberrant anterior root entry zones
  
  l WWS: O-Mannosyltransferase 2 (POMT2) ; Chromosome 14q24.3; Recessive
  
  • Epidemiology
    • 6 families linked to locus
    • 3 families with identified mutations
  • Genetic
    • Mutations: Homozygous R638X; c.1005+1G>A (splice site); T433X
  • POMT2 protein
    • Short transcript: Widely expressed
    • Long transcript: Expressed only in testes
    • Subcellular: Associated with endoplasmic reticulum
  • Clinical: Similar to other WWS syndromes
    • Onset
      • Age: Prenatal
      • Hydrocephalus
    • Hypotonia
    • Ophthalmic: Cataracts; Microphthalmia
  • Laboratory
    • Serum CK: High
    • MRI: Lissencephaly; Hydrocephalus; Hypoplasia of pons & cerebellum
    • Muscle biopsy
      • Fiber size: Varied
      • Endomysial connective tissue: Increased
      • Basophilic muscle fibers
      • α-dystroglycan staining: Reduced
  
  
• Santavuori congenital muscular dystrophy (Finnish; Muscle-eye-brain disease (MEB)) ²⁹
  l O-linked mannose β1,2-N-acetylglucosaminyltransferase (POMGnT1) ; Chromosome 1p32-p34; Recessive
  • POMGnT1 gene mutations
    • Types: Missense, Nonsense & Frameshift
    • More severe phenotype with mutations toward 5’ end of gene
  • POMGnT1 protein function
    • O-Mannosyl glycosylation
      • Transfers N-acetylglucosamine residue to an O-linked mannose
      • O-Mannosyl glycan required for binding between α-dystroglycan & laminin
    • ? Role in neuronal migration
    • Mutation effects: Reduced enzyme function
  • Epidemiology
    • Disease focus: Finnish (Founder effect)
    • Other: Turkish, French, Japanese & Korean families
  • Clinical
    • Severity: Milder than Walker-Warburg
    • Motor
      • Hypotonia: Congenital
      • Development: Slow
    • CNS: Severe mental retardation
    • Eye
      • Coarse trabecular meshwork in anterior chamber: Myopia (>-6 diopters); Glaucoma
      • Retinal dysplasia
      • Juvenile cataracts
    • Death
      • Age: 6 to 42 years
      • Longer survival than Walker-Warburg
  • Laboratory
    • Serum CK: Mild elevation
    • Visual evoked potentials: Giant
  • Muscle pathology
    • Infancy: Muscle fiber degeneration & regeneration
    • Dystrophic: Childhood
      • Muscle fiber size: Varied
      • Muscle fiber regeneration
      • Endomysial connective tissue: Increased
    • Connective tissue components
      • α-Dystroglycan: Reduced
      • Merosin: Reduced (to 10% to 20%)
      • Laminin-β2: Increased
  • CNS pathology
    • Brainstem: Thin
    • Cerebellar: Hypoplasia with absent inferior vermis
    • Cortex: Disorganization (cobblestone); Midline defects; Hydrocephalus
    • White matter: Abnormal, especially diffuse at young ages < 1.5 years

Congenital Muscular Dystrophy with Familial Junctional Epidermolysis Bullosa

• Genetics: Mutations are small deletions & duplications
• Plectin protein
  • Size: 500-kD
  • Structure: Contains intermediate filament & actin-binding domains
  • Family: Plakin
  • Tissue expression: Ubiquitous; Highest in stratified squamous epithelia, muscle & brain
  • Subcellular location: Concentrated at sites of stress
    • NMJ: Postsynaptic membrane
    • Muscle: Sarcolemma & Z-disks
    • Skin: Hemidesmosomes
    • Heart: Intercalated disks
  • Complexed with
    • Desmuslin : Associated with α-dystrobrevin
    • Desmin
    • Other: Microtubules, α-Spectrin, Nuclear lamin B, Integrin β4, Microtubule-associated proteins
  • Functions
    • Cytoskeletal linker
    • Mechanical integrity of cells: Formation of intermyofibrillar desmin cytoskeleton
    • Substrate for caspase 8 during CD95- & tumor necrosis factor receptor-mediated apoptosis
  • Disease association: Partial, but reduced, expression associated with milder disease
• Onset
  • Congenital
  • Weakness or Hypotonia
  • Skin lesions: Blistering
• Clinical
  • Skin: Blistering; Due to Trauma & Heat
  • Muscle
    • Weakness: Myopathy & Myasthenic syndrome
      • Distribution: Proximal, Distal, Facial & Ocular
      • Course: Slowly progressive; Many in wheelchair by 10 years
      • Degree of weakness may correlate with level of plectin expression
    • Diffuse muscle hypotrophy
  • Systemic
    • Elbow contractures
    • Infantile respiratory complications
    • Alopecia
    • Decayed teeth
    • Laryngeal webs
    • Urethral strictures
  • CNS: Brain atrophy; Enlarged ventricles
• Treatment
  • 3,4-diaminopyridine: Some improvement
  • Pyridostigmine: No benefit
• Laboratory
  • Serum CK: High; > 1,000
  • Electrophysiology
    • Repetitive Nerve Stimulation: Decrement
    • EMG: Myopathic; Irritable
    • Endplate physiology
      • Quantal release by impulse: Normal
      • MEPPs: Small
      • AChRs: Fetal & Adult AChRs at NMJs
  • Muscle pathology
    • Myopathic
      • Necrosis & Regeneration
      • Muscle fiber size: Varied
      • Internal nuclei
      • Connective tissue: Increased
      • Abnormal internal architecture on NADH stain
    • Spike-like sarcolemmal projections with Integrin β1D stain
    • Endplates: Chains of small regions over fiber surface
    • Plectin: Absent or reduced staining in muscle Z-lines & skin
    • Hemidesmosomal protein HD1: Reduced staining
    • Desmin: Focal deposits in most muscle fibers
    • Some patients: Rods; Cytoplasmic bodies; Rimmed vacuoles
    • Mitochondria³²
      • Increased number of COX- muscle fibers
      • Biochemistry: Reduced COX I (Complex I) & cytochrome c oxidase (Complex IV) activities
      • Morphology: Abnormal shape; Inclusions; Proliferation
      • Also see: Congenital muscular dystrophy with mitochondrial structural abnormalities

Congenital muscular dystrophy with mitochondrial structural abnormalities²

• Clinical
  • Motor
    • Weakness: Proximal; Slowly progressive
    • Hypotonic; Late walking
  • Cardiomyopathy: Dilated
  • Mental retardation
• CK: Mildly elevated
• Muscle pathology
  • Fiber size variation
  • Necrosis & regeneration
  • Mitochondria
    • SDH & COX staining
      • Increased at periphery of type 2 muscle fibers
      • Reduced in center of fibers (Normal SR in these regions)
    • EM: Enlarged mitochondria with abnormal structure
  • Merosin: Normal
• Also see: Congenital muscular dystrophy with junctional epidermolysis bullosa

From D Cummings MD

Congenital MD + Rigid Spine

Congenital muscular dystrophy with early spine rigidity

• Genetics
  • Selenocysteine incorporated into proteins at UGA codon
  • UGA codon normally a stop codon
  • Recognition of UGA as Selenocysteine codon
    • Requires insertion sequence (SECIS) in 3'UTR of transcripts
    • Sec redefinition element (SRE) located adjacent to the UGA codon
  • SEPN1 mutations
    • Nonsense: Frameshift; Stop codon; Splicing
    • Missense locations
      • Conserved domain
      • Near UGA codon: SRE element⁷³
      • In SECIS sequence
  • Mutations also cause
    • Minicore congenital myopathy syndromes
    • Congenital myopathy with desmin inclusions
    • Congenital fiber type size disproportion (Small type I fibers)
• SEPN1 protein⁴⁰
  • Selenoprotein family: All are enzymes
  • Structure
    • Size: 70 kDa
    • Contains single selenocysteine residue
    • Glycoprotein
  • Subcellular localization: Endoplasmic reticulum; Membrane
  • Levels
    • High: Most human fetal tissues; Proliferating cells
    • Lower in adult tissues
    • Skeletal muscle: Progressive decrease as myoblasts fuse to become myotubes
  • Function: ? Early development in cell proliferation or regeneration
• Selenoproteins
  • Catalyze oxidation/reduction reactions
  • Contain Selenocysteine (Sec) residue(s) located at enzymatic active site
  • Selenium deficiency: Causes
    • Cardiomyopathy (Keshan disease)
    • Muscular dystrophy in livestock
• Epidemiology
  • Family origins: Moroccan, Turkish, Iranian, Scandinavian
• Clinical features: Overlap with Minicore congenital myopathy syndromes
  • Weakness⁸: Variable seveity
    • Onset: Variable
      • Early: Birth to 1 year
      • Later: 1st decade
    • Early onset: Hypotonia; Poor head control
    • Distribution
      • Neck; Face; Proximal; Distal
      • Symmetric
    • Respiratory
      • Vital capacity
        • Often reduced: Minimal to 55% by 1st decade
      • Nocturnal hypoventilation: Central apnea during paradoxical sleep
      • Progressive failure
    • Walking: Never to < 18 months
    • Muscle size: Small, especially inner thighs & calves
    • Course
      • Early improvement with development
      • Then Non-progressive or Slow decline
  • Skeletal
    • Spine
      • Rigid: Onset 3 to 7 years; Limited flexion of neck & spine
      • Scoliosis: Onset 4 to 12 years; Progressive
    • Other contractures (50%): Elbow flexors; Hip extensors; Ankles; Knees
  • Cardiac: Minor conduction defects, or Normal
  • CNS: Normal intelligence; No white matter changes
  • Endocrine: Insulin resistance
• Laboratory
  • Serum CK: Normal
  • MRI of muscle
    • Selective involvement of muscles
    • Volume loss & Increased signal on T1
    • Involved muscles: Vastus lateralis; Biceps femoris
    • Spared muscles: Vastus medialis; Semitendinous; Adductor magnus; Gracilis
• Muscle pathology: Choose muscle to biopsy by MRI
  • Anatomical pattern: Variable involvement of different muscles
  • Fiber size: Variable
  • Muscle fibers
    • Necrosis: Occasional
    • Minicores
      • Short-length areas
      • Ultrastructure: Sarcomere disorganization & mitochondria depletion
      • Immunostaining: Filamin C; αB-crystalline
    • Fiber types: Type I muscle fiber predominance or small; Both types present
  • Endomysial connective tissue: Minimal to mild increase
  • Merosin: Normal

• Weakness: Never walk
• Rigidity of the spine and scoliosis: Very early onset

Congenital muscular dystrophy with respiratory failure & muscle hypertrophy (CMD1B; MDC1B)⁷

• Epidemiology: Arab & German families
• Clinical
  • Severe diaphragm involvement: Respiratory failure
  • Weakness
    • Neck
    • Proximal > Distal
    • Arms & Legs
    • Face: Mild
    • Walking: Onset at 1.5 to 2.5 years
    • No clear progression of weakness
  • Muscle hypertrophy: Generalized
  • Contractures
    • Ankles
    • Spine rigidity (50%)
  • Intellect: Normal
• Laboratory
  • Serum CK: Very high; 1,700 to 7,600
  • Brain: Normal MRI
• Muscle
  • Dystrophic changes
  • Connective tissue proteins: Reduced on some fibers
    • Merosin: Reduced; No mutations in Merosin gene
    • Integrins α-7 & β1D: Reduced
    • Heparan sulfate proteoglycans: Normal

Congenital Muscular Dystrophy with Muscle hypertrophy (MDC1C)^16,26

• Epidemiology: Mutations in 7 families
• Genetics
  • Allelic with LGMD 2I
  • Mutations: Missense
    • Ser221Arg, Ala455Asp, Pro448Leu, Tyr309Cys, Ser385Ter, Pro316Thr, Tyr465Ser
    • Tyr465Ser mutation adds potential new glycosylation site
  • No patients with 2 FKRP null alleles
  • Patients with L276I mutation usually have LGMD 2I
• FKRP protein
  • Ubiquitous
  • Highest levels in skeletal muscle, heart & placenta
  • Subcellular: Normal protein in Golgi
  • Function: ? Glycosyltransferase or phosphoryl-ligand transferase
  • More severe cases: Mutant protein⁵⁴
    • Location: Endoplasmic reticulum
    • Shorter half-life
    • Preferentially degraded by proteasome
• Clinical
  • Onset
    • First weeks of life
    • Hypotonia
    • Reduced movement & activity
  • Weakness
    • Diffuse: Limbs; Neck; Trunk; Face
    • Functional abilities
      • May sit unassisted
      • Inability to walk
  • Muscle size
    • Hypertrophy: Especially calf; Most patients
    • Wasting: Shoulder girdle; Other muscles
  • Contractures
    • Some patients
    • Knees; Ankles; Elbows; Spine
  • Skeletal: Small head; Scoliosis
  • CNS
    • Usually normal
    • Occasional patients with
      • Mild mental retardation: Psychomotor; Absent speech
      • Cerebellar cysts
• Laboratory
  • Serum CK
    • Very high: 3,000 to 8,000
    • May have lower levels with increasing age
  • EMG: Myopathic
  • Muscle biopsy
    • Varied fiber size
    • Connective tissue: Increased
    • Little degeneration or regeneration
    • Laminins
      • α2: Partial reduction around muscle fibers; Normal in nerve
      • α5: Increase
    • Dystroglycans
      • α-dystroglycan
        • Muscle staining: Marked reduction: Similar to changes seen in Fukuyama CMD
        • Western blot: Abnormal molecular weight
      • β-dystroglycan: Normal
  • Brain MRI: Normal or Cerebellar cysts
  • EKG: Normal
• Also see: CMD with muscle hypertrophy, mental retardation & cerebellar hypoplasia

Scleroatonic muscular dystrophy (Ullrich) ²¹

• Genetics
  • Mutations
    • Recessive (COL6A1, COL6A2 & COL6A3)
      • Truncating or Missense
      • Reduced or absent Collagen VI in muscle
      • Commonly: Located in triple helical domain; Alter glycine residues
    • Dominant (COL6A1, COL6A2 & COL6A3)
      • Inframe deletion or mutation
      • Dominant negative effect⁴¹: Interferes with dimer formation & secretion of molecule
      • Often in N-terminal region: Proximal to cysteine in triple helical domain
      • Family history of disease uncommon
  • Allelic with
    • Bethlem myopathy
    • Myosclerosis: COL6A2 mutation
    • Ossification of posterior longitudinal ligament: Mutations in different part of COL6A1 gene
  • Some patients with similar syndrome: Not linked to these loci; Normal Collagen VI
• Collagen VI protein
  • Ubiquitious extracellular matrix protein
  • Concentrated outside basal lamina
  • Ullrich myopathy muscle & fibroblasts
    • Mislocalized, Low or Absent
• Clinical features
  • Variable
    • Some with severe weakness
    • Some families with COL6A3 mutations have milder disease
  • Onset
    • May be reduced fetal movements
    • Congenital contractures
    • Hypotonia
  • Joints
    • Early
      • Hyperlaxity of distal joints
      • Distal arthrogryposis: Some patients
    • Contractures
      • Proximal > Distal
      • Knee contractures may limit walking
      • Spine: Rigidity; Kyphoscoliosis
      • Torticollis
      • May improve with increasing age
  • Weakness
    • Diffuse: Distal > Proximal; Neck flexors
    • Ambulation: May walk by age 1 to 2 years (30%); Majority never walk
    • Respiratory insufficiency
      • Onset: Hypoventilation in 1st decade
      • Failure: Not correlated with degree of weakness
    • Muscle wasting: Distal predominant
    • Course
      • Slowly progressive
      • Walking: Patients may never walk; Others walk for a limited time (3 to 6 years)
      • Death in 1st or 2nd decade associated with respiratory failure
  • Skin
    • Soft
    • Keratosis pilaris
    • Keloids
    • Atrophic scars
    • Striae
    • Petechiae
  • Skeletal
    • Prominent calcaneus of foot
    • Scoliosis
    • Rigid spine
  • Tendons: Similar to Ehlers-Danlos; Contractures
  • Cardiac: Normal
  • Intelligence: Normal
  • Laboratory features
    • Serum CK: Normal to 10x elevated
    • EMG: Myopathic
  • Muscle biopsy
    • Varied muscle fiber size: Some very small muscle fibers
    • Endomysial connective tissue: Progressive increase
    • Necrotic muscle fibers: Rare or Occasional
    • Lobulated fibers: Occasional
    • Collagen expression
      • Type VI
        • 2 patterns of pathology
          1. Absent from skeletal muscle & capillaries
          2. Absent on surface of muscle fibers but present in connective tissue
        • No correlation between pattern of pathology and clinical phenotype
      • Type IV: Upregulated
    • Ultrastructure
      • Muscle plasma membrane: Uneven, extension & folding
      • Basal lamina: Thickening & overproduction; Replication of capillary basement membrane
      • Capillary morphology⁴²: Small lumens; Increased pinocytotic vesicles in endothelial cells
      • Collagen: Disorganized fibrils
  • Gene testing: Utah

Congenital Muscular Dystrophy with Severe Mental Retardation & Abnormal Glycosylation (MDC1D)⁴³

• Epidemiology: 1 patient
• Genetics
  • 5th largest human gene
  • Mutations
    • Missense: Glu509Lys
    • Insertion (1bp): 1999insT
  • Other mutations in: myd mouse
• LARGE protein
  • Ubiquitously expressed
  • Highest levels in heart, brain & skeletal muscle
  • Two putative catalytic domains with homology to
    • α-glycosyltransferase (bacterial WaaIJ family)
      • Synthesis of outer membrane lipopolysaccaride
    • β-1,3-N-acetylglucosaminyltransferase (iGnT)
      • Synthesis of poly-N-acetyllactosamine backbone of erythrocyte i antigen
  • May play role in glycosylation of α-dystroglycan⁴⁷
• Onset
  • Age: 5 months
  • Global developmental delay
• Clinical
  • Congenital muscular dystrophy
    • Hypotonia
    • Slow improvement over 1st decade
    • Muscle hypertrophy
      • Moderate
      • Quadriceps; Calf; Arm muscle
      • Tongue: Normal
    • Muscle atrophy: None
    • Weakness
      • Proximal > Distal
      • Legs > Arms
      • Face: Mild weakness
      • EOM: Normal
  • CNS
    • Mental retardation: Profound
    • Mirror movements
    • Nystagmus: Lateral
    • Spasticity: Tone increased; Tendon reflexes increased; Extensor plantar
  • Contractures
    • Mild
    • Ankle & Elbow
• Laboratory
  • Serum CK: High; 400 to 4500
  • NCV: Normal Motor & Sensory
  • EMG: Myopathic
  • Electroretinogram: Small evoked response
  • CNS imaging
    • White matter changes: Periventricular to arcuate fibers; Anterior & Temporal
    • Structural abnormalities: Abnormal neuronal migration; Small brainstem
  • Pathology: Muscle
    • α-dystroglycan
      • Immunolabelling: Reduced
      • Immunoblotting with to glycosylated epitope: Reduced molecular weight of α-dystroglycan
      • Retains some laminin binding activity
    • Laminin α2: Normal
    • Dysferlin: Upregulated in myd mouse
  • Mouse model: myd mouse muscle

CMD with Adducted Thumbs, Ophthalmoplegia & Mental retardation ³⁴

• Epidemiology: Consanguinous Sicilian siblings
• Onset: Congenital
• Clinical
  • Joints: Adducted thumbs; Toe contractures; Hyperlordosis
  • Motor: Hypotonia; Delayed walking
  • Weakness: Diffuse; Facial; Severe
  • Ocular: Ophthalmoplegia; Ptosis
  • Cognitive: Mental retardation, IQ 65 to 70
• Laboratory
  • Serum CK: High, 130 to 750
  • NCV: Normal
  • MRI: Cerebellar hypoplasia, Mild
  • Muscle
    • Dystrophic: Varied fiber size; Increased endomysial connective tissue
    • Normal laminins & α-dystroglycan

Congenital muscular dystrophy with Muscle hypertrophy, Microcephaly & Mental retardation¹⁵

• Epidemiology: Italian children
• Onset
  • Birth
  • Hypotonia
• Clinical
  • Hypotonia
  • Joint contractures: Hips; Knees; Ankles: Elbows; Neck flexors
  • CNS: Psychomotor retardation; Absent speech
  • Motor: Inability to walk; Diffuse weakness
  • Muscle hypertrophy: Calf; Quadriceps; Tongue
  • Ocular: Normal
  • Course: Non-progressive
• Laboratory
  • Serum CK: Very high
  • Muscle biopsy
    • Dystrophic changes
      • Small muscle fibers
      • Connective tissue increased
      • Little degeneration or regeneration
    • Laminins
      • α2: Partial reduction
      • α5: Increased
  • Brain MRI
    • Posterior fossa: Enlarged cisterna magna; Cerebellar vermis ± hemisphere hypoplasia
    • White matter: Patchy signal, especially periventricular
  • EKG: Normal
• Also see: CMD with cerebellar cysts

Congenital muscular dystrophy⁵⁵

• Epidemiology: Palestinian family, consanguinous
• Onset
  • Age: Neonatal or in utero
  • Reduced fetal movements
  • Hypotonia
• Clinical
  • Motor
    • Early: Hypotonia; Reduced anti-gravity movements
    • Weakness
      • Proximal > Distal
      • Most severe: Trunk & Shoulder girdle muscles
      • Mild to moderate involvement: Face, Neck, Proximal limb
      • None: Extra-ocular, Bulbar
  • Muscle size: Small, No hypertrophy
  • Course
    • Some death in childhood or adult: 50% with respiratory infections
    • Motor: Static
    • Most survivors able to walk as children & adults
  • Joints
    • No contractures
    • Mild laxity in adults
  • Intelligence: Normal
• Laboratory
  • Serum CK: Normal or Minimally elevated
  • Brain CT: Normal
  • Echocardiogram: Normal
• Muscle pathology
  • Morphology: "Dystrophic"
  • Normal staining: Laminins (α2, α5, β1, β2), Dystrophin, Sarcoglycans (α, β, γ), α & β-Dystroglycan

OTHER CONGENITAL WEAKNESS

• Largest # of triplet repeats of any MD syndrome (> 1,000)
• Examine parents (esp mother) for evidence of disease

• Congenital FSH often presents with no clearly affected parent

• Acid Maltase
• Debranching Enzyme
• Branching Enzyme
• Carnitine Deficiency
• Mitochondrial (Cytochrome Oxidase Deficiency)

• Spinal Muscular Atrophy: 5q & X-linked
• Congenital Neuropathies: Hypomyelinating; CIDP

Broad A band disease

• Epidemiology: 2 sporadic cases
• Clinical
  • Onset: Neonatal
  • Hypotonia
  • Developmental delay: Motor; Speech
  • Progressive improvement in function
  • Retinal dystrophy: One patient
• Laboratory
  • Serum CK: Mildly high
  • EMG: Normal
• Muscle pathology
  • Broad A bands visible on plastic sections
  • Misalignment of myosin thick filaments

Trilaminar myopathy

• Epidemiology: 1 sporadic case
• Clinical
  • Onset: Birth
  • Tone: Increased resistance to passive movement
  • Contractures
  • Course: Increasing spontaneous movements
  • Cognition: Normal
• Laboratory
  • Serum CK: High (6x to 40x)
  • EMG: Normal
• Muscle pathology
  • Fiber size: Varied
  • Large fibers: Trilaminar appearance
    • NADH: Dark inner & outer zones
    • ATPase: Pale inner & outer zones
  • Ultrastructure
    • Central zone lacks organized myofibrils
    • AChRs: Extrajunctional, between intermediate & outer zones

Zebra body myopathy

• Epidemiology: 2 sporadic cases; ? clinical entity
• Clinical
  • Onset: Birth
  • Hypotonia
  • Weakness
    • Symmetric or Asymmetric
    • May be greater in arms
  • Muscle size: Small
  • Tendon reflexes: Normal
  • Course: static or slow improvement
• Laboratory
  • Serum CK: Normal or Mildly high
  • EMG: Myopathic
• Muscle pathology
  • Fiber size: Varied
  • Zebra bodies
    • Z-line material in stacks separated by thin filaments
    • May occur in normal muscle

Weakness with early skeletal disorders

• Tel Hashomer camptodactyly syndrome
    l Autosomal Recessive
  • Clinical features
    • Skeletal: Camptodactyly (flexed fingers); Club feet; Spina bifida - Cervical
    • Skin: absent interphalangeal creases; Whorls 7 or more fingers; Palmar creases
    • Abnormal sweat pores
    • Cardiac: Mitral valve prolapse
    • Myopathy: Wasting; Variable fiber size; High serum CK
    • Heterozygotes: Partial skeletal (5th finger camptodactyly) & skin manifestations
  
  
• Camera-Marugo-Cohen Syndrome
  • Clinical features
    • Obesity
    • Mental retardation
    • Skeletal: Body asymmetry; Camptodactyly; Clinodactyly
    • Muscle weakness: Proximal, Legs > Arms 50%; Congenital hypotonia 50%

Williams-Beuren syndrome

• Genetics
  • Microdeletion in region of highly repetitive DNA
  • 2° to recombination between misaligned repeat sequences flanking WBS region
• Clinical
  • Vascular stenoses: Supravalvular aortic; Coronary; Pulmonary; Renal
  • GU: Urethral stenosis; Small or solitary kidney
  • ENT: Elfin faces; Hoarse voice; Vocal cord paralysis
  • Gastrointestinal: Inguinal hernia; Constipation; Diverticulosis
  • Metabolic: Episodic dehydration; Hypertension; Hypercalcemia
  • Mental retardation: 65 IQ average
    • Deficient visuo-spatial ability
    • Relatively preserved verbal function
    • "Cocktail party" personality
    • Attention defecit
    • Hypersensitivity to sound
  • Joint contractures
  • Motor
    • Infants: Hypotonia; Delayed walking; Fatigue
    • Adults: Cramps; Myalgia; Fatigue
• Muscle pathology
  • Myopathy: Variable fiber size
  • Some with lipid storage & Carnitine deficiency

Neonatal perifascicular myopathy¹

• Onset
  • Age: Neonatal
  • Motor: Hypotonia & Weakness
• Clinical
  • Motor
    • Hypotonia
    • Weakness: Diffuse
  • CNS
    • Cognitive delay
    • Mental retardation: Mild
  • Course
    • Non-progressive
    • Improvement in motor skills with increasing age
• Muscle pathology
  • Muscle fibers: Perifascicular pattern of pathology
    • Atrophy
    • Immature, type 2C muscle fibers
  • Connective tissue
    • Alkaline phosphatase staining of perimysium
    • Cells: Macrophages or dendritic
  • Inflammation: Perivascular, near & around intermediate sized vessels

Immunoneurologic Disorder (Woods-Black-Norbury Syndrome)

• Males: Neonatal hypotonia; Early death
• Females: Spastic paraparesis
  • Weakness: Progressive
  • Tendon reflexes: Brisk
  • Bladder dysfunction
  • Night vision: reduced
  • IgG2 dficiency

Congenital absence, weakness, or hypoplasia of muscles

Extraocular muscles

• Congenital fibrosis of extraocular muscles (CFEOM)
  l CFEOM1
        KIF21A (Kinesin) ; Chromosome 12p11.2-q12; Dominant & Sporadic
  • Mutations⁴⁶
    • Heterozygous
    • Missense: R954W; R954Q; Other
    • Stalk region of protein: Most common
    • Some de novo: More in sporadic cases
  • KIF21A protein
    • Motor protein
    • Kinesin class: Same as KIF21B & KIF4
    • Other kinesin mutations
      • CMT 2A: KIF1Bβ
      • SPG 10: KIF5A
  • Clinical
    • Ptosis: Congenital; Bilateral
    • EOM
      • Common defect: Inability to elevate eye
      • Other: Little horizontal movement
    • Eyes fixed 20° to 30° below horizontal
    • Head tilt: Posterior
    • Blepharophimosis
  • Pathology
    • Developmental absence of the superior division of oculomotor nerve
    • Reduced # of midbrain α oculomotor neurons
    • Anomalous extraocular muscle insertion
    • Muscle changes: Superior rectus & Levator palpebrae superioris
  • Also see clinical variant: FEOM 3A
  
  l CFEOM2
        ARIX (PHOX2A) ; Chromosome 11q13.3-q13.4; Recessive
  • Mutations: Splice sites & Missense
  • ARIX protein
    • Homeodomain transcription factor
    • Required for cranial nerve III & IV development
  • Epidemiology: Saudi Arabia (Ala72Val); Turkey
  • Clinical
    • Limited extraocular movements
      • Eyes fixed in abduction
      • Deficient function of muscles innerved by the third or fourth cranial nerves
      • Can raise eyes above horizontal or have unilateral involvement
    • Ptosis
    • Visual acuity: Poor; Severe amblyopia, in eyes with pupil covered by ptotic lid
    • Pupils: Myotic; Fixed or sluggishly reactive to light or pupillary dilators
  
  l CFEOM3
        Chromosome 16q24.2-q24.3; Dominant
  • Variable expression
  • Nonprogressive
  • Often asymmetric
  • Ptosis
  • Extraocular movements: Limited
    • Deficient function of muscles innerved by the third or fourth cranial nerves
    • Can raise eyes above horizontal or have unilateral involvement
    • Mild: Limited vertical gaze
    • Severe: 1° gaze fixed in hypo- & exotropic position; Marked restriction of EOM
  
  l CFEOM with ulnar hand anomalies⁵⁸
        Chromosome 21qter; Recessive
  
  • Epidemiology: 1 Turkish family
  • Clinical
    • Ocular
      • Ophthalmoplegia
        • Muscles
          • Especially inferior oblique & superior rectus
          • Limited upgaze: Most common
          • Levator palpebrae: Some patients
          • Severe cases: Complete ophthalmoplegia
        • Non-progressive
        • Forced ductions: Normal
      • Blepharoptosis: Right eye
      • Head posture: Chin elevation
      • EOM pathology: Fibrosis
    • Hands
      • Postaxial oligodactyly/oligosyndactyly
        • Especially absent 5th finger
      • More severe on right side
  
  
• Duane's syndrome

  Click image for movie

  Duane syndrome

  • Clinical features: General
    • Restriction of abduction, adduction, or both
    • Eye adduction causes
      • Globe retraction
      • Palpebral fissue narrowing
    • Strabismus: Esotropia most common
    • Usually unilateral & sporadic
    • Bilateral syndromes
      • Amblyopia & Strabismus: More common
      • Especially familial cases
    • Associated congenital malformations common
      • Skeletal
      • Ear
      • Ocular
      • Neural
    • Pathology
      • Absent abducens nuclei + nerve
      • Lateral rectus muscle
        • Denervated
        • Aberrant innervation by inferior division of oculomotor nerve
              (Also innervates ipsilateral medial rectus muscle)
  
  
  • DURS1
    l Chromosome 8q13; ? Sporadic
    

    Duane-like phenomenon in patient diagnosed as chronic ocular myasthenia gravis. Mild ptosis in R eye on center gaze. (Top) Increased ptosis & retraction in R eye     with adduction (L gaze). (Bottom)

    • Genetic: Deletion in 8q rearranged region
    • Clinical: Multisystem disorder
      • Weakness of abduction
      • Retraction of eye & ptosis with adduction
      • Associated C2-C3 vertebral fusion (Klippel-Feil)
      • Thenar hypoplasia
      • Deafness
    
    
  • DURS2 ⁷²
    l α2-Chimaerin (CHN1) ; Chromosome 2q31; Dominant
    • Genetics: Mutations
      • Missense: Heterozygous
      • Gain-of-function: Increase α2-chimaerin RacGAP activity
      • Some mutations enhance
        • α2-chimaerin translocation to cell membrane
        • Ability of α2-chimaerin to self-associate
      • Functional effect: Axonal disorder
        • Aberrant branching and/or defasciculation of nerve
    • CHN1 protein
      • Rac-specific GTPase-activating: Down-regulates Rac activity
      • Binds to diacylglycerol (DAG), a membrane associated phorbol ester signaling lipid
      • Strongest expression during development in midbrain & hindbrain
    • Congenital ophthalmoplegia
      • Abduction: Absent or reduced
      • Adduction: Reduced in some patients
      • Eye retraction & ptosis on adduction
      • Higher incidence of
        • Bilateral involvement
        • Vertical movement abnormalities
    • Pathology
      • Absent abducens nerve & nucleus in pons
      • Hypoplastic oculomotor nerves: Small oculomotor-innervated muscles
    • Mice with loss of α2-chimaerin
      • Disrupted ephrin/EphA4 signaling
      • Elevated RacGTP levels
      • Phenotype: Hopping rabbit-like gait resulting from
      • Pathology: Excessive & aberrant midline crossing of corticospinal tract axons & spinal interneuron projections
    
    
  • Duane anomaly + Radial ray abnormalities & Deafness (DRRS; Okihiro syndrome)
    l Sal-like 4 (SALL4) ; Chromosome 20q13.13-q13.2; Dominant
    • Allelic with: IVIC syndrome
    • Clinical
      • Upper limb: Hypoplasia of thenar muscles; Absence of thumb & first metacarpal
      • Ocular: Duane syndrome; Coloboma
      • Renal: Malrotation; Absence
      • Ear: Deafness; Narrow external auditory meatus
    • Differential diagnosis: Holt-Oram syndrome
    
    
  • Bosley-Salih-Alorainey Syndrome (BSAS)
    l Homeobox A1 (HOXA1) ; Chromosome 7p15.3; Recessive
    
    • Epidemiology: Saudi-Arabian, Turkish & Native American (Navajo) families
    • Genetics
      • Mutations
        • Stop: 175-176insG, R26X, Y28X
        • Homozygous
      • Mutations in other HOX genes: Cause malformed distal extremities
    • Clinical
      • Duane syndrome: Bilateral
        • Horizontal gaze: Abduction & Adduction limited
        • Up & down gaze: Preserved
        • Convergence: Normal; Associated globe retraction
      • Deafness & Mutism (89%)
      • Motor development (66%): Delayed; Walking > 3 years
      • Other CNS (22%)
        • Mental retardation
        • Autism spectrum disorder
    • Malformations
      • Carotid
        • Hypoplasia or absence of skull canals & arteries: Internal carotid often absent
        • Compensatory enlargement of basilar & posterior communicating arteries
      • Ear: Absent cochlea, semicircular canals & vestibule
      • VI nerve: Absent
      • Normal: Cerebellum, Brainstem, Cerebrum
    • Allelic disorder: Athabascan (Navajo) brainstem dysgenesis syndrome (ABDS)
      • Mutation: R26X
      • Onset: Congenital
      • Clinical: BSAS +
        • Face weakness
        • Central hypoventilation
        • Vocal cord paralysis: 20%
        • CNS
          • Hypoventilation
          • Developmental delay: Global
          • Seizures: 50%
        • Heart
          • Congenital defects: 50%
          • Outflow tract anomalies in some
        • BAERs & Caloric testing: No response
      • Similar syndrome to HOXA1-/- mice
    
    
  • Other multisystem or sporadic Duane's
    • Karyotypic change on Chromosomes 4 or 22
    • Wildervanck syndrome
      • Duane anomaly
      • Klippel-Feil anomaly (fused cervical vertebrae)
      • Congenital perceptive deafness
      • Mostly seen in females
    • Bosley-Salih-Alorainey Syndrome (BSAS)
    
    
  
  
• Möbius Syndrome
  
  
• PEO (Horizontal gaze palsy) & Scoliosis
  l ROBO3 ; Chromosome 11q23-25; Recessive
  • Epidemiology: 10 families, Turkish, Indian, Pakistan, Greek, Arab
  • Onset: 1st decade or Congenital
  • Mutations: Missense; 1 bp insertion; Splice site
  • ROBO3 protein
    • Expressed by commissural axons in brainstem
    • ? Allows axons to cross the midline
  • Clinical
    • Gaze paresis
      • Horizontal: No conjugate horizontal smooth pursuit, saccades, or vestibuloocular reflex
      • Vertical: Spared
      • ? Supranuclear
      • Esotropia: 30%
    • Nystagmus: Pendular
    • Facial myokymia (1 patient)
    • Scoliosis: Mild to Moderate
    • Mental retardation: 30%
    • No weakness
  • MRI
    • Brainstem: Dysplastic in some patients
  
  
• Superior rectus muscle
  • External link: DJO
  
  
• Axenfeld-Rieger anomaly
  l Dominant
  • Eyes
    • Hypoplastic anterior iris
    • Absent eye muscles, partial
    • Proptosis
    • Hypertelorism
  • Ears: Sensorineural deafness, mild
  • CNS
    • Communicating hydrocephalus
    • Psychomotor retardation
  • Short stature
  
  
• Congenital ptosis, Hereditary
  l Type 1 ; Chromosome 1p32-p34.1; Dominant
  • Ptosis: Symmetric or Asymmetric
  • Normal eye movements
  • Penetrance: Incomplete
  
  l Type 2 ; Chromosome Xq24-q27.1; Dominant
  • Male = Female
  • Penetrance: High
  • Onset: Congenital
  • Bilateral: Symmetric
  • Normal eye movements
  
  
• ROCA syndrome
  
  Retardation of growth & development
  Ocular ptosis
  Cardiac defect
  Anal atresia
  
  • Clinical
    • Retardation: Growth; Mental
    • Face: Ptosis, Epicanthus, Broad nasal bridge, Low-set & abnormal ears
    • Congenital heart defect
    • Anal atresia
  
  
• Blepharophimosis: Palpebral fissure is reduced in horizontal dimension
  • Blepharophimosis 1 : + Ptosis & Epicanthus inversus
    l FOXL2 ; Chromosome 3q23; Dominant
    • Genetics
      • Polyalanine repeat expansions (30%): May cause blepharophimosis syndrome without ovarian failure
    • Clinical
      • Ptosis
      • Telecanthus
      • Lid phimosis
      • Epicanthus inversus: Small skin fold arising from lower lid running inwards and upwards toward nose
      • ± Ovarian failure
    
    
  • Saethre-Chotzen Syndrome (SCS; Blepharophimosis 2)
    l TWIST Chromosome 7p21; Dominant
    
    
  • Blepharophimosis with short stature
    l Autosomal recessive
    • Family: Yeminite-Jewish
    • Clinical
      • Eyes: Blepharophimosis; Ptosis; Ophthalmoplegia
      • Face: Prognathism; Synophrys; Thick eyebrows; Weak frontalis
      • Skeletal: Short stature; Syndactyty toes 2 & 3
      • CNS: Borderline mental retardation; Anosmia
    
    
  • Ohdo syndrome
    
    • Mental retardation
    • Congenital heart disease
    • Eyes: Blepharophimosis; Blepharoptosis
    • Teeth: Hypoplastic
    
    
  • Schwartz-Jampel syndrome
    
    
  • Dubowitz syndrome
    • Ptosis
    • Blepharophimosis
    • Lateral telecanthus
    • Skeletal
      • Microcephaly
      • Short stature
    • Mental retardation (50%)
  
  
  • Marden-Walker syndrome
  
  

Face

• Nosology: Cayler syndrome; Di George syndrome
• Genetics: Often paternally derived chromosome
• Facial weakness: Variable severity
  • Congenital
  • Mild: Unilateral lower lip
  • Severe: Complete facial paresis
• Cardiac
  • Atrial septal defect
  • Ventricular septal defect
• Myopathy²⁰
  • Strength: Normal
  • Serum CK: May be high
  • Muscle biopsy: Variation in fiber size; Increased glycogen
• Skeletal
  • Cervical vertebral fusion
  • Adducted thumbs
  • Facial dysmorphism
• Bifid uvula
• Immune
  • T-cell abnormalities
  • Thymic hypoplasia
• CNS (10%)
  • Microcephaly: Variable
  • Mental retardation

• Double knockout of MyoR (Musculin) and capsulin (TCF21)
• Phenotype
  • Absent muscles in 1st branchial arch: Masseter; Pterygoids, Medial & Lateral; Temporalis
  • Cleft palate
  • Diaphragmatic hernia: Posterior

Diaphragm

• Hereditary: Recessive & X-linked
  • Bilateral & left side reported
  • Specific syndromes
    • Fryns
    • Simpson-Golabi-Behmel
    • Tetrasomy 12p
    • Brachmann-de Lange syndrome
    • Lethal multiple pterygium
  • Myotubularin female carriers: Elevated hemidiaphragm
  • Diaphragmatic hernia
    • DIH1 : Chromosome 15q26.1
    • DIH2 : Chromosome 8p23.1
    • DIH3 : Zinc finger protein, multitype 2 (ZFPM2) ; Chromosome 8q23
• Traumatic
  • Associated with brachial plexus injury
  • Right side: 80%
  • Course: Biphasic worsening
    • 1st hours: Tachypnea & O₂ requirement
    • Days to weeks: Atelectasis or infection
  • Diagnosis: Chest fluoroscopy
  • Prognosis
    • Recovery: 50%; Onset in 1st 2 weeks
    • Mortality: 10% for unilateral & 50% for bilateral
• Treatment: Plication of affected diaphragm

Hands

• Cardiac: ASD; VSD; AV block
• Skeletal: Bilateral; Left > Right in 70%
  • Thumb (85%): Absence; Hypoplasia; Triphalangeal
  • Radius (64%): Absence or hypoplasia
  • Contractures: Elbow; Wrist
  • Severe cases: Phocomelia
• Absent or hypoplastic muscles
  • Thenar (100%): Non-opposing thumb
  • Trapezius: Scapular winging; Sloping shoulders
  • Other: Deltoid; Biceps; Triceps; Wrist Extensor; Ulnar abductors; Supinator
  • Lower limbs: Normal

• More frequent: Females; Left side
  
  

• Unilateral finger extensor hypoplasia
• Flexion contracture
• Polyneuropathy: Sensory with hypohydrosis
• Also see: Holt-Oram
  

From: P Bailey
Dextrocardia
Poland Syndrome

Trunk

• General
  • Male: Female = 2.4:1
  • Right: Left = 1.7:1
  • Prevalence: 1 in 30,000
  • Onset: ? 6th week of gestation
• Clinical manifestations: Variable
• Muscle Aplasia
  • Sternal head of pectoral
  • Other: Serratus anterior; Latissimus dorsi; Glutei;
      Infraspinatus & Supraspinatus
  • Unilateral: Most
• Hand anomalies: Ipsilateral, Hypoplastic
  • Simple syndactyly
  • Short fingers
  • More severe anomalies²⁸
  • External link: Radiology
• Craniofacial anomalies
  • Möbius syndrome
  • Ptosis
  • Craniofacial mandibular prognathism
  • Craniofrontonasal dysplasia
  • Romberg syndrome
  • External ear anomalies
• Skeletal anomalies
  • Spinal
    • Scoliosis
    • Hemivertebrae
    • Rib agenesis
    • Klippel–Feil syndrome : External link
  • Thoracic
    • Ribs, clavicle & sternum
    • Sprengel’s deformity
    • Pectus excavatum & carinatum
  • Lower limbs: Popliteal webs; Club foot; Toe syndactyly
• GI: GI hernia; Ulcerative colitis; Pyloric stenosis; Liver herniation
• GU: Renal agenesis; Ureteral reflux; Undescended testes
• Systemic features: Other
  • Axillary hair: Patchy absence
  • Breast & nipple aplasia
  • Cardiovascular
    • Dextrocardia
    • Atrial septal defect
    • Vascular malformations
  • Neoplasms: Occasional
    • Thoracic teratoma
    • Pleural fibroma
    • Hematopoetic: Leukaemia; Lymphoma
• Also see
  • Holt-Oram
  • Carey-Fineman-Ziter

• Contiguous gene syndrome with
  • Hydrocephalus
  • Duane's
• Also see: Holt-Oram
  
  

• Entrapment of suprascapular nerve: Adult onset
• Also see: Erb's palsy

• Urinary obstruction; Cryptorchidism
• Imperforate anus
• Skeletal: Pectus excavatum; Club foot; Hip dislocation
• Cardiac: Patent ductus arteriosus
  
  

Legs

• Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects
• Hypoplasia
  • Systemic: Lung; Thyroid
  • Psoas muscle
  • Cranial nerves V, VII, VIII, IX & X
  • CNS: Pons; Medulla; Cerebellum; Spinal cord

Multicore (Minicore) Disease ¹²

Multicores

• Genetics: Several associations
  l Ryanodine receptor ; Chromosome 19q13.1; Recessive
  l Selenoprotein N, 1 (SEPN1) ; Chromosome 1p35-p36; Recessive or Sporadic
  l Short-chain acyl–CoA dehydrogenase deficiency
  l Titin
  l Recessive or Sporadic; ? Dominant families
  
  • 50% of multicore disease not linked to RYR1 or SEPN1
• Onset
  • Age: Anti-natal to Childhood
  • Delayed motor milestones
• Clinical: General features
  • Four general presentations
    • Classic
      • Weakness: Axial predominance
      • Scoliosis: Severe
      • Respiratory insufficiency
    • Mild
      • Weakness: Generalized; Especially pelvic girdle
      • Hands: Weakness; Amyotrophy; Hyperlaxity
    • Ophthalmoplegia
    • Antenatal: Arthrogryposis
  • Features usually normal
    • Serum creatine kinase levels
    • Intellect
    • Cardiac
    • No malignant hyperthermia
• Clinical: Common form; More severe
  • Genetics: SEPN1 mutations common
  • Early onset features
    • Fetal movements: Reduced
    • Hypotonia
  • Weakness
    • Early
      • Motor delay
      • All eventually ambulant
    • Distribution
      • Axial > Proximal > Distal
      • Upper & Lower extremities
    • Facial: Common; Mild
    • Ocular
      • Ptosis
      • Ophthalmoplegia
        • Some patients
        • Partial to complete (10%) paresis
    • Respiratory: More common with
      • Age > 10 years
      • Scolosis > 60°
      • Nocturnal hypoventilation
    • Course: Non- or Slowly progressive
  • Skeletal
    • Contractures: Mild or absent
    • Ligamentous laxity
      • Feet: Flat or everted feet; Genu valgus
      • Knees: Hyperextended
      • Lumbar lourdosis
    • Rigid spine: Mild; 25%
    • Scoliosis: > 10 years
  • Cardiac (Occasional): Septal defects; Conduction block; Cardiomyopathy
  • Intelligence: Normal
  • No malignant hyperthermia
• Laboratory
  • CK: Normal or slightly elevated (20%)
  • EMG: Myopathic, especially > 4 years & Proximal muscles
  • Muscle MRI: Involvement of vasti; Sparing of rectus femoris
  • Pathology: Muscle
    • Muscle fiber size: Variable
    • Dystrophic features: Some patients
      • Regenerating muscle fibers
      • Endomysial connective tissue: Increased
    • Multiple small cores in individual muscle fibers
      • Histochemistry: Reduced activity on NADH & Mitochonrial stains
      • Short: Do not extend whole length of muscle fiber
      • Frequency: Present in 60% to 90% of muscle fibers
      • Occur in both type I & II muscle fibers
      • More prominent with greater age
      • Ultrastructure: Unstructured central regions; Disordered sarcomere
    • Type I muscle fibers
      • Predominance
      • Occasional smallness
    • Internal nuclei
• Multicore: Genetic variants
  • Selenoprotein N, 1 (SEPN1) mutation group
    • Inheritance: Recessive or Sporadic
    • Allelic with: Congenital MD with rigid spine
    • Frequency: 30% of Mini-Multicore families
    • Clinical: Overlap with Congenital MD with rigid spine
      • General: More severe, "typical" Minicore disease
      • Motor
        • Axial weakness
        • Respiratory failure
        • Preserved: Limb strength; Ambulation
        • Muscle bulk: Amyotrophy
      • Skeletal: Rigid spine; Scoliosis
      • Muscle: Cores smaller than with RYR1 mutations
  • Minicore disease with ophthalmoplegia
    • Genetics: Several associated genes
      • RYR1: Dominant or Recessive
      • SEPN1
      • Phenotype reported with Short-chain acyl–CoA dehydrogenase deficiency
    • Onset: Congenital or 1st year
    • Motor
      • Hypotonia
      • Feeding difficulties
      • Axial & shoulder girdle involvement
      • Respiratory function: Reduced; Occasional failure
      • Muscle MRI: More involvement of sartorius & soleus
    • Weight: Low
    • Scoliosis
  • Antenatal onset with arthrogryposis³³
    • Arthrogryposis, generalized
    • Head
      • Dolichocephaly
      • Prominent nasal root
      • Oblique palpebral fissures
      • High arched palate
      • Low-set ears
      • Short neck: With mild pterygium colli
    • Spine: Kyphosis or kyphoscoliosis, Early & severe
    • Other features
      • Thorax, bell-shaped
      • Clinodactyly,
      • Cryptorchidism, bilateral
      • Single palmar crease
    • Weaknes
      • Proximal
      • Mild
      • Vital capacity reduced
  • Mild phenotype of multicore syndrome: "Central core-like"
    • Epidemiology: Four families
    • Genetics
      • Recessive inheritance
      • Ryanodine receptor mutations (Or linked to 19q31.1)
        • RYR1 mutation: Homozygous; Missense; P3527S
      • Overlap with phenotype for central core syndrome: Missense V4849I
    • Clinical: Mild phenotype
      • Onset: Infancy or Childhood
      • Weakness
        • Severity: Moderate
        • Distribution: Proximal, Pelvic girdle & Axial; Hands
        • Respiratory
          • Vital capacity variably reduced: 50% to 100% of normal
          • No respiratory failure
      • Other muscle
        • Preserved bulk
        • Pain on exertion
      • Joints
        • Hyperlaxity
        • Hip dislocation
        • Arthrogryposis
    • Muscle pathology
      • Myopathic changes
      • Minicores or Cores: Larger than with SEPN1 mutations
      • ATPase stain: All muscle fibers type I
  • Congenital myopathy + Fatal dilated cardiomyopathy: Recessive
    • Epidemiology: Moroccan and Sudanese families
    • Titin mutations
      • Homozygous deletions
      • Out of frame
    • Clinical
      • Delayed motor milestones
      • Hypotonia at birth: Some patients
      • Weakness
        • Onset: < 1 year
        • Symmetric
        • Generalized: Proximal + Distal + Face
        • Legs > Arms
        • Ptosis: Some asymmetric
        • Course: Slowly progressive; Ambulation present in 2nd decade
      • Muscle size
        • Upper limbs: Atrophy
        • Legs: Pseudohypertrophy, especially thighs & calves
      • Contractures
        • Spinal rigidity
        • Joint & Neck
      • Cardiomyopathy
        • Progressive
        • Dilated
        • Onset ages: 5 to 12 years
        • Rhythm disturbances: Ventricular
        • Interstitial fibrosis
        • Sudden death
    • Serum CK: Mildly high
    • Muscle
      • Disruption of sarcomeric M-line protein complex: Truncated titins lacking C-terminal incorporated into sarcomeres
      • Minicores: Irregular borders
      • Central nuclei
      • Myopathy: Increased endomysial connective tissue; Later in childhood
      • Calpain-3 reduced
    • Allelic with
      • Finnish distal myopathy: Dominant inheritance
      • Dilated cardiomyopathy 1G: Dominant inheritance
      • LGMD 2J
      • Myopathy with early respiratory failure: R279W mutation
    • Mutation carriers: Normal

Congenital myopathy with excess of thin filaments⁵

• Actin gene mutations
  • Gly15Arg: Surface exposed residue
  • Val163Leu: Hydrophobic core
• Clinical
  • Hypotonia
  • Respiratory insufficiency
  • Cardiomyopathy
  • Course: Variable with same actin mutation
    • Death in 1st months: 2 patients
    • Survival to childhood: 1 patient
• Serum CK: Normal
• Muscle
  • Masses of thin filaments (Actin)
  • Nuclear ± cytoplasmic rods
  • Fiber size variation
• Other α-Actin syndromes
  • Congenital fiber type size disproportion: Actin mutations
  • Rod myopathy

Carey-Fineman-Ziter Syndrome

• Onset: Congenital
• Clinical
  • Myopathy
    • Non-progressive
    • Hypotonia
    • Muscle hypoplasia
      • Pectoral & Humeral muscles (Poland)
      • Often bilateral
  • Mobius syndrome
    • Ocular
      • Ophthalmoplegia
      • Ptosis
      • Palpebral fissures: Down slanted
    • VII nerve: Facial weakness, bilateral
    • X nerve
      • Dysphagia
      • Feeding disorders (100%)
  • Craniofacial
    • Macrocephaly
    • Triangular nose
    • Robin sequence
      • Micrognathia
      • Glossoptosis: Tongue displaced backward; May obstruct airway
      • Cleft palate (50%)
  • Skeletal
    • Scoliosis (40%)
    • Talipes (40%)
    • Equinovarus
    • Brachydactyly (70%)
  • Developmental delay
• CNS: Usually normal intelligence
• Laboratory
  • Electrophysiology
    • NCV: Normal
    • EMG: Small motor units; Fasciculations
  • Serum CK: Normal
  • Muscle biopsy
    • Fiber size variation
    • Degeneration
    • Regeneration (Desmin + fibers)
    • Fiber types: Type II predominance; Small type I

Reducing Body Myopathies^3,4

• Clinical syndromes
  • Severe infantile
      l Four-and-a-half-LIM protein 1 (FHL1) ; Chromosome Xq26-q27.2; Dominant or Semi-Dominant
    • Onset: 1st 4 years
    • Weakness: Proximal > Distal
    • Rapid progression
    • Fatal outcome < 10 years
  • Congenital myopathic
    • Delayed developmental milestones
    • Benign course
  • Childhood onset
  • Late (adult) onset ⁶
      l Four-and-a-half-LIM protein 1 (FHL1) ; Chromosome Xq26-q27.2; Dominant or Semi-Dominant
    • Genetics
      • Mutations: Missense; H123Y, C132F, C153R, C153Y
      • Allelic with: Scapuloperoneal (Hyaline body) myopathy, Type I
    • FHL1 protein
      • Mutation effects
        • Induces formation of aggresome-like inclusions
        • Inclusions incorporate both mutant & wild-type FHL1
        • Other proteins trapped in a dominant-negative manner
      • Other: See Scapuloperoneal (Hyaline body) myopathy, Type I
    • Clinical
      • Early development: Normal
      • Weakness
        • Scapuloperoneal
        • Asymmetric
        • Paraspinal muscles: May be involved
        • Progressive to diffuse involvement
      • Rigid spine: Some patients
      • Cardiomyopathy: Dilated; Some patients
      • Carrier females
        • May be symptomatic
        • More signs with skewed X-indactivation
    • Laboratory
      • Serum CK: Increased to 3x normal
      • EMG
        • Mixed neurogenic & myogenic patterns
        • May show spontaneous activity
• Muscle biopsy
  • Muscle fiber size: Variable
  • Increased acid phosphatase activity
  • Reducing bodies
    • Location: Cytoplasmic; Often near nucleus
    • Histochemistry staining
      • Trichrome
        • Dark green inclusions
        • ± Associated with eosinophilic cytoplasmic bodies
      • Menadione-NBT (without α-glycerophosphate): Positive
        • Mechanism: Reduce nitro-blue tetrazolium (NBT)
    • Contain aggresome-like proteins
      • Desmin
      • Ubiquitin
      • Luminal endoplasmic reticulum chaperone GRP78
      • γ-tubulin
      • FHL1
    • May be more common in type I muscle fibers
    • Rimmed vacuoles in some patients
    • Ultrastructure of reducing bodies
      • Structure: Granular tubulo-filamentous material (17 nm in diameter)
      • Location: At periphery of sarcoplasm & around nucleus
    • Immunocytochemistry
      • Contain proteins normally associated with nucleoli
      • Also stain for dystrophin, α-sarcoglycan, vimentin & ubiquitin
• Other disorders with reducing bodies
  • Acid maltase deficiency
  • Distal myopathies with rimmed vacuoles

Fingerprint Body Myopathy

• Epidemiology: Few sporadic cases
• Inheritance: Sporadic or Recessive
• Onset: Congenital
• Clinical
  • Weakness
    • Proximal > Distal: Limbs & Trunk
    • Symmetric
    • Sparing of cranial nerves
  • Hypotonia
  • Intellectual impairment: Occasional
  • Course: Nonprogressive or Slowly progressive
• Laboratory
  • Serum CK: High in some patients
  • EMG: Myopathic
• Muscle biopsy: Inclusions
  • Histochemistry: Ovoid; 1 to 10 μM; Red on H& E; Green on GT
  • Ultrastructure: Arrays of parallel osmiophilic lamellae resembling fingerprints
  • Fingerprint bodies also seen with
    • Myotonic dystrophy
    • OPD
    • Inflammatory myopathies
    • Malignant hyperthermia & Central cores²⁵

Congenital myopathy with apoptotic changes⁹

• Epidemiology: 1 Sporadic Japanese patient identified
• Clinical
  • Onset: Congenital hypotonia
  • Psychomotor development: Markedly delayed
  • Motor
    • Hypotonia
    • Muscle atrophy: Generalized
    • Myopathic face
  • Tendon reflexes: Normal
  • Contractures: Ankles
• Laboratory
  • Serum CK: Normal
  • Serum Lactate: Normal
• Muscle pathology
  • Muscle fibers
    • Small
    • Basophilic: Scattered
    • Acid phosphatase positive: Many
    • Immature (Type 2C): 40%
    • Vacuoles: 20% of fibers
  • Endomysial fibrosis: Mild
  • Nuclei: Condensation of chromatin; Fragmentation
  • Apoptosis related changes
    • Bax-positive (Pro-apoptotic) muscle fibers: 80%
    • No Bcl-2 positive (Anti-apoptotic) muscle fibers
    • Activated caspase-3 in fibers: 6%
    • TUNEL positive nuclei: 2%

Hyaline Body Myopathy

• Nosology: Also called
  • Myopathy with lysis of type I myofibrils
  • Myosin storage myopathy
• Genetics
  • Mutation
    • Missense
      • Arg1845Trp; His1904Leu
      • Location
        • Rod region of slow/β-cardiac MyHC
        • Exons 37 to 39
    • Heterozygous
  • Other MYH7 mutations cause
    • Hypertrophic cardiomyopathy
    • Hypertrophic cardiomyopathy with cores
    • Dilated cardiomyopathy (CMD 1S)
    • Distal myopathy (MPD1; Gowers-Laing)
    • Scapuloperoneal myopathy: Arg1845Trp
    • Neonatal hypotonia
• Clinical features
  • Variable penetrance
  • Onset: Infancy or early childhood
  • Motor
    • Early
      • Hypotonia
      • Delayed motor milestones
    • Weakness
      • Proximal ± Distal
      • Scapuloperoneal
      • Arms & Legs
      • Symmetric
      • May be severe & disabling
  • Course: Slowly or Non-progressive
  • Systemic: Occasional cardiac arrhythmias
• Laboratory
  • Serum CK: Normal or Mildly elevated
  • EMG: Myopathic
  • Muscle biopsy
    • Hyaline bodies
      • Subsarcolemmal
      • Eosinophilic
      • Mostly in Type I fibers
      • Lack oxidative or glycogen activity
      • May stain for myosin ATPase (Acid pH 4.3)
      • Ultrastructure
        • Matrix of granular & filamentous material
        • May be subsarcolemmal
        • Not membrane bound
        • Some intranuclear inclusions
    • Type I muscle fiber predominance
  • Hyaline bodies also noted in an adult onset scapuloperoneal myopathy

Congenital Myopathy with Muscle Spindle Excess¹⁸

• Epidemiology: Single case; No family history
• Clinical
  • Onset
    • Birth
    • Hypotonia
    • Arthrogryposis
  • Weakness
    • Diffuse
    • Respiratory failure
  • Areflexia
  • Face: Frontal hollowing; Flaccid cheeks; Triangular mouth; High arched palate
  • Arthrogryposis
  • Cardiomyopathy: Atrial tachycardia; Heart failure; Hypertrophic cardiomyopathy
  • Organomegaly
  • Neuroblastoma: Congenital; Adrenal
  • Course: Death at 14 months
• Laboratory
  • Normal metabolic studies
  • Brain MRI: Enlarged subarachnoid space & ventricles
  • EMG, RNS & NCV: Normal
  • Muscle pathology
  • Scattered atrophic muscle fibers
  • Muscle spindles: Excessive number, 1 or more per fascicle, especially in deltoid & quadriceps
• Other disorders with muscle spindle abnormalities
  • Myotonic dystrophy: Excessive number of intrafusil muscle fibers per spindle
  • Noonan's syndrome: Increased number of spindles
  • Over-expresion of NT-3 (Mice): Excessive number of spindles

Congenital Myopathy with Caps ⁵⁷

• Epidemiology: ~5 sporadic cases reported
• Genetics: TPM2
  • Mutation: Inframe deletion; Glu139del; Heterozygous
  • Allelic with: Nemaline rod myopathy; Distal arthrogryposis 1
  • Mutations not present in recessive cap myopathy patients
• Onset: Congenital or Childhood
• Clinical
  • Motor
    • Hypotonia
    • Weakness
      • Proximal & Distal
      • Face
      • Respiratory
    • Respiratory insufficiency: Severe cases
    • Course
      • Slowly progressive weakness
      • Severe disease: Death at 14 years in 1 patient
  • Skeletal
    • Face: Long narrow
    • Palate: High arched
    • Chest: Deformity; Scoliosis
• Laboratory
  • Serum CK: Mildly elevated or Normal
  • EMG: Myopathic
• Muscle pathology
  • Caps
    • Staining: Dark on Gomori trichrome
    • More common in type I muscle fibers
    • Regions at periphery of muscle fibers
    • Stain for: NADH; Esterase; Desmin; α-actinin; tropomyosin; Actin; SERCA2; Nebulin; Myotilin
    • Ultrastructure
      • Abnormal Z-line material
      • Disorganized myofibrillar architecture
  • Type I muscle fibers: Small

X-linked Mental retardation syndrome ¹⁴

• Onset
  • Birth to Childhood
  • CNS: Low weight; Delayed milestones
• Skeletal: Short stature; Small feet; Gap between 1st & 2nd toes; Hyperextensible joints; Kyphosis
• Obesity
• Small testes
• Prominent lower lip
• Neurological
  • Tremor: Fine; Upper limbs
  • Fine motor coodination: Reduced
  • Mental retardation
  • Behavioral: Reduced Attention span; Hyperactivity; Mood swings; Aggression
  • Motor: Wide based gait; Wheelchair needed
• Muscle wasting: Lower legs

Congenital Weakness with Diarrhea & Deafness

• Clinical
  • Weakness
    • Hypotonia at birth: Feeding difficulties
    • Myopathic faces
    • Tendon reflexes: Reduced
    • Improvement with age
  • Joint contractures
  • Diarrhea: Episodic with intercurrent infections; Secretory
  • Skin: Bullous eruptions; Resolves by 2 months
  • Deafness: Sensorineural
  • Microcephaly
  • Cryptorchidism: In male
• Laboratory
  • Muscle pathology: Scattered, small muscle fibes, often type II
  • Diarrhea-associated: Zinc deficiency; Electrolyte disorders
  • Alkaline phosphatase: Low

Congenital Fiber Type Size Disproportion⁵¹

• Definition
  • Onset
    • Age
      • Congenital or Childhood
      • Asymptomatic (4%)
    • Weakness
  • Muscle biopsy pathology: Bimodal fiber size
    • Type 1 muscle fibers 12% smaller diameter than Type 2
• Clinical: General features
  • Family history: 43%; Dominant or Recessive
  • Motor
    • Weakness
      • Extremities (95%): Diffuse or Proximal > Distal
      • Degree: Mild to Severe (27%)
      • Face (40%)
      • Bulbar (35%): Associated with more severe weakness
      • Respiratory (28%)
    • Hypotonia
  • Tendon reflexes: Reduced or Absent
  • Ocular
    • Ophthalmoplegia (19%): Worse prognosis
  • Intelligence: Normal
  • Skeletal (25%)
    • Arthrogryposis
    • Scoliosis
  • Course: Static (55%); Improving (36%); Slow progression (9%)
• Laboratory
  • Serum CK: Normal or < 3x upperlimit of normal
  • EMG: myopathic or some Neuropathic features
  • Muscle pathology
    • Fiber size variation
      • Degree: Mean = Type 1 fibers 41% smaller diameter than Type 2; Range up to 74%
      • Correlation: Larger size disparity with more severe clinical features
    • Type 2B fibers < 5% or absent: 35%
    • Type 1 fiber predominance (50%)
    • Internal or central nuclei (> 5%): 22%
    • Nemaline rods (6%)
• CFTD: Specific genetic syndromes
  l α-Actin ; Chromosome 1q42; Dominant
  • Mutations
    • Heterozygous
    • Missense: Leu221Pro; Asp292Val; Pro332Ser
    • Different from rod myopathy mutations
    • Location: Actin surface swept by tropomyosin during muscle activity
    • Frequency in CFTD: Unusual; 6%
  • Clinical: Severe phenotype
    • Onset: Congenital; Weakness
    • Weakness: Diffuse; Severe; Respiratory
    • No ophthalmoplegia
    • Course: Respiratory failure; Death < 4 years (2 of 3 patients
  • Muscle pathology
    • Type 1 muscle fibers: Small; 45% to 54% of Type 2
    • No rods
  • Other α-Actin disorders
    • Nemaline rod myopathy
    • Intranuclear rod myopathy
    • Rod myopathy with cores
    • Actin myopathy: Congenital myopathy with excess of thin filaments

l Selenoprotein-N, 1 (SEPN1) ; Chromosome 1p35-p36; Recessive⁶¹
• Genetics
  • Common mutation: G315S
• Clinical
  • SEPN1-like syndrome
    • Truncal hypotonia: Early
    • Strength
      • Neck weakness: Early
      • Respiratory impairment: Adolescence to early adulthood
      • Limb strength: Relatively preserved
    • Scoliosis
      • Progressive
      • Mid childhood to Adolescence
      • Relative lordosis of upper spine
  • Insulin resistance
• Muscle histology
  • Mean type 1 fiber diameter more than 12% smaller than type 2 fiber diameter
  • No multiminicore lesions

l CFTD2 ; Chromosome Xq13.1-q22.1; Recessive
• Epidemiology: Australian family
• Onset
  • Age: Congenital
  • Hypotonia & Weakness
• Clinical
  • Weakness
    • Ptosis: Bilateral
    • Face
    • Suck & cry: Weak cry
    • Hypotonia: Generalized
    • Respiratory insufficiency
  • Cardiomyopathy: Dilated; In one survivor
  • Course
    • Death in most: Respiratory failure; Age 6 to 14 weeks
    • Survivor: Facial & mild generalized weakness
• Laboratory
  • Serum CK: Normal
  • Lactate: Normal
  • Muscle biopsy: Type 1 muscle fiber smallness
• Carriers
  • Mild weakness: General & Face (Frontalis)