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CARDIAC + MYOPATHY

Amyloid Cardiomyopathies   Dilated   Hypertrophic   Isolated Carnitine Disorders Drugs   Dystrophies   Barth   Desmin   Dystrophinopathies   Emery-Dreifuss   Limb-girdle   McLeod   Myotonic   Scapuloperoneal "+"   Glycogenoses   Acid Maltase (Infantile)   Branching enzyme   Debrancher   Lamp-2   Triosephosphate isomerase Mitochondrial disorders Nemaline rod Other myopathies Periodic paralyses Polymyositis (SRP)

Also see: Selective disorders of cardiac muscle

Carnitine Disorders

Biochemistry   Fatty acid & Carnitine transport pathways   Fatty acid oxidation pathways General principles 1° Carnitine deficiencies   Multiple acyl–CoA dehydrogenase deficiency   Reduced Muscle carnitine uptake   Myopathic   Renal (OCTN2)   Systemic disorders 2° carnitine deficiencies Carnitine-acylcarnitine translocase deficiency CPT II deficiency

Carnitine

• Carnitine metabolism: General principles
  • Carnitine: General
    • Sources
      • Dietary (75%): Meat, fish, dairy products
      • Synthesis: Endogenous
        • From lysine & methionine in liver, brain & kidney
        • Synthetic pathway not present in muscle or heart
    • Distribution: 90% in muscle
    • Low molecular weight polar compound
    • Types
      • Active form: L-carnitine
      • Free carnitine (or L-carnitine): Nonacetylated form
      • Acyl-L-carnitine
        • All short-, medium- & long-chain esters
        • Involved in transfer of acyl groups from acyl coenzyme A (CoA)
    • Turnover
      • Absorption: Transport-mediated from GI tract
      • Reabsorption
        • Saturable renal tubular
        • 95–99% of filtered load
        • Vegetarians excrete markedly less L-carnitine than omnivores
        • Preferential excretion of short-chain carnitine esters
    • Plays roles in fatty acid metabolism: Oxidation of long-chain fatty acids
      • Transport of fatty acids from cytoplasm to mitochondria
        • Conversion of fatty acids to Fatty acid-CoA
        • Carnitine & Carnitine palmitoyltransferases I & II mediate transport
      • Modulates cellular & mitochondrial ratio of acyl CoA to free CoA
      • Transfer of acetyl and other short-chain acyl groups from peroxisomes to mitochondria
      • Oxidation of branched chain amino acids
      • Reesterification of triacylglycerol in the endoplasmic reticulum before secretion as very low density lipoproteins
      • Stabilization of cell membranes by removing long-chain acyl CoAs
      • Removal of excess acyl groups from the body
    • Energy source
      • Mitochondrial oxidation of fatty acids provides energy source
      • Chief energy sources for: Prolonged fasting; Skeletal muscle during exercise; Cardiac muscle
    • Types of deficiency
      • Primary: Due to deficient transport of carnitine into cells
      • Secondary
        • Free carnitine ® acyl-carnitine esters ® Lost in urine
        • Organic acidosis: Similar metabolic profile to Reyes & Valproate hepatic encephalopathy
        • Renal disease: End stage; Dialysis
          • Long term dialysis (Especially > 12 months): Reduces skeltal muscle carnitine by 30% to 50%
    • Loss of carnitine results in
      • Reduced Buffering of toxic acyl-CoA esters
      • Inhibition of mitochondrial systems
    • Hereditary disorders: 10 genetic defects in fatty acid pathway in infants & children
  • Clinical features: General
    • Coma after a period of starvation
    • Hypoketosis: Low serum ketone concentrations
    • Cardiomyopathy
    • Muscle: Weakness
  • Specific enzyme defects can include
    • LCAD
    • MCAD
    • Plasma-membrane carnitine transporter
    • Carnitine palmitoyltransferase I (CPT I)
    • CPT II deficiency
    • SCAD deficiency : 2 phenotypes
  
  
• Carnitine deficiency: Myopathic Form
  l ? Autosomal Recessive
  • Clinical
    • Onset age: Childhood - Early adult
    • Weakness: Symmetric; Proximal; ± Face & Tongue
    • No pain or rhabdomyolysis
    • Progression: Usually slow; Rarely acute; ? Exacerbations 2° pregnancy
    • Cardiac: Cardiomyopathy & Congestive heart failure in some patients
  • Laboratory
    • Serum CK: Moderately high
    • EMG: Myopathic
    • Muscle biopsy
      • Lipid storage
      • Low carnitine levels
  • Treatment
    • Diet: Low fat
    • Carnitine: 2 to 4 g/day (Children 100 mg/kg/day)
    • Drugs: ? Prednisone; Riboflavin
  
  
• Systemic Deficiency of Carnitine
  l Na⁺-dependent carnitine transporter (OCTN2; SLC22A5) ; Chromosome 5q31; Recessive
  • Genetics: Mutations
    • Most produce null alleles
    • Homozygous missense (E452K): Disease onset 7 years; Cardiomyopathy
    • Mutation effects on carnitine: Reduced carnitine-transporter
      • Impaired muscle uptake
      • Decreased renal tubular reabsorption
  • OCTN2 protein
    • Family: Carnitine/organic cation transporter
    • Expressed on surface membrane of cardiomyocytes
    • Upregulated by: Nuclear receptor PPARalpha
    • Other substrates: Quinidine; Verapamil
  • Clinical
    • Onset age: Infancy to 1st decade; Intrafamilial variation
    • General: Fatigability; Vomiting; Abdominal pain; Low height & weight
    • Hypoglycemia
    • Encephalopathy: Episodic; r/o Reyes syndrome
    • Myopathy
    • Cardiomyopathy
      • Dilated
      • Ventricular hypertrophy
      • Heterozygotes OCTN2 mutations: Predisposed to late-onset benign cardiac hypertrophy
    • Hepatomegaly
  • Lab
    • Carnitine levels: Low or absent in plasma & many tissues
    • Hyperammonemia
    • Urine: Low dicarboxylic acids; Leakage of carnitine
      • Normal in 2° carnitine deficiencies
  • Muscle: Lipid storage (Droplets)
  • Mouse model: Juvenile visceral steatosis (jvs)
  • Treatment
    • Acute episode: Intravenous glucose infusion
    • Avoid fasting
    • Low fat diet
    • L-carnitine (100 - 150 mg/kg/d oral)
  
  
• Carnitine deficiency: Produced by Systemic disorders¹³
  • Pathogenesis
    • Reduced Protein synthesis ® Reduced number of Carnitine carriers
    • Competitive inhibition for carnitine uptake
    • Increased excretion
  • Clinical
    • Hypotension: Intradialytic
    • Heart failure
    • Anemia:Eerythropoietin-resistant anemia
    • Muscle: Weakness; Low exercise capacity
  • Disorders
    • Systemic disease
      • Malnutrition
      • Sepsis
      • Organ failure: Renal; Liver; Endocrine
      • Organic aciduria
      • Reye's syndrome
      • Chronic myopathies
    • Treatment-related: Valproate; Zidovudine; Total parenteral nutrition
    • Pregnancy
    • Mitochondrial disorders
    • HIV infection: Especially with zidovudine treatment
    • Plasma acyl carnitines in 2° carnitine deficiency
    • Diphtheria toxin
  
  
• Carnitine palmitoyltransferase II (CPT2) deficiency
  l Chromosome 1p32; Recessive & Semi-Dominant
  • Adult onset form
    
    • Genetics
      • Clinical syndromes & Mutations
        • ~20 mutations described
        • Most cases with common mutations ± Heterozygous for 2nd mutation
          • Ser113Leu: 60% of adult myopathy cases; Mild disease
          • 413delAG: Ashkenazi Jews
          • Pro50His: 10%
        • Arg503Cys: Malignant hyperthermia with variable myopathy
        • Mutations: External database
      • Residual enzyme activity present with adult forms
      • Some mutations with manifestations in heterozygotes: Ser113Leu, Arg503Cys
      • Polymorphisms: 3 identified
        • May contribute to reduced CPT2 activity in combination with disease allele
      • Mutations most common in exons 4 & 5
    • CPT2 Protein
      • Single isoform
      • Homotetramer
      • Function
        • Mediates transport of Fatty acid-CoA across inner mitochondrial membrane
        • Involved in fatty acid β-oxidation
      • Metabolic defect promotes glycogen depletion
    • Clinical
      • Onset
        • Adolescent or Adult
        • Most common metabolic cause of repeated myoglobinuria
      • Rhabdomyolysis: After activities requiring fatty acid oxidation
        • Prolonged exercise
        • Cold
        • Diet: Low-carbohydrate, high-fat diet; Fasting
        • Infections
        • Valproate treatment⁷
      • Myopathy
        • Normal strength between attacks
        • Late-onset weakness in occasional patients
      • Myalgias: Less severe than VLCAD deficiency
      • More often symptomatic in males (80%)
    • Lab
      • Serum CK
        • Normal or mildly elevated (50%) between episodes
        • High with rhabdomyolysis
      • Serum long chain acylcarnitines & carnitine
        • High ratio of: (Palmitoylcarnitine (C16:0) + Oleoylcarnitine (C18:1))/Acetylcarnitine (C2)
        • Normal serum carnitine
      • Fasting: Normal rise of ketone bodies; No myoglobinuria
      • IV glucose: Improves exercise tolerance; Oral glucose not effective
    • Muscle
      • Morphology: Normal
      • CPT activity: Reduced by 80% to 90% in homozygotes
    • Treatment
      • Diet
        • Triheptanoin (anaplerotic)¹²
          • Dose: 30% of calories in diet
          • Effect: Increased exercise tolerance
        • ? Low fat; High carbohydrate
        • ? Frequent meals
      • Avoid exercise with fasting or infection
      • General anesthesia: IV glucose before & during
    • External links
      • Patient information (Spiral notebook)
      • Genetic testing (Buffalo): Common mutations
  • Infantile form
    
    • Genetics
      • Most cases with different mutations
      • Residual enzyme activity: Minimal (< 10%)
      • Tyr628Ser, Glu174Lys, Phe383Tyr mutations
        • Severe clinical disease: Infant form
        • Lower CPT2 enzyme activity
        • Hepatic involvement
    • Clinical
      • Hepatic
      • Cardiac
      • Muscle
  • Lethal neonatal
    • Clinical
      • Cardiac abnormalities: Arrythmias
      • Congenital anomalies
      • Neurologic: Lethargy, Seizures, Hypotonia, Hyperreflexia
      • Death: 1st weeks
    • Laboratory
      • Hypoketotic hypoglycemia
      • Carnitine: Reduced total & free
      • CPT II activity: Severely reduced
  • CPT II deficiency: Diagnostic testing
    • Biochemistry
    • Gene mutations
  
  
• Carnitine-acylcarnitine translocase deficiency
  l Chromosome 3p21.31; Recessive
  • Protein
    • Mitochondrial-membrane carrier protein
    • Shuttles substrates between cytosol & intramitochondrial matrix space
  • Clinical
    • Encephalopathy: Fasting induced coma & seizures
    • Cardiomyopathy
    • Muscle weakness
    • Respiratory: Episodic neonatal apnea
  • Metabolic: Hypoketosis; Hypoglycemia; Hyperammonemia
  • Treatment
    • Peritoneal dialysis with a permanent Tenckof catheter in situ
    • Enteral feeding: Frequent
    • High calories, Low protein, Long-chain fatty acids, Medium-chain triglyceride oil
  
  
• Multiple acyl–CoA dehydrogenase deficiency (MADD; Glutaricaciduria IIA)
  l Electron transfer flavoprotein, α polypeptide ; Chromosome 15q23-q25; Recessive
  • Allelic with: Coenzyme Q10 deficiency
  • Onset: Adult; 3rd & 4th decade
  • Myopathy²
    • Proximal
    • Weakness: May become severe
    • Myalgias: Some patients
    • Progression: Subacute over months
  • Laboratory
    • Serum CK: High
    • EMG: Myopathic
    • Muscle biochemistry
      • Carnitine levels Reduced
      • Catalytic activity of mitochondrial complex I Reduced
    • Muscle pathology: Vacuolar myopathy; Lipid storage
  • Treatment
    • Riboflavin (100 mg/day)
    • ± Carnitine (4 g/day)
    • Coenzyme Q10
    • Corticosteroids
  • Neonatal forms: Features
    • Acidosis
    • Hypoglycemia
    • Sweaty feet odor
    • Death
  
  
• Reduced muscle carnitine uptake¹
  • Onset: Infantile
  • Respiratory insufficiency
    • Chronic central alveolar hypoventilation
    • Nocturnal respiratory disorder (Ondine syndrome): Sleep apnea
    • Acidosis
  • Motor dysfunction: Hypotonia; Feeding disorder
  • Cardiomyopathy: Cardiomegaly
  • Muscle
    • Low carnitine
    • Lipid storage myopathy
    • ? Disorder of sarcolemmal carnitine carriers
  • Lab: Plasma carnitine normal
  • Treatment: ? Carnitine supplementation
  
  
• SCAD deficiency : 2 phenotypes
  l Short-chain acyl-CoA dehydrogenase ; Chromosome 12q22-qter; Recessive
  • Infant onset
    • Clinical
      • Failure to thrive
      • Developmental delay
      • Seizures
      • Hypotonia
      • Muscle weakness
    • Laboratory
      • Acute metabolic acidosis
      • Ethylmalonate excretion
      • SCAD deficiency: Generalized
      • No episodes of nonketotic hypoglycemia
  • Middle age onset
    • Chronic lipid storage myopathy
    • May have associated ophthalmoplegia & multicores
    • SCAD deficiency: Localized to skeletal muscle

Dilated cardiomyopathies ± Myopathy

• Genetics
  • Mutations
    • Usually produce stop codons
    • Types
      • Frameshifts with deletions
      • Point mutations: Stop codons
      • Missense mutations: 2 described
      • Splice site
    • Evenly distributed through gene
    • No clear correlation between mutation & phenotype
  • Large gene deletion may produce co-occurrence of
    • Duchenne dystrophy
    • Chronic granulomatous disease
    • Retinitis pigmentosa
  • Other polymorphisms define Kell blood groups
  • Some Japanese families without XK mutation
• Kell glycoprotein
  • Location: Erythrocyte membrane
  • Function
    • Zinc metalloproteinase
    • Cleaves endothelin-3 to bioactive peptide
    • Homology to CED-8: ? Role in programmed cell death
  • McLeod syndrome: Reduced expression on erythrocytes
  • ? Associated proteins
    • Huntingtin: Huntington's disease
    • Chorein: Autosomal-recessive Chorea-Acanthocytosis
  • Muscle location
    • Type II muscle fibers
    • Intracellular: Sarcoplasmic reticulum
    • Staining is absent in McLeod myopathy
• Epidemiology
  • Disease frequency: 0.5 to 1 per 100,000
• Clinical
  • Onset
    • Age: Adult; Range 27 to 72; Mean 5th decade
    • Signs: Fatigue; Movement disorder; Seizure
  • Weakness (65%)
    • Severity: Usually mild; Occasionally severe or none
    • Distribution: Proximal; Symmetric; Legs > Arms
    • Increases with age
  • Other muscle features
    • Muscle atrophy: May be generalized
    • Fatigue with exercise
    • Rhabdomyolysis⁹: Associated with hyperkinesis & neuroleptic drugs
  • Polyneuropathy
    • Sensory loss: Reduced vibration sense in feet (40%)
    • Tendon reflexes: Reduced; Legs (90%) ± Arms (60%)
    • Symptoms: Rare
  • CNS
    • Movement disorders
      • Onset: 2nd to 6th decade
      • Distribution: Limbs; Trunk; Face
      • Types: Chorea (100%); Dystonia; Face hyperkinesia; Vocalizations; Dysarthria
    • Seizures: Onset > 40 years
    • Psychiatric syndromes (45% to 83%)
    • Cognitive disorders (54%): Memory & Executive functions
    • Pathology: Atrophy of cerebrum & caudate
  • Systemic
    • Hepato-Splenomegaly (40%)
    • Cardiomyopathy (66%)
      • Onset > 40 years
      • Cardiomegaly: Dilated or restrictive
      • Atrial fibrillation
      • Congestive heart failure
      • Often cause of death
  • Management
    • Autologous blood donation: Avoids incompatibility hazards
    • Symptomatic treatment: Epilepsy, Cardiac & Psychiatric features
    • Chorea: Porly responsive to treatment
• Female carriers: Occcasional female affected due to skewing of X-inactivation
  • Acanthocytosis: Mild
  • CNS: Chorea; Occasional psychiatric syndrome
  • Serum CK: Mildly increased
• Laboratory
  • Hematologic
    • Acanthocytosis⁶: 100%
      • Thorny shaped red cells
      • May be marked: 35%
      • Differential diagnosis: A-β-lipoproteinemia; Chorea-Acanthocytosis
    • Erythrocytes: Reduced Expression of Kell blood group & Kx surface antigen (100%)
    • Hemolysis: Persistent; Low grade
  • Serum enzymes
    • CK: High (100%); 2,000 to 5,000; Range 1.5 to 15x normal
    • LDH: High (91%)
  • EMG
    • Myopathic (14%)
    • Neuropathic (79%)
  • Nerve conduction testing
    • CMAPs: Small amplitude
    • SNAPs: Small amplitude
    • Conduction velocities: Normal
  • Muscle pathology³: Myopathic
    • Variation in muscle fiber size
    • Nuclei: Internal
    • Necrosis & Regeneration of muscle fibers
      • Occasional
      • Severe cases: May be prominent
    • Cell infiltrates: Occasional patients; Predominantly macrophages; Few lymphocytes
    • Fiber type changes
      • Type I predominance
      • Type II atrophy
  • Nerve pathology
    • Axonal loss
    • ± Demyelination
  • Leg muscle imaging
    • MRI: Sparing of quadriceps
    • CT: Asymmetric involvement of thighs & lower legs (calves)
  • CNS imaging
    • Caudate atrophy
    • MR: Abnormal signal in basal ganglia, increased T2 in lateral putamen

From: The Barth Syndrome Foundation Registry

• Genetics
  • Mutations
    • Locations: In all exons & some adjacent intron sequences
    • Stop & Missense
  • No strong genotype-phenotype correlations
    • ? More severe heart disease with some exon 8 mutations
  • Allelic with Cardiomyopathy, Dilated 3A (X-linked fatal infantile)
• Tafazzin protein
  • Superfamily: Acyl transferases involved in phospholipid synthesis
  • Isoforms: 10 different proteins
    • Membrane anchored types
      • Contain hydrophobic N-terminus (1st 2 exons)
      • High levels in heart & skeletal muscle
    • Cytosolic types
      • Lack hydrophobic sequence
      • High levels in leukocytes & fibroblasts
  • Function
    • ? Involved in biosynthesis of phosphatidylglycerol (PG) & cardiolipin
• Also see: Barth-like syndrome with mtRNA Leu mutations
• Clinical features
  • Onset
    • Infancy
    • Hypotonia
    • Cardiomyopathy: Neonatal to < 1 year
  • Myopathy: Non-progressive; Relatively mild
    • Early
      • Hypotonia
      • Delayed motor development
    • Weakness
      • Proximal > Distal: May be diffuse
      • Waddling gait
      • Gower's sign
      • Mild: No respiratory insufficiency or wheelchair dependence
      • Myopathic facies: Some patients
    • Muscle mass: Reduced
    • Fatigue
    • Myalgias
  • CNS
    • Learning disability
    • Headaches
  • Short stature
    • Proportionate (-2 SD)
    • May eventually grow to normal height
  • Cardiac syndromes: May vary within families
    • Noncompaction of left ventricular myocardium
      • Isolated: No additional cardiac defects (pulmonary atresia)
      • Lethal early course
      • Ultrasonogram: Spongy structure of left ventricular wall
      • Also caused by α-dystrobrevin mutations
    • Dilated cardiomyopathy (CMD 3A)
    • Ventricular hypertrophy
    • Endocardial fibroelastosis: With longstanding cardiac disease
    • Ventricular tachycardia: May be fatal
    • Course
      • Some progressive: May need cardiac transplantation
      • Others resolve with time
  • GI: Diarrhea
  • Phenotype may vary greatly within and between families
  • Course: Patients who survive childhood may become healthy adults
• Variant syndrome: Isolated left ventricular noncompaction (LVNC)
• Female carriers
  • Clinically normal
  • Skewed X inactivation common
    • X chromosome with mutation often selectively inactivated
    • Usually occurs when mutated gene is on maternal chromosome
    • Inactivation may be > 95%
    • Other skewed inactivation syndromes
      • Wiskott-Aldrich syndrome
      • α-thalassemia/mental retardation syndrome
      • Bruton X-linked agammaglobulinemia
      • Increases in older females
• Lab
  • Serum CK: Normal
  • Muscle: Mild myopathic
    • ± Lipid accumulation, or Type 1 fiber predominance
  • Mitochondrial disorder
    • Electron transfer chain variably affected: Complex I deficiency + other
    • Morphologically abnormal inner mitochondrial membranes in cardiac muscle
    • Deficient mitochondrial phospholipid: Tetralinoleoyl-Cardiolipin (L₄-CL)
  • Endomyocardium: Mitochondria with tightly packed, concentric cristae
  • Blood: Increased 3-methylglutaconic; Low cholesterol
  • Immune deficiency
    • Neutropenia: Recurrent
      • Neutrophils 0 to 500
      • Maturation stop at promyelocyte stage
      • May be normal when patient is well
      • May predispose to lethal infections in neonatal period
      • Associated with chronic aphthous stomatitis: Usually due to Candida
      • Treatment: ? Granulocyte colony stimulating factor (G-CSF)
    • Early infections
    • Pyodermia
  • Urine
    • Increased levels of some branched-chain organic acids
      • 3-methylglutaconic acid
      • 3-methylglutaric acid
      • 2-ethylhydracrylic acid
    • 3-methylglutaconic acid may be high normal in urine in older patients
• Course
  • Some: Death in childhood due to cardiac failure or sepsis
  • Many: Slow improvement in cardiac, motor & infectious signs
• Treatment: Manage heart failure;? Pantothenic acid

• Genetics
  • Maternal inheritance
  • Mutation: A3243G
• Clinical
  • Onset: 1st months
  • Failure to thrive
  • Motor: Weakness; Milestones severely delayed; Respiratory failure
  • Cardiomyopathy: Dilated; Progress to congestive heart failure
• Laboratory
  • Lactic acidosis
  • CBC normal
  • Serum CK: Mildly elevated, early
  • Serum carnitine: Mildly reduced
  • Urine: High 3-methylglutaconic & 2-ethylhydracrylic acid
  • Cholesterol: Low in blood
  • Muscle
    • Histochemistry
      • Type 2 predominance
      • Varied fiber size
      • Ragged red fibers; Diffusely reduced COX activity; SDH increased
    • Mitochondrial biochemistry: Low Complexes I & IV

• Epidemiology: Canadian Dariusleut Hutterite population
• Mutation: Splicing site; IVS3-1 G>C
• DNAJC19 protein
  • Mitochondrial inner membrane protein (TIM): ? Component of TIM23 inner membrane translocase complex
  • DNAJ domain-containing
  • ? Involved in molecular chaperone systems of Hsp70/Hsp40 type
  • Other TIMM protein disorder: Mohr-Tranebjaerg syndrome
• Cardiac
  • Cardiomyopathy: Dilated
  • Conduction defects: Long Q-T syndrome
  • Early-onset: < 3 years
• Cerebellar
  • Ataxia
  • Motor delay
  • Course
    • 100% after 2 years of age
    • Non-progressive
    • Independent ambulation achieved
• Other CNS
  • Optic atrophy: Some patients
  • Mental retardation: Mild
  • Seizures: Occasional patient
• Systemic
  • Testicular dysgenesis: Cryptorchidism to severe perineal hypospadias
  • Growth failure (100%)
• Skeletal muscle: No myopathy
• Laboratory
  • Organic aciduria
    • 3-methylglutaconic
    • 3-methylglutaric
    • Other organic aciduria: Barth syndrome
  • Hepatic enzymes: Mildly elevated
  • Anemia: Normochromic, Microcytic

Hypertrophic cardiomyopathy with myopathy

• With central cores in skeletal muscle
    l Myosin - Cardiac β heavy chain (MYH7) ; Chromosome 14q11.2-q13; Dominant
  • Other MYH7 mutations cause
    • Hypertrophic cardiomyopathy with ventricular arrhythmias
    • Dilated cardiomyopathy (CMD 1S)
    • Distal myopathy (MPD1; Gowers-Laing)
    • Hyaline body myopathy
  • Clinical features
    • Familial hypertrophic cardiomyopathy
    • ? Normal strength
    • Muscle biopsy
      • Central cores
      • Type I muscle fiber predominance
• Mid-left Ventricular Chamber Type
  l Myosin light chain, Ventricular and skeletal slow type (MYL3)
  l Chromosome 3p; Dominant
    l ? Mutations at hinge region between heavy & light myosin chains
  • Muscle biopsy: Myopathic with ragged red fibers
    
• Other familial hypertrophic cardiomyopathies with normal skeletal muscle
• Mitochondrial

• Selective Cardiomyopathy
• Congenital & infantile
• Kearns-Sayre
• Multisystem
• PEO
• Congenital muscular dystrophy with mitochondrial structural change

Other disorders with cardiomyopathy

• Amyloid
• Congenital myopathy with spindle excess
• Desmin (Cardiomyopathy) Myopathy
• Encephalopathy with necrotizing myopathy, cardiomyopathy & cataracts
  l Autosomal recessive
• Limb Girdle Dystrophy
  • Dysrhythmias
  • Type 2D: Rare
• Mulibrey Nanism
• Nemaline rod congenital myopathy: Dilated
• Periodic paralysis - Hyperkalemic & Hypokalemic: Cardiac failure
• Polymyositis: Cardiac failure or Arrhythmias
• Scapuloperoneal muscular dystrophy with mental retardation & lethal cardiomyopathy
• Uruguay Facio-Cardio-Musculo-Skeletal Syndrome
• Williams-Beuren syndrome

Drugs + Cardiomyopathy

• Hypertrophic cardiomyopathy
• Dilated cardiomyopathy
• Errors of Fatty acid oxidation - 2° disorders of carnitine metabolism
    (See 1° disorders of Carnitine metabolism)
• Mitochondrial
• Other
  • Congestive cardiomyopathy with conduction defects
  • Amyloid

MULIBREY NANISM

• Mutations
  • Frameshift, deletion or insertion
  • Produce truncated protein
  • Disease category: Peroxisomal biogenesis disorder
• Protein
  • Zinc finger protein: RING-B-box-coiled-coil (RBCC) family
  • Contains TRAF domain: Interacts with other proteins
  • Coiled-coil domain: Homo-oligomerization; Subcellular localization
  • Location: Peroxisomal; Granular cytoplasmic
  • Mutant proteins may have defective targeting or function
• Epidemiology
  • Most common in Finland
• Clinical: Muscle-Liver-Brain-Eye Nanism
  • Onset: Birth (Prenatal)
  • Muscle: Hypotonia 80%
  • Cardiac: Constrictive pericarditis
  • Skeletal
    • Prenatal growth failure
    • Slender stature
    • Cystic dysplasia of tibia (30%)
    • Long shallow (J-shaped) sella turcica (95%)
  • GI: Hepatomegaly
  • Skin: Naevi flammei (70%)
  • Small voice
  • Eye
    • Choroid hypoplasia
    • Retinal yellowish dots & pigment dispersion
    • Wilms tumor (4%)
  • Endocrine: Gland hypoplasia
  • CNS: Probably normal