Spinal Muscular Atrophy

[Includes: Arthrogryposis Multiplex Congenita-Spinal Muscular Atrophy (AMC-SMA); Spinal Muscular Atrophy I (Werdnig-Hoffmann Disease, SMA1); Spinal Muscular Atrophy II (SMA II); Spinal Muscular Atrophy III (Kugelberg-Welander Disease, SMA III); Spinal Muscular Atrophy IV (SMA IV)]

Clinical Diagnosis

The diagnosis of spinal muscular atrophy (SMA) is established in individuals with the following:

• Evidence of degeneration and loss of anterior horn cells (i.e., lower motor neurons) in the spinal cord and brainstem

• A history of motor difficulties

• Evidence of motor unit disease on physical examination

• Diagnostic changes in the SMN1 gene

The following classification of SMA is based on age of onset and maximum function attained.

Prenatal

• Arthrogryposis multiplex congenita (i.e., congenital joint contractures involving at least two regions of the body) [Bingham et al 1997]

• Weakness at birth

• Facial weakness: minimal

SMA I

• Onset 0-6 months

• Poor muscle tone

• Muscle weakness

• Lack of motor development; never achieves ability to sit without support

• Facial weakness: minimal or absent

• Fasciculation of the tongue: seen in most but not all affected individuals [Byers & Banker 1961, Iannaccone et al 1993]

• Postural tremor of the fingers: seen occasionally [Spiro 1970, Fredericks & Russman 1979]

• Mild contractures: often at the knees, rarely at the elbows

• Absence of tendon reflexes

• No sensory loss

• Alert appearance

• Normal cerebral function including intellect

SMA II

• Onset of muscle weakness usually after six months of age; achieves ability to sit independently when placed in a sitting position

• Finger trembling: almost invariably present

• Low muscle tone (flaccidity) [Moosa & Dubowitz 1973, Fredericks & Russman 1979]

• Absence of tendon reflexes in approximately 70% of individuals [Iannaccone et al 1993]

• Average intellectual skills during the formative years and above average by adolescence [von Gontard et al 2002]

SMA III

• Onset usually after ten months of age but in some cases earlier; achieves ability to walk at least 25 meters

• Weakness manifest as frequent falls or trouble walking up and down stairs at age two to three years

• Proximal limb weakness; the legs more severely affected than the arms

SMA IV. "Adult" onset of muscle weakness

Testing

The following testing has been used in the past to establish the diagnosis of SMA but currently has little role in the diagnosis of most individuals with SMA and is used primarily if molecular genetic testing of the SMN1 gene is normal.

Electromyography (EMG). EMG reveals denervation and diminished motor action potential amplitude. The EMG regular spontaneous motor unit activity, a unique feature in SMA, is seen most commonly in SMA I and occasionally in SMA II, but not in SMA III [Buchthal & Olsen 1970, Hausmanowa-Petrusewicz & Karwanska 1986]. A reduced interference pattern is seen with maximal effort; polyphasic waves, positive sharp waves, and fibrillations are present in all individuals with SMA.

Nerve conduction velocities (NCV). Motor and sensory NCVs are normal.

Muscle histology. Muscle biopsy reveals group atrophy of type 1 and type 2 muscle fibers as opposed to the normal checkerboard pattern. Rare angulated and large type 1 fibers are scattered throughout (Dubowitz muscle biopsy).

Nerve histology. Hypomyelination of the peripheral nerve is observed in the prenatal form; otherwise, the nerves show normal histology [Korinthenberg et al 1997, MacLeod et al 1999, Hergersberg et al 2000].

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

Genes. The two genes associated with SMA are SMN1 and SMN2. The two genes are adjacent to each other. The SMN2 gene copy number (arranged in tandem in cis configuration on each chromosome) is variable, ranging from zero to five.

SMN1 and SMN2 differ by five base pairs; none of these differences change the amino acids encoded by the genes.

• SMN1. The SMN1 (survival motor neuron) gene is believed to be the primary SMA disease-causing gene.

• SMN2The presence of three or more copies of SMN2 is correlated with a milder phenotype [Prior et al 2004, Yamashita et al 2004, Soler-Botija et al 2005, Swoboda et al 2005]. See Genotype-Phenotype Correlations.

Molecular genetic testing: Clinical uses

• Diagnostic testing

• Prognostication (See Genotype-Phenotype Correlations)

• Carrier testing

• Prenatal diagnosis

Molecular genetic testing: Clinical methods

• SMN1 targeted mutation analysis. Targeted mutation analysis is used to detect deletion of exons 7 and 8 of SMN1.

  • Approximately 95-98% of individuals with a clinical diagnosis of SMA lack exon 7 in both copies of SMN1 (i.e., they are homozygous for the deletion) [Bussaglia et al 1995, Lefebvre et al 1995, Parsons et al 1996, Hahnen et al 1997, McAndrew et al 1997, Talbot et al 1997, Parsons et al 1998, Ogino & Wilson 2002].

  • Approximately 2-5% of individuals with a clinical diagnosis of SMA are compound heterozygotes for deletion of SMN1 exon 7 and an intragenic mutation of SMN1.

• SMN1 sequence analysis. Sequence analysis of all SMN1 exons and intron/exon borders may be used to identify the intragenic SMN1 mutations present in the 2-5% of individuals who are compound heterozygotes. The SMN1 and SMN2 genes are very large and exonic regions must be individually amplified; therefore, sequence analysis does not detect exonic deletions or duplications.

• Duplication analysis to determine SMN2 copy number. The number of copies of the SMN2 gene ranges from zero to five. Quantitative PCR is currently used for the accurate determination of SMN2 copy number [Anhuf et al 2003].

• SMA carrier testing: gene dosage analysis. Targeted mutation analysis is not reliable for carrier detection as it does not quantitate the number of SMN1 gene copies. A PCR-based dosage assay, called "SMA carrier testing" or "SMN gene dosage analysis," can determine the number of SMN1 gene copies, thus permitting highly accurate carrier detection.

• Linkage analysis. Linkage analysis is available for families in which direct DNA testing (mutation analysis and/or sequence analysis) is not informative. It may be used for confirmation of carrier testing and prenatal testing results.

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in Spinal Muscular Atrophy

Test Method	Mutations Detected	Mutation Detection Rate 1		Test Availability
		Homozygotes	Compound Heterozygotes
Targeted mutation analysis	Deletion of exon 7 of SMN1	~95-98%	~2-5%	Clinical
Sequence analysis	Intragenic SMN1 mutation	0%
Deletion/duplication analysis	SMN2 copy number	NA	NA

1. Mailman et al 2002

Interpretation of test results

• For issues to consider in interpretation of sequence analysis results, click here.

• Sequence analysis cannot determine whether a point mutation is in the SMN1 gene or the SMN2 gene (unless one of these genes is absent); therefore, finding a mutation does not signify that the mutation is in SMN1. However, several point mutations have now been described in more than one person. Identification of a previously reported point mutation provides evidence that the mutation is in SMN1.

• Failure to identify a mutation by sequence analysis is sufficient evidence to conclude that an intragenic mutation is not present in the SMN1 gene.

Interpretation of negative carrier test results is problematic in the following cases:

• The finding of two SMN1 genes on a single chromosome, which occurs in about 4% of the general population [McAndrew et al 1997]. The presence of two SMN1 genes on a single chromosome has serious counseling implications because a carrier with two SMN1 genes on one chromosome is misdiagnosed as a non-carrier by the SMA dosage carrier test.

• De novo mutations occur in 2% of individuals with SMA and signify that only one parent is a carrier

See also Genetic Counseling, Carrier Detection [McAndrew et al 1997].

Genetically Related (Allelic) Disorders

No other phenotypes are associated with mutation of SMN1.

Natural History

SMA phenotypes. SMA is characterized by muscle weakness and atrophy resulting from progressive degeneration and loss of the anterior horn cells in the spinal cord (i.e., lower motor neurons) and the brainstem nuclei. The onset of weakness ranges from before birth to adolescence or young adulthood. The weakness is almost always symmetric and progressive. Before the advent of molecular diagnosis, attempts were made to classify SMA into discrete subtypes; however, it is now apparent that the phenotype of SMA associated with disease-causing mutations of the SMN gene spans a broad continuum without clear delineation of subtypes. Nonetheless, the existing classification system (Table 2) based on age of onset and maximum function attained is useful for prognosis and management.

Congenital axonal neuropathy. Congenital axonal neuropathy manifests as severe weakness of prenatal onset, joint contractures, facial diplegia, ophthalmoplegia, and respiratory failure at birth requiring immediate endotracheal intubation and ventilation. Decreased fetal movement and polyhydramnios are common [Korinthenberg et al 1997].

AMC-SMA association (arthrogryposis multiplex congenita-spinal muscular atrophy). AMC-SMA manifests as severe weakness of prenatal onset and AMC (i.e., congenital joint contractures involving at least two regions of the body). Decreased fetal movement, polyhydramnios, and breech presentation are common. Typically, affected infants have absence of movement except for extraocular and facial movement. Death usually occurs from respiratory failure before one month of age [Banker 1985, Burglen et al 1996, Bingham et al 1997]. However, one report describes a child who is not ventilator-dependent at five years of age [Falsaperla et al 2001].

SMA I (acute spinal muscular atrophy; Werdnig-Hoffmann disease). SMA I manifests as severe weakness before age six months. Affected children are not able to sit without support at any time. Proximal, symmetric muscle weakness, lack of motor development, and poor muscle tone are the major clinical manifestations. Mild contractures are often noted at the knees and, rarely, at the elbows. In the neonatal period or during the first few months, the infants with the gravest prognosis have problems sucking or swallowing and often show abdominal breathing. The muscles of the face are relatively spared; the diaphragm is not involved until late in the course of disease. The heart is normal. Of note, a peculiar tremor of the electrocardiographic baseline has been attributed to fasciculation of limb and chest wall muscles [Russman & Fredericks 1979, Coletta et al 1989].

Fasciculation of the tongue is seen in most but not all individuals [Byers & Banker 1961, Iannaccone et al 1993]. A postural tremor of the fingers is seen only occasionally in SMA I [Spiro 1970, Fredericks & Russman 1979]. Most individuals die before age two years [Ignatius 1994, Thomas & Dubowitz 1994]. However, on occasion, individuals whose weakness was thought to have started before age six months are still sitting in adolescence or adulthood [Iannaccone et al 1993, Zerres & Rudnik-Schoneborn 1995].

Those individuals who have chosen to receive respiratory support may live longer than age two years [Bach et al 2002].

SMA II (chronic spinal muscular atrophy; Dubowitz disease). SMA II manifests as onset usually between six and 12 months of age. Maximum motor milestone attained is the ability to sit independently when placed. Although poor muscle tone may be evident at birth or within the first few months of life, individuals with SMA II may gain motor milestones slowly [Iannaccone et al 1993]. Often concerns are not raised until a child is not sitting independently by age nine to 12 months or is not standing by age one year. Finger trembling and general flaccidity are common [Moosa & Dubowitz 1973, Fredericks & Russman 1979]. Affected individuals on average lose the ability to sit independently by the mid-teens [Russman et al 1996].

SMA III (juvenile spinal muscular atrophy; Kugelberg-Welander disease). SMA III manifests after one year of age. Individuals with SMA III walk independently but may fall frequently or have trouble walking up and down stairs at age two to three years. The legs are more severely affected than the arms. Prognosis generally correlates with the maximum motor function attained [Russman et al 1983]. Individuals with SMA III who have never climbed stairs without using a rail lose walking ability by the mid-teens [Russman et al 1996]. Individuals who develop normal walking skills prior to the onset of weakness can maintain this ability until the third or fourth decade of life.

SMA IV. The onset of muscle weakness is usually in the second or third decade of life. The findings are similar to those described for SMA III [Brahe et al 1995, Clermont et al 1995, Zerres et al 1995].

Complications of SMA. Poor weight gain, sleep difficulties, pneumonia, scoliosis, and joint contractures are common complications of SMA.

An unexplained potential complication of SMA is severe metabolic acidosis with dicarboxylic aciduria and low serum carnitine levels during periods of intercurrent illness or fasting [Kelley & Sladky 1986, Crisp et al 1989]. Whether these metabolic abnormalities are primary or secondary to the underlying defect in SMA is unknown. Some investigators have suggested that underweight individuals with SMA with minimum muscle mass are at risk for recurrent hypoglycemia or ketosis [Bruce et al 1995, Tein et al 1995]. The problem is self-limiting; individuals typically recover in two to four days.

Life expectancy and prognosis of SMA. Whether the loss of function observed in all individuals with SMA is caused by loss of motor units or other factors such as scoliosis, progressive contractures, and pulmonary insufficiency is difficult to determine [Hausmanowa-Petrusewicz et al 1992]. Of the individuals studied by Russman et al (1992) over a period of 18 months, none lost strength in the individual muscle groups studied, but four lost functional abilities. In a cross-sectional study of 120 individuals with SMA, Merlini et al (2004) noted that individuals no longer ambulant were weaker than those who were still ambulant, concluding that loss of muscle strength correlated with loss of function. Given the study design these conclusions need be considered tentative.

In a physiological outcome study, Swoboda et al (2005) showed a correlation between motor unit number estimation (MUNE) and disease severity. In addition to MUNE, the measurement of compound motor action potential can be used to determine outcome.

A review of life expectancy of 569 individuals with SMA II and SMA III from Germany and Poland found that 68% of individuals with SMA II were alive at 25 years of age and that life expectancy of individuals with SMA III was not different from that of the general population [Zerres et al 1997].

Pregnancy. Women with SMA may experience exacerbation of muscle weakness during pregnancy [Rudnik-Schoneborn et al 1992]. Complications of pregnancy in ten of 12 women with SMA included premature labor in four, prolonged labor in three, and delayed post-partum recovery in six. No deleterious effects were observed in the offspring.

Neuropathology. Studies reveal a decreased number of motor neurons (and varying stages of chromatolysis and acute degeneration of anterior horn cells) and gliosis in the anterior horns of the spinal cord as well as a decreased number of lower cranial motor neurons.

Genotype-Phenotype Correlations

SMN1 produces a full-length survival motor neuron (fl SMN) protein necessary for lower motor neuron function [Lefebvre et al 1995]. SMN2 mostly encodes a protein that is lacking in exon 7, thereby producing a less stable protein.

No correlation exists between the loss of SMN1 exons 7 and 8 and the severity of disease.

Accumulating data indicate that the presence of three or more copies of SMN2 is correlated with a milder phenotype [Velasco et al 1996, McAndrew et al 1997, Parsons et al 1998, Mailman et al 2002]. The most recent data [Mailman et al 2002] are summarized in Table 3. Of note, three unrelated individuals homozygous for the SMN1 deletion who had five copies of SMN2 were asymptomatic [Prior et al 2004]. These cases demonstrate that expression levels consistent with five copies of the SMN2 gene may compensate for the absence of the SMN1 gene.

Those with the phenotype of SMA I have as little as 9% of the normal amount of full-length SMN (fl SMN), those with SMA II have 14%, and those with SMA III, about 18%. Once full-length protein levels approach 23% of normal levels, motor neuron function appears normal. Carriers usually have 45-55% full-length SMN protein.

Nomenclature

Severe SMA or SMA I is still called Werdnig-Hoffmann disease by many [Werdnig 1891, Hoffmann 1892].

SMA II was called chronic SMA prior to the current classification.

SMA III has had the eponym juvenile SMA or Kugelberg-Welander disease [Kugelberg & Welander 1956].

Prevalence (Table 4)

Evaluations at Initial Diagnosis to Establish the Extent of Disease

The following issues need to be addressed independent of SMA type:

• Nutrition/feeding assessment

  • Time required to complete a feeding

  • Evidence of fatigue during a feeding/meal

  • Weight plotted on standard growth curves

• Respiratory function assessment

  • Normal breathing pattern versus abdominal breathing pattern

  • Forced vital capacity (FVC); in children over the age four years, the hand-held spirometer is accurate. When FVC is above 40%, decompensation during respiratory infection is less likely than when FVC is less than 40%.

• Sleep asssessment. Consideration of a sleep study if the child snores during sleep or awakes fatigued in the morning

• Activities of daily living. Assessment of equipment needed for independence, such as a power-chair and other equipment in the home to improve the quality of life for the affected individual and the caregiver

• Orthopedic evaluation. Attention to the development of contractures, scoliosis, and hip dislocation

Treatment of Manifestations

Nutrition/feeding. When there are concerns, a feeding gastrostomy is appropriate and can be removed if oral intake becomes adequate.

Respiratory function. Inevitably, the respiratory function deteriorates [Samaha et al 1994]. Some children with SMA I can survive beyond two years of age when offered tracheotomy or non-invasive respiratory support [Bach et al 2002].

Options for management including "do not attempt to resuscitate" status should be discussed before respiratory failure occurs [Samaha et al 1994]. This discussion should be initiated when abdominal breathing is noted and/or the forced vital capacity is less than 30%.

Children relying on non-invasive respiratory support have fewer hospitalizations after age five years, may be free from daytime ventilator use, and are able to express themselves verbally. Non-invasive respiratory support is labor intensive, demands commitment, and depends upon the availability of facilities. Bush and colleagues (2005) argue that nighttime nasal intermittent positive pressure (NIPPV) and occasional daytime NIPPV are reasonable; they do not currently recommend full-time NIPPV. Miske et al (2004) use the mechanical in-exsufflator (MI-E) in treatment of neuromuscular conditions. MI-E delivers a positive pressure insufflation followed by an expulsive exsufflation, simulating a normal cough and is helpful in the management of respiratory infections in individuals with SMA.

Sleep disorders. In a study of seven persons with SMA, Mellies et al (2004) noted that sleep disorder breathing developed prior to respiratory failure. Puruckherr et al (2004) described a 46-year-old man with SMA III whose increasing daytime fatigue caused by snoring and apnea at night resolved with nighttime use of continuous positive airway pressure with a nasal mask.

Orthopedic. Children with SMA I rarely require orthopedic intervention because they do not live long enough to develop spinal deformity, hip dislocation, or contractures.

Scoliosis is a major problem in SMA II and in half of those with SMA III [Brown et al 1989, Merlini et al 1989, Rodillo et al 1989]. Before age ten years, approximately 50% of children with SMA, especially those who are non-ambulatory, develop spinal curvatures of more than 50 degrees, the threshold for surgery. Scoliosis repair can be carried out safely if the forced vital capacity is greater than 40%. The use of an orthosis does not prevent scoliosis, but does allow the affected individual to be upright rather than recumbent. Although individuals lose some upper extremity function following operative intervention, the advantages of a stable trunk and the opportunity to sit upright unassisted outweigh the disadvantages. Whether scoliosis repair prevents further deterioration of pulmonary function is unclear.

A retrospective review of a large series concluded that surgery is not needed for asymptomatic hip dislocation [Sporer & Smith 2003].

Surveillance

Individuals are evaluated at least every six months; weaker children are evaluated more frequently.

Nutritional state, respiratory function and orthopedic status (spine, hips, and joint range of motion) are assessed at each visit.

Therapies Under Investigation

Pre-clinical evaluation of drugs and other interventions is underway [Escolar et al 2001, Iannaccone & Hynan 2003, Swoboda et al 2005].

Increasing the activity of the SMN2 gene is one of the major strategies under consideration. The following are some medications/chemicals under investigation:

• Histone deacetylase (HDAC) inhibitors can increase the level of fl-SMN [Kernochan et al 2005].

• Valproic acid [Brichta et al 2003, Sumner et al 2003] increases SMN protein in skin fibroblasts.

• Phenylbutyrate, a drug used in the treatment of urea acid cycle disorders, increased full-length SMN2 transcripts in skin fibroblasts [Andreassi et al 2004]. Oral phenylbutyrate increased SMN expression in white blood cells [Brahe et al 2005]. In a pilot trial phenylbutyrate improved function in the short term in ten persons with SMA [Mercuri et al 2004].

• Hydroxyurea, a medication that enhances the expression of human fetal hemoglobin [Stevens 1999] also modifies gene expression and increases SMN levels in skin fibroblasts from individuals with SMA [Grzeschik et al 2005].

• Indoprofen, a non-steroidal anti-inflammatory drug (NSAID), increases SMN2 levels in fibroblasts of individuals with SMA [Lunn et al 2004].

• An open-label pilot trial of Rilutek (Riluzole) in infants with SMA is currently under way at ten participating centers. The Phase 1 trial showed it to be safe, but the power was insufficient to show benefit [Russman et al 2003].

• A multicenter randomized, double-blind study of the effect of gabapentin in individuals with SMA II and III showed benefit to muscle strength but no improvement in motor or respiratory function [Miller et al 2001, Merlini et al 2003]. However, a double-blind one-year study showed that gabapentin was not beneficial in SMA [Miller et al 2001].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Spinal muscular atrophy is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• Approximately 98% of parents of an affected child are heterozygotes and, therefore, carry a disease-causing mutation in the SMN1 gene.

• About 2% of parents are not carriers of a SMN1 mutation as their affected child has a de novo disease-causing mutation [Wirth et al 1997]. The majority of de novo mutations are paternal in origin [Wirth et al 1997].

• Heterozygotes are asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

• Even if a child with SMA appears to have inherited one disease-causing allele from a carrier parent and to have a de novo mutation resulting in the other disease-causing mutation, germline mosaicism in the parent without an identifiable mutation needs to be considered [Campbell et al 1998]; therefore, it is reasonable to consider sibs of such an individual to be at risk for SMA.

• Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

Offspring of a proband

• Only individuals with the milder forms of SMA are likely to reproduce. All of their offspring are carriers.

• The unrelated reproductive partner of an individual with a mild form of SMA should be offered carrier testing. If the partner shows at least two SMN1 copies, the partner has a one in 670 probability of being a carrier (taking into consideration the 2% frequency of two SMN1 copies on the same chromosome and the small risk of an intragenic SMN1 mutation). Thus, the risk to such a couple of having an affected child is one in 1340.

Other family members. Each sib of an obligate heterozygote is at a 50% risk of being a carrier.

Carrier Detection

Carrier detection may be considered for the following individuals:

• Parents of a single affected child with SMA in whom the diagnosis has been confirmed with direct DNA testing. Carrier detection for such parents has three limitations:

  • A de novo mutation in the SMN gene, occurring in approximately 2% of individuals [Wirth et al 1995]. This is a high rate when compared to most autosomal recessive disorders.

  • The finding of two SMN1 genes on a single chromosome, which occurs in about 4% of the general population [McAndrew et al 1997]. The presence of two SMN1 genes on a single chromosome has serious counseling implications because a carrier with two SMN1 genes on one chromosome is misdiagnosed as a non-carrier by the SMA dosage carrier test.

  • Carriers with one normal allele and one intragenic SMN1 gene mutation

Because of de novo mutational events and the presence of two SMN1 genes on a single chromosome, approximately 6% of parents of a single child affected with SMA have normal results of SMN dosage testing. Thus, the finding of normal SMN1 dosage in a parent significantly reduces, but does not eliminate, the risk of the parent being a carrier for SMA. Further study by linkage analysis including other family members may allow clarification of these two situations, since documentation of a de novo mutation in the child reduces the couple's risk of having additional affected children.

• Parents of an affected deceased child with SMA on whom no molecular testing of SMN was performed. Tissue, such as muscle biopsies and paraffin tissue samples, available from deceased individuals can often provide enough DNA for genetic testing; however, if DNA is not available, both parents could be offered SMA carrier (dosage) testing. Issues with test result interpretation include the following:

  • If both parents are found to be carriers, the diagnosis of SMA in the proband is most likely and prenatal testing can be offered.

  • If only one parent is Δ7 SMN1 heterozygous, testing of additional family members of the parent with two SMN1 gene copies may be informative.

  • If both parents show at least two SMN1 copies, it is extremely unlikely that the affected child had SMA caused by mutations at the SMN locus.

• At-risk relatives of an individual with SMA who is homozygous for Δ7 SMN1. In this instance, the risk that the dosage test will produce a false negative or uncertain result because of the presence of two SMN1 copies on one chromosome is 4%.

• Unrelated reproductive partners of an individual known to be heterozygous for a familial disease-causing mutation in SMN1or an individual at risk of being heterozygous for a SMNdisease-causing mutation. These unrelated reproductive partners are individuals who are at no known increased risk of being heterozygous for a SMN disease-causing mutation. A reproductive partner showing at least two SMN1 copies has an approximately one-in-670 probability of being a carrier (taking into consideration the 2% frequency of two SMN1 copies on the same chromosome and the small risk of intragenic mutations).

Related Genetic Counseling Issues

Family planning. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of availability of prenatal testing is before pregnancy.

DNA banking. Because of the complex nature of the SMN mutations causing SMA, the difficulty in performing molecular genetic testing now, and the likelihood that testing methods will improve in the future, consideration should be given to banking the DNA of any individual known or suspected of having SMA. In this manner, a DNA sample would be available to family members who seek genetic counseling and testing in the future. See DNA Banking for a list of laboratories offering this service.

Prenatal Testing

High-risk pregnancy. Prenatal diagnosis is possible for fetuses at 25% risk when the disease-causing SMN mutations in both parents are known or when linkage has been established in the family. Analysis of fetal DNA obtained either through chorionic villus sampling (CVS) at about 10-12 weeks' gestation or amniocentesis usually performed at about 15-18 weeks' gestation is possible for the known parental SMN1 gene mutations or for the previously identified linked markers. The situations in which prenatal testing is likely to occur and the issues in test result interpretation are the following:

• The couple are the parents of a child with SMA. It would be predicted that a fetus with the same genotype (i.e., molecular genetic test result) as a previously affected sib would have similar clinical findings.

• One or both parents are heterozygous for SMNdisease-causing mutations detected during testing of relatives and their partners. In this instance, interpretation of test results may be difficult and should be done in the context of formal genetic counseling.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Low-risk pregnancy. For the fetus with reduced fetal movement at no known increased risk for SMA, SMA needs to be considered, as do the disorders discussed in Differential Diagnosis [Macleod et al 1999].

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified in an affected family member in a research or clinical laboratory [Moutou et al 2003, Malcov et al 2004]. For laboratories offering PGD, see .

Molecular Genetic Pathogenesis

SMA may be the result of a genetic defect in the biogenesis and trafficking of the spliceosomal snRNP complexes. The SMN protein interacts with proteins known to be involved in the small nuclear ribonucleoprotein particle complex as well as with the survival motor neuron-interacting protein SIP. Consequently, the motor neurons of individuals with SMA are impaired in their capacity to produce specific mRNAs and as a result become deficient in proteins that are necessary for the growth and function of these cells. Thus, SMA may be a disorder affecting splicing; however, the reasons for specific motor neuron death as a consequence of SMN1 mutations are not yet known. The SMN protein has also been reported to influence several other cellular activities such as transcription, ribosomal assembly, and apoptosis [Strasswimmer et al 1999, Lefebvre et al 2002, Vyas et al 2002].

Despite the few differences in the coding regions between SMN1 and SMN2, the two genes do not encode identical proteins. SMN1 produces full-length transcripts and SMN2 primarily produces transcripts lacking exon 7 because the C-to-T transition in SMN2 exon 7 disrupts an exon-splicing enhancer sequence [Lorson et al 1999]. Therefore, SMA arises because the SMN2 gene cannot fully compensate for the lack of expression of mutated SMN1. However, when the SMN2 copy number is increased, the small amount of full-length transcript generated by SMN2 is often able to produce a milder type II or III phenotype.

Normal allelic variants: The SMN region on chromosome 5q12.2-q13.3 is unusually complex, with repetitive sequences, pseudogenes, retrotransposable elements, deletions, and inverted duplications [Biros & Forrest 1999]. Unaffected individuals have two copies of the SMN gene arranged in tandem on each chromosome; these are referred to as SMN1 (telomeric copy) and SMN2 (centromeric copy). Other terms that have been used to identify SMN1 are telSMN, SMNt, and SMNT; other terms that have been used to identify SMN2 are cenSMN, SMNc, ^c BCD541, and SMNC. Both SMN1 and SMN2 contain nine exons and differ only in eight nucleotides (five are intronic and three are exonic, located within exons 6, 7, and 8) [Biros & Forrest 1999].

The presence of a SMA carrier with two SMN1 copies on one chromosome was definitively proven utilizing hybrids monosomal for human chromosome 5 [Mailman et al 2001].

Pathologic allelic variants: It is the loss of the telomeric copy of the SMN(SMN1) gene that leads to development of SMA. Individuals with SMA are either homozygous for a deletion of exon 7 of SMN1 (Δ7 SMN1) or are compound heterozygotes for Δ7 SMN1 and a intragenic mutation of SMN1. Deletions of the SMN1 gene appear to be directly involved in SMA, since exon 7 — or exons 7 and 8 — of SMN1 are undetectable in more than 95% of individuals irrespective of their clinical type, either as a result of homozygous deletions, or because of conversion of sequences of SMN1 into those of the SMN2 gene.

Normal gene product: Evidence supports a role for SMN in snRNP (small nuclear ribonuclearprotein) biogenesis and function [Fischer et al 1997, Liu et al 1997, Pellizzoni et al 1998]. SMN has been shown to be required for pre-mRNA splicing. Immunofluorescence studies using a monoclonal antibody to the SMN protein have revealed that the SMN protein is localized to novel nuclear structures called 'gems;' gems appear similar to and possibly interact with coiled bodies, which are thought to play a role in the processing and metabolism of small nuclear RNAs [Liu & Dreyfuss 1996]. SnRNPs and possibly other splicing components require regeneration from inactivated to activated functional forms. The function of SMN is in the reassembly and regeneration of these splicing components [Pellizzoni et al 1998].

Abnormal gene product: Mutant SMN, such as that found in individuals with SMA, lacks the splicing-regeneration activity of wild-type SMN.

Literature Cited

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

Revision History

• 3 April 2006 (me) Comprehensive update posted to live Web site

• 15 July 2004 (br) Revision: Management

• 17 October 2003 (me) Comprehensive update posted to live Web site

• 24 February 2000 (me) Review posted to live Web site

• 28 February 1999 (br) Original submission