Spinal muscular atrophy (SMA) is characterized by progressive muscle weakness resulting from degeneration and loss of the anterior horn cells (i.e., lower motor neurons) in the spinal cord and the brain stem nuclei. Onset ranges from before birth to adolescence or young adulthood. Poor weight gain, sleep difficulties, pneumonia, scoliosis, and joint contractures are common complications. Before the genetic basis of SMA was understood, it was classified into clinical subtypes; however, it is now apparent that the phenotype of SMA associated with disease-causing mutations of SMN1 spans a continuum without clear delineation of subtypes. Nonetheless, classification by age of onset and maximum function achieved is useful for prognosis and management; subtypes include:
- SMA 0 (proposed), with prenatal onset and severe joint contractures, facial diplegia, and respiratory failure;
- SMA I, with onset before age six months;
- SMA II, with onset between age six and 12 months;
- SMA III, with onset in childhood after age 12 months and ability to walk at least 25 meters achieved; and
- SMA IV, with adult onset.
The diagnosis of SMA is based on molecular genetic testing. Mutations in SMN1 are known to cause SMA; increases in SMN2 copy number often modify the phenotype. SMN1 (survival motor neuron 1) is the primary gene in which mutation causes SMA. About 95%-98% of individuals with SMA are homozygous for a deletion or gene conversion of SMN1 to SMN2 and about 2%-5% are compound heterozygotes for an SMN1 deletion or conversion mutation and an SMN1 intragenic mutation. SMN1 deletion or conversion mutation is typically detected by demonstrating the absence of exon 7, since it can be easily differentiated from exon 7 of SMN2. Note that the SMN1 to SMN2 conversion mutations cannot be differentiated from SMN1 deletions by standard deletion testing, as both result in the absence of SMN1 exon 7.
SMA carrier testing, a gene dosage assay, allows determination of the number of SMN1 copies by measuring the number of exon 7-containing SMN1 copies. This test can be difficult to interpret because instead of having the normal two copies of SMN1, one on each chromosome, some carriers have the two SMN1 copies on one chromosome (in cis configuration) and some carriers have an SMN1 intragenic mutation that is not detected by the dosage testing. Furthermore, 2% of individuals with SMA have one SMN1 allele resulting from a de novo mutation, meaning that only one parent is a carrier of an SMN1 mutation. Because of these complexities in carrier test interpretation, SMA carrier testing should be provided in the context of formal genetic counseling.
Treatment of manifestations: When nutrition is a concern in SMA, placement of a gastrostomy tube is appropriate. As respiratory function deteriorates, tracheotomy or noninvasive respiratory support is offered. Sleep-disordered breathing can be treated with nighttime use of continuous positive airway pressure. Surgery for scoliosis in individuals with SMA II and SMA III can be carried out safely if the forced vital capacity is greater than 30%-40%. A power chair and other equipment may improve quality of life.
Surveillance: Evaluation every six months or more frequently for children who are weak to assess nutritional state, respiratory function, and orthopedic status (spine, hips, and joint range of motion).
SMA is inherited in an autosomal recessive manner. Each pregnancy of a couple who have had a child with SMA has an approximately 25% chance of producing an affected child, an approximately 50% chance of producing an asymptomatic carrier, and an approximately 25% chance of producing an unaffected child who is not a carrier. These recurrence risks deviate slightly from the norm for autosomal recessive inheritance because in about 2% of cases the affected individual has a de novo SMN1 mutation on one allele; in these instances only one parent is a carrier of an SMN1 mutation, and thus the sibs are not at increased risk for SMA. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutations in a family have been identified.
The diagnosis of spinal muscular atrophy (SMA) is established in individuals with the following:
- A history of motor difficulties
- Evidence of motor unit disease on physical examination
- Pathogenic changes in SMN1
The clinical classification of SMA is based on age of onset and maximum function attained:
- 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
- Onset age 0-6 months
- Poor muscle tone
- Muscle weakness
- Lack of motor development; ability to sit without support never achieved
- Facial weakness: minimal or absent
- Mild contractures: often at the knees, rarely at the elbows
- Absence of tendon reflexes
- No sensory loss
- Alert appearance
- Normal cerebral function including intellect
- Onset of muscle weakness usually after age six months; ability to sit independently achieved when placed in a sitting position
- 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]
- Onset usually after age ten months, in some cases earlier; ability to walk at least 25 meters achieved
- Weakness manifests 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
- "Adult" onset of muscle weakness
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 SMN1 does not identify mutations.
- 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 & Karwańska 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.
Molecular Genetic Testing
Genes. Mutations in SMN1 are known to cause SMA; increases in SMN2 copy number often modify the phenotype. The two genes are adjacent to each other.
In the general population:
- Most people have one copy of SMN1 on each chromosome; however, about 5%-8% of the population has two copies of SMN1 on a single chromosome. This may lead to serious consequences (false negatives) when one determines carrier status (see Interpretation of the results of carrier testing).
- The number of SMN2 copies (arranged in tandem in cis configuration on each chromosome) ranges 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. SMN1 (survival motor neuron 1) is the primary SMA-related gene.
- Approximately 95%-98% of individuals with a clinical diagnosis of SMA are homozygous for a deletion or gene conversion of SMN1, typically determined by lack of exon 7 in both copies of SMN1 (i.e., they are homozygous for deletion of at least exon 7) [Bussaglia et al 1995, Lefebvre et al 1995, Parsons et al 1996, Hahnen et al 1997, McAndrew et al 1997, Talbot et al 1997, Ogino & Wilson 2002].
Linkage analysis may be possible for families in which direct DNA testing (targeted mutation analysis and/or sequence analysis) is not informative. For these families, it may be used for confirmation of carrier testing and prenatal testing results.
Interpretation of test results in a symptomatic individual
- Because sequence analysis cannot determine whether an inactivating mutation is in SMN1 or SMN2, one of the following is required to confirm that the mutation is present in SMN1:
- Establish that the inactivating mutation has previously been reported in SMN1;
- Use a long-range PCR protocol or subcloning, which facilitates specific analysis of SMN1.
- Failure to identify a mutation by sequence analysis is sufficient to conclude that an intragenic mutation is not present in the SMN1 coding sequence
Interpretation of the results of carrier testing. Approximately 6% of parents of a child with SMA resulting from a homozygous SMN1 deletion have normal results of SMN1 dosage testing for the following two reasons:
- About 4% of carriers have two copies of SMN1 on a single chromosome [McAndrew et al 1997] and a deletion on the other chromosome. These carrier individuals with two copies of SMN1 on one chromosome are misdiagnosed as non-carriers by the SMN1 dosage test (i.e., a false negative test result). (See Testing Strategy, To Determine Carrier Status.)
- De novo deletion of exon 7 of one SMN1 allele occurs in 2% of individuals with SMA; thus, only one parent is a carrier.
To Confirm/Establish the Diagnosis in a Proband Suspected of Having SMA
- Perform SMN1 targeted mutation analysis*
- If exon 7 is deleted from both copies of SMN1, the diagnosis of SMA is confirmed.
- If exon 7 is deleted from one copy of SMN1, perform sequence analysis of all SMN1 exons and intron/exon borders to determine if the proband is a compound heterozygote for deletion of exon 7 of SMN1 and an intragenic SMN1 mutation.
- If exon 7 is present in both copies of SMN1, consider other diagnoses (see Differential Diagnosis).
Instead of targeted mutation analysis for deletion of exon 7, SMN1 dosage analysis typically used for carrier testing can be used as an initial and sensitive screen to identify affected individuals who are heterozygous for the deletion of SMN1 and who are likely to also have an intragenic SMN1 mutation.
To establish prognosis based on number of copies of SMN2 present, SMN2 copy number is determined (see Genotype-Phenotype Correlations).
To Determine Carrier Status
Carrier status of parents of more than one child with molecularly confirmed SMA
- If the children are confirmed to have exon 7 deleted from both copies of SMN1, perform SMN1 targeted mutation analysis on both parents:
- When exon 7 is found to be deleted from one copy of SMN1 in both parents, their carrier status is confirmed.
- When exon 7 is found to be deleted from one copy of SMN1 in only one parent, the parent in whom the exon 7 SMN1 deletion was not identified is likely to have one chromosome 5 with two copies of SMN1 and one chromosome 5 with no copies of SMN1 (i.e., an SMN1 2/0 genotype).
- If the children are confirmed to be compound heterozygotes for an exon 7 deletion on one copy of SMN1 and an intragenic mutation on the other copy of SMN1, perform SMN1 dosage analysis on both parents:
- One parent is expected to have the SMN1 deletion.
- Perform molecular genetic testing for the intragenic SMN1 mutation identified in the child on the parent in whom the exon 7 deletion was not detected.
- If the intragenic SMN1 mutation identified in the child is not identified in leukocyte DNA from the parent, it is likely that the parent has germline mosaicism for the intragenic SMN1 mutation.
Carrier status of parents of a child with molecularly confirmed SMA who is a simplex case (i.e., a single occurrence in a family)
- If the child is confirmed to have exon 7 deleted from both copies of SMN1, first perform SMN1 dosage analysis on both parents.
- If exon 7 is found to be deleted from one copy of SMN1 in both parents, carrier status is confirmed in the parents.
- If exon 7 is found to be deleted from one copy of SMN1 in only one parent, possible explanations include:
- The parent in whom the exon 7 SMN1 deletion was not identified may have one chromosome 5 with two copies of SMN1 and one chromosome 5 with no copies of SMN1 (i.e., a 2/0 SMN1 genotype).
Note: (1) Testing additional family members of the parent with the 2/0 SMN1 genotype may be informative: usually one of his/her parents has a deletion (1/0 SMN1 genotype) and the other parent has three or more SMN1 copies (2/1 SMN1 genotype). (2) If the parent of a child with SMA who has one chromosome 5 with two copies of SMN1 and one chromosome 5 with no copies of SMN1 (i.e., a 2/0 SMN1 genotype) has children with a known carrier, the children are at 25% risk to have SMA as the result of inheriting the chromosome 5 with no copies of SMN1 from this parent and the chromosome 5 with the SMN1 exon 7 deletion or SMN1 intragenic mutation from the carrier parent.
- The child may have a de novo deletion of exon 7.
- If the child is confirmed to have exon 7 deleted from one copy of SMN1 and an intragenic mutation in the other copy of SMN1, first perform SMN1 dosage analysis on both parents:
- Typically one parent is found to have the SMN1 deletion.
- Molecular genetic testing for the intragenic SMN1 mutation identified in the child should be performed on the parent in whom the exon 7 deletion was not detected.
- If the intragenic SMN1 mutation is identified in the parent, carrier status is confirmed in that parent.
- If the intragenic SMN1 mutation identified in the child is not identified in the parent, possible explanations include:
- De novo intragenic SMN1 mutation in the child;
- Germline mosaicism for the intragenic SMN1 mutation in the parent.
Carrier status of parents of a deceased child with suspected but not molecularly confirmed SMA
- As a first step attempt to test any available tissue samples, such as muscle biopsies (even if imbedded in paraffin) and bloodspots from newborn screening, as these samples can often provide enough DNA for molecular genetic testing.
- If DNA is not available, perform SMN1 dosage analysis on both parents:
- If exon 7 is found to be deleted from one copy of SMN1 in both parents, carrier status is confirmed in the parents.
- If exon 7 is found to be deleted from one copy of SMN1 in only one parent, sequence analysis of SMN1 should be considered in the parent in whom the deletion was not detected.
- If exon 7 is not found to be deleted from one copy of SMN1 in either parent, alternate diagnoses should be considered.
Carrier testing for persons not known to have a family history of SMA (e.g., for the reproductive partner of a carrier) requires SMN1 dosage analysis. If such an individual is found to have at least two SMN1 copies, the probability of being a carrier is approximately 1/670 (taking into consideration the 2% frequency of two SMN1 copies on the same chromosome and the small risk of being a carrier for an intragenic SMN1 mutation).
Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variants in the family.
Genetically Related (Allelic) Disorders
No phenotypes other than those described in this GeneReview are associated with mutation of SMN1.
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 brain stem 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 mutation of SMN 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 [Russman et al 1983]
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) 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 age one month [Banker 1985, Bürglen et al 1996, Bingham et al 1997]. One report describes a child who is not ventilator dependent at age five years [Falsaperla et al 2001].
SMA I (acute spinal muscular atrophy; Werdnig-Hoffmann disease) 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 children [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 children with SMA I 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 retained the ability to sit in adolescence or adulthood [Iannaccone et al 1993, Zerres et al 1997]. There is some evidence that with improved respiratory care and nutrition, life expectancy has changed for the better [Oskoui et al 2007]. Those individuals who received respiratory support may live longer than age two years [Bach et al 2002].
SMA II (chronic spinal muscular atrophy; Dubowitz disease) manifests as onset usually between ages six and 12 months. 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.
SMA III (juvenile spinal muscular atrophy; Kugelberg-Welander disease) manifests after age one year. 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. 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.
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 concentrations during periods of intercurrent illness or fasting [Kelley & Sladky 1986]. 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
The current classification system is based on age at onset and maximum motor function achieved (Table 2).
SMA I. Children with SMA I manifest weakness prior to age six months and never sit independently. The life expectancy is less than two years with some exceptions [Ignatius 1994, Thomas & Dubowitz 1994]. In a prospective study over a three-year period 31 of 34 children died before age two years [Cobben et al 2008]. These data are consistent with earlier literature. However, there is some evidence that improved respiratory care and nutrition extend life expectancy [Oskoui et al 2007].
SMA II. Early literature suggested the existence of a benign form of SMA that did not progress [Dubowitz 1964, Gardner-Medwin et al 1967, Munsat et al 1969]; however, subsequent studies with longer-term follow up showed otherwise [Russman et al 1983]. The life expectancy of persons with SMA II is not known with certainty. Anecdotal information shows that some live into adolescence and as late as the third or fourth decade [Byers & Banker 1961, Russman et al 1983, Hausmanowa-Petrusewicz et al 1992, Russman et al 1992, Zerres et al 1997]. Forced vital capacity decreases in all individuals with SMA.
SMA III. These individuals clinically manifest weakness after age 18 months, are able to walk independently, and have an indefinite life span. In some cases, those who are diagnosed prior to age 18 months still develop the ability to walk; although they lose their ability to walk by age 15 years, they have a “normal life expectancy.” Those who develop weakness after they have started to walk normally usually retain the ability to walk into their 30s or 40s [Russman et al 1996, Rudnik-Schöneborn et al 2001].
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  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 persons with SMA, Merlini et al  noted that individuals no longer ambulatory were weaker than those who remained ambulatory, concluding that loss of muscle strength correlated with loss of function. Given the study design, these conclusions need to be considered tentative.
In a physiologic outcome study, Swoboda et al  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 help 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 age 25 years and that life expectancy of individuals with SMA III was not different from that of the general population [Zerres et al 1997].
No correlation exists between the loss of SMN1 exon 7 and the severity of disease: the homozygous exon 7 deletion is observed with about the same frequency in all phenotypes.
Survival motor neuron protein level. SMN1 produces a full-length survival motor neuron protein necessary for lower motor neuron function [Lefebvre et al 1995]. SMN2 mostly encodes a survival motor neuron protein that is lacking in exon 7, thereby producing a less stable protein. SMA is caused by low levels of SMN protein rather than complete absence of the protein.
- Number of SMN2 copies. When SMN1 is mutated, SMA results because SMN2 cannot fully compensate for the lack of functional SMN protein. However, when the SMN2 copy number is increased, small amounts of full-length transcripts generated by SMN2 produce protein, and are able to function and result in the milder SMA II or SMA III phenotype
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]. Data from Mailman et al  are summarized in Table 3. More recently, Prior et al  reported three asymptomatic unrelated individuals homozygous for an SMN1 deletion who had five copies of SMN2, demonstrating that expression levels consistent with five copies of SMN2 may compensate for the lack of SMN1 expression.
- Other modifier genes outside the SMA region. In addition to the SMN2 copy number, other modifying factors influence the phenotypic variability of SMA. There are very rare families reported in which markedly different degrees of disease severity are present in affected sibs with the same SMN2 copy number. These discordant sib pairs, who share the same genetic background around the SMA locus, would indicate that there are other modifier genes outside the SMA region.
- Differences in splicing factors may allow more full-length expression from SMN2 and account for some of the variability observed between discordant sibs [Hofmann et al 2000]. It was also found that in some rare families with unaffected SMN1-deleted females, the expression of plastin 3 (PLS3 at chromosomal locus Xq23) was higher than in their SMA-affected counterparts. PLS3 was shown to be important for axonogenesis and therefore may act as a protective modifier [Oprea et al 2008].
- SMN2 sequence variants. In contrast to the above observations, Prior et al  recently described three unrelated individuals with SMA whose SMN2 copy numbers did not correlate with the observed mild clinical phenotypes; they were found to have a single base substitution, NM_017411.3:c.859G>C (p.Gly287Arg) in exon 7 of SMN2 that created a new exonic splicing enhancer (ESE) element. The new ESE increased the amount of exon 7 inclusion and full-length transcripts generated from SMN2, thus resulting in the less severe phenotypes.
These data demonstrate that the SMA phenotype may be modified not only by the number of SMN2 copies, but also by SMN2 sequence variants. Thus, it should not be assumed that all SMN2 alleles are equivalent and it is appropriate to investigate SMN2 for sequence changes that may have a positive or negative effect on SMN2 transcription.
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].
Congenital axonal neuropathy. Korinthenberg et al  indicated that three siblings with SMN1 pathogenic variants reported by them were the same infants reported by others to have congenital hypomyelination neuropathy or axonopathy [Boylan & Cornblath 1992].
Infants with spinal muscular atrophy and respiratory distress (SMARD) with diaphragmatic and intercostal muscle weakness. It is now known that SMARD spans a phenotypic spectrum. A cluster analysis of 141 individuals with SMARD with no evidence of SMN1 pathogenic variants revealed three distinct groups characterized by one of the following [Guenther et al 2007]:
- Congenital respiratory failure with congenital contractures
- Respiratory distress with onset between ages six weeks and six months. A clinical clue is the observation of hip flexion with minimal or no movement of the distal muscle groups. In fact, some authors have included this entity under the heading of ‘distal SMA.’
- Respiratory distress after age six months without congenital contractures
Of special note is SMARD1, first described in 1974, which is now known to be caused by mutation of IGHMBP2, the gene encoding the immunoglobulin μ-binding protein [Grohmann et al 2001, Grohmann et al 2003]. The life expectancy in children with this disorder is very ‘limited’ [Grohmann et al 2001, Grohmann et al 2003]. A recent report describes two full sibs with the identical IGHMBP2 abnormality, one dying at age six months and the other alive at age 12 years with limb weakness but only mild sleep hypoventilation. This observation suggests that other compensatory mechanisms may play a role in determining the phenotype in SMARD1 [Joseph et al 2009].
For SMA I and SMA III, the differential includes other causes of the ‘floppy infant’:
- Central nervous system abnormalities. Cranial imaging may be helpful in identifying these abnormalities.
- Chromosomal abnormalities and specifically Prader-Willi syndrome need to be considered. High-resolution chromosome analysis and, for Prader-Willi syndrome, methylation analysis can distinguish these abnormalities.
- Peroxisome biogenesis disorders, Zellweger syndrome spectrum are suspected if the child has lost skills previously acquired or if hepatosplenomegaly is present. Measurement of plasma very-long-chain fatty acid (VLCFA) levels shows elevation of C26:0 and C26:1 and the ratios C24/C22 and C26/C22. Pathogenic variants in 12 different genes of the PEX family are causative.
- Glycogen storage disease type II (Pompe disease; infantile acid maltase deficiency) is suspected when cardiomegaly is present. Mutation of GAA is causative.
- Primary diseases of muscle need to be considered. Among these are nemaline myopathy, central core disease, X-linked myotubular myopathy, congenital myotonic dystrophy type 1, and congenital muscular dystrophy. The diagnosis of a specific type of muscle disease rests on the presence of the specific ultrastructural changes on muscle biopsy and/or genetic testing.
- Congenital myasthenia gravis (see Congenital Myasthenic Syndromes) may be recognized by abnormal EMG responses to repetitive nerve stimulation and, in some cases, genetic testing.
Other disorders to consider are trauma of the cervical spinal cord, especially with breech delivery, spinal muscular atrophy with infantile cerebellar atrophy, and spinal muscular atrophy associated with brain atrophy [Chou et al 1990, Yohannan et al 1991].
Peripheral neuropathies (see Charcot-Marie-Tooth Hereditary Neuropathy Overview), including the Guillain-Barré syndrome, are part of the differential diagnosis.
Regression of motor skills associated with intact or exaggerated deep tendon reflexes suggest cerebral white matter diseases such as X-linked adrenoleukodystrophy.
SMA III is considered in the differential diagnosis of Duchenne muscular dystrophy (DMD), which is suspected when serum creatine kinase concentration is ten to 20 times greater than normal. DMD is confirmed by molecular genetic studies of DMD or muscle biopsy.
Congenital myopathies may also present with a clumsy gait and difficulty walking up and down stairs. Metabolic myopathies, including glycogen storage diseases (see GSD2) and lipid myopathies, need to be considered.
Other disorders with motor neuron disease may be confused with SMA: X-linked spinal and bulbar muscular atrophy (SBMA), also known as Kennedy disease, is a gradually progressive neuromuscular disorder in adult men in which degeneration of lower motor neurons results in proximal muscle weakness, muscle atrophy, and fasciculations beginning between ages 20 and 50 years. Individuals with SBMA often show gynecomastia, testicular atrophy, and reduced fertility as a result of androgen insensitivity. Identification of a CAG trinucleotide repeat expansion in the androgen receptor gene is diagnostic.
Hexosaminidase A deficiency results in lysosomal storage of the specific glycosphingolipid, GM2 ganglioside. The juvenile, chronic, and adult-onset variants have onset after infancy, slow progression, and variable neurologic findings, including progressive dystonia, spinocerebellar degeneration, and lower motor neuron disease. Diagnosis is by enzyme deficiency or molecular testing.
"Monomelic muscular atrophy" is predominantly a cervical form of spinal muscular atrophy. Rarely, the tongue may be affected; other cranial nerves are spared [Goutières et al 1991, Hageman et al 1993].
Fazio-Londe disease is a motor neuron disease limited to the lower cranial nerves, which starts in the second decade of life and progresses to death in one to five years.
Distal spinal muscular atrophy is characterized by initial weakness and wasting of distal muscles, followed by weakness of other muscle groups. A fascioscapuloperoneal distribution of spinal muscular atrophy, a bulbospinal muscular atrophy in adults, and spinal muscular atrophy with initial involvement of the proximal muscles have also been described.
A congenital form of lower extremity SMA has been described; it is unclear whether the distal muscles are weaker than the proximal muscles. If so, this would be included under the rubric of distal spinal muscular atrophy [Mercuri et al 2004a].
Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease involving both the upper motor neurons (UMN) and lower motor neurons (LMN), may begin with pure lower motor neuron signs.
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with spinal muscular atrophy (SMA), the following evaluations are recommended:
- 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 assessment. 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
- Medical genetics consultation
Treatment of Manifestations
The management of children with SMA starts with the diagnosis and classification into one of the five categories. A consensus document on the diagnosis and treatment of children with SMA has been developed [Wang et al 2007] (full text).
Health Issues Specific to SMA
Pulmonary. Children with SMA I can survive beyond age two years when provided tracheostomy or noninvasive respiratory support [Bach et al 2002, Bach et al 2003, Bach 2008]. Options for management, including ‘do not attempt to resuscitate’ status, should be discussed with the parents/care providers 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%.
With noninvasive respiratory support, children have fewer hospitalizations after age five years; they may not need daytime ventilation and are able to express themselves verbally. Questions as to whether this intervention is appropriate for children with SMA I (Werdnig-Hoffmann disease) have been raised [Bush et al 2005, Wang et al 2007, Ryan 2008]. Ryan  posits that this type of intervention is ‘futile’ (as the children become ‘locked in’ with no motor movement) and questions the resulting quality of life [Wang et al 2007].
Use of an intermittent positive-pressure breathing device (mechanical in-exsufflator) in the treatment of children with neuromuscular diseases, including children with SMA, has proven effective in expanding lung volumes and clearing airway secretions [Dohna-Schwake et al 2006]. A prospective study found that children younger than age eight years had difficulty using the in-exsufflator [Fauroux et al 2008]. A controlled clinical trial is needed to evaluate the value of this intervention.
Nutrition. Wang et al  describe the nutritional difficulties experienced by children with SMA I. Bulbar dysfunction is universal in SMA I and gastrostomy should be considered early on. The bulbar dysfunction eventually becomes a serious problem for persons with SMA II and only very late in the course of disease for those with SMA III. Gastrointestinal dysmotility results in constipation, delayed gastric emptying, and potentially life-threatening gastroesophageal reflux.
In a review of feeding difficulties in patients with SMA II, Messina et al  interviewed a total of 125 patients and/or their caretakers by telephone; the patients ranged from age 15 months through 47 years. The most frequently reported problems were limited mouth opening and difficulty chewing; 25% experienced swallowing difficulties and only six of 102 weighed greater than two standard deviations for their age. Although these data were obtained in 1999 [Granger et al 1999], it seems that they are just now influencing care [Author, personal observation].
Urinary incontinence. An analysis of 95 persons with SMA suggested that incontinence was higher in SMA I and II than in controls. However, this study raises more questions than it provides answers, as the information was gathered via questionnaires completed by the affected children’s parents [von Gontard et al 2001] and issues such as the cause of the incontinence were not addressed.
Scoliosis is a major problem in most persons with SMA II and in half of those with SMA III [Evans et al 1981, Brown et al 1989, Merlini et al 1989]. Before age ten years, approximately 50% of affected children, especially those who are nonambulatory, develop spinal curvatures of more than 50 degrees, which require surgery. Scoliosis repair is carried out safely if the forced vital capacity is greater than 30%-40%. The use of an orthosis prior to surgical intervention does not prevent scoliosis but does allow the affected individual to be upright rather than prone. Some younger children cannot tolerate orthoses, resulting in more rapid progression of their spine curvature.
Use of the vertical expandable prosthetic titanium rib (VEPTR) is a possible treatment for severe scoliosis. Chandran and colleagues described the use of VEPTR in 11 children with SMA who were followed for an average of 43 months after the initial surgery [Chandran et al 2011]. The average age at time of surgery was six years. Five individuals had a diagnosis of SMA type I and six were diagnosed with SMA type II. The 11 children underwent 45 surgical procedures; 12 growing rod implantations with 34 lengthenings were undertaken. No surgical complications were identified. Medical complications were seen in two affected individuals, namely, postoperative pneumonia and anemia.
Hip dislocation is another orthopedic concern in SMA. A retrospective review of a large series of cases suggests that asymptomatic hip dislocation does not require surgery [Sporer & Smith 2003].
Behavior problems in children and adolescents with SMA have been the subject of at least one report [Laufersweiler-Plass et al 2003]. Compared to sibs and normal controls, children with SMA were, in fact, quite well adjusted. Concern was raised about unaffected sibs of children with SMA, who had a two- to threefold higher rate of behavioral problems than children without SMA.
Sleep disorders. Questions about sleeping problems should be part of the routine care of those with SMA. In a study of seven people with SMA, Mellies et al  noted that sleep-disordered breathing developed prior to respiratory failure. Puruckherr et al  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.
Pain in those with SMA is a problem that has not been adequately studied [Author, personal observation].
Individuals with SMA are evaluated at least every six months; weaker children are evaluated more frequently.
At each visit nutritional state, respiratory function, and orthopedic status (spine, hips, and joint range of motion) are assessed.
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Antisense oligonucleotide treatment. An antisense oligonucleotide (ASO), ASO-10-27, corrected SMN2 splicing and restored SMN expression in mice motor neurons after intracerebroventricular injection [Hua et al 2011]. Systemic administration of ASO-10-27 robustly rescued severe SMA mice much more effectively than intracerebroventricular administration; subcutaneous injections extended the median life span by 25-fold. An open-label Phase I clinical trial completed in individuals with SMA type II-III showed that this drug could be delivered directly to the cerebral spinal fluid via lumbar puncture in this population with acceptable tolerability (ClinicalTrials.gov ID: NCT01494701), leading to two additional clinical studies: one with multiple doses in individuals with SMA type II-III (ClinicalTrials.gov ID: NCT01703988) and one in infants with SMA type I ClinicalTrials.gov ID: NCT01839656). Trials are currently underway and results are not yet available.
Quinazoline-related compounds. A cell-based high-throughput screening program by Jarecki et al identified a class of pharmaceutical compounds referred to as quinazoline derivatives. These compounds increased SMN2 promoter activity, altered SMN mRNA levels or mRNA splicing patterns and increased SMN protein levels and nuclear gem numbers in cells derived from affected individuals [Jarecki et al 2005]. Oral administration of three quinazoline-related compounds to neonatal mice has shown a dose-dependent increase in SMN promoter activity. Further, delivery of these compounds to SMA mice significantly increased the mean life span by approximately 21%-30% [Butchbach et al 2010]. This finding led to a recently completed Phase Ia trial in healthy volunteers; results are not yet available.
Several trials of different medications have been conducted, but only two randomized placebo-controlled trials have been published.
Gabapentin. A randomized-controlled trial of gabapentin in persons with SMA older than 18 years, using functional, strength, and pulmonary testing as the outcome measurements, showed no difference between treated and placebo groups after one year [Miller et al 2001].
Phenylbutyrate. A preliminary open-label study of phenylbutyrate suggested efficacy [Mercuri et al 2004b], but a three week-long double-blind placebo controlled trail, which did not use surrogate markers as one of the outcome criteria, failed to support earlier findings [Mercuri et al 2007].
Olesoxime (TRO19622) is currently being tested in a Phase II trial in affected individuals. Olesoxime prevents neuronal death and promotes neuroregeneration. The study is currently ongoing and results are not yet available.
- A six-month open label pilot project with albuterol showed an increase in strength as determined by myometry, and an increase in forced vital capacity, suggesting that a double-blind study was warranted [Kinali et al 2002].
- An open-label study of salbutamol in 23 persons with SMA II noted “slightly increased strength and endurance;” however, no control group was used for comparison. Furthermore, the authors note that in previous control studies of medications even the control group seemed to improve slightly over the course of a year. Therefore, they raise caution that although salbutamol is potentially effective, a double-blind study must be performed before suggesting that albuterol should become part of the treatment of SMA [Pane et al 2008].
Riluzole. In one clinical study, three of seven children who were on the active medication for SMA I were still living at ages 5, 3.5, and 2.5 years; the three children on placebo died before age 18 months [Russman et al 2003]. A three-year follow-up study after the publication showed that the children on riluzole had died, suggesting that it is not effective in the treatment of SMA [Author, personal observation].
Histone deacetylase inhibitors have been shown to increase SMN expression and protein levels in the cytoplasm and nuclei of cells from the SMA mouse model as well as in human fibroblasts and lymphocytes [Chang et al 2001, Brichta et al 2003, Sumner et al 2003, Andreassi et al 2004, Brahe et al 2005]. The upregulation may result from histone acetylation-mediated expression of SMN2 [Kernochan et al 2005]. At least two drugs in this category have been studied: phenylbutyrate (results noted above) and valproic acid.
- Valproate. The seven adults with SMA III/IV who were given valproate in an open-label retrospective study for a mean duration of eight months “felt” better, showed some improvement in muscle strength using objective measurements, and noted subjective functional changes [Weihl et al 2006]. The authors propose that a double-blind controlled study will be necessary in order to show efficacy.
- Aclarubicin, a third-generation histone deacetylase inhibitor, restored SMN protein levels to cells derived from persons with SMA I [Andreassi et al 2001]. A clinical trial for this medication is not underway at this time.
- A second-generation histone deacetylase inhibitor that increases SMN2 expression, can be given orally, and crosses the blood-brain barrier has been identified. It is possible that this chemical is now ready for human trials [Hahnen et al 2006].
Hydroxyurea is a medication that enhances expression of the human gene encoding fetal hemoglobin. Treatment of cultured lymphocytes from individuals with SMA with hydroxyurea resulted in a time-related and dose-dependent increase in the ratio of full-length to truncated messenger RNA and significantly increased SMN protein levels and intranuclear protein levels [Grzeschik et al 2005]. Clinical trials with hydroxyurea in SMA are underway. In a study of 33 persons with SMA II and III who were treated with hydroxyurea for one week, Liang et al  showed increased expression of SMN2 in lymphoid cell lines; however, this study did not include a functional analysis.
Drug trials in the SMA mouse model have suggested other approaches to the development of medication for potential human trials.
- Neuronal SMN expression has been found to correct spinal muscular atrophy in mice with severe SMA while muscle-specific SMN expression had no phenotypic effect [Gavrilina et al 2008]. The authors point out that previous studies had shown that the copy number of SMN2 affects the amount of SMN protein produced and the severity of the SMA phenotype. In this project, they note that expression of full-length SMN protein in neurons can correct the severe SMA phenotype in mice. The implication is that a medication that could affect the amount of SMN2 protein could help persons with this condition.
- Genetic conversion of SMN2 to SMN1 has also been described as an approach to the treatment of spinal muscular atrophy [DiMatteo et al 2008].
- Corti et al  described neural stem cell transplantation in the SMA mouse model in which spinal cord neural stem cells isolated from normal mice were grafted intrathecally into the spinal cords of affected mice. Neuromuscular function and life expectancy improved in the treated mice.
Of note, myostatin, a transforming growth factor-beta family member that inhibits muscle growth, has not been effective in ameliorating the findings in the SMA mouse model [Sumner et al 2009].
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.
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 SMN1 pathogenic variant.
- Heterozygotes are asymptomatic.
Sibs of a proband
- At conception, each sib of an affected individual has an approximately 25% chance of being affected, an approximately 50% chance of being an asymptomatic carrier, and an approximately 25% chance of being unaffected and not a carrier. Note: If the parent of a child with SMA who has one chromosome 5 with two copies of SMN1 and one chromosome 5 with no copies of SMN1 (i.e., a 2/0 SMN1 genotype) has children with a known carrier, the children are at 25% risk of having SMA as the result of inheriting the chromosome 5 with no copies of SMN1 from this parent and the chromosome 5 with the SMN1 exon 7 deletion or SMN1 intragenic mutation from the carrier parent.
Even if a child with SMA appears to have inherited one pathogenic allelic variant from a carrier parent and to have a de novo mutation resulting in the other pathogenic variant, germline mosaicism for an SMN1 mutation 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 of a proband. Each sib of an obligate heterozygote is at a 50% risk of being a carrier.
Molecular genetic testing may be considered to determine the carrier status of:
- Parents of more than one child with molecularly confirmed SMA;
- Parents of a child with molecularly confirmed SMA who represents a simplex case (i.e., a single occurrence in a family);
- Parents of a child with suspected but not molecularly confirmed SMA;
- Persons not known to have a family history of SMA, who are often reproductive partners of known carrier.
See Testing Strategy, To Determine Carrier Status.
Related Genetic Counseling Issues
- The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
- It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.
High-risk pregnancy. Prenatal diagnosis is possible for fetuses at 25% risk when the SMN1 pathogenic variants 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 approximately ten to 12 weeks' gestation or amniocentesis usually performed at approximately 15 to 18 weeks' gestation is possible for the known parental SMN1 pathogenic variants 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 an SMN1 pathogenic variant detected during testing of relatives and their partners. In this instance:
- Interpretation of test results and prediction of clinical findings in an affected child may be difficult and should be done in the context of formal genetic counseling.
- An SMN2 copy number determination on the prenatal specimen may help to better predict the phenotype of the affected child.
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 the Differential Diagnosis [MacLeod et al 1999].
GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.
- Families of SMA (Spinal Muscular Atrophy)925 Busse RoadElk Grove Village IL 60007Phone: 800-886-1762 (toll-free); 847-367-7620Fax: 847-367-7623Email: firstname.lastname@example.org
- Medline Plus
- National Library of Medicine Genetics Home Reference
- National Organization for Rare Disorders (NORD)55 Kenosia AvenuePO Box 1968Danbury CT 06813-1968Phone: 800-999-6673 (toll-free); 203-744-0100; 203-797-9590 (TDD)Fax: 203-798-2291Email: RN@rarediseases.org; email@example.com; firstname.lastname@example.org
- NCBI Genes and Disease
- Claire Altman Heine Foundation, Inc.A foundation whose focus is support and funding of population-based SMA carrier screening, and increasing awareness of SMA in both the public and medical communities1112 Montana Avenue#372Santa Monica CA 90403Phone: 310-260-3262Fax: 310-393-7154Email: email@example.com
- Muscular Dystrophy Association - USA (MDA)222 South Riverside PlazaSuite 1500Chicago IL 60606Phone: 800-572-1717Email: firstname.lastname@example.org
- International SMA Patient RegistryIndiana University School of Medicine, Department of Medical & Molecular Genetics410 West Tenth StreetHS 4000Indianapolis IN 46202-3002Phone: 866-482-0248Fax: 317-278-1100Email: email@example.com
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
|208100||ARTHROGRYPOSIS MULTIPLEX CONGENITA, NEUROGENIC TYPE; AMCN|
|253300||SPINAL MUSCULAR ATROPHY, TYPE I; SMA1|
|253400||SPINAL MUSCULAR ATROPHY, TYPE III; SMA3|
|253550||SPINAL MUSCULAR ATROPHY, TYPE II; SMA2|
|271150||SPINAL MUSCULAR ATROPHY, TYPE IV; SMA4|
|600354||SURVIVAL OF MOTOR NEURON 1; SMN1|
|601627||SURVIVAL OF MOTOR NEURON 2; SMN2|
|602595||SMN-INTERACTING PROTEIN 1; SIP1|
|603519||SURVIVAL MOTOR NEURON DOMAIN-CONTAINING PROTEIN 1; SMNDC1|
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, translation of these two genes does not produce 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 SMN2 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 type III phenotype.
SMN1 and SMN2
Gene structure. 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 genes encoding SMN protein that are 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: telSMN, SMNt (t for telomeric), SMNT
- Other terms that have been used to identify SMN2: cenSMN, SMNc (c for centromeric), BCD541, SMNC
SMN1 and SMN2 each comprise nine exons and differ only in eight nucleotides (five are intronic; three are exonic, one each located within exons 6, 7, and 8) [Biros & Forrest 1999].
The presence of two SMN1 copies on one chromosome in a carrier for SMA was definitively proven utilizing hybrids monosomal for human chromosome 5 [Mailman et al 2001]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.
Pathogenic allelic variants. It is the loss of SMN1 that leads to development of SMA. Individuals with SMA are either homozygous for a deletion of at least exon 7 of SMN1 or are compound heterozygotes for such a deletion along with an intragenic SMN1 inactivating mutation. Deletions of SMN1 appear to be directly involved in SMA, because exon 7 of SMN1 is undetectable in more than 95% of individuals with SMA irrespective of the clinical subtype of SMA, either as a result of homozygous deletions or gene conversion of SMN1 sequence into SMN2 sequences.
Normal gene product. Evidence supports a role for SMN protein in snRNP (small nuclear ribonuclear protein) 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 SMN have revealed that SMN 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.
Published Guidelines/Consensus Statements
- Wang CH, Finkel RS, Bertini ES, Schroth M, Simonds A, Wong B, Aloysius A, Morrison L, Main M, Crawford TO, Trela A; Participants of the International Conference on SMA Standard of Care. Consensus statement for standard of care in spinal muscular atrophy (pdf). Available online. 2007. Accessed 7-18-14. [PubMed: 17761659]
- Andreassi C, Angelozzi C, Tiziano FD, Vitali T, De Vincenzi E, Boninsegna A, Villanova M, Bertini E, Pini A, Neri G, Brahe C. Phenylbutyrate increases SMN expression in vitro: relevance for treatment of spinal muscular atrophy. Eur J Hum Genet. 2004;12:59–65. [PubMed: 14560316]
- Andreassi C, Jarecki J, Zhou J, Coovert DD, Monani UR, Chen X, Whitney M, Pollok B, Zhang M, Androphy E, Burghes AH. Aclarubicin treatment restores SMN levels to cells derived from type I spinal muscular atrophy patients. Hum Mol Genet. 2001;10:2841–9. [PubMed: 11734549]
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- Chandran S, McCarthy J, Noonan K, Mann D, Nemeth B, Guiliani T. Early treatment of scoliosis with growing rods in children with severe spinal muscular atrophy: a preliminary report. J Pediatr Orthop. 2011;31:450–4. [PubMed: 21572284]
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- 14 November 2013 (me) Comprehensive update posted live
- 27 January 2011 (me) Comprehensive update posted live
- 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
Ohio State University
Oregon Health and Science University
Initial Posting: February 24, 2000; Last Update: November 14, 2013.
University of Washington, Seattle, Seattle (WA)
Prior TW, Russman BS. Spinal Muscular Atrophy. 2000 Feb 24 [Updated 2013 Nov 14]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.