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Spinal Muscular Atrophy

, PhD, FACMG and , MD.

Author Information

Initial Posting: ; Last Update: December 22, 2016.

Summary

Clinical characteristics.

Spinal muscular atrophy (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 symmetric, proximal > distal, and progressive. Before the genetic basis of SMA was understood, it was classified into clinical subtypes; however, it is now apparent that the phenotype of SMN1-associated SMA spans a continuum without clear delineation of subtypes. Poor weight gain with growth failure, restrictive lung disease, scoliosis, joint contractures, and sleep difficulties are common complications.

Diagnosis/testing.

The diagnosis of SMA is established in a proband with a history of motor difficulties, evidence of motor unit disease on physical examination, and identification of biallelic pathogenic variants in SMN1 on molecular genetic testing. Increases in SMN2 copy number often modify the phenotype.

Management.

Treatment of manifestations: When nutrition is a concern in SMA, placement of a gastrostomy tube early in the course of the disease is appropriate. Formal consultation with a pulmonologist familiar with SMA is indicated. As respiratory function deteriorates, tracheotomy or noninvasive respiratory support is offered. Surgical repair for scoliosis should be considered based on progression of the curvature, pulmonary function, and bone maturity.

Surveillance: Evaluation every six months or more frequently for weaker children to assess nutritional state, respiratory function, and orthopedic status.

Genetic counseling.

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 about 2% of affected individuals have a de novo SMN1 variant on one allele; in these instances, only one parent is a carrier of an SMN1 variant, 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 diagnosis of SMA has been confirmed by molecular genetic testing in an affected family member.

GeneReview Scope

Spinal Muscular Atrophy: Included Phenotypes
  • Spinal muscular atrophy 0
  • Spinal muscular atrophy I
  • Spinal muscular atrophy II
  • Spinal muscular atrophy III
  • Spinal muscular atrophy IV

For synonyms and outdated names see Nomenclature.

Diagnosis

Suggestive Findings

Spinal muscular atrophy (SMA) should be suspected in individuals with the following:

  • History of motor difficulties, especially with loss of skills
  • Proximal muscle weakness
  • Hypotonia
  • Areflexia/hyporeflexia
  • Tongue fasciculations
  • Evidence of motor unit disease on physical examination

Establishing the Diagnosis

A consensus document on the diagnosis of children with SMA has been developed [Wang et al 2007].

The diagnosis of SMA is established in a proband with a history of motor difficulties, evidence of motor unit disease on physical examination, and identification of biallelic pathogenic variants in SMN1 on molecular genetic testing (see Table 1).

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

  • Single-gene testing. Gene-targeted deletion/duplication analysis to determine the dosage of SMN1 is performed first for the SMN1 exon 7. If exon 7 is deleted from one copy of SMN1, perform sequence analysis of SMN1. If exon 7 is present in both copies of SMN1, consider other diagnoses (see Differential Diagnosis).
    Because SMN1 sequence analysis cannot determine whether a putative inactivating variant is in SMN1 or SMN2 (see Molecular Genetics), one of the following is required to confirm that the variant is present in SMN1:
    • Establish that the inactivating variant has previously been reported in SMN1
      OR
    • Sequence a long-range PCR product or a subclone of SMN1
    Note: Gene-targeted deletion/duplication analysis to determine SMN2 copy number can be performed to provide additional information for clinical correlation if the diagnosis of SMA is confirmed on molecular genetic testing (see Genotype-Phenotype Correlations).
  • A multigene panel that includes SMN1 and SMN2 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if serial single-gene testing (and/or use of a multigene panel) fails to confirm the diagnosis in an individual with features of SMA.
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Spinal Muscular Atrophy

Type of TestingGene 1Proportion of SMA Attributed to Pathogenic Variants in This GeneProportion of Pathogenic Variants 2 Detectable by this Method
Sequence analysis 3Gene-targeted deletion/duplication analysis 4
Diagnostic, carrier, prenatalSMN1~100%2%-5% 595%-98% 6
PrognosticSMN2NANASee footnote 7
1.

See Table A. Genes and Databases for chromosome locus and protein.

2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR and multiplex ligation-dependent probe amplification (MLPA) to detect single-exon deletions or duplications. Note that SMN1 and SMN2 are nearly identical; therefore, gene-targeted microarray cannot be used to determine SMN1 and SMN2 copy number.

5.

Detects the 2%-5% of individuals who are compound heterozygous for an intragenic pathogenic variant and an SMN1 deletion of at least exon 7 [Parsons et al 1998, Wirth 2000]

6.
7.

Note: Gene-targeted deletion/duplication analysis of SMN2 can be performed to provide additional phenotype information if the diagnosis of SMA is confirmed on molecular genetic testing. The number of copies of SMN2 may range from zero to five. Quantitative PCR and MLPA methods are often designed to detect both SMN1 and SMN2 copy number [Anhuf et al 2003, Arkblad et al 2006, Scarciolla et al 2006] (see Genotype-Phenotype Correlations).

Testing to determine carrier status is reviewed in Genetic Counseling.

Clinical Characteristics

Clinical Description

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 symmetric, proximal > distal, and progressive.

SMA Phenotypes

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 SMN1 pathogenic variants 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.

Table 2.

Spectrum of SMA Phenotypes

PhenotypeAge of OnsetLife SpanMotor MilestonesOther Findings
SMA 0Prenatal<6 monthsNone achieved
  • Severe neonatal hypotonia
  • Severe weakness
  • Early respiratory failure
  • Facial diplegia
SMA I<6 monthsMost often ≤2 years, but may live longerSit w/support only
  • Mild joint contractures
  • Normal or minimal facial weakness
  • Variable suck & swallow difficulties
SMA II6-18 months70% alive at age 25 yearsIndependent sitting when placedPostural tremor of fingers
SMA III>18 monthsNormalIndependent ambulation
SMA IVAdulthoodNormalNormal

SMA 0 (congenital SMA) presents with severe weakness and hypotonia present at birth. There may be a history of decreased in utero movements and joint contractures. Infants with SMA type 0 have severe respiratory compromise and rarely survive past age six months [Dubowitz 1999, MacLeod et al 1999].

SMA I (severe 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, those infants with the gravest prognosis have problems sucking or swallowing, leading to growth failure and recurrent aspiration. Weakness of the intercostal respiratory muscles with relative preservation of diaphragm musculature leads to characteristic "bell-shaped" chest and paradoxic respiration (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. Fasciculation of the tongue is seen in most but not all children. A postural tremor of the fingers is seen only occasionally.

Older natural history data show 68% mortality by age two years and 82% by age four years [Zerres et al 1997, Munsat & Davies 1996]. With improved respiratory and nutritional supportive care, survival has improved. More recent prospective studies of children with SMA type 1 have shown median survival of 24 months [Oskoui et al 2007] and median time to either death or full-time noninvasive ventilation (>16 hours/day) of 13.5 months [Finkel et al 2014].

SMA II (intermediate spinal muscular atrophy, Dubowitz disease) manifests as onset usually between ages six and 12 months. 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. The maximum motor milestone attained is the ability to sit independently when placed. Affected individuals on average lose the ability to sit independently by the mid-teens. Finger trembling and general flaccidity are common. Scoliosis is common. Progressive respiratory muscle weakness leads to restrictive lung disease that is associated with morbidity and mortality in these individuals.

The life expectancy of persons with SMA II is not known with certainty. Anecdotal information shows that some live into adolescence and others as late as the third or fourth decade. 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 [Zerres et al 1997].

SMA III (juvenile spinal muscular atrophy, Kugelberg-Welander disease) typically manifests after age 18 months. The legs are more severely affected than the arms. Individuals walk independently but may fall frequently or have trouble walking up and down stairs at age two to three years. Some individuals who are diagnosed prior to age 18 months still develop the ability to walk, although most will lose that ability with time. In a retrospective study of individuals with SMA types II and III, for those with onset before age three years the probability of walking ten years after onset was 70%, while those with onset after age three years maintained this skill longer, with nearly 60% ambulatory 40 years after onset [Zerres et al 1997]. This group also evaluated life expectancy of 569 individuals with SMA II and SMA III from Germany and Poland and found that life expectancy of those with SMA III was not different from that of the general population [Zerres et al 1997].

SMA IV. The onset of muscle weakness is usually in the second or third decade of life. Findings are similar to those described for SMA III [Brahe et al 1995, Clermont et al 1995, Zerres et al 1997]. Life expectancy is normal.

Complications of SMA

Poor weight gain with growth failure, restrictive lung disease, scoliosis, joint contractures, and sleep difficulties are common complications of SMA.

Nutrition. Wang et al [2007] describe the nutritional difficulties experienced by children with SMA I. Bulbar dysfunction is universal in SMA I. 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 with aspiration. Growth failure can be addressed with gastrostomy tube placement as needed.

Pulmonary. Individuals with SMA, particularly type I and II, show progressive respiratory decline. Respiratory failure is usually the cause of death in these subtypes. Decreased respiratory function leads to impaired cough with inadequate clearance of lower airway secretions, hypoventilation during sleep, and recurrent pneumonia.

Orthopedic. Scoliosis is a major problem in most persons with SMA II and in half of those with SMA III. 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. Progressive scoliosis impairs lung function and in severe cases cardiac output. Progressive scoliosis is treated with surgery when appropriate. Joint contractures and hip dislocation are also common in SMA.

Metabolic acidosis. 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. Although the etiology of these metabolic derangements remains unknown, one recent report suggests that aberrant glucose metabolism may play a role [Bowerman et al 2012]. Prolonged fasting should be avoided in individuals with SMA.

Genotype-Phenotype Correlations

SMN1. No correlation exists between the type of SMN1 pathogenic variants and the severity of disease: the homozygous exon 7 deletion is observed with approximately the same frequency in all phenotypes.

SMN2. The number of copies (dosage) of SMN2 (arranged in tandem in cis configuration on each chromosome) ranges from zero to five (see Molecular Genetics). The presence of three or more copies of SMN2 is correlated with a milder phenotype [Mailman et al 2002, Prior et al 2004, Yamashita et al 2004, Soler-Botija et al 2005, Swoboda et al 2005]. It was estimated, from studies performed by Zheleznyakova et al [2011], that an affected child with four SMN2 copies is at an 88% risk of having type III SMA. Small amounts of full-length transcripts generated by SMN2 produce functional protein, and result in the milder SMA II or SMA III phenotype. Data from Mailman et al [2002] are summarized in Table 3. Prior et al [2004] 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.

In contrast to the above observations, Prior et al [2009] 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 – 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.

Putative modifier of SMA phenotype. It was also found that in some rare families with unaffected homozygous SMN1-deleted females, the expression of plastin 3 (encoded by PLS3 at chromosome 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]. Overexpresssion of PLS3 has also been shown to rescue the axonal growth defects in zebrafish with reduced smn levels [Hao et al 2012].

Table 3.

SMN2 Copy Number in SMA I vs SMA III

SMN2 Copy NumberNormalIn SMA IIn SMA IIITotal (SMA I + SMA III)
014.4%00
132%7 (13.5%)0 (0%)7 (4.9%)
251%43 (82.7%)0 (0%)43 (30.3%)
34%2 (3.9%)70 (77.8%)72 (50.7%)
40 (0%)20 (22.2%)20 (14.1%)
Total5290142

Nomenclature

Severe SMA or SMA I is still called Werdnig-Hoffmann disease by many [Hoffmann 1892, Werdnig 1971].

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.

Incidence of SMA and Estimated Carrier Frequency

CountryDisease Incidence per 100,000 Live BirthsCarrier FrequencyReference
England41/90Pearn [1978]
Italy7.8 (all SMA)1/57Mostacciuolo et al [1992]
4.1 (SMA I)
Germany101/50Thieme et al [1993], Mailman et al [2002]
USA 18.31/54Sugarman et al [2012]
1.

Included a pan ethnic population; the carrier risk for individuals who identified themselves as of northern European background ("Caucasian") was 1/47, Ashkenazi Jewish 1/67, Asian 1/59, Hispanic 1/68, Asian Indian 1/52, and African American 1/72 [Sugarman et al [2012].

Differential Diagnosis

Table 5.

Disorders to Consider in the Differential Diagnosis of Spinal Muscular Atrophy (SMA)

Age of OnsetDisorderGene(s) or RegionMOIClinical Features
Overlapping w/SMADistinguishing from SMA
Congenital to <6 monthsX-linked infantile spinal muscular atrophyUBA1XLHypotonia, weakness, areflexiaMultiple congenital contractures, fractures
Spinal muscular atrophy and respiratory distress 1 (SMARD1) 1 (OMIM 604320)IGHMBP2ARWeakness, respiratory failure, hypo- or areflexiaDistal predominant weakness, diaphragmatic paralysis
Prader-Willi syndrome15q11.2-q13HypotoniaPoor respiratory effort is rare.
Myotonic dystrophy type 1DMPKADHypotoniaAbsence of tongue fasciculations
Congenital muscular dystrophyMany genesAR
AD
Hypotonia, weaknessCNS, eye involvement
Peroxisome biogenesis disorders, Zellweger syndrome spectrumPEX family of genesARHypotoniaLoss of skills, hepatosplenomegaly
Congenital myasthenic syndromesMany genesAR
AD
HypotoniaOphthalmoplegia, ptosis, intermittent respiratory failure
Glycogen storage disease type II (Pompe disease)GAAARHypotoniaCardiomegaly
Other: congenital myopathies 2, metabolic/mitochondrial myopathies 3, peripheral neuropathies 4
>6 monthsBotulismNANAProximal muscle weaknessProminent cranial nerve palsies, acute onset
Later childhoodGuillain-Barré syndromeUnknownMuscle weaknessSubacute onset, sensory involvement
Duchenne muscular dystrophyDMDXLHypotoniaSerum creatine kinase concentration 10-20x > normal
Hexosaminidase A deficiency (juvenile, chronic, and adult-onset variants)HEXAARLower motor neuron diseaseSlow progression, progressive dystonia, spinocerebellar degeneration
Fazio-Londe syndrome (see Riboflavin Transporter Deficiency Neuronopathy)SLC52A2
SLC52A3
ARProgressive bulbar palsyLimited to lower cranial nerves; progresses to death in 1-5 yrs
Monomelic amyotrophy (Hirayama disease) (OMIM 602440)UnknownMuscle weaknessPredominantly cervical; tongue may be affected (rare); other cranial nerves spared
Other: peripheral neuropathies 4, muscular dystrophies 5
AdulthoodSpinal and bulbar muscular atrophyARXLProximal muscle weakness, muscle atrophy, fasciculationsGradually progressive; gynecomastia, testicular atrophy, reduced fertility
Amyotrophic lateral sclerosisMany genesAD
AR
XL
May begin w/pure lower motor neuron signsProgressive neurodegeneration; involves both upper & lower motor neurons

MOI = mode of inheritance

AD = autosomal dominant

AR = autosomal recessive

XL = X-linked

1.

SMARD spans a phenotypic spectrum [Guenther et al 2007].

2.
3.

Metabolic/mitochondrial myopathies (see Glycogen Storage Diseases [GSD I, GSD II, GSD III, GSD IV, GSD V, GSD VI] and Mitochondrial Disorders Overview)

4.
5.

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].

Management

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 older than 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. Consider a sleep study if the child snores during sleep or awakes fatigued in the morning.

Activities of daily living. Assess 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. Evaluate for development of contractures, scoliosis, and hip dislocation.

Other. Consultation with a clinical geneticist and/or genetic counselor is recommended.

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].

Health Issues Specific to SMA

Nutrition. Bulbar dysfunction is universal in SMA I and gastrostomy should be considered early in the course of the disease. 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.

Pulmonary. Children with SMA I and II, and more rarely type III, have progressive decline in pulmonary function. Formal consultation with a pulmonologist familiar with SMA is indicated. Guidelines for assessment and intervention are published as part of the Consensus Statement for Standard of Care in Spinal Muscular Atrophy [Wang et al 2007].

Options for management (depending on family preference) include no respiratory support, noninvasive ventilation, and tracheotomy with mechanical ventilation. These options should be discussed with the parents/care providers before respiratory failure occurs. The type of respiratory support is dependent on the individual's respiratory status, quality-of-life goals, and reduction in respiratory complications. Palliative care, with or without noninvasive ventilator support, is an option for the most severely affected individuals.

Indications for noninvasive ventilation in SMA include hypoventilation, as demonstrated by decreased oxygen saturation by pulse oximetry or obstructive sleep apnea. Noninvasive ventilation has been shown to improve sleep breathing parameters in SMA I and II [Petrone et al 2007]. Noninvasive ventilation with BiPAP is commonly used in SMA as it may improve chest wall and lung development and is proposed to reduce lung infections and pulmonary comorbidity in SMA. Tracheotomy for chronic ventilation is an option that can be discussed with individuals and their families; however, it is controversial, especially in SMA I.

Airway clearance can be addressed with a mechanical in-exsufflator in conjunction with suctioning and chest physiotherapy, especially in the setting of acute illness. Use of mechanical in-exsufflation in the treatment of children with neuromuscular diseases, including children with SMA, appears to reduce pulmonary complications [Chatwin et al 2003, Miske et al 2004].

Scoliosis occurs frequently in individuals with SMA II. Surgical repair should be considered based on progression of the curvature, pulmonary function, and bone maturity. Use of spinal orthosis prior to surgical intervention is common; however, there is insufficient evidence that spinal orthotics alter scoliosis.

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 types I and II 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. No surgical complications were identified. Medical complications were seen in two affected individuals: postoperative pneumonia and anemia.

A newer technology involving magnetically controlled growing rods (MAGEC rods) allows for gradual outpatient distractions controlled by an external remote device. Early case reports for this device are becoming available, although experience is not specific to SMA [La Rosa et al 2017].

Hip dislocation is another orthopedic concern in SMA. A retrospective review of a large series of affected individuals suggests that asymptomatic hip dislocation does not require surgery [Sporer & Smith 2003].

Prevention of Secondary Complications

Comprehensive care for individuals with SMA should be provided according to the published Consensus Statement for Standard of Care in Spinal Muscular Atrophy [Wang et al 2007]. See Treatment of Manifestations.

Surveillance

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

No therapy for SMA is currently available, however a number of compounds have been studied and newer approaches (including some directed at increasing full-length SMN protein from SMN2 and gene replacement therapy) are being actively investigated.

Small-Molecule Therapy Approaches

Increasing SMN protein production. Candidate molecules have been identified through cell-based high-throughput screening assays and include histone deacetylase inhibitors, aminoglycosides, and quinazolone derivatives.

Histone deacetylase inhibitors (HDACIs) are small molecules that 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]. However, clinical trials of HDACIs (including phenylbutyrate and valproic acid) have shown no difference in functional outcome measures compared with placebo [Mercuri et al 2007, Swoboda 2010].

Another molecule, hydroxyurea, a non-HDACI, was also found to increase SMN levels in SMA cell lines, but this compound failed to show improvement in a clinical trial [Chen et al 2010]. Salbutamol, a β-adrenergic agonist, also increases SMN protein in SMA fibroblasts [Angelozzi et al 2008]. Clinical experience to date is limited to two open-label studies of salbutamol/albuterol which have reported improved motor outcomes [Kinali et al 2002, Pane et al 2008]; no randomized, placebo-controlled trials have been performed to date.

Quinazolone derivatives are another class of molecules identified through cell-based high-throughput screening programs. 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]. Further, delivery of these compounds to SMA mice significantly increased the mean life span (i.e., by ~21%-30%) [Butchbach et al 2010].

Neuroprotective and Other Approaches

Other small molecules that have been tested but did not show proven benefit in SMA include: gabapentin [Miller et al 2001], creatine [Wang et al 2007], and riluzole [Russman et al 2003]. Olesoxime (TRO19622), a novel neuroprotective molecule, is currently under investigation in SMA (NCT02628743). Finally, a novel troponin activator (CK-2127107) is currently in a Phase II trial for SMA (NCT02644668).

RNA-Based Therapy Approaches

Therapeutic approaches in this category aim to alter SMN2 splicing to increase the proportion of transcripts containing exon 7 and thus increase full-length SMN protein. Antisense oligonucleotides (ASOs) are single-stranded RNA molecules specifically designed to target complementary sequences in the SMN2 transcript leading to inclusion of exon 7. 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 25-fold. Encouraging pre-clinical data in SMA mouse models has subsequently led to a number of current clinical trials. Phase I and II open-label studies in SMA types I-III have shown that this drug could be delivered directly to the cerebral spinal fluid via lumbar puncture in this population with acceptable tolerability (NCT01494701, NCT01703988, NCT01839656). Thus, Ionis Pharmaceuticals has since completed enrollment for two Phase III trials of the ASO ISIS-SMNRx for the treatment of infants with SMA I (NCT02193074) and children with SMA II (NCT02292537). Results of these trials are not yet available. Finally, a trial in presymptomatic infants with genetically diagnosed SMA with this compound is also underway (NCT02386553).

At least two other SNM2 splicing modifiers are currently in clinical trials in SMA, including Novartis Pharmaceuticals LMI070 (NCT02268552) and Roche RG7916 (NCT02633709). Results of these trials are not yet available.

Gene Therapy

Gene replacement therapy with viral delivery of SMN1 is also under investigation in SMA. Foust and colleagues demonstrated that IV delivery of adeno-associated virus 9 (AAV9) carrying SMN1 on postnatal day 1 to SMA mice led to a normal life span (>400 days) compared with 16 days in the untreated mice [Foust et al 2010]. Based on these results, a Phase I trial of AAV9 containing SMN1 (AVXS-101), delivered intravenously to infants with type I SMA, was undertaken (NCT02122952).

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

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 (i.e., carriers of one SMN1 pathogenic variant).
  • About 2% of parents are not carriers of an SMN1 pathogenic variant, as their affected child has a de novo pathogenic variant [Wirth et al 1997]. The majority of de novo pathogenic variants are paternal in origin [Wirth et al 1997].
  • Heterozygotes are asymptomatic and are not at risk of developing the disorder.

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: Recurrence risk in sibs is the same (i.e., ~25%) if one parent of the proband has a [2+0] SMN1 genotype (see Carrier Detection) and the other parent has an SMN1 exon 7 deletion [1+0] or SMN1 intragenic variant.
  • Recurrence risk in sibs of a proband with one pathogenic variant known to have been inherited from a carrier parent and one apparently de novo pathogenic variant (i.e., one of the parents does not have an identifiable SMN1 pathogenic variant) is presumed to be low. However, due to the possibility that the parent in whom an SMN1 pathogenic variant was not identified has germline mosaicism for an SMN1 variant, these sibs should still be considered at risk for SMA [Campbell et al 1998].

Offspring of a proband

  • Only individuals with the milder forms of SMA are likely to reproduce. All of their offspring are carriers. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
  • 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 pathogenic variant). Thus, the risk to such a couple of having an affected child is one in 1340.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an SMN1 pathogenic variant.

Carrier (Heterozygote) Detection

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 a reproductive partner of known carrier.
    Note: In the general population most people have one copy of SMN1 on each chromosome ([1+1] configuration); however, about 5%-8% of the population have two copies of SMN1 on a single chromosome and a deletion on the other chromosome, known as a [2+0] configuration. Individuals with a [2+0] SMN1 configuration will have a false negative carrier screening result.

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]. These carrier individuals with two copies of SMN1 on one chromosome (a [2+0] genotype) are misdiagnosed as non-carriers by the SMN1 dosage test (i.e., a false negative test result).
    A specific haplotype block is associated with a [2+0] genotype in the Ashkenazi Jewish population [Luo et al 2014].
  • De novo deletion of exon 7 of one SMN1 allele occurs in 2% of individuals with SMA; thus, only one parent is a carrier.
  • In the United States pan ethnic population, the calculated a priori carrier frequency is 1/54 with a detection rate of 91.2%. Therefore, an individual from this pan ethnic population with normal SMN1 dosage testing would have a ~1/500 residual risk of being a carrier [Sugarman et al 2012].

Determining Carrier Status

In 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 deletion/duplication 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 variant 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 pathogenic variant identified in the child on the parent in whom the exon 7 deletion was not detected.
  • If the intragenic SMN1 variant 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 pathogenic variant.

In parents of a child with molecularly confirmed SMA who represents 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 pathogenic variant 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 pathogenic variant 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 pathogenic variant identified in the child should be performed on the parent in whom the exon 7 deletion was not detected.
  • If the intragenic SMN1 pathogenic variant is identified in the parent, carrier status is confirmed in that parent.
  • If the intragenic SMN1 pathogenic variant identified in the child is not identified in the parent, possible explanations include:
    • De novo intragenic SMN1 pathogenic variant in the child;
    • Germline mosaicism for the intragenic SMN1 pathogenic variant in the parent.

In 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 pathogenic variant).

Related Genetic Counseling Issues

Family planning

  • 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.

Prenatal Testing and Preimplantation Genetic Diagnosis

High-risk pregnancy. Once the SMN1 pathogenic variants in both parents are known or linkage has been established in the family, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for SMA [Moutou et al 2003, Malcov et al 2004] are possible.

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.

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].

Resources

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.

  • Cure SMA
    925 Busse Road
    Elk Grove Village IL 60007
    Phone: 800-886-1762 (toll-free)
    Email: familysupport@curesma.org
  • FightSMA
    8016 Staples Mill Road
    Richmond VA 23228-2713
    Phone: 703-299-1144
    Email: web@fightsma.org
  • Medline Plus
  • My46 Trait Profile
  • National Library of Medicine Genetics Home Reference
  • National Organization for Rare Disorders (NORD)
    55 Kenosia Avenue
    PO Box 1968
    Danbury CT 06813-1968
    Phone: 800-999-6673 (toll-free); 203-744-0100; 203-797-9590 (TDD)
    Fax: 203-798-2291
    Email: RN@rarediseases.org; genetic_counselor@rarediseases.org; orphan@rarediseases.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 communities
    1112 Montana Avenue
    #372
    Santa Monica CA 90403
    Phone: 310-260-3262
    Fax: 310-393-7154
    Email: deb@preventsma.org
  • Muscular Dystrophy Association - USA (MDA)
    222 South Riverside Plaza
    Suite 1500
    Chicago IL 60606
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • International SMA Patient Registry
    Indiana University School of Medicine, Department of Medical & Molecular Genetics
    410 West Tenth Street
    HS 4000
    Indianapolis IN 46202-3002
    Phone: 866-482-0248
    Fax: 317-278-1100
    Email: smareg@iupui.edu

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Spinal Muscular Atrophy: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Spinal Muscular Atrophy (View All in OMIM)

253300SPINAL MUSCULAR ATROPHY, TYPE I; SMA1
253400SPINAL MUSCULAR ATROPHY, TYPE III; SMA3
253550SPINAL MUSCULAR ATROPHY, TYPE II; SMA2
271150SPINAL MUSCULAR ATROPHY, TYPE IV; SMA4
600354SURVIVAL OF MOTOR NEURON 1; SMN1
601627SURVIVAL OF MOTOR NEURON 2; SMN2
602595GEM-ASSOCIATED PROTEIN 2; GEMIN2
603519SURVIVAL MOTOR NEURON DOMAIN-CONTAINING PROTEIN 1; SMNDC1

Molecular Genetic Pathogenesis

SMN1 produces a full-length survival motor neuron protein necessary for lower motor neuron function [Lefebvre et al 1995]. SMN2 predominantly produces a survival motor neuron protein that is lacking in exon 7, a less stable protein. SMA is caused by loss of SMN1 because SMN2 cannot fully compensate for loss of SMN1-produced protein. However, when the SMN2 (dosage) 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: SMN1 (telomeric copy, NM_000344.3) and SMN2 (centromeric copy, NM_017411.3).

  • 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 (5 intronic; 3 exonic, 1 each located within exons 6, 7, and 8) [Biros & Forrest 1999]. SMN1 and SMN2 share more than 99% nucleotide identity, and both are capable of encoding a 294-amino acid RNA-binding protein, SMN, which is required for efficient assembly of snRNP complexes.

For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Loss of SMN1 causes SMA. Individuals with SMA are either homozygous for a deletion of at least exon 7 of SMN1 or are compound heterozygous for such a deletion along with an intragenic SMN1 inactivating pathogenic variant. 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 (possible because of their high nucleotide identity).

Table 6.

SMN2 Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.859G>Cp.Gly287ArgNM_017411​.3
NP_059107​.1

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. 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]. 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]. SnRNPs and possibly other splicing components require regeneration from inactivated to activated functional forms. SMN is required for reassembly and regeneration of these splicing components [Pellizzoni et al 1998]. SMN accomplishes this in a modular way, bringing together several RNA-binding proteins with several RNAs, facilitating the assembly of specific proteins on the target RNAs.

The SMN protein has also been reported to influence other cellular activities such as apoptosis and translational regulation [Strasswimmer et al 1999, Lefebvre et al 2002, Vyas et al 2002]. SMN modulates apoptosis by blocking the activation of several caspases and other key regulators of cell survival [Anderton et al 2013]. SMN regulates translation by associating with polysomes, resulting in repression of translation [Sanchez et al 2013].

Abnormal gene product. SMA may be the result of a genetic defect in the biogenesis and trafficking of the spliceosomal snRNP complexes. Mutated SMN, such as that found in individuals with SMA, lacks the splicing-regeneration activity of wild-type SMN. Reduced SMN lowers the capacity of cells to assemble the snRNPs, which leads to altered levels of spliceosomal components and defects in splicing, and impaired capacity to produce specific mRNAs and their encoded proteins that are necessary for cellular growth and function. It remains unclear how a defect of splicing results in a motor neuron-specific disorder [Workman et al 2012].

References

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. American Society of Gene and Cell Therapy 19th Annual Meeting. 2007.

Literature Cited

  • Anderton RS, Meloni BP, Mastaglia FL, Boulos S. Spinal muscular atrophy and the antiapoptotic role of survival of motor neuron. Mol Neurobiol. 2013;47:821–32. [PubMed: 23315303]
  • 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]
  • Angelozzi C, Borgo F, Tiziano FD, Martella A, Neri G, Brahe C. Salbutamol increases SMN mRNA and protein levels in spinal muscular atrophy cells. J Med Genet. 2008;45:29–31. [PubMed: 17932121]
  • Anhuf D, Eggermann T, Rudnik-Schöneborn S, Zerres K. Determination of SMN1 and SMN2 copy number using TaqMan technology. Hum Mutat. 2003;22:74–8. [PubMed: 12815596]
  • Arkblad EL, Darin N, Berg K, Kimber E, Brandberg G, Lindberg C, Holmberg E, Tulinius M, Nordling M. Multiplex ligation-dependent probe amplification improves diagnostics in spinal muscular atrophy. Neuromuscul Disord. 2006;16:830–8. [PubMed: 17049859]
  • Biros I, Forrest S. Spinal muscular atrophy: untangling the knot? J Med Genet. 1999;36:1–8. [PMC free article: PMC1762953] [PubMed: 9950358]
  • Bowerman M, Swoboda KJ, Michalski JP, Wang GS, Reeks C, Beauvais A, Murphy K, Woulfe J, Screaton RA, Scott FW, Kothary R. Glucose metabolism and pancreatic defects in spinal muscular atrophy. Ann Neurol. 2012;72:256–68. [PMC free article: PMC4334584] [PubMed: 22926856]
  • Brahe C, Servidei S, Zappata S, Ricci E, Tonali P, Neri G. Genetic homogeneity between childhood-onset and adult-onset autosomal recessive spinal muscular atrophy. Lancet. 1995;346:741–2. [PubMed: 7658877]
  • Brahe C, Vitali T, Tiziano FD, Angelozzi C, Pinto AM, Borgo F, Moscato U, Bertini E, Mercuri E, Neri G. Phenylbutyrate increases SMN gene expression in spinal muscular atrophy patients. Eur J Hum Genet. 2005;13:256–9. [PubMed: 15523494]
  • Brichta L, Hofmann Y, Hahnen E, Siebzehnrubl FA, Raschke H, Blumcke I, Eyupoglu IY, Wirth B. Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy. Hum Mol Genet. 2003;12:2481–9. [PubMed: 12915451]
  • Bussaglia E, Clermont O, Tizzano E, Lefebvre S, Bürglen L, Cruaud C, Urtizberea JA, Colomer J, Munnich A, Baiget M, Melki J. A frame-shift deletion in the survival motor neuron gene in Spanish spinal muscular atrophy patients. Nat Genet. 1995;11:335–7. [PubMed: 7581461]
  • Butchbach ME, Rose FF Jr, Rhoades S, Marston J, McCrone JT, Sinnott R, Lorson CL. Effect of diet on the survival and phenotype of a mouse model for spinal muscular atrophy. Biochem Biophys Res Commun. 2010;391:835–40. [PMC free article: PMC2839161] [PubMed: 19945425]
  • Campbell L, Daniels RJ, Dubowitz V, Davies KE. Maternal mosaicism for a second mutational event in a type I spinal muscular atrophy family. Am J Hum Genet. 1998;63:37–44. [PMC free article: PMC1377239] [PubMed: 9634516]
  • 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]
  • Chang JG, Hsieh-Li HM, Jong YJ, Wang NM, Tsai CH, Li H. Treatment of spinal muscular atrophy by sodium butyrate. Proc Natl Acad Sci U S A. 2001;98:9808–13. [PMC free article: PMC55534] [PubMed: 11504946]
  • Chatwin M, Ross E, Hart N, Nickol AH, Polkey MI, Simonds AK. Cough augmentation with mechanical insufflation/exsufflation in patients with neuromuscular weakness. Eur Respir J. 2003;21:502–8. [PubMed: 12662009]
  • Chen TH, Chang JG, Yang YH, Mai HH, Liang WC, Wu YC, Wang HY, Huang YB, Wu SM, Chen YC, Yang SN, Jong YJ. Randomized, double-blind, placebo-controlled trial of hydroxyurea in spinal muscular atrophy. Neurology. 2010;75:2190–7. [PubMed: 21172842]
  • Chou SM, Gilbert EF, Chun RW, Laxova R, Tuffli GA, Sufit RL, Krassikot N. Infantile olivopontocerebellar atrophy with spinal muscular atrophy (infantile OPCA + SMA). Clin Neuropathol. 1990;9:21–32. [PubMed: 2407400]
  • Clermont O, Burlet P, Lefebvre S, Bürglen L, Munnich A, Melki J. SMN gene deletions in adult-onset spinal muscular atrophy. Lancet. 1995;346:1712–3. [PubMed: 8551862]
  • Dubowitz V. Very severe spinal muscular atrophy (SMA type 0): an expanding clinical phenotype. Eur J Paediatr Neurol. 1999;3:49–51. [PubMed: 10700538]
  • Finkel RS, McDermott MP, Kaufmann P, Darras BT, Chung WK, Sproule DM, Kang PB, Foley AR, Yang ML, Martens WB, Oskoui M, Glanzman AM, Flickinger J, Montes J, Dunaway S, O'Hagen J, Quigley J, Riley S, Benton M, Ryan PA, Montgomery M, Marra J, Gooch C, De Vivo DC. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology. 2014;83:810–7. [PMC free article: PMC4155049] [PubMed: 25080519]
  • Fischer U, Liu Q, Dreyfuss G. The SMN-SIP1 complex has an essential role in spliceosomal snRNP biogenesis. Cell. 1997;90:1023–9. [PubMed: 9323130]
  • Foust KD, Wang X, McGovern VL, Braun L, Bevan AK, Haidet AM, Le TT, Morales PR, Rich MM, Burghes AH, Kaspar BK. Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN. Nat Biotechnol. 2010;28:271–4. [PMC free article: PMC2889698] [PubMed: 20190738]
  • Guenther UP, Varon R, Schlicke M, Dutrannoy V, Volk A, Hübner C, von Au K, Schuelke M. Clinical and mutational profile in spinal muscular atrophy with respiratory distress (SMARD): defining novel phenotypes through hierarchical cluster analysis. Hum Mutat. 2007;28:808–15. [PubMed: 17431882]
  • Hahnen E, Schonling J, Rudnik-Schöneborn S, Raschke H, Zerres K, Wirth B. Missense mutations in exon 6 of the survival motor neuron gene in patients with spinal muscular atrophy (SMA). Hum Mol Genet. 1997;6:821–5. [PubMed: 9158159]
  • Hao T, Wolman M, Granato M, Beattie CE. Survival motor neuron affects plastin 3 protein levels leading to motor defects. J Neurosci. 2012;32:5074–84. [PMC free article: PMC3355766] [PubMed: 22496553]
  • Hoffmann J. Familial spinal muscular atrophy in infancy (article in German). Dtsch Z Nervenheilkd. 1892;3:427–70.
  • Hua Y, Sahashi K, Rigo F, Hung G, Horev G, Bennett CF, Krainer AR. 2010. Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model. Nature. 2011;478:123–6. [PMC free article: PMC3191865] [PubMed: 21979052]
  • Jarecki J, Chen X, Bernardino A, Coovert DD, Whitney M, Burghes A, Stack J, Pollok BA. Diverse small-molecule modulators of SMN expression found by high-throughput compound screening: early leads towards a therapeutic for spinal muscular atrophy. Hum Mol Genet. 2005;14:2003–18. [PubMed: 15944201]
  • Kelley RI, Sladky JT. Dicarboxylic aciduria in an infant with spinal muscular atrophy. Ann Neurol. 1986;20:734–6. [PubMed: 3813501]
  • Kinali M, Mercuri E, Main M, De Biasia F, Karatza A, Higgins R, Banks LM, Manzur AY, Muntoni F. Pilot trial of albuterol in spinal muscular atrophy. Neurology. 2002;59:609–10. [PubMed: 12196659]
  • Kugelberg E, Welander L. Heredofamilial juvenile muscular atrophy simulating muscular dystrophy. AMA Arch Neurol Psychiatry. 1956;75:500–9. [PubMed: 13312732]
  • La Rosa G, Oggiano L, Ruzzini L. Magnetically controlled growing rods for the management of early-onset scoliosis: a preliminary report. J Pediatr Orthop. 2017;37:79–85. [PubMed: 26192879]
  • Lefebvre S, Bürglen L, Reboullet S, Clermont O, Burlet P, Viollet L, Benichou B, Cruaud C, Millasseau P, Zeviani M, Le Paslier D, Frézal J, Cohen D, Weissenbach J, Munnich A, Melki J. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80:155–65. [PubMed: 7813012]
  • Lefebvre S, Burlet P, Viollet L, Bertrandy S, Huber C, Belser C, Munnich A. A novel association of the SMN protein with two major non-ribosomal nucleolar proteins and its implication in spinal muscular atrophy. Hum Mol Genet. 2002;11:1017–27. [PubMed: 11978761]
  • Liu Q, Dreyfuss G. A novel nuclear structure containing the survival of motor neurons protein. EMBO J. 1996;15:3555–65. [PMC free article: PMC451956] [PubMed: 8670859]
  • Liu Q, Fischer U, Wang F, Dreyfuss G. The spinal muscular atrophy disease gene product, SMN, and its associated protein SIP1 are in a complex with spliceosomal snRNP proteins. Cell. 1997;90:1013–21. [PubMed: 9323129]
  • Luo M, Liu L, Peter I, Zhu J, Scott SA, Zhao G, Eversley C, Kornreich R, Desnick RJ, Edelmann L. An Ashkenazi Jewish SMN1 haplotype specific to duplication alleles improves pan-ethnic carrier screening for spinal muscular atrophy. Genet Med. 2014;16:149–56. [PubMed: 23788250]
  • MacLeod MJ, Taylor JE, Lunt PW, Mathew CG, Robb SA. Prenatal onset spinal muscular atrophy. Eur J Paediatr Neurol. 1999;3:65–72. [PubMed: 10700541]
  • Mailman MD, Heinz JW, Papp AC, Snyder PJ, Sedra MS, Wirth B, Burghes AH, Prior TW. Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2. Genet Med. 2002;4:20–6. [PubMed: 11839954]
  • Malcov M, Schwartz T, Mei-Raz N, Yosef DB, Amit A, Lessing JB, Shomrat R, Orr-Urtreger A, Yaron Y. Multiplex nested PCR for preimplantation genetic diagnosis of spinal muscular atrophy. Fetal Diagn Ther. 2004;19:199–206. [PubMed: 14764971]
  • McAndrew PE, Parsons DW, Simard LR, Rochette C, Ray PN, Mendell JR, Prior TW, Burghes AH. Identification of proximal spinal muscular atrophy carriers and patients by analysis of SMNT and SMNC gene copy number. Am J Hum Genet. 1997;60:1411–22. [PMC free article: PMC1716150] [PubMed: 9199562]
  • Mercuri E, Bertini E, Messina S, Solari A, D'Amico A, Angelozzi C, Battini R, Berardinelli A, Boffi P, Bruno C, Cini C, Colitto F, Kinali M, Minetti C, Mongini T, Morandi L, Neri G, Orcesi S, Pane M, Pelliccioni M, Pini A, Tiziano FD, Villanova M, Vita G, Brahe C. Randomized, double-blind, placebo-controlled trial of phenylbutyrate in spinal muscular atrophy. Neurology. 2007;68:51–5. [PubMed: 17082463]
  • Miller RG, Moore DH, Dronsky V, Bradley W, Barohn R, Bryan W, Prior TW, Gelinas DF, Iannaccone S, Kissel J, Leshner R, Mendell J, Mendoza M, Russman B, Samaha F, Smith S. A placebo-controlled trial of gabapentin in spinal muscular atrophy. J Neurol Sci. 2001;191:127–31. [PubMed: 11677003]
  • Miske LJ, Hickey EM, Kolb SM, Weiner DJ, Panitch HB. Use of the mechanical in-exsufflator in pediatric patients with neuromuscular disease and impaired cough. Chest. 2004;125:1406–12. [PubMed: 15078753]
  • Mostacciuolo ML, Danieli GA, Trevisan C, Muller E, Angelini C. Epidemiology of spinal muscular atrophies in a sample of the Italian population. Neuroepidemiology. 1992;11:34–8. [PubMed: 1608493]
  • Moutou C, Gardes N, Viville S. Duplex PCR for preimplantation genetic diagnosis (PGD) of spinal muscular atrophy. Prenat Diagn. 2003;23:685–9. [PubMed: 12913876]
  • Munsat T, Davies K. Spinal muscular atrophy. 32nd ENMC International Workshop. Naarden, The Netherlands, 10-12 March 1995. Neuromuscul Disord. 1996;6:125–7. [PubMed: 8664564]
  • Ogino S, Wilson RB. Genetic testing and risk assessment for spinal muscular atrophy (SMA). Hum Genet. 2002;111:477–500. [PubMed: 12436240]
  • Oprea GE, Krober S, Mcwhorter ML, Rossoll W, Muller S, Krawczak S, Bassell GJ, Beattie CE, Wirth B. Plastin 3 is a protective modifier os autosomal recessive spinal muscular atrophy. Science. 2008;320:524–7. [PMC free article: PMC4908855] [PubMed: 18440926]
  • Oskoui M, Levy G, Garland CJ, Gray JM, O'Hagen J, De Vivo DC, Kaufmann P. The changing natural history of spinal muscular atrophy type 1. Neurology. 2007;69:1931–6. [PubMed: 17998484]
  • Pane M, Staccioli S, Messina S, D'Amico A, Pelliccioni M, Mazzone ES, Cuttini M, Alfieri P, Battini R, Main M, Muntoni F, Bertini E, Villanova M, Mercuri E. Daily salbutamol in young patients with SMA type II. Neuromuscul Disord. 2008;18:536–40. [PubMed: 18579379]
  • Parsons DW, McAndrew PE, Iannaccone ST, Mendell JR, Burghes AH, Prior TW. Intragenic telSMN mutations: frequency, distribution, evidence of a founder effect, and modification of the spinal muscular atrophy phenotype by cenSMN copy number. Am J Hum Genet. 1998;63:1712–23. [PMC free article: PMC1377643] [PubMed: 9837824]
  • Parsons DW, McAndrew PE, Monani UR, Mendell JR, Burghes AH, Prior TW. An 11 base pair duplication in exon 6 of the SMN gene produces a type I spinal muscular atrophy (SMA) phenotype: further evidence for SMN as the primary SMA-determining gene. Hum Mol Genet. 1996;5:1727–32. [PubMed: 8922999]
  • Pearn J. Incidence, prevalence, and gene frequency studies of chronic childhood spinal muscular atrophy. J Med Genet. 1978;15:409–13. [PMC free article: PMC1013753] [PubMed: 745211]
  • Pellizzoni L, Kataoka N, Charroux B, Dreyfuss G. A novel function for SMN, the spinal muscular atrophy disease gene product, in pre-mRNA splicing. Cell. 1998;95:615–24. [PubMed: 9845364]
  • Petrone A, Pavone M, Testa MB, Petreschi F, Bertini E, Cutrera R. Noninvasive ventilation in children with spinal muscular atrophy types 1 and 2. Am J Phys Med Rehabil. 2007;86:216–21. [PubMed: 17314706]
  • Prior TW, Krainer AR, Hua Y, Swoboda KJ, Snyder PC, Bridgeman SJ, Burghes AH, Kissel JT. A positive modifier of spinal muscular atrophy in the SMN2 gene. Am J Hum Genet. 2009;85:408–13. [PMC free article: PMC2771537] [PubMed: 19716110]
  • Prior TW, Swoboda KJ, Scott HD, Hejmanowski AQ. Homozygous SMN1 deletions in unaffected family members and modification of the phenotype by SMN2. Am J Med Genet A. 2004;130A:307–10. [PMC free article: PMC4349519] [PubMed: 15378550]
  • Russman BS, Iannaccone ST, Samaha FJ. A phase 1 trial of riluzole in spinal muscular atrophy. Arch Neurol. 2003;60:1601–3. [PubMed: 14623733]
  • Sanchez G, Dury AY, Murray LM, Biondi O, Tadesse H, El Fatimy R, Kothary R, Charbonnier F, Khandjian EW, Cote J. A novel function for the survival motorneuron protein as a translational regulator. Hum mol Genet. 2013;22:668–84. [PubMed: 23136128]
  • Scarciolla O, Stuppia L, De Angelis MV, Murru S, Palka C, Giuliani R, Pace M, Di Muzio A, Torrente I, Morella A, Grammatico P, Giacanelli M, Rosatelli MC, Uncini A, Dallapiccola B. Spinal muscular atrophy genotyping by gene dosage using multiple ligation-dependent probe amplification. Neurogenetics. 2006;7:269–76. [PubMed: 16865356]
  • Soler-Botija C, Cusco I, Caselles L, Lopez E, Baiget M, Tizzano EF. Implication of fetal SMN2 expression in type I SMA pathogenesis: protection or pathological gain of function? J Neuropathol Exp Neurol. 2005;64:215–23. [PubMed: 15804053]
  • Sporer SM, Smith BG. Hip dislocation in patients with spinal muscular atrophy. J Pediatr Orthop. 2003;23:10–4. [PubMed: 12499935]
  • Strasswimmer J, Lorson CL, Breiding DE, Chen JJ, Le T, Burghes AH, Androphy EJ. Identification of survival motor neuron as a transcriptional activator-binding protein. Hum Mol Genet. 1999;8:1219–26. [PubMed: 10369867]
  • Sugarman EA, Nagan N, Zhu H, Akmaev VR, Zhou Z, Rohlfs EM, Flynn K, Hendrickson BC, Scholl T, Sirko-Osadsa DA, Allitto BA. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens. Eur J Hum Genet. 2012;20:27–32. [PMC free article: PMC3234503] [PubMed: 21811307]
  • Sumner CJ, Huynh TN, Markowitz JA, Perhac JS, Hill B, Coovert DD, Schussler K, Chen X, Jarecki J, Burghes AH, Taylor JP, Fischbeck KH. Valproic acid increases SMN levels in spinal muscular atrophy patient cells. Ann Neurol. 2003;54:647–54. [PubMed: 14595654]
  • Swoboda KJ, Prior TW, Scott CB, McNaught TP, Wride MC, Reyna SP, Bromberg MB. Natural history of denervation in SMA: relation to age, SMN2 copy number, and function. Ann Neurol. 2005;57:704–12. [PMC free article: PMC4334582] [PubMed: 15852397]
  • Swoboda KJ. Seize the day: Newborn screening for SMA. Am J Med Genet A. 2010;152A:1605–7. [PubMed: 20583173]
  • Talbot K, Ponting CP, Theodosiou AM, Rodrigues NR, Surtees R, Mountford R, Davies KE. Missense mutation clustering in the survival motor neuron gene: a role for a conserved tyrosine and glycine rich region of the protein in RNA metabolism? Hum Mol Genet. 1997;6:497–500. [PubMed: 9147655]
  • Thieme A, Mitulla B, Schulze F, Spiegler AW. Epidemiological data on Werdnig-Hoffmann disease in Germany (West-Thuringen). Hum Genet. 1993;91:295–7. [PubMed: 8478016]
  • Vyas S, Bechade C, Riveau B, Downward J, Triller A. Involvement of survival motor neuron (SMN) protein in cell death. Hum Mol Genet. 2002;11:2751–64. [PubMed: 12374765]
  • 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. J Child Neurol. 2007;22:1027–49. [PubMed: 17761659]
  • Werdnig G. Two early infantile hereditary cases of progressive muscular atrophy simulating dystrophy, but on a neural basis. 1891. Arch Neurol. 1971;25:276–8. [PubMed: 4952838]
  • Wirth B. An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy. Hum Mutat. 2000;15:228–37. [PubMed: 10679938]
  • Wirth B, Schmidt T, Hahnen E, Rudnik-Schöneborn S, Krawczak M, Muller-Myhsok B, Schonling J, Zerres K. De novo rearrangements found in 2% of index patients with spinal muscular atrophy: mutational mechanisms, parental origin, mutation rate, and implications for genetic counseling. Am J Hum Genet. 1997;61:1102–11. [PMC free article: PMC1716038] [PubMed: 9345102]
  • Workman E, Kolb SJ, Battle DJ. Spliceosomal small nuclear ribonucleoprotein biogenesis defects and motor neuron selectivity in spinal muscular atrophy. Brain Res. 2012;1462:93–9. [PMC free article: PMC3448484] [PubMed: 22424789]
  • Yamashita M, Nishio H, Harada Y, Matsuo M, Yamamoto T. Significant increase in the number of the SMN2 gene copies in an adult-onset Type III spinal muscular atrophy patient with homozygous deletion of the NAIP gene. Eur Neurol. 2004;52:101–6. [PubMed: 15305106]
  • Yohannan M, Patel P, Kolawole T, Malabarey T, Mahdi A. Brain atrophy in Werdnig-Hoffmann disease. Acta Neurol Scand. 1991;84:426–8. [PubMed: 1776391]
  • Zerres K, Rudnik-Schöneborn S, Forrest E, Lusakowska A, Borkowska J, Hausmanowa-Petrusewicz I. A collaborative study on the natural history of childhood and juvenile onset proximal spinal muscular atrophy (type II and III SMA): 569 patients. J Neurol Sci. 1997;146:67–72. [PubMed: 9077498]
  • Zheleznyakova GY, Kiselev AV, Vakharlovsky VG, Rask-Anderson M, Chavan R, Egorova AA, Schioth HB, Baranov VS. Genetic and expression studies of SMN2 gene in Russian patients with spinal muscular atrophy type II and III. BMC Med Genet. 2011;12:96. [PMC free article: PMC3146920] [PubMed: 21762474]

Suggested Reading

  • Bove KE, Iannaccone ST. Atypical infantile spinomuscular atrophy presenting as acute diaphragmatic paralysis. Pediatr Pathol. 1988;8:95–107. [PubMed: 3399458]
  • Bromberg MB, Swoboda KJ. Motor unit number estimation in infants and children with spinal muscular atrophy. Muscle Nerve. 2002;25:445–7. [PMC free article: PMC4334581] [PubMed: 11870724]
  • Burghes AH. When is a deletion not a deletion? When it is converted. Am J Hum Genet. 1997;61:9–15. [PMC free article: PMC1715883] [PubMed: 9245977]
  • Escolar DM, Henricson EK, Mayhew J, Florence J, Leshner R, Patel KM, Clemens PR. Clinical evaluator reliability for quantitative and manual muscle testing measures of strength in children. Muscle Nerve. 2001;24:787–93. [PubMed: 11360262]
  • Kaufmann P, Muntoni F., International Coordinating Committee for SMA Subcommittee on SMA Clinical Trial Design. Issues in SMA clinical trial design. The International Coordinating Committee (ICC) for SMA Subcommittee on SMA Clinical Trial Design. Neuromuscul Disord. 2007;17:499–505. [PMC free article: PMC3250230] [PubMed: 17300938]
  • Lunn MR, Wang CH. Spinal muscular atrophy. Lancet. 2008;371:2120–33. [PubMed: 18572081]
  • Main M, Kairon H, Mercuri E, Muntoni F. The Hammersmith functional motor scale for children with spinal muscular atrophy: a scale to test ability and monitor progress in children with limited ambulation. Eur J Paediatr Neurol. 2003;7:155–9. [PubMed: 12865054]
  • Nelson L, Owens H, Hynan LS, Iannaccone ST. AmSMART Group. The gross motor function measure is a valid and sensitive outcome measure for spinal muscular atrophy. Neuromuscul Disord. 2006;16:374–80. [PubMed: 16632361]
  • Vital A, Vital C, Coquet M, Hernandorena X, Demarquez JM. Congenital hypomyelination with axonopathy. Eur J Pediatr. 1989;148:470–2. [PubMed: 2920756]
  • Wirth B, Rudnik-Schöneborn S, Hahnen E, Rohrig D, Zerres K. Prenatal prediction in families with autosomal recessive proximal spinal muscular atrophy (5q11.2-q13.3): molecular genetics and clinical experience in 109 cases. Prenat Diagn. 1995;15:407–17. [PubMed: 7644431]
  • Zerres K, Rudnik-Schöneborn S. Natural history in proximal spinal muscular atrophy. Clinical analysis of 445 patients and suggestions for a modification of existing classifications. Arch Neurol. 1995;52:518–23. [PubMed: 7733848]
  • Zerres K, Rudnik-Schöneborn S, Forkert R, Wirth B. Genetic basis of adult-onset spinal muscular dystrophy. Lancet. 1995;346:1162. [PubMed: 7475624]

Chapter Notes

Revision History

Erika Finanger, MD (2016-present)
Thomas W Prior, PhD, FACMG (2000-present)
Barry S Russman, MD; Oregon Health and Science University (2000-2016)

Revision History

  • 22 December 2016 (sw) Comprehensive update posted live
  • 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
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