Clinical characteristics.

Spinal muscular atrophy (SMA) is characterized by muscle weakness and atrophy resulting from progressive degeneration and irreversible 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 adulthood. The weakness is symmetric, proximal > distal, and progressive. Before the genetic basis of SMA was understood, it was classified into clinical subtypes based on maximum motor function achieved; however, it is now apparent that the phenotype of SMN1-associated SMA spans a continuum without clear delineation of subtypes. With supportive care only, poor weight gain with growth failure, restrictive lung disease, scoliosis, and joint contractures are common complications; however, newly available targeted treatment options are changing the natural history of this disease.

Diagnosis/testing.

The diagnosis of SMA is established in a proband with a history of motor difficulties or regression, proximal muscle weakness, reduced/absent deep tendon reflexes, evidence of motor unit disease, AND/OR by the identification of biallelic pathogenic variants in SMN1 on molecular genetic testing. Increases in SMN2 copy number often modify the phenotype.

Management.

Treatment of manifestations: Therapies targeted to the underlying disease mechanism include nusinersen (Spinraza^®; an antisense oligonucleotide) for the treatment of all types of SMA and onasemnogene abeparvovec-xioi (Zolgensma^®; gene replacement therapy) for the treatment of type I SMA. These targeted treatments may prevent the development or slow the progression of some features of SMA; efficacy is improved when treatment is initiated before symptom onset. It is unclear what the long-term effect of these treatments will be or if new phenotypes will arise in treated individuals.

Proactive supportive treatment by a multidisciplinary team is essential to reduce symptom severity, particularly in the most severe cases of SMA. When nutrition or dysphagia is a concern, placement of a gastrostomy tube early in the course of the disease is appropriate. Standard therapy for gastroesophageal reflux disease and chronic constipation. Formal consultation and frequent follow up with a pulmonologist familiar with SMA is necessary. As respiratory function deteriorates, tracheotomy or noninvasive respiratory support may be offered. Surgical repair for scoliosis should be considered based on progression of the curvature, pulmonary function, and bone maturity. Surgical intervention for hip dislocation for those with pain.

Surveillance: Presymptomatic individuals require monitoring for the development of symptoms to determine appropriate timing to initiate targeted and/or supportive therapies. Multidisciplinary evaluation every six months or more frequently for weaker children is indicated to assess nutritional state, respiratory function, motor function, and orthopedic status, and to determine appropriate interventions.

Agents/circumstances to avoid: Prolonged fasting, particularly in the acutely ill infant with SMA.

Evaluation of relatives at risk: It is appropriate to determine the genetic status of younger, apparently asymptomatic sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of targeted treatment.

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.

Suggestive Findings

Scenario 1. Abnormal newborn screening (NBS) result

• NBS for spinal muscular atrophy (SMA) is primarily based on real-time PCR that detects the common SMN1 deletion and may also detect SMN2 copy number on dried blood spots [Chien et al 2017].
• Follow-up molecular genetic testing confirmation of a positive NBS result is recommended (see Establishing the Diagnosis).

Scenario 2. Symptomatic individual who has EITHER atypical findings associated with later-onset SMA OR infantile-onset SMA that has not been treated (either because NBS was not performed or because it yielded a false negative result)

• History of motor difficulties, especially with loss of skills
• Proximal > distal muscle weakness
• Hypotonia
• Areflexia/hyporeflexia
• Tongue fasciculations
• Hand tremor
• Recurrent lower respiratory tract infections or severe bronchiolitis in the first few months of life
• Evidence of motor unit disease on electromyogram

Establishing the Diagnosis

The diagnosis of SMA is established in a proband with a history of motor difficulties or regression, proximal muscle weakness, reduced/absent deep tendon reflexes, and evidence of motor unit disease; AND/OR by identification of biallelic pathogenic variants in SMN1 on molecular genetic testing (see Table 1). Increases in SMN2 copy number often modify the phenotype.

Molecular Genetic Testing Approaches

Scenario 1. Abnormal newborn screening (NBS) result

When NBS results suggest the diagnosis of SMA, confirmatory molecular genetic testing typically includes single-gene testing. Gene-targeted deletion/duplication analysis to determine the dosage of SMN1 is performed first for the SMN1 exon 7. If one copy of SMN1 exon 7 is present, 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).

See Figure 1 for a summary of the diagnostic algorithm for SMA as published by Mercuri et al [2018].

Figure 1.

Diagnostic algorithm for SMA

Scenario 2. A symptomatic individual with findings associated with later-onset SMA or untreated infantile-onset SMA (resulting from NBS not performed or false negative NBS result)

Molecular genetic testing approaches can include single-gene testing (see above) or use of a multigene panel that includes SMN1, SMN2, and other genes of interest (see Differential Diagnosis). Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change 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 this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in Spinal Muscular Atrophy

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Type of Testing	Gene 1	Proportion of SMA Attributed to Pathogenic Variants in Gene	Proportion of Pathogenic Variants 2 Detectable by Method
			Sequence analysis 3	Gene-targeted deletion/ duplication analysis 4
Diagnostic, carrier, prenatal	SMN1	~100%	2%-5% 5	95%-98% 6, 7
Prognostic	SMN2	NA	NA	See footnote 8.

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. 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 used may 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.

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]

7.

False negatives may occur because 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 of sub-Saharan African heritage have a higher proportion of the [2+0] configuration [Verhaart et al 2017] (see Carrier Detection, Interpretation of the results of carrier testing).

8.

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 Description

SMA is characterized by muscle weakness and atrophy resulting from progressive degeneration and irreversible 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 adulthood. The weakness is symmetric, proximal greater than distal, 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 SMN1 pathogenic variants spans a broad continuum without clear delineation of subtypes. Newly approved treatment options (see Management, Treatment of Manifestations, Table 7) are changing the natural history of SMA phenotypes and blurring the boundaries even further [Tizzano & Finkel 2017]. Nonetheless, the existing classification system (Table 2) based on age of onset and maximum function attained with supportive care only is useful for prognosis and management.

SMA 0 presents with severe weakness, hypotonia, and respiratory distress at birth. There may be a history of decreased in utero movements, joint contractures, and atrial septal defects. Infants with SMA type 0 have severe respiratory compromise/failure and, with supportive care only, rarely survive past age six months [Dubowitz 1999, MacLeod et al 1999]. There have not been any published reports of infants with SMA 0 who have been treated with nusinersen or gene therapy (see Table 7).

SMA I manifests as marked weakness and developmental motor regression before age six months. The mean age of symptom onset is 2.5 months [Lin et al 2015]. Infants may acquire head control and ability to roll, but quickly lose these abilities. With supportive care only, affected children do not achieve the ability to sit independently. Proximal, symmetric muscle weakness, lack of motor development with regression of motor function, reduced or absent deep tendon reflexes, and poor muscle tone are the major clinical manifestations. Mild contractures are often noted at the knees and, rarely, at the elbows.

With supportive care only, fasciculation of the tongue is seen in most but not all infants. While the muscles of the face are relatively spared at initial presentation, bulbar weakness is present in the neonatal period or during the first few months, and infants frequently 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 diaphragm is not involved until late in the course of disease. Cognitive function is normal. Severe symptomatic bradycardia has been noted in a study of the long-term survival of ventilator-dependent individuals with SMA I [Bach 2007].

With supportive care only, prospective studies of children with SMA I have shown median survival of 24 months [Oskoui et al 2007]; however, more recent studies have shown a median time to either death or >16 hours/day of ventilation of 8-13.5 months [Finkel et al 2014, Kolb et al 2017]. With proactive respiratory and nutritional supportive care, survival is improving [Grychtol et al 2018]. Promising new treatments are changing the natural history of SMA I, particularly when treatment is initiated before onset of symptoms (see Table 7).

SMA II usually manifests between ages six and 12 months; the mean age of symptom onset is 8.3 months [Lin et al 2015]. 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 until about age five years. With supportive care only, the maximum motor milestone attained is the ability to sit independently when placed. Affected individuals then have a slow decline in motor function and on average lose the ability to sit independently by the mid-teens [Mercuri et al 2016]. Hand tremor is common. Deep tendon reflexes are decreased to absent. Scoliosis is common with progression of disease. Cognition is normal. Cardiac abnormalities are unlikely to develop [Finkel et al 2018]. Progressive respiratory muscle weakness leads to restrictive lung disease that is associated with morbidity and mortality in these individuals.

With supportive care only, the life expectancy of persons with SMA II is not known with certainty. A review of life expectancy of 240 individuals with SMA II from Germany and Poland found that 68% of individuals with SMA II were alive at age 25 years [Zerres et al 1997]. The ability to stand is directly correlated with better pulmonary function and long-term survival. This natural history, however, will likely be improved by newer treatments (see Table 7).

SMA III typically manifests after age 18 months with a mean age of onset of 39 months ± 32.6 months [Lin et al 2015]. The legs are more severely affected than the arms. With supportive care only, individuals walk independently but proximal muscle weakness may lead to more frequent falls or trouble walking up and down stairs. Fatigue can adversely affect quality of life and function significantly.

Most children with SMA III treated only with supportive care make gains in their motor function until about age six years and then experience a slow decline in function until about puberty. Puberty (until age ~20) may be associated with a more rapid decline in function for adolescents with SMA III.

With supportive care only, adulthood is then associated with another, much slower decline in function [Montes et al 2018]. Although individuals with SMA III develop the ability to walk, the vast majority will lose that ability with time. If symptom onset is before age three years, loss of ambulation typically occurs in the second decade. However, if symptom onset is between ages three and 12 years, loss of ambulation may occur in the fourth decade [Wadman et al 2017]. Individuals with SMA III have little to no respiratory muscle weakness. Cardiac and cognitive functions are normal. In a retrospective study of individuals with SMA, the life expectancy of 329 individuals with SMA III from Germany and Poland treated only with supportive care was not different from that of the general population [Zerres et al 1997]. This natural history, however, will likely be improved by newer treatments (see Table 7).

SMA IV typically presents with muscle weakness in the second or third decade of life. There is a specific pattern of muscle involvement, with weakness disproportionately affecting the deltoids, triceps, and quadriceps. There may be a loss of patellar reflexes, with sparing of the deep tendon reflexes in the upper extremities and Achilles. Individuals may have a hand tremor. Cardiac and cognitive functioning is normal. With supportive care only, findings are similar to but less severe than those described for SMA III, and if loss of ambulation occurs, it may be after the fifth decade [Brahe et al 1995, Clermont et al 1995, Zerres et al 1997, Wadman et al 2017]. Life expectancy is normal. SMA IV is the least common form of SMA and affects fewer than 5% of individuals with SMA [Kolb et al 2017].

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. Small amounts (up to a quarter) of full-length transcripts generated by SMN2 produce functional protein and result in the milder SMA II or SMA III phenotype. 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 two copies of SMN2 is approximately 80% predictive of the SMA I phenotype, whereas the presence of four or more copies of SMN2 is approximately 88% predictive of achieving the ability to ambulate with supportive care only (SMA III/IV) [Calucho et al 2018]. Modifying factors that are not fully understood are likely to contribute to the variability in clinical severity, as can be easily demonstrated with individuals who have three copies of SMN2. Data from Calucho et al [2018] are summarized in Table 3.

Other putative modifiers of SMA phenotype

• A single-base substitution – c.859G>C (p.Gly287Arg) – in exon 7 of SMN2 has been identified as a disease modifier resulting in a milder disease [Prior et al 2009]. This substitution creates a new exon splicing enhancer (ESE) element. The new ESE increased the amount of exon 7 inclusion and number of full-length transcripts generated from SMN2.
• In some rare families with unaffected females who have biallelic SMN1 deletions, 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].

Nomenclature

SMA I was previously known as Werdnig-Hoffmann disease or acute SMA [Hoffmann 1892, Werdnig 1971].

SMA II was called chronic SMA or Dubowitz disease prior to the current classification.

SMA III has had the eponym "Kugelberg-Welander disease" and has also been referred to as juvenile SMA [Kugelberg & Welander 1956].

SMA IV may also be referred to as adolescent- or adult-onset SMA.

Prevalence

The exact prevalence of SMA is unknown. Historical studies evaluating the prevalence of SMA were limited by lack of genetic confirmation and may underestimate the prevalence of more severe phenotypes due to the shortened life span. It has been suggested that the overall prevalence of SMA is between one and two per 100,000 people [Verhaart et al 2017]. In regions or groups with high consanguinity rates, the incidence of SMA can be higher.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with SMA, the affected individual should be referred to a multidisciplinary clinic.

Regardless of SMA subtype, clinical care should be based on an individual's current functional status. Issues to consider are listed in Table 6.

Treatment of Manifestations

Currently, there is no cure for SMA. Two treatment options that are targeted to the underlying mechanism that leads to SMA have become available and have been shown to have a positive effect on disease progression (see Table 7). These treatments are likely to also have a positive impact on the natural history of SMA [Finkel et al 2017, Mendell et al 2017, Finkel et al 2018, Mercuri et al 2018], particularly if treatment is initiated prior to symptom onset.

The decision of when to initiate targeted therapy after detection of an affected individual via newborn screening relies on genotype and presence of symptoms [Glascock et al 2018]. After confirmatory SMN1 genetic testing:

• Targeted treatment is recommended for all individuals who have two or three copies of SMN2, regardless of whether symptoms are present;
• For individuals who have one copy of SMN2, targeted treatment is left to the discretion of the treating physician, taking into account the severity of symptoms, which may have been present prenatally or at birth;
• For individuals with four or more copies of SMN2, targeted treatment can be deferred until symptom onset, although careful monitoring for the development of symptoms by a neuromuscular expert is recommended.

Supportive treatment of children with SMA is guided by the underlying subtype but should be individualized to the affected individual and his/her current functional status (nonsitter, sitter, or walker) [Finkel et al 2018]. The proportion of affected individuals who develop a given complication and the severity of the complication depends on which subtype of SMA is involved and whether targeted treatment is initiated before or after symptom onset [Shorrock et al 2018] (see Table 8).

Prevention of Primary Manifestations

See Table 7.

Surveillance

Presymptomatic individuals should be monitored for the development of symptoms to determine appropriate timing to initiate targeted and/or supportive therapies. A treatment algorithm for the evaluation of presymptomatic infants has been published [Glascock et al 2018].

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

Multidisciplinary surveillance at each visit includes assessments of nutritional state, respiratory function, and orthopedic status (spine, hips, and joint range of motion).

Agents/Circumstances to Avoid

Prolonged fasting should be avoided, particularly in the acutely ill infant with SMA [Mercuri et al 2018].

Evaluation of Relatives at Risk

It is appropriate to determine the genetic status of younger, apparently asymptomatic sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of targeted treatment and preventive measures.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

There have been two published studies surveying the pregnancy experience of women with SMA [Awater et al 2012, Elsheikh et al 2017] as well as an international workshop on pregnancy in neuromuscular disorders [Norwood & Rudnik-Schöneborn 2012]. From the collective experience, it appears that women with SMA may have an increased rate of preterm birth (27%) and need for cesarean section (41%) [Awater et al 2012, Elsheikh et al 2017] compared to unaffected women. While local anesthesia is preferred to general anesthesia in women with SMA, an epidural can be difficult in people with severe scoliosis or spinal fusions [Awater et al 2012, Finkel et al 2018]. Women with SMA may also experience a persistent worsening of their general muscle weakness after delivery (32%) [Awater et al 2012, Elsheikh et al 2017]. Severe respiratory distress with maternal hypercapnia and hypoxemia was attributed to one stillbirth at 26 weeks' gestation [Awater et al 2012]. Due to the risk of respiratory failure, it is recommended that women with neuromuscular disorders, including those with SMA, obtain baseline pulmonary function prior to becoming pregnant, with frequent monitoring during pregnancy [Norwood & Rudnik-Schöneborn 2012].

No human pregnancies have been reported to have occurred during/after treatment with nusinersen. It is also unknown if nusinersen is excreted through human breast milk. Animal models do not show an increased risk for adverse fetal outcome with nusinersen exposure, or risk for future male or female infertility. However, as the risk to a developing human fetus has not been determined, it has been recommended that women discontinue treatment with nusinersen prior to conception.

There have not been any reported cases of pregnant women with SMA treated with gene therapy.

Therapies Under Investigation

A number of different therapeutic approaches are in development, including further studies on the approved therapeutics discussed above. Newer approaches (including some directed at increasing full-length SMN protein from SMN2, use of gene therapy to restore SMN1, and SMN-independent approaches) are being actively investigated; see Shorrock et al [2018].

SMN2-targeted therapeutic 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 are single-stranded RNA molecules specifically designed to target complementary sequences in the SMN2 transcript leading to inclusion of exon 7. Nusinersen also works through this mechanism. At least two additional SNM2 splicing modifiers are currently in clinical trials in SMA, including Novartis Pharmaceuticals LMI070 (NCT02268552) and Roche RG7916 (NCT02633709). Both of these agents are delivered orally. Results of these trials are not yet available.

SMN-independent approaches. Molecules directed at increasing muscle strength in individuals with SMA are also under investigation. CK-107 is a tropinin complex activator proposed to cause increased muscle force output [Andrews et al 2018]. This molecule is being studied in a Phase II trial (NCT02644668) in individuals with SMA II-IV. The trial has recently completed enrollment; results are not yet available.

A myostatin inhibitor SRK-015 has recently initiated enrollment in a Phase II trial (NCT03921528) in those with SMA II or III [Long et al 2019].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Spinal muscular atrophy is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• Approximately 98% of parents of an affected child are heterozygotes (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

• The offspring of an individual with SMA are obligate heterozygotes for an SMN1 pathogenic variant.
• The unrelated reproductive partner of an individual with 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 1,340.

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 Detection

Molecular genetic testing to determine carrier status is recommended for:

• 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 (see Population Screening) who are reproductive partners of known carriers.

Note: Preconception carrier screening for SMA in individuals with and without a family history of SMA has been recommended by the ACMG and ACOG (see Population Screening).

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] and in black individuals of sub-Saharan African heritage [Verhaart et al 2017].
• 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].

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic 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 Testing

High-risk pregnancy. Once the SMN1 pathogenic variants in both parents are known or linkage has been established in the family, prenatal testing and preimplantation genetic testing for SMA [Moutou et al 2003, Malcov et al 2004] are possible. Although 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, there can be intrafamilial variability in phenotypic presentation. An SMN2 copy number determination on the prenatal specimen may help to better predict the phenotype of the affected child.

Note: 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.

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].

Molecular 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.

Author History

Erika Finanger, MD (2016-present)
Meganne E Leach, MSN, PNP (2019-present)
Thomas W Prior, PhD, FACMG (2000-present)
Barry S Russman, MD; Oregon Health and Science University (2000-2016)

Revision History

• 3 December 2020 (aa/ha) Revision: GARS1-related infantile-onset SMA added to Table 5
• 14 November 2019 (ma) Comprehensive update posted live
• 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 live
• 15 July 2004 (br) Revision: Management
• 17 October 2003 (me) Comprehensive update posted live
• 24 February 2000 (me) Review posted live
• 28 February 1999 (br) Original submission

Published Guidelines / Consensus Statements

• Finkel RS, Mercuri E, Meyer OH, Simonds AK, Schroth MK, Graham RJ, Kirschner J, Iannaccone ST, Crawford TO, Woods S, Muntoni F, Wirth B, Montes J, Main M, Mazzone ES, Vitale M, Snyder B, Quijano-Roy S, Bertini E, Davis RH, Qian Y, Sejersen T, et al. Diagnosis and management of spinal muscular atrophy: part 2: pulmonary acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018;28:197–207. [PubMed: 29305137]
• Glascock J, Sampson J, Haidet-Phillips A, Connolly A, Darras B, Day J, Finkel R, Howell RR, Klinger K, Kuntz N, Prior T, Shieh PB, Crawford TO, Kerr D, Jarecki J. Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening. J Neuromuscul Dis. 2018;5:145–58. [PMC free article: PMC6004919] [PubMed: 29614695]
• Mercuri E, Finkel RS, Muntoni F, Wirth B, Montes J, Main M, Mazzone ES, Vitale M, Snyder B, Quijano-Roy S, Bertini E, Davis RH, Meyer OH, Simonds AK, Schroth MK, Graham RJ, Kirschner J, Iannaccone ST, Crawford TO, Woods S, Qian Y, Sejersen T, et al. Diagnosis and management of spinal muscular atrophy: part 1: recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018;28:103–115. [PubMed: 29290580]

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