Alternative titles; symbols
SNOMEDCT: 64383006; ICD10CM: G12.0; ICD9CM: 335.0; ORPHA: 70, 83330; DO: 13137;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5q13.2 | Spinal muscular atrophy-1 | 253300 | Autosomal recessive | 3 | SMN1 | 600354 |
A number sign (#) is used with this entry because spinal muscular atrophy type I (SMA1) is caused by mutation or deletion in the telomeric copy of the SMN gene, known as SMN1 (600354), on chromosome 5q13.
Changes in expression of the centromeric copy of SMN, SMN2 (601627), are known to modify the phenotype.
Spinal muscular atrophy refers to a group of autosomal recessive neuromuscular disorders characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy (summary by Wirth, 2000).
Four types of SMA are recognized depending on the age of onset, the maximum muscular activity achieved, and survivorship: type I, severe infantile acute SMA, or Werdnig-Hoffman disease; type II (253550), or infantile chronic SMA; type III (253400), juvenile SMA, or Wohlfart-Kugelberg-Welander disease; and type IV (271150), or adult-onset SMA. All types are caused by recessive mutations in the SMN1 gene.
Lunn and Wang (2008) provided a detailed review of clinical features, molecular pathogenesis, and therapeutic strategies for SMA.
Many groups observed the occurrence of different SMA subtypes within the same family, suggesting different manifestations of a single disease entity. Ghetti et al. (1971) reported that in many families 'malignant' Werdnig-Hoffmann disease coexisted with the Werdnig-Hoffmann disease with a prolonged course, the Wohlfart-Kugelberg-Welander disease with infantile onset, and the Wohlfart-Kugelberg-Welander disease with juvenile onset. Pearn et al. (1973) suggested that both the age of onset and the age of death were important in delineating this disorder and that therefore it should be called the infantile acute form of Werdnig and Hoffmann.
Feingold et al. (1977) referred to 'acute' and 'chronic' forms of infantile spinal muscular atrophy.
Zerres and Grimm (1983) presented a pedigree in which 2 males died at the age of 13 and 19 months, respectively, of the Werdnig-Hoffmann type of spinal muscular atrophy; a son and daughter of a great-aunt of theirs died at the age of 6 and 3.4 years, respectively, of Werdnig-Hoffmann disease, and a 59-year-old son of a great-uncle of theirs suffered from SMA of the Kugelberg-Welander type, with onset at age 12 years.
Thomas and Dubowitz (1994) found a correlation between age of onset and age of death in 2 cohorts of patients with spinal muscular atrophy, consisting of 36 and 70 patients, respectively. In one cohort, the shortest survival was 5 hours, and the longest was 19 months. In the other cohort, the mean age of onset was 1.6 months and the mean age of death was 9.6 months. The data further suggested that patients with onset before 2 months of age have a poor prognosis, with earlier death than those with slightly later onset who still fulfill the diagnostic criteria for type I.
Lumaka et al. (2009) reported a boy from central Africa with classic type 1 SMA confirmed by genetic analysis. He presented at birth with axial hypotonia and poor spontaneous movements. By age 5.5 months, he had extreme hypotonia, was unable to hold his head up, and showed psychomotor delay. He had joint laxity, severe proximal muscle weakness, umbilical hernia, atrial septal defect, and recurrent pulmonary infections resulting in death by age 10 months. EMG studies showed evidence for an alpha-motor neuron defect. An older brother who died at 10 months was reportedly similarly affected. Lumaka et al. (2009) noted that this was the first documented report of SMA type 1 in central Africa.
Pathologic Findings
Muscle biopsies of infantile spinal muscular atrophy demonstrate large numbers of round atrophic fibers and clumps of hypertrophic fibers that are type 1 by the ATPase reaction. Soubrouillard et al. (1995) performed immunohistochemical analyses of biopsied skeletal muscle from 23 cases of infantile SMA to determine the expression of developmentally regulated cytoskeletal components, including desmin (125660), NCAM (116930), vimentin (193060), and embryonic and fetal forms of the myosin heavy chain. Strong NCAM and developmental myosin heavy chain expression was present in atrophic fibers.
By analysis of a questionnaire-based retrospective study of 65 patients with SMA type 1, Rudnik-Schoneborn et al. (2008) concluded that congenital heart defects may result from severe SMN deficiency. Among these patients, 4 (6%) had 1 copy of SMN2, 56 (86%) had 2 copies, and 5 (8%) had 3 copies. Three (75%) of the 4 patients with a single SMN2 copy had congenital SMA with atrial or ventricular septal defects. Six of the 56 patients with 2 copies of SMN2 showed minor cardiac anomalies that resolved spontaneously, including a patent foramen ovale (PFO) in 4 infants, associated with a hypertrophic septum in 1, a patent ductus arteriosus (PDA) in 1 patient, and a PDA combined with a PFO in another patient. A small apical ventricular septal defect along with PDA was seen in 1 patient with classic SMA I who died at 11 months. She was the child of consanguineous parents who had lost 4 other children due to alleged sudden infant death syndrome. No cardiac malformation was documented in the 5 patients with 3 SMN2 copies. In a literature review, Rudnik-Schoneborn et al. (2008) noted that most reported SMA patients with heart defects had a severe disease course, congenital or prenatal onset, congenital contractures, respiratory distress from birth, and a very short life span, most likely associated with only 1 SMN2 copy.
Ebert et al. (2009) reported the generation of induced pluripotent stem cells from skin fibroblast samples taken from a child with spinal muscular atrophy type 1. These cells expanded robustly in culture, maintained the disease genotype, and generated motor neurons that showed selective deficits compared to those derived from the child's unaffected mother. Ebert et al. (2009) stated that this was the first study to show that human induced pluripotent stem cells can be used to model the specific pathology seen in a genetically inherited disease. Ebert et al. (2009) suggested that since animal models for SMA1 are nonviable, the generation of these pluripotent stem cells would allow more detailed studies of the pathophysiology of SMA1 in the motor neuron.
Brandt (1949) reported a large study of familial infantile progressive muscular atrophy involving 112 cases in 70 families. Segregation analysis yielded results consistent with autosomal recessive inheritance. Almost 6% of the parents were consanguineous, a value 8 times that in controls.
Marquardt et al. (1962), among others, described the disorder in twins. Hogenhuis et al. (1967) reported studies of a Chinese family in which 4 of 8 sibs succumbed to Werdnig-Hoffmann disease.
See 600354 for details on the molecular diagnosis of SMA.
Prenatal Diagnosis
Daniels et al. (1992) and Melki et al. (1992) demonstrated the feasibility of prenatal diagnosis of SMA by the linkage principle.
Wirth et al. (1995) presented their experience with 109 prenatal diagnoses performed in 91 families at risk of SMA by use of polymorphic microsatellites in the region 5q11.2-q13.3. Of the 109 prenatal diagnoses performed, 29 fetuses were diagnosed to be at more than 99% risk of developing the disease, while in 7 additional pregnancies no exact prediction could be made due to a recombination event in 1 parental haplotype.
Oprea et al. (2008) discovered that unaffected SMN1-deleted females exhibit significantly higher expression of plastin-3 (PLS3; 300131) than their SMA-affected counterparts. The authors demonstrated that PLS3 is important for axonogenesis through increasing the F-actin level. Overexpression of PLS3 rescued the axon length and outgrowth defects associated with SMN downregulation in motor neurons of SMA mouse embryos and in zebrafish. Oprea et al. (2008) concluded that defects in axonogenesis are the major cause of SMA, thereby opening new therapeutic options for SMA and similar neuromuscular diseases.
Wen et al. (2010) described a potential link between stathmin (STMN1; 151442) and microtubule defects in SMA. Stathmin was identified by screening Smn-knockdown NSC34 cells through proteomics analysis. Stathmin was aberrantly upregulated in vitro and in vivo, leading to a decreased level of polymerized tubulin, which was correlated with disease severity. Reduced microtubule densities and beta-3-tubulin (TUBB3; 602661) levels in distal axons of affected SMA-like mice and an impaired microtubule network in Smn-deficient cells were observed, suggesting an involvement of stathmin in those microtubule defects. Furthermore, knockdown of stathmin restored the microtubule network defects of Smn-deficient cells, promoted axon outgrowth, and reduced the defect in mitochondria transport in SMA-like motor neurons. The authors concluded that aberrant stathmin levels may play a detrimental role in SMA.
Kye et al. (2014) found that expression of microRNA-183 (MIR183; 611608), but not its primary transcript, was increased in Smn-knockdown rat primary neurons, concomitant with impaired axonal growth, impaired local translation of Mtor (601231) in neurites, and reduced Mtor pathway-dependent neurite protein synthesis. Mir183 was also elevated in SMA model mice and in SMA patient-derived fibroblasts. Codepletion of Mir183 and Smn in rat neurons rescued the axonal phenotype and increased Mtor expression in neurites. Kye et al. (2014) identified an Mir183-binding site in the 3-prime UTR of the Mtor transcript, and Mir183 bound directly to this site and inhibited Mtor translation. Inhibition of Mir183 in vivo partly alleviated the disease phenotype in SMA model mice. Kye et al. (2014) concluded that axonal MIR183 and the MTOR pathway contribute to SMA pathology.
Chang et al. (2001) reported results suggesting that sodium butyrate may be helpful in the treatment of SMA. They found that this agent increased the amount of exon 7-containing SMN protein in lymphoid cell lines from SMA patients by changing the alternative splicing pattern of exon 7 in the SMN2 gene. Oral administration of sodium butyrate to intercrosses of heterozygous pregnant knockout-transgenic SMA-like mice decreased the birth rate of severe types of SMA-like mice, and SMA symptoms were ameliorated for all 3 types of SMA-like mice.
Brichta et al. (2003) showed that in fibroblast cultures derived from SMA patients treated with therapeutic doses of valproic acid (VPA), the level of full-length SMN2 mRNA/protein increased 2- to 4-fold. This upregulation of SMN was most likely attributable to increased levels of HTRA2-beta-1 (see 606441) as well as to SMN gene transcription activation. VPA was also able to increase SMN protein levels through transcription activation in organotypic hippocampal rat brain slices. Additionally, valproic acid increased the expression of other serine-arginine (SR) family proteins, which may have important implications for other disorders affected by alternative splicing.
In a study of valproic acid (VPA) treatment in 10 SMA carriers and 20 patients with SMA1, SMA2, or SMA3, Brichta et al. (2006) found that VPA increased peripheral blood full-length SMN mRNA and protein levels in 7 carriers, increased full-length SMN2 mRNA in 7 patients, and left full-length SMN2 mRNA levels unchanged or decreased in 13 patients. The effect on protein levels in carriers was more pronounced than on mRNA levels, and the variability in augmentation among carriers and patients suggested to the authors that valproic acid interferes with transcription of genes encoding translation factors or regulates translation or SMN protein stability.
In fibroblast cultures from patients with SMA I, SMA II, or SMA III, Andreassi et al. (2004) found a significant increase in SMN2 gene expression (increase in SMN2 transcripts of 50 to 160% in SMA1, and of 80 to 400% in SMA2 and SMA3) and a more moderate increase in SMN protein expression in response to treatment with 4-phenylbutyrate (PBA). PBA treatment also resulted in an increase in the number of SMN-containing nuclear structures (GEMS). The authors suggested a potential use for PBA in treatment of various types of SMA.
Grzeschik et al. (2005) reported that cultured lymphocytes from patients with SMA showed increased production of the full-length SMN mRNA and protein in response to treatment with hydroxyurea. The findings suggested that hydroxyurea promoted inclusion of exon 7 during SMN2 transcription.
In a review of questionnaire-based data on 143 SMA patients, Oskoui et al. (2007) found that patients born from 1995 to 2006 had a 70% reduction in the risk of death compared to patients born from 1980 to 1994. However, when controlling for demographic and clinical care variables, the association was no longer significant. Treatment with ventilation for more than 16 hours per day, use of a mechanical insufflation-exsufflation device, and gastrostomy tube feedings showed a significant effect in reducing the risk of death. An amino acid diet had no significant effect on survival. Oskoui et al. (2007) concluded that the increased use of specific proactive management tools has been successful in enhancing survival of patients with SMA.
Angelozzi et al. (2008) found that salbutamol increased full-length SMN2 mRNA transcript levels in fibroblasts derived from patients with SMA I, II, and III. The maximum increase (over 200%) was observed after 30 to 60 minutes. This rapid rise correlated with decreased levels of SMN2 with deletion of exon 7. Salbutamol treatment also resulted in increased SMN protein levels and nuclear gems.
Yuo et al. (2008) found that treatment of SMA lymphoid cell lines with an Na+/H+ exchange inhibitor resulted in increased expression of SMN2 mRNA with exon 7 and increased SMN protein production in SMA cells. The underlying mechanism appeared to be upregulation of the splicing factor SRp20 (603364) in the nucleus. The findings were consistent with an effect of cellular pH on SMN splicing.
Ebert et al. (2009) reported the generation of induced pluripotent stem cells from skin fibroblast samples taken from a child with spinal muscular atrophy type 1. These cells expanded robustly in culture, maintained the disease genotype, and generated motor neurons that showed selective deficits compared to those derived from the child's unaffected mother. Ebert et al. (2009) stated that this was the first study to show that human induced pluripotent stem cells can be used to model the specific pathology seen in a genetically inherited disease. Ebert et al. (2009) suggested that since animal models for SMA1 are nonviable, the generation of these pluripotent stem cells would allow more detailed studies of the pathophysiology of SMA1 in the motor neuron.
Through chemical screening and optimization, Naryshkin et al. (2014) identified orally available small molecules that shift the balance of SMN2 splicing toward the production of full-length SMN2 mRNA with high selectivity. Administration of these compounds to delta-7 mice, a model of severe SMA, led to an increase in SMN protein levels, improvement of motor function, and protection of the neuromuscular circuit. These compounds also extended the life span of the mice.
By homozygosity testing of 4 consanguineous families with SMA type I, Gilliam et al. (1990) linked the disorder to chromosome 5q11.2-q13.3, the same region to which the more chronic forms SMA II and SMA III had been mapped.
Melki et al. (1990) independently demonstrated that SMA type I, like types II and III, was linked to markers at chromosome 5q12-q14. By in situ hybridization of 2 markers closely flanking the SMA I gene, Mattei et al. (1991) refined the assignment to 5q12-q13.3.
Daniels et al. (1992) used in situ hybridization to refine the mapping of SMA I to 5q12.2-q13 near marker D5S6. Brzustowicz et al. (1992) identified 2 flanking loci, MAP1B (157129) and D5S6, which are separated by an interval of approximately 2 cM. Wirth et al. (1993) narrowed the assignment to a region of about 4 cM and defined a new proximal genetic border by the locus D5S125. The closest marker on the distal side of SMA was found to be MAP1B, which has its 5-prime end directed toward the centromere.
Lien et al. (1991) used a polyclonal antiserum directed against the C-terminal domain of dystrophin (300377) to isolate a cDNA encoding an antigenically cross-reactive protein. Physical mapping of this gene placed it at 5q13 in close proximity to the SMA locus. A genetic linkage analysis of SMA families using a dinucleotide repeat polymorphism related to the dystrophin-like gene showed tight linkage to SMA mutations. The brain-specific expression of the gene likewise suggested possible association with SMA.
By a combination of genetic and physical mapping, Melki et al. (1994) constructed a yeast artificial chromosome (YAC) contig of the 5q13 region spanning the SMN disease locus and showing the presence of low copy repeats. Analysis of allele segregation at the closest genetic loci in 201 SMA families demonstrated inherited and de novo deletions in 9 unrelated SMA patients. Moreover, deletions were strongly suggested in at least 18% of SMA type I patients by the observation of marked deficiency of heterozygosity for the loci studied. The results indicated that deletion events were statistically associated with the severe form of spinal muscular atrophy.
Thompson et al. (1995) identified several coding sequences unique to the SMA region. A genomic fragment detected by 1 cDNA was homozygously deleted in 17 of 29 (58%) type I SMA patients. Only 2 of 235 unaffected controls showed the deletion, and both were carriers of the disease. These data suggested that deletion of at least part of this novel gene is directly related to the phenotype of SMA.
Biros and Forrest (1999), Wirth (2000), and Ogino and Wilson (2004) provided reviews of the complex molecular basis of SMA. SMN1 and SMN2 lie within the telomeric and centromeric halves, respectively, of a large inverted repeat on chromosome 5q. The coding sequence of SMN2 differs from that of SMN1 by a single nucleotide in exon 7 (840C-T), which results in decreased transcription and deficiency of the normal stable SMN protein. Approximately 94% of individuals with SMA lack both copies of SMN1 exon 7, resulting in substantial loss of the protein. Loss of exon 7 can result from deletion or the 840C-T change, in which SMN1 is essentially converted to SMN2 (gene conversion) (Lorson et al., 1999). Loss of SMN1 can also occur by other mechanisms, such as large deletions or point mutations. Most of the SMN protein is derived from the SMN1 gene; however, the SMN2 gene can contribute a small amount of SMN protein, thus modifying the genotype. For a detailed discussion of the molecular genetics of SMA, see 600354.
Lefebvre et al. (1995) identified the SMN gene, which they termed 'survival motor neuron,' within the SMA candidate region on chromosome 5q13, and demonstrated deletion or disruption of the gene in 226 of 229 patients with SMA.
In a separate publication accompanying that by Lefebvre et al. (1995), Roy et al. (1995) identified a different gene on chromosome 5q13.1, neuronal apoptosis inhibitory protein (NAIP; 600355). They found that the first 2 coding exons of this gene were deleted in approximately 67% of type I SMA chromosomes compared with 2% of non-SMA chromosomes, and reverse transcriptase-PCR analysis revealed internally deleted and mutated forms of the NAIP transcript in type I SMA individuals and not in unaffected individuals. Roy et al. (1995) suggested that mutations in the NAIP locus resulted in a failure of a normally occurring inhibition of motor neuron apoptosis that occurs during development, thus contributing to the SMA phenotype. In a discussion of these seemingly discordant findings, Lewin (1995) suggested that a mutation in either of the 2 genes could result in SMA or that a mutation in both genes was necessary for the disease. Gilliam (1995) discussed the evidence that either the NAIP gene or the SMN gene, or perhaps both, are involved in the causation of SMA.
Matthijs et al. (1996) identified homozygous deletion of exon 7 of the SMN1 gene in 34 of 38 patients with SMA. Of these 34 patients, the deletion was associated with homozygous deletion of exon 8 in 31 patients and with heterozygous deletion of exon 8 in 2 patients; both copies of exon 8 were present in 1 patient. In 1 family, a normal father of the proband had only 1 copy of the SMN gene and lacked both copies of the SMN2 gene, showing that a reduction of the total number of SMN genes to a single SMN copy is compatible with normal life. In another family, a de novo deletion of a paternal SMN2 gene was found in a normal sister of a girl with SMA I. Matthijs et al. (1996) suggested that 'this region of chromosome 5q shows some special characteristics which should lead to caution' in the molecular diagnosis of SMA I. Deletions of the SMN gene were not found in 4 of the patients with SMA I.
Hahnen et al. (1996) reported molecular analysis of 42 SMA patients who carried homozygous deletions of exon 7 but not of exon 8 in the SMN1 gene. Additional homozygous deletions of exon 8 in the SMN2 gene were found in 2 of the patients. By a simple PCR test, Hahnen et al. (1996) demonstrated the existence of hybrid SMN genes (i.e., genes composed of both the centromeric SMN2 and the telomeric SMN1). They reported a high frequency of hybrid SMN genes in SMA patients with Czech or Polish background. Hahnen et al. (1996) identified a single haplotype for half of the hybrid genes analyzed, suggesting that in these cases the SMA chromosomes shared a common origin.
Alias et al. (2009) found homozygous absence of SMN1 exons 7 and 8 in 671 (90%) of 745 Spanish SMA patients. Thirty-seven patients (5%) had homozygous absence of exon 7 but not exon 8, due to the presence of hybrid genes. The majority of the remaining 5% of patients had smaller deletions or point mutations. However, only 1 mutant allele was identified in 7 (0.9%) patients. Data stratification by SMA type showed that females had a significantly higher frequency of type I SMA compared to males.
Modifying Factors
Stratigopoulos et al. (2010) evaluated blood levels of PLS3 (300131) mRNA transcripts in 88 patients with SMA, including 29 males under age 11 years, 12 males over age 11, 29 prepubertal girls, and 18 postpubertal girls in an attempt to examine whether PLS3 was a modifier of the phenotype. PLS3 expression was decreased in the older patients of both sexes. However, expression correlated with phenotype only in postpubertal girls: expression was greatest in those with SMA type III, intermediate in those with SMA type II, and lowest in those with SMA type I, and correlated with residual motor function as well as SMN2 copy number. Stratigopoulos et al. (2010) concluded that the PLS3 gene may be an age- and/or puberty-specific and sex-specific modifier of SMA.
For a detailed discussion of genotype/phenotype correlations in spinal muscular atrophy, see 600354.
Burlet et al. (1996) found large-scale deletions involving both the SMN gene and its upstream (C212-C272) and downstream (NAIP) flanking markers in 43% of 106 unrelated SMA patients. However, they noted that smaller rearrangements can still result in disease, since 27% of patients with severe disease lacked only the SMN gene. They also pointed out that deletion of the SMN gene may produce mild disease and referred to an article by Cobben et al. (l995) in which deletions of the SMN gene were found in unaffected sibs of patients with SMA. Burlet et al. (1996) suggested that other genetic mechanisms might be involved in the variable clinical expression of the disease.
Using pulsed field gel electrophoresis to map deletions in the SMN gene, Campbell et al. (1997) found that mutations in SMA types II and III, previously classed as deletions, were in fact due to gene-conversion events in which the telomeric SMN1 was replaced by its centromeric counterpart, SMN2. This resulted in a greater number of SMN2 copies in type II and type III patients compared with type I patients and enabled a genotype/phenotype correlation to be made. Campbell et al. (1997) also demonstrated individual DNA-content variations of several hundred kilobases, even in a relatively isolated population from Finland. This explained why no consensus map of this region of 5q had been produced. They suggested that this DNA variation may be due to a 'midisatellite' array, which would promote the observed high deletion and gene conversion rate. Burghes (1997) discussed the significance of the findings of Campbell et al. (1997) and presented a model (Figure 3) of alleles present in the normal population and in severe and mild forms of SMA. Campbell et al. (1997), Burghes (1997) raised the question of whether the centromeric SMN2 gene might be activated to compensate for the deficiency of SMN1 as a therapeutic strategy in SMA.
Samilchuk et al. (1996) carried out deletion analysis of the SMN and NAIP genes in 11 cases of type I SMA and 4 cases of type II SMA. The patients were of Kuwaiti origin. They also analyzed samples from 41 healthy relatives of these patients and 44 control individuals of Arab origin. They found homozygous deletions of exons 7 and 8 of the SMN gene in all SMA patients studied. Exon 5 of the NAIP gene was homozygously absent in all type I SMA patients, but was retained in the type II patients. Among relatives, they identified 1 mother was had homozygous deletion of NAIP. All of the control individuals had normal SMN and NAIP. Samilchuk et al. (1996) concluded that the incidence of NAIP deletion is much higher in the clinically more severe cases (type I SMA) than in the milder forms, and all of the type II SMA patients in their study had at least one copy of the intact NAIP gene.
Somerville et al. (1997) presented a compilation of genotypes for the SMN1 and NAIP genes from their own laboratory and those of others as reported in the literature. Bayesian analyses were used to generate probabilities for SMA when deletions were present or absent in SMN1. They found that when the SMN1 exon 7 was deleted, the probability of SMA could reach greater than 98% in some populations, and when SMN1 was present, the probability of SMA was approximately 17 times less than the prior population risk. Deletion of NAIP exon 5, as well as SMN1 exon 7, was associated with a 5-fold increased risk of type I SMA. Case studies were used to illustrate differing disease risks for pre- and postnatal testing, depending on the presence of information about clinical status or molecular results. These analyses demonstrated that deletion screening of candidate genes can be a powerful tool in the diagnosis of SMA.
Novelli et al. (1997) investigated the effects of gender on the association between NAIP gene deletion and disease severity in SMA. NAIP deletions were screened in 197 SMA patients lacking SMN; the results obtained were correlated with disease severity in male and female samples separately. No significant relationship between deletion size and clinical phenotype was observed among male patients, whereas in females the absence of NAIP was strongly associated with a severe phenotype (p less than 0.0001). SMA I was found in 75.6% of females and only 52.5% of males lacking NAIP. These results provided a possible molecular explanation for the sex-dependent phenotypic variation observed in SMA patients.
Using comparative genomics to screen for modifying factors in SMA among sequences evolutionarily conserved between mouse and human, Scharf et al. (1998) identified a novel transcript, H4F5 (603011), which lay closer to SMN1 than any previously identified gene in the region. They found that a multicopy microsatellite marker that was deleted in more than 90% of type I SMA chromosomes was embedded in an intron of the SMN1 gene, indicating that H4F5 may also be deleted in type I SMA, and thus was a candidate phenotypic modifier for SMA. In comparison with the high rate of H4F5 deletions in type I SMA, Scharf et al. (1998) found that the deletion frequency in type II SMA chromosomes was between that of type I and control chromosomes, whereas the frequency in type III chromosomes was only slightly higher than in controls.
Jedrzejowska et al. (2008) reported 3 unrelated families with asymptomatic carriers of a biallelic deletion of the SMN1 gene. In the first family, the biallelic deletion was found in 3 sibs: 2 affected brothers with SMA3 and a 25-year-old asymptomatic sister. All of them had 4 copies of the SMN2 gene. In the second family, 4 sibs were affected, 3 with SMA2 and 1 with SMA3, and each had 3 copies of SMN2. The clinically asymptomatic 47-year-old father had the biallelic deletion and 4 copies of SMN2. In the third family, the biallelic SMN1 deletion was found in a girl affected with SMA1 and in her healthy 53-year-old father who had 5 copies of SMN2. The findings again confirmed that an increased number of SMN2 copies in healthy carriers of the biallelic SMN1 deletion is an important SMA phenotype modifier, but also suggested that other factors play a role in disease modification.
Rudnik-Schoneborn et al. (2009) reviewed the clinical features of 66 German patients with SMA type 1 caused by homozygous deletion of the SMN1 gene. Reduced fetal movements were recorded in 33% of pregnancies. Sixteen (24%) patients showed onset of weakness in the first week of life; the overall mean age at death was 9 months. Four (6.1%) patients with 1 SMN2 gene copy had severe SMA type '0' with joint contractures and respiratory distress from birth. All died within a few months of age. Among the 57 (86.3%) patients with 2 SMN2 copies, the mean age at onset was 1.3 months, and the mean age at disease endpoint (death or need for permanent ventilation) was 7.8 months. Among the 5 (7.6%) of patients with 3 SMN2 copies, the mean age at onset was 3.4 months and the mean age at endpoint was 28.9 months (range, 10 to 55 months). Rudnik-Schoneborn et al. (2009) noted that much of the observed clinical variability in SMA type 1 likely depends on the number of SMN2 copies, and suggested that the SMN2 copy number should be considered in clinical trials.
Czeizel and Hamula (1989) and Czeizel (1991) estimated the prevalence of Werdnig-Hoffmann disease in Hungary to be 1 per 10,000 live births. The occurrence in sibs was 32%, a figure considered consistent with autosomal recessive inheritance complicated by greater ascertainment of families with more than 1 affected child.
From an epidemiologic study of acute and chronic childhood SMA in Poland, Spiegler et al. (1990) cited a frequency of 1.026 cases per 10,000, a gene frequency of 0.01428, and a carrier frequency of 1 in 35. Spiegler et al. (1990) reviewed various other reports on the frequency of SMA. For an 8-year period (1980-1987) in the State of North Dakota, Burd et al. (1991) found an incidence of 1 in 6,720 births (14 in 94,092). In an Italian population, Mostacciuolo et al. (1992) found an overall prevalence at birth for SMA types I, II, and III to be 7.8 in 100,000 live births. Type I alone accounted for 4.1 in 100,000 live births. Assuming that the 3 types are clinical manifestations of allelic mutations, the locus mutation rate would be about 70 x 10(-6) and the frequency of heterozygotes about 1 in 57.
Wilmshurst et al. (2002) performed DNA studies in 30 unrelated and racially diverse patients with SMA residing in the Western Cape of South Africa. Four had SMA type I, 16 had type II, and 10 had type III. All patients were found to be homozygous for the loss of either exon 7 or exons 7 and 8 of the SMN1 gene. Thus, all patients from the Western Cape, which included 12 black South Africans, were no different genetically or phenotypically from the internationally recognized form of typical SMA.
Zaldivar et al. (2005) found that the incidence of SMA type I in Cuba was 3.53 per 100,000 live births. When the population was classified according to self-reported ethnicity, the incidence was 8 per 100,000 for whites, 0.89 per 100,000 for blacks, and 0.96 per 100,000 for those of mixed ethnicity. Zaldivar et al. (2005) concluded that SMA I may occur less frequently in those of African ancestry.
In a detailed review, Lunn and Wang (2008) stated that the incidence of SMA was 1 in 10,000 livebirths and that the carrier frequency was 1 in 50. In a reply, Wilson and Ogino (2008) stated that carrier testing had revealed a carried frequency of 1 in 38, which extrapolates to an incidence of 1 in 6,000 livebirths under Hardy-Weinberg equilibrium. Wilson and Ogino (2008) postulated that the numerical differences could be due to embryonic lethality or clinically atypical SMA.
Hendrickson et al. (2009) genotyped more than 1,000 specimens from various ethnic groups using a quantitative real-time PCR assay specific for the 840C-T change in exon 7, which results in loss of SMN1. The observed 1-copy SMN1 carrier rate was 1 in 37 (2.7%) among Caucasians, 1 in 46 (2.2%) among Ashkenazi Jews, 1 in 56 (1.8%) 56 among Asians, 1 in 91 (1.1%) among African Americans, and 1 in 125 (0.8%) among Hispanics. In all groups except African Americans the 2-copy genotype was the most common. However, African American specimens had an unusually high frequency of alleles with multiple copies of SMN1 (27% compared to 3.3-8.1%). The authors noted that alleles with increased numbers of SMN1 copies increase the relative risk of being a carrier due to the inability of many methods to detect the rare SMN1 genotype consisting of 1 allele with zero copies and the other allele with 2 or more copies.
Using denaturing high-performance liquid chromatography (DHPLC) as a screening tool to determine SMN copy number, Sheng-Yuan et al. (2010) found a heterozygous deletion of SMN1 exon 7 in 41 (2.39%) of 1,712 cord blood samples from Chinese infants, indicating a carrier state. Thirteen different genotypic groups characterized by SMN1:SMN2 copy number ratio were identified overall. Carrier genotypes were similar among 25 core families with the disorder, with the '1+0' SMN1 genotype accounting for 90.9% of carriers, although 2 of 44 parents had the rare '2+0' genotype. Sheng-Yuan et al. (2010) developed an assay based on reverse dot blot for rapid genotyping of exon 7 deletional SMA. Sheng-Yuan et al. (2010) concluded that the carrier rate of SMA in China is 1 in 42 and that approximately 2,306 newborns are affected each year.
Chong et al. (2011) identified a shared haplotype encompassing the SMN1/SMN2 genes in a Hutterite patient from South Dakota and 3 Hutterite patients from Montana. An 8-generation pedigree connected these 4 individuals to their most recent common ancestors, who were a couple born in the 1790s. All 4 patients carried zero copies of SMN1 and 4 copies of SMN2, indicating that the haplotype carrying the deletion of SMN1 also carries 2 copies of SMN2. The carrier frequency for this haplotype was 12.9% in South Dakota Hutterites. The phenotypic expression of this phenotype was relatively mild, and 1 asymptomatic homozygous adult was identified. Chong et al. (2011) identified a 26-SNP haplotype that could be used for screening in this population.
Among 23,127 ethnically diverse individuals screened for SMA1 carrier status, Lazarin et al. (2013) identified 405 carriers (1.8%), for an estimated carrier frequency of approximately 1 in 57. Fifteen 'carrier couples' were identified.
Becker (1964) suggested an allelic model for the clinically distinct subtypes of SMA: 3 or more normal alleles (a, a', a'') in addition to the pathologic gene a(+). The genotype a'a(+) was thought to lead to Kugelberg-Welander phenotype and the a''a(+) genotype to the Werdnig-Hoffmann phenotype. Bouwsma and Leschot (1986) extended the allele hypothesis of Becker. They presented clinical and genetic findings in 18 patients from 7 pedigrees showing an unusual genetic pattern not consistent with simple autosomal recessive inheritance. In 6 of the 7 pedigrees, different types of SMA were present. However, Muller et al. (1992) presented evidence rejecting the Becker hypothesis. In a sample of 4 sibships in which both SMA type II and SMA type III occurred, the segregation of linked markers indicated that the same allele was involved. The finding suggested that other factors, genetic or environmental, must determine disease severity in SMA.
Kleyn et al. (1991) excluded both the HEXB locus (606873) and the GM2-activator protein locus (GM2A; 613109), both of which are located on chromosome 5, as the site of the mutation in SMA. Recombination between HEXB and SMA eliminated this enzyme as a candidate site. Furthermore, the gene encoding the activator protein was found to map distal to the SMA I locus (Heng et al., 1993).
Exclusion of the Wobbler Mouse and a Canine Model
Kaupmann et al. (1992) mapped the 'wobbler' locus (wr) (see 614633) to proximal mouse chromosome 11. The wobbler mouse (genotype wr/wr) shows motoneuron disease and gonadal dysfunction. Kaupmann et al. (1992) stated that the wobbler was an unlikely model for human SMA because it shows also a striking spermiogenesis defect which has not been reported for male SMA patients who have reached adolescence.
Des Portes et al. (1994) also mapped the mouse 'wobbler' mutation to mouse chromosome 11, about 1 cM from the glutamine synthetase gene (138290); several crossovers excluded glutamine synthetase from being a candidate gene for the wobbler mutation. The murine equivalent of the human 5q region is mainly situated on chromosomes 13 and 11, and the closest published marker for human spinal muscular atrophy, D5S39, was mapped to mouse chromosome 13. Thus, it seemed unlikely that the wobbler mutation and the common human spinal muscular atrophies were genetically identical, despite their similar phenotype.
Blazej et al. (1998) concluded that autosomal dominant canine spinal muscular atrophy, which has pathologic and clinical features similar to various forms of human motor neuron disease, was molecularly distinct from human spinal muscular atrophy. They studied the canine SMN gene in affected and unaffected dogs and found no germline mutations in the SMN gene in affected dogs. Analysis of a panel of canine/rodent hybrid cell lines revealed that the SMN gene did not map to the same chromosome in the dog as did the canine spinal muscular atrophy.
Other Animal Models
Hsieh-Li et al. (2000) produced mouse lines deficient for mouse Smn and transgenic mouse lines that expressed human SMN2 (601627). Smn -/- mice died during the periimplantation stage. In contrast, transgenic mice harboring SMN2 in the Smn -/- background showed pathologic changes in the spinal cord and skeletal muscles similar to those of SMA patients. The severity of the pathologic changes in these mice correlated with the amount of SMN protein that contained the region encoded by exon 7. The results demonstrated that SMN2 can partially compensate for lack of SMN1. The variable phenotypes of Smn -/- SMN2 mice reflected those seen in SMA patients, thus providing a mouse model for that disease.
Frugier et al. (2000) used the Cre/loxP recombination system and a neuron-specific promoter to generate transgenic mice with selective expression in neural tissue of an SMN construct missing exon 7. Unlike mice missing SMN exon 7 in all tissues (an embryonic lethal phenotype), those with a neuron-specific defect displayed a severe motor deficit with tremors. The mutated SMN protein lacked the normal C terminus and was dramatically reduced in motor neuron nuclei. Histologic analysis revealed a lack of GEMS (gemini of coiled bodies, which are normal nuclear structures) and the presence of large aggregates of coilin, a coiled body-specific protein (600272). The authors concluded that the lack of nuclear targeting of SMN is the biochemical defect in SMA, which leads to muscle denervation of neurogenic origin.
Studying Brown-Swiss cattle, Medugorac et al. (2003) mapped the bovine spinal muscular atrophy locus to chromosome 24. Before performing a genomewide linkage analysis, they investigated 2 candidate chromosome segments: the proximal part of bovine chromosome 20 and the complete bovine chromosome 29. These regions are orthologous to human chromosome segments responsible for SMA1 and SMA with respiratory distress (SMARD1; 604320), respectively. No abnormalities were found in these regions. The linkage region on chromosome 24 contains the homolog of the BCL2 gene (151430) on human chromosome 18q. Medugorac et al. (2003) suggested that the gene encoding the apoptosis-inhibiting protein BCL2 is a promising candidate for bovine SMA and that the disorder in Brown-Swiss cattle offers an attractive animal model for a better understanding of human SMA and for a probable antiapoptotic synergy of SMN-BCL2 aggregates in mammals.
Chan et al. (2003) isolated a Drosophila smn mutant with point mutations in the smn gene similar to those found in SMA patients. Zygotic smn mutant animals showed abnormal motor behavior; smn gene activity was required in both neurons and muscle to alleviate this phenotype. Excitatory postsynaptic currents were reduced while synaptic motor neuron boutons were disorganized in mutants, indicating defects at the neuromuscular junction. Clustering of a neurotransmitter receptor subunit in the muscle at the neuromuscular junction was also severely reduced.
In a mouse model of SMA, Kariya et al. (2008) demonstrated that the earliest structural defects of the disorder appeared in the distal muscles and involved the neuromuscular synapse even before the appearance of overt symptoms. Insufficient SMN protein arrested the postnatal development of the neuromuscular junction (NMJ), impairing the maturation of postsynaptic acetylcholine receptor (AChR) clusters. Presynaptic defects at the distal ends of alpha-motor neurons included poor terminal arborization, intermediate filament aggregates, and misplaced synaptic vesicles. These defects were reflected in functional deficits at the NMJ characterized by intermittent neurotransmission failures. Kariya et al. (2008) suggested that SMA might best be described as a NMJ synaptopathy.
In severe SMA mice (Smn -/-;SMN2 +/+) Gavrilina et al. (2008) found that transgenic embryonic expression of full-length SMN under the prion (176640) promoter in brain and spinal cord neurons rescued the phenotype. Mice homozygous for the transgene survived for an average of 210 days, compared to 4.6 days in control SMA mice, and lumbar motor neuron root counts in the transgenic mice were normal. High levels of SMN in neurons were observed at embryonic day 15. In contrast, transgenic expression of SMN solely in skeletal muscle using the human skeletal actin promoter resulted in no improvement of the SMA phenotype or extension of survival in SMA mice. However, 1 transgenic strain with high SMN expression in muscle and low SMN expression in brain showed increased survival to 160 days, indicating that even mild neuronal SMN expression can affect the phenotype. Gavrilina et al. (2008) concluded that expression of full-length SMN in neurons can correct the severe SMA phenotype in mice, whereas high SMN levels in mature skeletal muscle alone has no impact.
Murray et al. (2010) investigated the presymptomatic development of neuromuscular connectivity in differentially vulnerable motor neuron populations in Smn -/-;SMN2 +/+ mice. Reduced Smn levels had no detectable effect on morphologic correlates of presymptomatic development in either vulnerable or stable motor units, indicating that abnormal presymptomatic developmental processes were unlikely to be a prerequisite for subsequent pathologic changes to occur in vivo. Microarray analyses of spinal cord from 2 different severe SMA mouse models demonstrated that only minimal changes in gene expression were present in presymptomatic mice. In contrast, microarray analysis of late-symptomatic spinal cord revealed widespread changes in gene expression, implicating extracellular matrix integrity, growth factor signaling, and myelination pathways in SMA pathogenesis. Murray et al. (2010) suggested that reduced Smn levels induce SMA pathology by instigating rapidly progressive neurodegenerative pathways in lower motor neurons around the time of disease onset, rather than by modulating presymptomatic neurodevelopmental pathways.
Wishart et al. (2010) showed that reduced levels of Smn led to impaired perinatal brain development in a mouse model of severe SMA. Regionally selective changes in brain morphology were apparent in areas normally associated with higher Smn levels in the healthy postnatal brain, including the hippocampus, and were associated with decreased cell density, reduced cell proliferation, and impaired hippocampal neurogenesis. A comparative proteomics analysis of the hippocampus from SMA and wildtype littermate mice revealed widespread modifications in expression levels of proteins regulating cellular proliferation, migration, and development when Smn levels were reduced. Wishart et al. (2010) proposed roles for SMN protein in brain development and maintenance.
Therapeutic Strategies
In SMA-like mouse embryonic fibroblasts and human SMN2-transfected motor neuron cells, Ting et al. (2007) found that sodium vanadate, trichostatin A, and aclarubicin effectively enhanced SMN2 expression by inducing Stat5 (601511) activation. This resulted in enhanced SMN2 promoter activity with an increase in both full-length and deletion exon 7 SMN transcripts in human cells with SMN2. Knockdown of Stat5 expression disrupted the effects of sodium vanadate on SMN2 activation, but did not influence SMN2 splicing, suggesting that Stat5 signaling is involved in SMN2 transcriptional regulation. Constitutive expression of the activated Stat5 mutant Stat5A1*6 profoundly increased the number of nuclear gems in SMA patient lymphocytes and reduced SMA-like motor neuron axon outgrowth defects.
Narver et al. (2008) found that in a transgenic mouse model of SMA (Smn +/-, SMN2 +/+, SMN-delta-7) early treatment with the HDAC (601241) inhibitor, trichostatin A (TSA), plus nutritional support extended median survival by 170%. Treated mice continued to gain weight, maintained stable motor function, and retained intact neuromuscular junctions long after TSA was discontinued. In many cases, ultimate decline of mice appeared to result from vascular necrosis, raising the possibility that vascular dysfunction is part of the clinical spectrum of severe SMA. Narver et al. (2008) concluded that early SMA disease detection and treatment initiation combined with aggressive ancillary care may be integral to the optimization of HDAC inhibitor treatment in human patients.
Meyer et al. (2009) created an optimal exon 7 inclusion strategy based on a bifunctional U7 snRNA (RNU7-1; 617876) construct that targets the 3-prime part of exon 7 and carries an ESE sequence that can attract stimulatory splice factors. This construct induced nearly complete exon 7 inclusion of an SMN2-reporter in HeLa cells and of endogenous SMN2 in SMA type I patient fibroblasts. Introduction of the U7-ESE-B construct in a severe mouse model of SMA resulted in a clear suppression of disease-associated symptoms, ranging from normal life span with pronounced SMA symptoms to full weight development, muscular function, and ability of female mice to carry to term and feed a normal-sized litter. Exon 7 inclusion in total spinal RNA increased from 26% to 52%, and SMN protein levels increased, albeit only to levels one-fifth of that seen wildtype mice.
Workman et al. (2009) showed that SMN(A111G), an allele capable of snRNP assembly (A111G; 600354.0015), can rescue mice that lacked Smn and contained either 1 or 2 copies of SMN2 (SMA mice). The correction of SMA in these animals was directly correlated with snRNP assembly activity in spinal cord, as was correction of snRNA levels. These data support snRNP assembly as being the critical function affected in SMA and suggests that the levels of snRNPs are critical to motor neurons. Furthermore, SMN(A111G) could not rescue Smn-null mice without SMN2, suggesting that both SMN(A111G) and SMN from SMN2 may undergo intragenic complementation in vivo to function in heteromeric complexes that have greater function than either allele alone. The oligomer composed of limiting full-length SMN and SMN(A111G) had substantial snRNP assembly activity. The SMN(A2G) (A2G; 600354.0002) and SMN(A111G) alleles in vivo did not complement each other, leading to the possibility that these mutations could affect the same function.
Mattis et al. (2009) examined the potential therapeutic capabilities of a novel aminoglycoside, TC007. In an intermediate SMA mouse model (Smn -/-; SMN2 +/+; SMN-delta-7), when delivered directly to the central nervous system, TC007 induced SMN in both the brain and spinal cord, significantly increased life span (approximately 30%), and increased ventral horn cell number, consistent with its ability to increase SMN levels in induced pluripotent stem cell-derived human SMA motor neuron cultures.
Butchbach et al. (2010) tested a series of C5-quinazoline derivatives for their ability to increase SMN expression in vivo. Oral administration of 3 compounds (D152344, D153249, and D156844) to neonatal SMN-delta-7 mice resulted in a dose-dependent increase in Smn promoter activity in the central nervous system. Oral administration of D156844 significantly increased the mean life span of SMN-delta-7 SMA mice by approximately 20-30% when given prior to motor neuron loss.
Bowerman et al. (2010) showed that Smn depletion led to increased activation of RhoA (165390), a major regulator of actin dynamics, in the spinal cord of an intermediate SMA mouse model. Treating these mice with Y-27632, which inhibits ROCK (601702), a direct downstream effector of RhoA, dramatically improved their survival. This life span rescue was independent of Smn expression and was accompanied by an improvement in the maturation of the neuromuscular junctions and an increase in muscle fiber size in the SMA mice. Bowerman et al. (2010) proposed a role for disruption of actin cytoskeletal dynamics to SMA pathogenesis and suggested that RhoA effectors may be viable targets for therapeutic intervention in the disease.
Ackermann et al. (2013) found that ubiquitous overexpression of human PLS3 (300131) in mice with a mild SMA phenotype improved motor ability and neuromuscular junction function and moderately increased survival compared with control SMA mice. Expression of PLS3 did not improve the morphology of heart, lung, or intestine, and it did not improve motor ability or survival in mice with a severe SMA phenotype. The authors noted that these findings were consistent with observations in humans showing that PLS3 provides full protection against SMA only in SMN1-deleted individuals with 3 to 4 SMN2 copies, but not in those with 2 SMN2 copies. In mildly affected SMA mice, PLS3 delayed axon pruning until postnatal day 8, which counteracted the poor synaptic activity observed in control SMA mice. F-actin content was increased in presynapses, leading to improved neuromuscular connectivity, restored active zone content of synaptic vesicles, improved organization of the ready releasable vesicle pool, increased endplate and muscle fiber size, and improved neurotransmission.
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