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. SMA is the second most common lethal, ... 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. SMA is the second most common lethal, autosomal recessive disease in Caucasians after cystic fibrosis (219700) (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.
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. ... 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.
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 ... 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.
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% ... 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 Arabic 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.
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 ... 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.
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 ... 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.