Spinal Muscular Atrophy, Type Iii
A number sign (#) is used with this entry because spinal muscular atrophy type III (SMA3) is caused by homozygous or compound heterozygous mutation in the SMN1 gene (600354) on chromosome 5q13.
DescriptionSMA is an autosomal recessive neuromuscular disorder characterized by progressive proximal muscle weakness and atrophy affecting the upper and lower limbs. By convention, SMA is classified into 4 types: I (SMA1; 253300), II (SMA2; 253550), III (SMA3), and IV (271150), by increasing age at onset and decreasing clinical severity. SMA1 is the most severe form of the disorder and often results in death in early childhood. SMA3, known as the juvenile form, tends to show onset in childhood or adolescence (summary by Fraidakis et al., 2012).
Clinical FeaturesKugelberg and Welander (1956) reported 5 children, among the 12 offspring of normal parents, with a juvenile form of spinal muscular atrophy; 2 of the 5 were monozygotic twins.
Levy and Wittig (1962) described proximal muscular atrophy in 2 half brothers, with onset at 13 and 16 years. Onset of the juvenile form is usually between 2 and 17 years of age. Atrophy and weakness of proximal limb muscles, primarily in the legs, is followed by distal involvement. Usually the cases are diagnosed as limb-girdle muscular dystrophy until they are studied fully. Twitchings (fasciculations) are an important differentiating sign. Muscular biopsy and electromyography show the true nature of the process as a lower motor neuron disease. Pulmonary dysfunction is often a cause of morbidity in these patients.
Samaha et al. (1994) studied forced vital capacity longitudinally in 40 SMA patients ranging in age from 5 to 18 years. Although the majority of the patients grew in height, only 35% showed an increase in height-adjusted forced vital capacity. In the most seriously affected patients, all lost height-adjusted forced vital capacity over time. Furukawa et al. (1968) reported 2 families, each with affected brother and sister. The parents in one family were first cousins. The authors pointed out that in their cases, as well as in those in the literature, the symptoms of female patients were mild and the clinical course slow whereas male sibs were severely affected. They interpreted this as sex-influence.
Bundey and Filomeno (1974) described a black sibship in which 5 sibs out of 10 had this disorder.
Pearn et al. (1978) reported a spinal muscular atrophy syndrome characterized by adolescent onset, gross hypertrophy of the calves, and a slowly progressive clinical course. One of their families with 2 affected brothers and 2 affected maternal uncles probably had Kennedy disease (313200), an X-linked form of SMA with which calf hypertrophy has been observed.
Fraidakis et al. (2012) reported 2 unrelated French men, aged 44 and 50 years, with SMA type III. Both had onset of slowly progressive proximal lower limb weakness beginning in adolescence, followed by proximal upper limb weakness. At age 44, the first patient patient had proximal lower limb amyotrophy, proximal upper and lower limb weakness, and absence of lower limb reflexes; he used a cane to walk. Muscle biopsy and EMG showed a chronic neuropathic process. The second patient developed muscle cramps and was wheelchair-bound at age 48. Physical examination showed severe motor deficit and amyotrophy in the pelvic and shoulder girdles, as well as severe motor deficit and amyotrophy in the distal limb muscles. EMG was consistent with severe chronic denervation at all extremities. Fraidakis et al. (2012) commented on the relatively mild disease course in these patients and suggested that there were likely compensatory factors affecting expression of the SMN genes.
InheritanceSpira (1963) described 7 affected members in 2 sibships of a family with proximal spinal muscular atrophy. In each case the affected persons were offspring of a first-cousin marriage, consistent with autosomal recessive inheritance.
Pearn et al. (1978) reviewed 141 cases of SMA with onset before age 14 years (excluding SMA type I, or Werdnig-Hoffmann disease). Autosomal recessive inheritance could account for over 90% of cases. In these, onset was before age 5 and usually before age 2 years. The disorder was compatible with life into the third decade. A small group of cases appeared to be either new dominant mutations or phenocopies. Hausmanowa-Petrusewicz et al. (1985) called this the mild childhood and adolescent type of spinal muscular atrophy and emphasized the significance of sex influence (Hausmanowa-Petrusewicz et al., 1984). Zerres et al. (1987) advanced Becker's allelic model as a possible explanation for unusual pedigrees with spinal muscular atrophy. Because of the finding of linkage of SMA I, II (SMA2; 253550), and III to the same region, 5q11.2-q13.3 (Brzustowicz et al., 1990), it is likely that these are allelic disorders.
Clinical ManagementIn fibroblast cultures from patients with SMA1, SMA2, or SMA3, Andreassi et al. (2004) found a significant increase in SMN2 gene (601627) 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.
Weihl et al. (2006) reported increased quantitative muscle strength and subjective function in 7 adult patients with SMA3/SMA4 who were treated with oral valproate for a mean duration of 8 months. Most patients reported improvement within a few months of beginning treatment. The authors noted that previous studies (see Brichta et al., 2003) had suggested that inhibitors of histone deacetylase, such as valproate, may increase SMN2 gene transcription and result in increased production of full-length SMN protein.
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 VPA interferes with transcription of genes encoding translation factors or regulates translation or SMN protein stability.
CytogeneticsBrzustowicz et al. (1994) detected paternal isodisomy for chromosome 5 in a 2-year-old boy with type III SMA. Examination of 17 short-sequence repeat polymorphisms spanning a large part of the chromosome produced no evidence of maternally inherited alleles. Cytogenetic analysis showed a normal male karyotype, and fluorescence in situ hybridization with probes closely flanking the SMA locus confirmed the presence of 2 copies of chromosome 5. No developmental abnormalities other than those attributable to classic childhood-onset SMA were present.
In an analysis of uniparental disomy cases, Kotzot (1999) found only one example of uniparental disomy involving chromosome 5, that of Brzustowicz et al. (1994). No reports were found of uniparental disomy of chromosomes 12, 17, 18, and 19. On the other hand, 33 examples of chromosome 16 UPD were found, all of them maternal except 1. The bases of UPD are always 2 events: 2 meiotic; 1 meiotic and 1 mitotic; or 2 mitotic. Abnormal phenotypes result from an aberrant imprint, homozygosity of autosomal recessive gene mutations, homozygosity of X-chromosomal mutations in females, and father-to-son transmission of X-linked traits. The most frequent mechanism of UPD appears to be fertilization of a disomic gamete by a gamete monosomic for the same chromosome and subsequent loss of the normally inherited chromosome (trisomy rescue). This mechanism might result in mosaicism in the placenta or even in a subset of fetal tissues. This low level mosaicism can remain undetected and renders the delineation of a phenotype difficult. In general, the phenotype of cases with UPD is determined by mosaicism, genomic imprinting, nonmendelian inheritance of monogenic disorders, or a combination of these factors. Kotzot (1999) reviewed the entire bibliography of UPD other than that involving chromosome 15 and found a predominance of maternal versus paternal UPD (approximately 3 in 1) and a nonuniform chromosomal distribution.
Molecular GeneticsMatthijs et al. (1996) used an SSCP assay for the molecular diagnosis of 58 patients with SMA, including 8 patients (6 Belgian and 2 Turkish) with SMA III. The SSCP assay discriminates between the SMN gene (600354) and the almost identical centromeric BCD541 repeating unit. In 7 of the 8 SMA III patients, homozygous deletion of exon 7 of the SMN gene was detected. In 6 of the 7, the deletion was associated with homozygous deletion of exon 8, and in 1 it was associated with heterozygous deletion of exon 8. Deletion of the SMN gene was not found in 1 Belgian patient with typical manifestations of SMA III.
In families with proximal spinal muscular atrophy affecting individuals in 2 generations, Rudnik-Schoneborn et al. (1996) examined whether there was pseudodominant inheritance of the regular autosomal recessive form or a dominant form of SMA which is not linked to 5q (see 158590). Four families had affected members in 2 generations who showed SMN gene deletions. The range of variability in severity was striking. In family 4, the father had onset at age 16, whereas the son had onset in the first year; both had deletion of exons 7 and 8 of the SMN gene. Even more striking was family 3, in which the father had onset 'in youth' and the first son was asymptomatic thus far, whereas the second son had onset at 6 months of age (SMA I); all 3 had deletion of exons 7 and 8 of the SMN gene. Two sons had inherited different haplotypes from their affected father and shared identical maternal haplotypes. Rudnik-Schoneborn et al. (1996) noted that, although homozygous deletions in the telomeric copy of the SMN gene can be detected in 95% to 98% of patients with early-onset SMA types I and II (Hahnen et al., 1995), as many as 10% to 20% of patients with type III SMA do not show deletions. Since no molecular genetic test was available to support a locus other than that on 5q, the question of heterogeneity remained an important issue in proximal SMA. Given an incidence of more than 1/10,000 for autosomal recessive SMA (what Rudnik-Schoneborn et al. (1996) referred to as 'SMA 5q'), patients with autosomal recessive SMA have a recurrence risk of approximately 1% to their offspring.
In 2 unrelated French men with onset of SMA type III in adolescence, Fraidakis et al. (2012) identified compound heterozygosity for a deletion of the SMN1 gene (600354.0021) and a missense mutation affecting the same codon in exon 3 (Y130C, 600354.0019 and Y130H, 600354.0020, respectively). Both missense mutations affected highly conserved residues in the Tudor domain, but the patients had a relatively mild form of the disorder. One patient had 1 copy of SMN2 and the other had 2 copies of SMN2. Fraidakis et al. (2012) commented on the relatively mild disease course in these patients and suggested that there were likely compensatory factors affecting expression of the SMN genes.
Modifying Factors
Feldkotter et al. (2002) developed a quantitative test for either SMN1 or SMN2 to analyze SMA patients for their SMN2 copy number and to correlate the SMN2 copy number with type of SMA and duration of survival. The quantitative analysis of SMN2 copies in 375 patients with type I, type II, or type III SMA showed a significant correlation between SMN2 copy number and type of SMA as well as duration of survival. Thus, 80% of patients with type I SMA carried 1 or 2 SMN2 copies and 82% of patients with type II SMA carried 3 SMN2 copies, whereas 96% of patients with type III SMA carried 3 or 4 SMN2 copies. Among 113 patients with type I SMA, 9 with 1 SMN2 copy lived less than 11 months, 88 of 94 with 2 SMN2 copies lived less than 21 months, and 8 of 10 with 3 SMN2 copies lived 33 to 66 months. On the basis of SMN2 copy number, Feldkotter et al. (2002) calculated the posterior probability that a child with homozygous absence of SMN1 will develop type I, type II, or type III SMA.
Wirth et al. (2006) analyzed SMN2 copy number in 115 patients with SMA3 or SMA4 (271150) who had confirmed homozygous absence of SMN1 and found that 62% of SMA3 patients with age of onset less than 3 years had 2 or 3 SMN2 copies, whereas 65% of SMA3 patients with age of onset greater than 3 years had 4 to 5 SMN2 copies. Of the 4 adult-onset (SMA4) patients, 3 had 4 SMN2 copies and 1 had 6 copies. Wirth et al. (2006) concluded that SMN2 may have a disease-modifying role in SMA, with a greater SMN2 copy number associated with later onset and better prognosis.
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.
In a 42-year-old woman with a mild form of SMA type III, despite a homozygous absence of SMN1 exon 7, Prior et al. (2009) identified a homozygous variant (G287R; 601627.0001) in the SMN2 gene. In vitro functional expression studies showed that the variant resulted in the creation of an exonic splicing enhancer element and increased the amount of full-length SMN2 transcripts compared to wildtype. The SMN1 genotype (0 SMN1, 0 SMN2) predicted a more severe disorder (SMA1; 253300), but the SMN2 variant increased SMN2 transcripts, resulting in a less severe phenotype. The same G287R variant was identified in heterozygosity in 2 additional unrelated patients with mild forms of SMA, who were predicted to have a more severe form of the disorder from their genotypes (0 SMN1/1 SMN2 and 0 SMN1, 2 SMN2).
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.
Riessland et al. (2017) identified NCALD (606722), a negative regulator of endocytosis, as a modifying factor in SMA. They identified 5 asymptomatic members of a 4-generation Mormon family from Utah who were homozygous for SMN1 deletions and had 4 SMN2 copies, resembling a genotype associated with type 3 SMA. Linkage analysis combined with transcriptome-wide expression analysis identified significant downregulation of NCALD in these individuals compared to controls. The decreased expression of NCALD was associated with 2 polymorphisms on chromosome 8q: a 2-bp insertion (rs147264092) in intron 1 of the NCALD gene and a 17-bp deletion (rs150254064) located 600-kb upstream of NCALD. These 2 variants were also found in an unrelated patient with a homozygous SMN1 deletion and only 1 copy of SMN2: this genotype would have been predicted to result in perinatal lethality, but the patient survived for 9 months. Cellular studies in SMN-deficient cells showed that knockdown of Ncald triggered motor neuron differentiation and restored neurite and axonal growth. Knockdown of Ncald in several SMA animal models ameliorated SMA-associated pathologic defects and improved endocytosis and synaptic function. The findings suggested that decreased levels of NCALD may act as a protective modifier in SMA, and that perturbed synaptic vesicle endocytosis plays a role in the pathogenesis of the disease.
Population GeneticsIn a carrier screening of autosomal recessive mutations involving 1,644 Schmiedeleut (S-leut) Hutterites in the United States, Chong et al. (2012) identified deletion of SMN1 exon 7 in heterozygous state in 179 individuals among 1,415 screened and in homozygous state in 2, giving a carrier frequency of 0.127 (1 in 8). The carrier frequency in other populations is 1 in 35 (Hendrickson et al., 2009). One adult was homozygous for the SMA-causing deletion. She was previously reported by Chong et al. (2011). At the time of the initial evaluation she was 41 years old and asymptomatic. She subsequently died of cancer at the age of 50 without any symptoms related to SMA, according to her close relatives.
HistoryA dominant form represented by the mother and 2 children described by Ford (1961) may also exist and this may be the same as what has been termed scapuloperoneal amyotrophy (181400).
Animal ModelSimon et al. (2010) analyzed Smn +/- mice, a model of type III/IV SMA, electrophysiologically and histologically to characterize single motor units. Smn +/- mice exhibit progressive loss of motor neurons and denervation of motor endplates starting at 4 weeks of age. Confocal analysis revealed pronounced sprouting of innervating motor axons. As ciliary neurotrophic factor (CNTF; 118945) is highly expressed in Schwann cells, Simon et al. (2010) investigated its role in a compensatory sprouting response and maintenance of muscle strength in this mouse model. Genetic ablation of CNTF resulted in reduced sprouting and decline of muscle strength in Smn +/- mice. The authors concluded that CNTF is necessary for a sprouting response and thus may enhance the size of motor units in skeletal muscles of Smn +/- mice.
Although human SMN1 and SMN2 both encode the SMN protein, the SMN2 gene is unable to compensate for the loss of SMN1 protein in SMA patients. A translationally silent T at nucleotide +6 of SMN2 exon 7 instead of SMN1's C causes the final RNA product to be improperly regulated, with the majority of SMN2 pre-mRNA transcripts lacking exon 7. While humans have both SMN1 and SMN2 genes, mice and other mammals have only a single Smn gene. Using mouse and human SMN minigenes and homologous recombination, Gladman et al. (2010) created a mouse model of SMA by inserting the SMN2 C-to-T nucleotide alteration into the endogenous mouse Smn gene. The C-to-T mutation was sufficient to induce exon 7 skipping in the mouse minigene as in the human SMN2. When the mouse Smn gene was humanized to carry the C-to-T mutation, keeping it under the control of the endogenous promoter, and in the natural genomic context, the resulting mice exhibited exon 7 skipping and mild adult-onset SMA characterized by muscle weakness, decreased activity, and an alteration of muscle fiber size. Gladman et al. (2010) proposed that the Smn C-to-T mouse is a model for the adult-onset form of SMA (type III/IV) known as Kugelberg-Welander disease.