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 symmetric 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 symmetric muscle weakness and atrophy. SMA is the second most common lethal, autosomal recessive disease in Caucasians after cystic fibrosis (CF; 219700) (Wirth, 2000).
Fried and Emery (1971) suggested the existence of a distinct form of spinal muscular atrophy intermediate in severity between the infantile form SMA type I and juvenile form SMA III. The intermediate form, which they designated SMA II, ... Fried and Emery (1971) suggested the existence of a distinct form of spinal muscular atrophy intermediate in severity between the infantile form SMA type I and juvenile form SMA III. The intermediate form, which they designated SMA II, is characterized by onset usually between 3 and 15 months and survival beyond 4 years and usually until adolescence or later. Proximal muscle weakness is the cardinal feature as in other forms of spinal muscular atrophy. They presented 14 cases, of whom 2 were sibs. The parents were all unaffected and nonconsanguineous. Imai et al. (1995) demonstrated peripheral but not central conduction abnormalities in patients with SMA II. Pearn et al. (1973) used a method of sib-sib correlation introduced by Haldane (1941) to support the existence of separate 'acute' and 'chronic' forms of spinal muscular atrophy. Hanson and Bundey (1974) described 2 brothers in a sibship of 4. They suggested that SMA I and SMA III may be due to homozygosity of allelic genes, and SMA II could represent the genetic compound. Hausmanowa-Petrusewicz et al. (1985) referred to this as the infantile chronic form of SMA. Imai et al. (1995) demonstrated peripheral but not central conduction abnormalities in patients with SMA II.
Matthijs et al. (1996) used an SSCP assay for the molecular diagnosis of 58 patients with SMA, including 12 patients (7 Belgian and 5 Turkish) with SMA II. This assay discriminates between the SMN gene (600354) and the ... Matthijs et al. (1996) used an SSCP assay for the molecular diagnosis of 58 patients with SMA, including 12 patients (7 Belgian and 5 Turkish) with SMA II. This assay discriminates between the SMN gene (600354) and the almost identical centromeric BCD541 repeating unit. In 11 of the 12 patients, homozygous deletion of exon 7 of the SMN gene was detected. Of these 11, the deletion was associated with homozygous deletion of exon 8 in 10 and with heterozygous deletion of exon 8 in 1. Deletion of the SMN gene was not found in 1 Turkish patient with atypical manifestations of SMA II. Samilchuk et al. (1996) carried out deletion analysis of the SMN gene and the neighboring NAIP (600355) gene in 11 cases of type I SMA and in 4 type II SMA cases. The patients were of Kuwaiti origin. They also analyzed samples from 41 healthy relatives of these patients and 44 control individuals of Arabic origin. Samilchuk et al. (1996) 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. They noted that there findings were consistent with the previously reported observations 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. - Modifying Factors Jedrzejowska et al. (2008) reported 3 unrelated families with asymptomatic carriers of the 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 (601627). 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. 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.