Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is an autosomal recessive disorder with a carrier frequency of 1/50, which affects 1/6000

to 1/10,000 live-born children. Thus, SMA is the second most common autosomal recessive lethal disease after cystic fibrosis. In this disorder, anterior horn cells degenerate, resulting in hypoto-nia, symmetrical muscle weakness, and wasting of voluntary muscles. The childhood spinal muscular atrophies are divided into three types (I, II, III) according to age of onset, rate of progression, and age at death. Historically, the diagnosis and classification has been made on clinical and pathological findings. Recent advances in the understanding of the genes responsible for SMA might allow confirmation of the diagnosis of SMA in symptomatic individuals and prenatal or presymptomatic diagnosis in family members.

Spinal muscular atrophy I (SMA I) or Werdnig-Hoffman disease represents 25% of all SMA cases. Onset occurs prena-tally or in early infancy, with the mean onset at 1.5-3 mo. Muscle weakness and hypotonia are severe and reflexes are absent. The disease progresses rapidly with death occurring between 9 mo and 3 yr.

Spinal muscular atrophy II is an intermediate form; infants usually develop normally for 6 mo before disease onset. These infants could learn to sit alone, but do not walk unassisted. Survival into adulthood has been reported.

Spinal muscular atrophy III (Kugelberg-Welander juvenile spinal muscular atrophy) has onset between the ages of 3 and 18 yr or later and has a slower clinical course (42). Atrophy and weakness of proximal muscles occur first and could be followed by distal involvement.

4.1. GENETICS All three forms of SMA are linked to 5q12-13 and might be allelic (43). Four genes, the survival motor neuron gene (SMN) (44), neuronal apoptosis inhibitory protein (NAIP) (45), BTF2p44 (46), and a putative RNA binding protein H4F5 (47), are mapped to this region. Since the cloning and sequencing of SMN gene in 1996, much has been learned about the role of this gene in the genetics and pathogenesis of SMA (48). A centromeric (SMN2) and a telomeric (SMN1) copy of the SMN gene is present in a 500-kb chromosomal region containing an inverted duplication (44). Additionally, the genes for NAIP, BTF2p44, and H4F5 are also present as a centromeric and telomeric copy, in the same chromosomal region. The telomeric copy of SMN (SMN1) and/or NAIP, BTF2p44, and H4F5 have been shown to be deleted in affected SMA patients, although it is now well established that mutations or deletions in SMN1 are the major contributors to disease in SMA. Single-strand conformational polymorphism (SSCP) analysis of the SMN gene have shown that approx 96% of SMA type I, 94% of type II, and 82% of type III patients have homozygous deletions of exons 7 and/or 8 of the telomeric copy of the SMN gene (SMN1) (49). Five percent of patients with SMA present as compound heterozygotes with a subtle intragenic mutation on one chromosome and a deletion/gene conversion on the other chromosome. In contrast to deletions, gene conversions result in an increase in centromeric SMN gene (SMN2) copy number and are associated with milder phe-notypes seen in SMA III. However, there have also been reports of asymptomatic parents of affected children who have the same homozygous deletions in this region (49) and cases of severe forms of SMA associated with an increased SMN2 copy number. Additionally, there has been a report of one member of a sibpair having SMA I and the other having SMA III (50). This implies that there might be other modifying genes involved in the expression of SMA that influence the severity of expression of this disease. NAIP, which is located in the proximal portion of the SMA region, is reported to have deletions in 67% of type

I SMA chromosomes, but only 2% of non-SMA chromosomes (45). NAIP is more commonly deleted in SMA I than in types

An emerging cellular role of SMN protein in spliceosomal snRNP biogenesis places SMA into a growing group of disorders of RNA metabolism along with Fragile X syndrome and myotonic dystrophy. This is based on the interaction of SMN with several spliceosomal Sm core proteins as well as auto oligomgerization. Exons 6 and 7 of the SMN gene contain the functionally relevant domain(s) reponsible for the auto-oligomerization of the SMN protein. Exon skipping and/or mutations within this region have been shown to result in reduced self-association and loss of protein function (52). The molecular basis for the inability of SMN2 to compensate for the loss of SMN1 exon 7 has recently been understood. A C > T transition in SMN2 exon 7 disrupts an exonic splicing enhancer, a cis element that normally promotes inclusion of specific exons in pre-mRNA splicing. This results in the skipping of SMN2 exon 7 and alters the molecular structure of the SMN2 protein product (53). The role of the other genes in the development of SMA is not yet clearly defined, although it has been postulated that a mutation in NAIP could lead to a failure of normally occurring inhibition of motor neuron apoptosis (45).

4.2. MOLECULAR DIAGNOSIS Historically, linkage analysis was utilized for prenatal diagnosis of SMA in affected families (54). Recently, identification of sequence differences has been used to distinguish SMN1 from SMN2. The sequence difference includes eight nucleotides, five of which are intronic and three of which are exonic, located within exons 6, 7, and 8 (44,48). These nucleotide differences are used for the molecular diagnosis of SMA by restriction enzyme digestions. This PCR-based assay includes DraI and DdeI digestions to distinguish between SMNI and the highly homologous SMN2. These approaches detect homozygous deletions in the SMN gene and so can be used to confirm the diagnosis in affected individuals. However, these strategies cannot be used for carrier testing or to differentiate between a true deletion and a gene conversion of SMN1 to SMN2. Use of this assay for prenatal detection of SMA is currently hampered by reports of asymptomatic individuals with homozygous deletions (47,55). Testing strategies using SSCP analysis to screen for abnormalities of exons 7 and 8 in the SMN gene followed by confirmatory sequencing studies or restriction enzyme digestion to distinguish centromeric and telomeric copies of exons 7 and 8 in SMN gene have been evaluated (55). However, the SSCP approach is not used because of the added disadvantage of detecting polymorphisms that resemble homozygous deletions of SMN exon 7 (56).

Dosage analysis for the quantitative determination of a single-copy nondeleted SMN1 gene has recently been developed and is available in a limited number of clinical laboratories (57). However, these carrier tests do not detect 4% of SMA carriers who have two copies of SMN1 on one chromosome and a null allele on the other, because they appear to be normal based on the SMN1 dosage analysis. Additionally, these assays do not identify carriers of SMA harboring subtle intragenic mutations in the SMN1 gene. Many investigators are working to fully elucidate the genetic mechanism of this disorder, which should result in improved molecular diagnosis.

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