Abstract
Spinal muscular atrophy (SMA) is an autosomal recessive inherited disorder caused by alterations in the survival motor neuron I (SMN1) gene. SMA patients are classified as type I-IV based on severity of symptoms and age of onset. About 95% of SMA cases are caused by the homozygous absence of SMN1 due to gene deletion or conversion into SMN2. PCR-based methods have been widely used in genetic testing for SMA. In this work, we introduce a new approach based on TaqMan(®)real-time PCR for research and diagnostic settings. DNA samples from 100 individuals with clinical signs and symptoms suggestive of SMA were analyzed. Mutant DNA samples as well as controls were confirmed by DNA sequencing. We detected 58 SMA cases (58.0%) by showing deletion of SMN1 exon 7. Considering clinical information available from 56 of them, the patient distribution was 26 (46.4%) SMA type I, 16 (28.6%) SMA type II and 14 (25.0%) SMA type III. Results generated by the new method was confirmed by PCR-RFLP and by DNA sequencing when required. In conclusion, a protocol based on real-time PCR was shown to be effective and specific for molecular analysis of SMA patients.
Highlights
Spinal muscular atrophy (SMA) is a genetic disorder characterized by symmetric proximal muscle weakness due to degeneration of the anterior horn cells of the spinal cord
We evaluated exon 8 of the survival motor neuron gene (SMN) genes by PCR-RFLP analysis, and the presence of SMN1 exon 8 was detected in 8 out of these 58 confirmed SMA patients (13.8%), indicating the occurrence of gene conversion events in these patients
Molecular analysis to detect the lack of SMN1 has been proven to be a specific tool for the diagnosis of SMA patients
Summary
Spinal muscular atrophy (SMA) is a genetic disorder characterized by symmetric proximal muscle weakness due to degeneration of the anterior horn cells of the spinal cord. Based on the severity of symptoms and age of onset, SMA is divided into four clinical types (Zerres and RudnikSchoneborn, 1995). Type I [Werdnig-Hoffman disease, Online Mendelian Inheritance in Man (OMIM) 253300] is the most severe form, characterized by muscle weakness and hypotonia within first days/months of life, resulting in death before the age of two. Type II (OMIM 253550) is characterized by proximal muscle weakness with onset between six to 12 months after birth, inability to walk and variable survival. Type III (Kugelberg-Welander disease, OMIM 253400) is marked by proximal muscle weakness after the age of 18 months, with survival to adulthood. Type IV (OMIM 271150) shows similar findings to those described for SMA III, except that the onset of muscle weakness usually only occurs in the second or third decade of life. SMA is an autosomal recessive disease with a prevalence of 1 in 10,000 and a carrier incidence of 1 in 50 (Ogino and Wilson, 2002)
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