ABSTRACT
Introduction: Childhood-onset proximal spinal muscular atrophies (SMAs) are an autosomal recessive, clinically heterogeneous group of neuropathies characterised by the selective degeneration of anterior horn cells. SMA has an estimated incidence of 1 in 10,000 live births. The causative genes are survival motor neuron (SMN) gene and neuronal apoptosis inhibitory protein (NAIP) gene. Deletions of the telomeric copy of SMN gene (SMN1) have been reported in 88.5% to 95% of SMA cases, whereas the deletion rate for NAIP gene (NAIP) is between 20% and 50% depending on the disease severity. The main objective of this study was to genetically characterise the childhood onset of SMA in Iran. Materials and Methods: Molecular analysis was performed on a total of 75 patients with a clinical diagnosis of SMA. In addition to common PCR analysis for SMN1 exons 7 and 8, we analysed NAIP exons 4 and 5, along with exon 13, as a internal control, by bi-plex PCR. Results: The homozygous-deletion frequency rate for the telomeric copy of SMN exons 7 and 8 in all types of SMA was 97%. Moreover, exons 5 and 6 of NAIP gene were deleted in approximately 83% of all SMA types. Three deletion haplotypes were constructed by using SMN and NAIP genotypes. Haplotype A, in which both genes are deleted, was seen in approximately 83% of SMA types I and II but not type III. It was also found predominantly in phenotypically severe group with an early age of onset (i.e., less than 6-month-old). We also report 34 of our prenatal diagnosis. Conclusions: To our knowledge, the present study is the first one giving detailed information on SMN and NAIP deletion rates in Iranian SMA patients. Our results show that the frequency of SMN1 homozygous deletions in Iran is in agreement with previous studies in other countries. The molecular analysis of SMA-related gene deletion/s will be a useful tool for pre- and postnatal diagnostic.
Proximal spinal muscular atrophy (SMA) is one of the most common autosomal recessive disorders. It is characterised by degeneration of the anterior horn cells of the spinal cord, resulting in symmetrical limb muscle atrophy and weakness. SMA has an estimated incidence of 1 in 10,000 live births.1 Its severe form is the most common genetic disorder lethal to infants, whereas its milder form is the second most common paediatric neuromuscular disorder after Duchenne muscular dystrophy. The clinical picture of SMA is quite variable and childhood SMA has been classified into 3 types on the basis of the age of onset and clinical course.2,3 Type I, Werdnig-Hoffmann disease, is the most acute and severe, with an onset before the age of 6 months and death usually occurring before the age of 2. Affected children are unable to sit without support. Type II (the intermediate, chronic form) has an onset before the age of 18 months, and death after 2 years. Affected children are unable to stand or walk without aid. Type III, Kugelberg-Welander disease, is the mild form of SMA, with an onset after 18 months of age. These patients learn to walk unaided for long periods in their lives. An adult-onset form is also known, termed type IV by Pearn et al.4 In the past, a clinical diagnosis of SMA was confirmed by muscle biopsy and sometimes electromyography (EMG). Typically, muscle biopsy shows degeneration of muscle fibres without inflammation, fibrosis or histochemical abnormality. These procedures are invasive, time consuming, and could give non-conclusive results in very young infants. All 3 clinical types of childhood SMA have been mapped by linkage analysis to 5q135-8 with 2 SMA-related genes in the SMA critical region.9,10 This region is duplicated on the long arm of chromosome 5, resulting in 2 copies of survival motor neuron (SMN) and neuronal apoptosis inhibitory protein (NAIP) genes in the human genome. The 2 copies of SMN gene, a telomeric copy (SMN2) and a centromeric copy (SMN1), are nearly identical. The SMN1 gene has been recognised to be responsible for SMA because of homozygous deletions, sequence conversions, or intragenic mutations in SMN1 result in childhood onset of SMA.9-11 The NAIP gene deletions, in exons 5 and 6, tend to be found in cases with more severity in phenotype, and therefore seem to affect the disease severity.12
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