Abstract
Amyotrophic lateral sclerosis is the most common motor neuron disease of the adulthood. Genetic analyses performed on cases with sporadic ALS (sALS) and familial ALS (fALS) have revealed mutations most commonly in the genes C9orf72, SOD1, TARDBP, FUS, and UBQLN2. The aim of this study was to investigate the presence and incidence of these most common genomic alterations in these genes of 30 ALS cases. Increase in the number of hexanucleotide repeats within the gene C9orf72 was investigated using the fragment analysis method. A heterozygote c.-45 + 162_-45 + 163insGGGGCC alteration was observed in the first intron of the C9orf72 gene in only two sALS cases (6.6%), c.72 + 133C>T alteration was observed in the first intron of the SOD1 gene in six fALS and two sALS cases (26.6%), a c.169 + 41C>A alteration was observed in the second intron of the same gene in one case, a c.239 + 34A>C alteration was observed in the third intron of the same gene in three fALS cases (10%), and a c.714 + 67_714 + 68insG alteration was observed in the fifth intron of the TARDBP gene in six sALS cases (20%). Three different genomic alterations were detected in the FUS gene; two silent variants p.G49G (c.147C>A) in 3 cases (10%) and p.Y97Y (c.291C>T) in 25 cases (83%) and an intronic variant c.1067-61T˃C in 4 cases (13%). A novel missense variant, p.G457H (c.1371G>C), was observed in the UBQLN2 gene in one case with sALS. Our study has revealed three novel and previously reported genomic alterations in the ALS-related genes.
Highlights
Amyotrophic lateral sclerosis (ALS) is a progressive and clinically heterogeneous neurodegenerative disease that may result in muscle weakness, paralysis, and death due to affected motor neurons within the cerebral cortex, brain stem, and spinal cord (Brooks, 1994)
It is known that both the familial and sporadic cases have the same clinical and pathological findings, and many mutations observed in familial ALS cases have been detected in sporadic ALS cases
The most extended family among familial ALS (fALS) cases was family number I, which included 4 cases with the precise diagnosis (III-1, III-5, III-8, and IV-5), 2 pre-symptomatic individuals (IV-1 and IV-7), a 35-year-old male individual with affected father and brother (IV-6), a 50-year-old female individual whose brother had the diagnosis (III-2), and an 80-year-old individual being the oldest member of the family (II-1)
Summary
Amyotrophic lateral sclerosis (ALS) is a progressive and clinically heterogeneous neurodegenerative disease that may result in muscle weakness, paralysis, and death due to affected motor neurons within the cerebral cortex, brain stem, and spinal cord (Brooks, 1994). The incidence and prevalence of the disease have been reported to be approximately 2/100,000 and 5/100,000 worldwide. In the USA, approximately 25,000 patients with ALS have been reported and the disease has been classified as the “orphan” disease since it is below the limit of 200,000 (Rowland & Shneider, 2001). The cases' cause of death is due to respiratory distress developed as a result of weakness in respiratory muscles. Autosomal recessive, and X-linked inheritance of the disease demonstrate the genetic heterogeneity of the disease among cases with familial ALS (Maruyama et al, 2010)
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