Abstract
Amyotrophic lateral sclerosis (ALS) is frequently caused by mutations in the SOD1 gene. Here, we report the first SOD1 variant in Malta, an archipelago of three inhabited islands in southern Europe. We describe a patient with a sporadic form of ALS living on the island of Gozo in which the heterozygous SOD1 c.272A>C; p.(Asp91Ala) variant was detected. The patient had a late onset (79 years), sensory impairments and rapid disease progression culminating in respiratory failure. ALS has not yet developed in any of the three additional family members in which the D91A variant was identified. None of the healthy controls from the Maltese population were found to carry this variant. This report underscores the high prevalence of the D91A variant in Europe, despite the presence of a North-South gradient in its frequency, and confirms that this variant can be associated with dominant cases in Mediterranean countries.
Highlights
Amyotrophic lateral sclerosis (ALS) is an adult-onset, rapidly progressing, neurodegenerative disease
We have recently showed that Maltese ALS patients do not have deleterious variants in C9orf72, SOD1, TARDBP or FUS genes indicating that the most commonly mutated ALS genes globally do not have a major impact on the ALS population in Malta [14]
We describe a sALS patient living in Gozo in which the heterozygous D91A variant was detected
Summary
Amyotrophic lateral sclerosis (ALS) is an adult-onset, rapidly progressing, neurodegenerative disease. All SOD1 deleterious variants show autosomal dominant inheritance except the p.Asp91Ala or D91A variant ( known as D90A; dbSNP155 ID rs80265967), which shows recessive inheritance, initially described in ALS cases from Sweden, Norway and Finland [4]. Heterozygous SOD1 D91A ALS patients have been described in various European populations [5] including those in southern Italy [6, 7]. SOD1 D91A ALS patients have a heterogenous clinical phenotype with homozygotes displaying slow progression with long survival, while heterozygotes have a more variable clinical pattern [4]. Establishing whether SOD1 D91A is pathogenic in the heterozygous state in particular populations, is imperative, considering that patients can be better informed about whether they can benefit from gene-specific treatments presently in development including SOD1-specific antisense oligonucleotide, Tofersen [11]
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