SOD1 D91A variant in the southernmost tip of Europe: a heterozygous ALS patient resident on the island of Gozo

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.

Fig. 1. Geographical distribution of proband and siblings on the Maltese archipelago.

SOD1 D91A proband resided in Victoria, the capital city of Gozo. Most sibs also reside in this locality. One sib has since relocated to mainland Malta.

Fig. 2. Three-generation family pedigree.

The arrow indicates the proband. Circles are females whilst squares are males. A diagonal arrow indicates that the individual is deceased. Filled symbols indicate individuals affected with ALS. SOD1 D91A allele status is indicated for the individuals analysed. In addition to the proband, SOD1 D91A was identified in two brothers and a sister. The wild-type sequence was present in two brothers and a sister. Date of birth and date of death are indicated where available. Two brothers and two sisters of the index patient died at different ages from cancer. No biological material of the deceased individuals was available for analyses.

Fig. 3. Partial SOD1 gene sequence.

Top panel shows wild-type DNA. Middle and bottom panels show a heterozygous cytosine to adenine change at position 272 (c.272A>C) in the ALS affected proband (II:1) and one unaffected sibling (II:10), respectively.