MOTOR NEURON DISORDERS AND NEUROPATHIES: EP.243 Young-onset SOD1-ALS caused by a novel homozygous mutation, a family report

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal disease primarily affecting motor neurons. In Europe and North America, about 5 % of ALS patients report a positive family history (familial ALS, fALS). The remaining is classified as sporadic ALS (sALS). A genetic basis for ALS has been demonstrated for both fALS and sALS and variants in >40 genes have been associated with ALS. Following linkage analysis in families with Mendelian dominantly inherited fALS, mutations in the gene encoding the free radical scavenging enzyme Cu/Zn superoxide dismutase 1 (SOD1) were discovered in 1993. Since then, more than 200 mutations in SOD1 have been described. We here report a novel SOD1 homozygous mutation with an early onset, rapidly progressive phenotype in a family with two affected members from southern Egypt. The parents are cousins with three children. At age 10 years old, the youngest son initially developed a foot drop of one limb followed by a rapidly progressive disease affecting the other limbs and bulbar innervated muscles. He died from respiratory failure at the age of 12 years. At age 25 years, the eldest sister developed ALS with a similar phenotype. She is still alive at age 28 years. Both patients were diagnosed to have ALS according to the revised El Escorial criteria. SOD1 DNA analysis was performed using bi-directional Sanger sequencing of the 5 exons and adjacent 30-50 bp intronic sequences. Mutations in a number of other ALS-causing genes were excluded. Genetic screening revealed a novel exon 3 homozygous p.Ser69Pro SOD1 mutation in the affected female patient; while her parents and unaffected younger brother are heterozygous for the mutation (no sample is available from the deceased son). So, we report a novel homozygous p.Ser69Pro SOD1 mutation associated with early onset of asymmetrical weakness of lower limbs with a rapidly ascending paresis. It is likely that her deceased brother had the same genotype. The early onset and rapidity of evolution of disease suggest a strong dose-effect of the mutant SOD1 protein. Exon 3 mutations in SOD1 are frequently associated with reduced disease penetrance but we cannot exclude the possibility that the p.Ser69Pro SOD1 also predisposes heterozygous individuals for ALS later in life.