First insights into familial ALS in Egypt reveal genetic variations and disease progression

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive degeneration of motor neurons, leading to muscle weakness and eventually death. While significant strides have been made in understanding ALS genetics, particularly in European populations, there is a gap in knowledge regarding ALS in African populations, including Egypt. This study offers the first insights into the genotype and phenotype of familial ALS (fALS) in Egypt, highlighting early onset, high consanguinity rates, and genetic variations that may contribute to the disease's progression. The findings reveal distinct characteristics compared to European and other African populations, emphasizing the importance of studying ALS genetics across diverse populations to uncover new pathways and mechanisms involved in motor neuron degeneration.

The study included eleven Egyptian families of self-reported Arab origin, with 32 affected subjects. The mean age at onset (AAO) of the first paresis was significantly lower than the estimated mean age of ALS in Africa and at least one decade lower than the AAO of fALS in Europe. The mean age at diagnosis indicated a longer time to diagnosis, likely due to the lack of specialized centers for motor neuron diseases and early disease onset. The relatively high ALSFRS-R score at diagnosis and the increased diagnostic lag suggested a slower disease progression, with some cases reaching 21 years. Consanguinity was reported in 8 out of 11 families, with the parents of the probands being first-degree cousins in 7 families, indicating a coefficient of inbreeding of at least 0.0625.

Genetic testing of 29 participants, including 15 affected and 14 unaffected family members, was conducted for C9orf72 hexanucleotide repeat expansion, ATXN-2 polyQ expansion, and whole exome sequencing followed by variant analysis within a virtual panel comprising 42 known ALS-genes. Eight out of 11 families (72.7%) had variants in known ALS-associated genes, with high consanguinity explaining the discovery of homozygous variants in 5 out of 8 (62.5%) consanguineous families. The frequency of SOD1 variants in the cohort was higher than the general fALS frequency but lower than in certain Asian and European populations. The cohort's general SOD1 phenotype was characterized by spinal onset without cognitive impairment, with disease progression being relatively slow for heterozygous forms but very rapid for the homozygous form.

The study also identified variants in other ALS-associated genes, including C9orf72, TARDBP, SPG11, and MAPT. Notably, only one family showed C9orf72 HRE, supporting its lower frequency in non-European populations. The report describes the implications of these genetic findings on disease progression and potential therapeutic options, particularly the new SOD1 antisense oligonucleotide drug. The high rate of consanguinity in the studied families also has significant therapeutic implications for genetic therapies. This report underscores the need for further research into ALS genetics across African populations and the establishment of population-based ALS registries in African countries to better understand the disease's genetic landscape and develop effective treatments.