Dear Editor,
Significant progress has been made in understanding the genetics of amyotrophic lateral sclerosis (ALS), particularly in European populations. However, a substantial proportion of familial ALS (fALS) cases remain genetically unexplained. Emerging evidence suggests that ALS phenotypes and genetic risk factors may vary across ethnicities and regions. Investigating the genetic architecture of ALS in understudied populations could uncover new pathways and mechanisms contributing to motor neuron degeneration.
Despite observations of earlier ALS onset, juvenile cases, and slower disease progression in African patients [
1,
2], there is limited data on the genetic landscape of ALS in African populations. Only recently, a Tunisian study on 11 ALS families reported a higher frequency of
C9orf72 than
SOD1 variants, a high frequency of
TARDBP p.G294A, and the presence of homozygous
SOD1 and
TARDBP variants [
3]. Another recent study on Southern Africans reported a higher frequency of
C9orf72 than
SOD1 variants in fALS patients [
4]. We have recently reported a novel homozygous p.Ser69Pro
SOD1 mutation associated with severe young-onset ALS in an Egyptian ALS family [
5]. The current report summarizes the first findings about the genotype-phenotype aspects in an Egyptian fALS cohort.
Eleven Egyptian families of self-reported Arab origin were included in the study, with 32 affected subjects (Supplementary Material). The main characteristics of the whole cohort have been summarized in Table S1. Male to female ratio was 1.28. The mean age at onset (AAO) of the first paresis (41.28 ± 16.9 years) is lower than the estimated mean age of ALS in Africa [
1,
6] and at least one decade lower than the AAO of fALS in Europe. The mean age at diagnosis (44 ± 17 years) indicates a longer time to diagnosis than in Europe and North America, generally 10–16 months. The lack of specialized centers for motor neuron diseases and the early disease onset could explain the diagnostic delay [
7]. The relatively high ALSFRS-R score at diagnosis (34.2 ± 7.8) and the increased diagnostic lag could implicate a slow disease progression, reaching 21 years in some cases. Based on the data available, the rate of decline in ALSFRS-R score is 0.43 points per month (Tab.1). Consanguinity was reported in 8 out of 11 families (72.7%); among them, the proband’s parents were first-degree cousins in 7 families (Table S1, Fig. S1), implicating a coefficient of inbreeding
(F) of at least 0.0625.
A total of 29 participants, including 15 affected and 14 unaffected family members, were genetically tested for C9orf72 hexanucleotide repeat expansion (HRE), ATXN-2 polyQ expansion, and whole exome sequencing followed by variant analysis within a virtual panel comprising 42 known ALS-genes (Table S2). If no class 3 (uncertain significance), 4 (likely pathogenic), or 5 (pathogenic) variants were found in these genes, according to ACMG recommendations, the data were further analyzed on the exome level with no pre-determined gene panel (Supplementary Material). The genotype–phenotype aspects for all families and the results of the variant analysis are summarized in Tab.1 and Table S3, respectively.
Eight out of 11 families (72.7%) had variants in known ALS-associated genes (4
SOD1, 1
C9orf72, 1
TARDBP, 1
SPG11, 1
MAPT). High consanguinity explains the discovery of homozygous variants in 5 out of 8 (62.5%) consanguineous families, but homozygous variants reported in the Middle East, such as
OPTN [
8], were absent in our cohort.
The frequency of
SOD1 variants in our cohort (4 out of 11 families, 36.4%) is higher than the general fALS frequency (20%) but lower than Japanese, Belgian, Chinese, and Scottish fALS pedigrees. Our cohort’s general
SOD1 phenotype is characterized by spinal onset without cognitive impairment. Two out of four families showed bulbar involvement at diagnosis. Disease progression was relatively slow for heterozygous forms but very rapid for the homozygous form. The homozygous p.Ser69Pro variant (family 7) has been recently published separately [
5]. It was associated with juvenile ALS and severe phenotype with rapid progression, following an autosomal recessive pattern of inheritance. Heterozygous missense variants at position 38 (exon 2) have been reported across different populations since 1993. In our study, we report a different amino acid substitution at the same position (p.Gly38Glu) associated with a young onset (33 years) and slow progression (family 5). The variant p.Gly11Ala, found in our cohort (family 11), was associated with spinal onset at 57 years and slow progression and has been recently reported in a Chinese patient [
9]. The p.Glu41Gly variant has been previously reported in an Italian ALS family with spinal onset at 64 years and slow progression [
10], which aligns with the phenotype in family 10.
In our cohort, only one family showed C9orf72 HRE (9%), supporting its lower frequency in non-European populations. The atypical presentation of young age at onset and late bulbar involvement in family 2 does not align with the usual “European” phenotype. TARDBP variants, such as p.Met337Val and p.Ala382Thr, have been found in familial and sporadic ALS patients across populations. While the p.Met337Val variant was associated with bulbar onset and prolonged survival, this cohort reports both spinal and bulbar onset with faster progression for the bulbar onset for the same variant (family 4). SPG11 variants, the most common cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum, have been associated with autosomal recessive juvenile ALS with slow progression. In this cohort, family 8 carried a homozygous SPG11 frameshift deletion associated with young-onset ALS with very rapid progression.
In addition to the known ALS genes mentioned above, exome analysis revealed variants in 3 other candidate genes: ATP13A2, VRK1, and DNAJB2. Their ALS implications are yet to be confirmed. ATP13A2, previously linked to autosomal recessive juvenile-onset atypical Parkinson’s disease (Kufor-Rakeb syndrome), has been recently associated with ALS and ALS-like phenotypes in European patients, highlighting motor neuropathy as a key symptom with ATP13A2 loss-of-function variants. This report describes a homozygous ATP13A2 frameshift variant (p.Ala332Leufs*2) in family 1 with early-onset (24 years) “definite” ALS, where the proband’s heterozygous older brother was phenotypically normal, indicating an autosomal recessive pattern. Following the association of some rare homozygous pathogenic VRK1 variants with spinal muscular atrophy with pontocerebellar hypoplasia (SMA-PCH), homozygous, heterozygous, and compound heterozygous VRK1 variants have been linked to a phenotypic spectrum of motor neuron diseases across various populations. This report describes a likely pathogenic, homozygous VRK1 p.Asp222Gly variant in the catalytic domain, associated with an adult-onset “probable” ALS phenotype characterized by mild symptoms and slow progression without cerebellar signs. The heterozygous proband’s nephews in their 40s were phenotypically normal (family 3).
Homozygous DNAJB2 variants have been linked to autosomal recessive distal SMA and Charcot-Marie-Tooth disease. Given DNAJB2’s role in resolving TDP-43 aggregates, its genetic contribution to ALS has been predicted to reveal variants different from those found in distal hereditary motor neuropathy. This report describes an early-onset, rapidly progressing “definite” ALS case with bulbar onset (family 9), associated with a homozygous DNAJB2 p.Arg62Leu variant, which differs from previously reported variants. No other family members were genetically tested.
This report on fALS in Egypt reveals distinctive characteristics compared to European and other African populations. The high frequency of SOD1 variants suggests potential therapeutic options for Egyptian patients with the new SOD1 antisense oligonucleotide drug. Due to high consanguinity rates, identifying homozygous variants like SOD1 p.Ser69Pro aids in understanding ALS pathogenesis and has important therapeutic implications for genetic therapies. Based on predictions that the highest increase in ALS in the coming years will be in Africa, studying ALS genetics across African populations is mandatory and necessitates establishing population-based ALS registries in African countries.
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