Retinitis pigmentosa prior to familial ALS caused by a homozygous cilia and flagella-associated protein 410 mutation

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by the loss of both upper and lower motor neurons. Approximately 10% of patients with ALS have a family history of the disease, and 22 genes have already been reported to be implicated in ALS.1 In previous reports, some of the genes implicated in ALS were associated with visual dysfunctions; however, no cases have yet reported patients presenting clinically both ALS and ocular abnormalities.1 Recently, a large case-controlled genome-wide association study (GWAS) of ALS revealed cilia and flagella-associated protein 410 ( CFAP410 ), previously called as C21orf2 .2 CFAP410 is causative for axial spondylometaphyseal dysplasia (SMDAX), which presents with retinitis pigmentosa (RP), and retinal dystrophy (RD) with or without macular staphyloma.3 However, no hereditary ALS cases have yet reported CFAP410 variants. In this letter, we provide the first description of siblings with RP and ALS with the causative CFAP410 mutation. They showed RP until their fourth decade and muscle weakness of the extremities started more than 10 years after the diagnosis of RP. The pedigree chart of the affected family is presented in figure 1A. Their parents (I-1 and I-2) were consanguineous and neurologically healthy. Figure 1 (A) Pedigree chart of the affected family. Shaded boxes represent affected members. Symbols having diagonal lines represent deceased individuals. Unaffected family members exhibited no abnormalities during their medical examinations. (B) Sanger sequencing revealed that the patients had exon 4 of a CFAP410 homozygous variant (c.319T>C, p.Y107H) and that the non-affected sibling had a heterozygous variant of CFAP410 . (C) Heterozygous CFAP410 variants of amyotrophic lateral sclerosis (ALS) (black) were previously detected except for exon 2. On the other hand, causative …