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Retinitis pigmentosa prior to familial ALS caused by a homozygous cilia and flagella-associated protein 410 mutation
  1. Takashi Kurashige1,2,
  2. Hiroyuki Morino3,
  3. Yukiko Matsuda3,
  4. Tomoya Mukai4,
  5. Tomomi Murao1,
  6. Megumi Toko2,
  7. Kodai Kume3,
  8. Ryosuke Ohsawa3,
  9. Tsuyoshi Torii1,
  10. Hiroshi Tokinobu4,
  11. Hirofumi Maruyama2,
  12. Hideshi Kawakami3
  1. 1 Department of Neurology, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan
  2. 2 Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
  3. 3 Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
  4. 4 Department of Neurology, Hiroshima Prefectural Hospital, Hiroshima, Japan
  1. Correspondence to Dr Takashi Kurashige, Neurology, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure 737-0023, Japan; takashi-kurashige{at}

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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.

Genetic analysis

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 …

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  • Contributors TKu, HMo, HMa and HK contributed to the study concept and design. TKu, TMukai, TMurao, MT, TT and HT contributed to clinical data equitation and analysis. HMo, YM, KK, RO, and HK contributed to the genetic analysis. TKu, HMo, HMa and HK contributed to drafting the manuscript and figures.

  • Funding This work was partially supported by a Grant-in-Aid for Scientific Research (B; grant no. JP26293211), the Funding Programme for Next Generation World-Leading Researchers (LS088) from JSPS, a Grant-in-Aid for Scientific Research on Innovative Areas (‘Brain Environment’; grant no. JP23111008) from MEXT, Grants-in-Aid for Research on Rare and Intractable Diseases from the Research Committee on the Establishment of Novel Treatments for Amyotrophic Lateral Sclerosis of AMED (grant no. 16ek0109013h0003) and a Grant from the Takeda Science Foundation.

  • Competing interests None declared.

  • Patient consent for publication Obtained.

  • Ethics approval The Institutional Review Boards of Hiroshima University.

  • Provenance and peer review Not commissioned; externally peer reviewed.