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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 C21orf2.2CFAP410 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.
We performed high-density single nucleotide polymorphism (SNP) typing and homozygosity fingerprinting as previously reported.4 The patients had the identity by the decent (IBD) segments of the patients (II-2 and II-6) in chromosomes 1, 12, 15 and 21. Whole-exome sequencing (WES) also revealed 53 homozygous specific variants. Among these variants, homozygous variants of CFAP410 and paxillin (PXN) exist in IBD segments. Combined annotation dependent depletion method also generated higher scores of CFAP410 (26.4) and PXN (25.9). In in silico analysis, a homozygous CFAP410 variant (c.319T>C, p.Y107H) was evaluated as a damaging variant by both PolyPhen-2 and SIFT, while a PXN variant was evaluated as benign by SIFT. No mutations were identified in previously reported causative genes of ALS. The repeat-primed PCR could not detect the large C9orf72 repeat expansion. Sanger sequencing for patients and the non-affected sibling (II-4) revealed that the patients had a homozygous CFAP410 variant and that the non-affected sibling had a heterozygous CFAP410 variant (figure 1B). CFAP410 was reported as a susceptible gene by previous GWAS of ALS, thus, we evaluated this variant as causative. The CFAP410 mutation is located in exon 4, corresponding to the leucine-rich repeat C-terminal domain (LRRCT) (figure 1C).
The index case (II-2) is a patient at the sixties who presented with slowly progressive muscle weakness, dysphagia and RP. She had RP in her childhood. Fasciculation was observed at her upper extremities at the fifties, and muscle weakness of her extremities began 3 years after fasciculation was observed. At the sixties, she showed muscle weakness, hyperactive deep tendon reflexes, a positive jaw reflex and dysphagia. Chest X-ray (CXR) (figure 1D) and CT revealed no bone and brain abnormalities. Needle electromyography (nEMG) showed both active and chronic denervations in the cervical and lumbosacral regions. Wechsler Adult Intelligence Scale version 3 (WAIS-III) revealed that she had higher verbal IQ (129). She was diagnosed as ALS. She started to use a wheelchair, long-term nutrition by percutaneous endoscopic gastrostomy and non-invasive positive pressure ventilation. Two years later, her head CT did not show any significant change. Four years later, she was bedridden.
Her sister (II-6) also had RP in her childhood. She was diagnosed as Crohn’s disease at the fourth decade. At the fifties, she showed muscle weakness of the extremities and was ambulatory without assistance. Fasciculation was scattered in her bilateral hands, and her jaw jerk reflex and deep tendon reflexes of the upper extremities were hyperactive. CXR and CT also revealed no bone abnormalities. nEMG showed both active and chronic denervations in the cervical region, and chronic denervation in the truncal and lumbosacral regions. WAIS-III revealed that she had higher verbal IQ (124). Head MRI showed no atrophies including precentral gyrus (figure 1E), but motor cortex showed low signals in T2-weighted imaging (figure 1F). She was diagnosed as ALS. Seven years later, she was still ambulatory without assistance. Her visual field became narrow, and fundus photos and optical coherence tomography through the macular area showed thinning of the photoreceptor layer outside the macula and disappearance of the ellipsoid zone out of the macular area (figure 1G).
A large GWAS approach found that CFAP140 was a susceptible gene for ALS,2 but as yet, there have been no reports of patients with ALS with mutations of CFAP410. For the first time, we present the clinical manifestations of patients with autosomal recessive ALS with RP harbouring a homozygous causative mutation of CFAP410 (c.319T>C, p.Y107H).
High-density SNP typing, homozygosity fingerprinting and WES showed the homozygous variants of both CFAP410 and PXN. The variant of PXN was evaluated as a benign variant by SIFT, while the variant of CFAP410 was evaluated as probably damaging by both PolyPhen-2 and SIFT. This CFAP410 mutation is located in LRRCT (figure 1C), whose dysfunction causes reduced levels and affected localisations of CFAP410 protein products.3 In addition, CFAP410 interacts with NEK1, whose homozygous loss-of-function variants are implicated in up to 2% of patients with ALS. Patients with NEK1 mutation did not show dementia,5 which were similar to our patients.
On the other hand, compound heterozygous CFAP410 variants (formed by c.319T>C (p.Y107H) and other variants) locating in both LRRCT and extra-LRRCT were previously identified in patients with SMDAX and RD.3CFAP410 variants identified in both SMDAX and sporadic ALS were only c.218G-C transition (p.R73P) existing in the LRR domain of the CFAP410 protein.2 3 In addition, homozygous or compound heterozygous variants existing only in the LRRCT of CFAP410 were not previously reported in both sporadic ALS and SMDAX.
In conclusion, we provided the first description of siblings with RP and ALS caused by CFAP410. They showed RP until their fourth decade and muscle weakness of their extremities started more than 10 years after their diagnosis of RP.
We thank the study family for their generous participation.
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.
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