Late-onset autosomal recessive cerebellar ataxia and neuropathy with a novel splicing mutation in the ATM gene.

Hideyuki Shimazaki ,Ryo Sugaya,Imaharu Nakano,Junya Kobayashi,Shigeru Fujimoto

doi:10.31083/j.jin.2020.01.1239

Abstract

Autosomal recessive cerebellar ataxias comprise many types of diseases. The most frequent autosomal recessive cerebellar ataxias are Friedreich ataxia, but other types are relatively rare. We encountered a consanguineous family with two cases of late-onset cerebellar ataxia with neuropathy. We performed whole-exome sequencing in one patient and confirmed by Sanger sequencing in other family members. Neurological examination revealed cerebellar ataxia, hand tremor, and neck dystonia, distal muscle wasting, and diminished tendon reflexes. The patients had no conjunctival telangiectasia or immunodeficiency. Blood examination revealed slightly elevated α-fetoprotein. Brain MRI demonstrated marked cerebellar atrophy and mild brainstem atrophy. The electrophysiologic study and nerve biopsy showed axonal neuropathy. Whole-exome sequencing revealed a novel homozygous missense variant (NM_000051.3: c.496G > C) in the ataxia-telangiectasia mutated gene. This homozygous variant was found in another patient, co-segregated within the family members-this variant results in aberrant splicing (skipping exon 5) on RT-PCR analysis. We identified the ataxia-telangiectasia mutated variant in an adult, late-onset autosomal recessive cerebellar ataxias family. We should consider ataxia-telangiectasia even in late-onset autosomal recessive cerebellar ataxias without telangiectasia or immunodeficiency.

Highlights

We identified the ataxia-telangiectasia mutated variant in an adult, late-onset autosomal recessive cerebellar ataxias family
Autosomal recessive cerebellar ataxias (ARCA) comprise numerous types of diseases that are characterized by early-onset cerebellar ataxia with additional clinical features, including peripheral neuropathy, oculomotor apraxia, involuntary movements, and retinal abnormalities
Ataxiatelangiectasia is relatively rare in Japan (Morio et al, 2009), as well as autosomal recessive cerebellar ataxia type 1 (SYNE1 mutation) (Izumi et al, 2013), ANO10 (Maruyama et al, 2014), and TTC19 (Morino et al, 2014)

Summary

Introduction

Autosomal recessive cerebellar ataxias (ARCA) comprise numerous types of diseases that are characterized by early-onset cerebellar ataxia with additional clinical features, including peripheral neuropathy, oculomotor apraxia, involuntary movements, and retinal abnormalities. Ataxiatelangiectasia is relatively rare in Japan (Morio et al, 2009), as well as autosomal recessive cerebellar ataxia type 1 (SYNE1 mutation) (Izumi et al, 2013), ANO10 (Maruyama et al, 2014), and TTC19 (Morino et al, 2014). AT is characterized by ataxia, conjunctival telangiectasia, susceptibility to infections and malignancy, neuropathy, oculomotor apraxia, and elevated α-fetoprotein (AFP). Late-onset Ataxia-telangiectasia, so-called 'AT variant,' is known to show atypical neurological features (Verhagen et al, 2009)

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Conclusion