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

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, cosegregated 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.

The natural history of ataxia-telangiectasia (A-T): A systematic review

“…Of the 18246 cases, family history of A-T was reported in 1274 cases ( Table 2 ) and 142 cases (53 studies) had 199 illnesses or symptoms other than A-T in a relative ( Fig 3A ). 1279 cases (109 studies [ 15 , 53 , 65 , 71 , 72 , 78 , 87 , 88 , 95 , 99 – 101 , 109 , 110 , 115 , 118 – 221 ]) were the children of consanguineous relationships, and 186 cases (86 studies [ 23 , 33 , 41 , 50 , 54 , 62 , 63 , 65 , 71 , 74 , 84 , 88 , 95 , 111 , 116 , 142 , 146 , 151 – 153 , 188 , 208 – 210 , 212 , 214 , 216 , 218 , 219 , 221 – 277 ]) were reported as being born of non-consanguineous relationships.…”

“…1219 cases (177 studies [ 18 , 28 , 31 , 33 , 36 , 38 , 41 , 42 , 47 – 49 , 52 , 57 , 59 , 62 , 63 , 65 , 66 , 72 , 73 , 75 , 76 , 80 , 84 , 87 , 95 , 99 , 100 , 103 , 106 , 108 , 109 , 111 , 116 , 118 – 120 , 122 , 123 , 126 , 129 , 131 , 138 – 141 , 143 , 147 , 159 , 165 , 166 , 174 – 176 , 179 , 181 , 190 , 191 , 202 , 206 ,…”

“…62 cases (27 studies [ 33 , 38 , 41 , 49 , 53 , 55 , 72 , 118 , 120 , 123 , 139 , 143 , 186 , 208 , 212 , 213 , 338 , 358 , 366 , 368 , 372 , 388 , 392 , 519 , 528 , 683 , 684 ]) reported an abnormal EMG. The youngest age at which an abnormal EMG was reported was 4 years 0 months.…”