Frequency of FMR1 Premutation Alleles in Patients with Undiagnosed Cerebellar Ataxia and Multiple System Atrophy in the Japanese Population

• Published in: Cerebellum (London, England) Vol. 21; no. 6; pp. 954 - 962
• Main Authors: Almansour, Asem, Ishiura, Hiroyuki, Mitsui, Jun, Matsukawa, Takashi, Matsukawa, Miho Kawabe, Shimizu, Hideaki, Sugiyama, Atsuhiko, Toda, Tatsushi, Tsuji, Shoji
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-12-2022; Springer Nature B.V
• Subjects: Alleles; Ataxia; Atrophy; Biomedical and Life Sciences; Biomedicine; Cerebellar ataxia; Cerebellum; FMR1 protein; Fragile X syndrome; Genetic screening; Intellectual disabilities; Males; Neurobiology; Neurodegenerative diseases; Neurology; Neurosciences; Original Article; Patients; Tremor; CGG repeats; Ataxia; Fragile X; FXTAS
• ISSN: 1473-4230; 1473-4222; 1473-4230
• DOI: 10.1007/s12311-021-01329-5

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder caused by
FMR1
premutation expansion of CGG repeats. FXTAS can be misdiagnosed with many neurodegenerative disorders manifesting with cerebellar ataxias owing to their overlapping clinical and radiological features. The frequency of the
FMR1
premutation allele in Japan has not been fully determined. Herein, we aimed to determine the frequency of
FMR1
premutation alleles in Japanese patients with undiagnosed cerebellar ataxia and multiple system atrophy, using repeat-primed PCR in 186 patients with adult onset of undiagnosed cerebellar ataxia and 668 patients with multiple system atrophy, to identify expanded CGG repeats as well as to detect AGG interruptions within the expanded alleles. The size of expansions was estimated using fragment length analysis of PCR products obtained by conventional PCR employing a pair of unique primers flanking the repeat sequence. We identified
FMR1
premutation alleles in three male patients. One patient revealed 84 repeat units with one AGG interruption and another patient showed 103 repeat units. Both had presented with sporadic cerebellar ataxia, giving an estimated frequency of 3.7% among Japanese male patients with sporadic cerebellar ataxia with age at onset above 50 years. One patient with the clinical diagnosis of multiple system atrophy harbored 60 repeat units with four AGG interruptions.
FMR1
intermediate alleles were observed in two males and one female among the multiple system atrophy patients. We found that genetic tests for
FMR1
premutation should be considered in Japanese male patients with cerebellar ataxia with the age at onset above 50 years.