Objective: To report a novel heterozygous missense mutation of TGM6 in a patient with cerebellar ataxia.

Background: Mutations in TGM6 have been recently implicated in the pathogenesis of spinocerebellar ataxia type 35 (SCA35), a rare autosomal dominant disease, marked by cerebellar degeneration. The associated phenotype includes slow progressive postural instability and incoordination of gait, cerebellar dysarthria, dysmetria, saccadic slowing and pyramidal signs. TGM6, a member of the transglutaminase superfamily specifically expressed in the central nervous system, is involved in proteins cross-linking. Even though it is established that mutations of TGM6 described so far reduce transglutaminase activity, the precise molecular pattern impaired is still unclear.

Method: We performed a neurological evaluation and genetic analysis of a patient with late-onset, progressive cerebellar ataxia and pyramidal tract signs.

Results: A novel TGM6 heterozygous mutation (R342W) was detected in a patient with late-onset, progressive cerebellar ataxia, pyramidal tract signs, cerebellar dysarthria and ocular dysmetria. A cerebellar atrophy was confirmed by brain imaging. The mutation, located at a highly conserved position, was rare (AF= 0.02%) and predicted as pathogenic by in silico tools.

Conclusion: In summary, we described the clinical phenotype of an Italian SCA35 patient, who was confirmed to have a novel heterozygous missense mutation of TGM6. Despite its rare frequency among general population, we suggest to consider SCA35 genetic testing in case of undiagnosed cerebellar ataxia.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-novel-tgm6-heterozygous-mutation-in-a-patient-with-cerebellar-ataxia/