Article

Multiple System Atrophy and Amyotrophic Lateral Sclerosis in a Family With Hexanucleotide Repeat Expansions in C9orf72

JAMA neurology 04/2014; 71(6). DOI: 10.1001/jamaneurol.2013.5762
Source: PubMed

ABSTRACT

Importance:
Here we report a family with coexistence of multiple system atrophy (MSA) and amyotrophic lateral sclerosis (ALS) with hexanucleotide repeat expansions in C9orf72.

Observations:
A 65-year-old woman had a 2-year history of ataxia with autonomic dysfunction but without motor neuron signs. She was diagnosed as having MSA based on her clinical history and the hot cross bun sign on brain magnetic resonance imaging. Her 62-year-old brother had progressive weakness, fasciculations, hyperreflexia, and active denervation on electromyography without cerebellar ataxia. He was diagnosed as having ALS. Both patients had a greater than 1000/2 hexanucleotide expansion in C9orf72.

Conclusions and relevance:
Patients with hexanucleotide repeat expansions in C9orf72 can present with MSA as well as ALS or frontotemporal dementia. We report this family with coexisting MSA and ALS, highlighting the phenotypic variability in neurologic presentations with hexanucleotide repeat expansions in C9orf72.

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    • "The C9ORF72 hexanucleotide repeat expansion might, at most, only play a minor role in cerebellar ataxia, and the rarity of the co-occurrence of the mutation and cerebellar ataxia suggests that other environmental or genetic modifiers are influencing the manifestation. For example, in the case reported by Goldman, et al.[9], other environmental or genetic modifiers might have contributed to the pathological process of C9ORF72 mutation. Recently, transmembrane protein 106B (TMEM106B) was reported to be a genetic modifier of C9ORF72 hexanucleotide repeat expansion mutation in FTD[17]. "
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    ABSTRACT: The GGGGCC hexanucleotide expansion in the C9ORF72 gene is the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in Caucasian populations. The phenotypic spectrum of C9ORF72 hexanucleotide repeat expansion mutation has been reported to include parkinsonian syndrome, Huntington's disease-like syndrome and dementia syndrome. Although few individuals with cerebellar ataxia have also anecdotally been found to harbor the mutation, the relationship between the mutation and cerebellar ataxia awaits further clarification. We hereby screened for the presence of the C9ORF72 hexanucleotide repeat expansion in 331 patients with multiple system atrophy-cerebellar variant and 98 unrelated patients with molecularly un-assigned spinocerebellar ataxia in Taiwan utilizing a repeat-primed polymerase chain reaction assay. We found that none of the 429 patients had the C9ORF72 hexanucleotide repeat expansion mutation. Therefore, our study does not support that the mutation plays a significant role in cerebellar ataxia. Copyright © 2014. Published by Elsevier B.V.
    Full-text · Article · Nov 2014 · Journal of the Neurological Sciences

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