Objective: To present a unique case of ataxia that adds to the genotypic variants associated with the GRM1 gene implicated in SCA44

Background: Heterozygous dominant mutations in GRM1 assigned to the locus SCA44 were identified in two different families presenting with adult onset cerebellar ataxia with pyramidal signs by Watson et al in 2017. We report a novel variant in the same gene at exon 5, c.1453C>A (p.Gln485Lys) in a patient with adult onset of cerebellar features

Method: We present a case report of a 71 year old Caucasian woman with a family history of gait impairment and falls in her mother and maternal grandmother during their late middle ages. The patient reported the onset of unexplained falls at the age of 66 attributed to a subjective sense of imbalance. Three years later she noticed tremors in her hands. The progressive nature of her tremors and gait imbalance made her quit her job as a hairdresser. She has had word finding difficulty and short-term memory impairment more recently in the last year and now uses a walker most of the time

Results: Physical exam was pertinent for spooning of fingers of left hand with arms outstretched, postural and mild intention tremors in hands, associated and mirror movements of the extremities, mild dysmetria with finger chase and heel shin rub, ataxic gait, generalised hyper-reflexia, decreased pin prick sensation upto calves and absent vibration in the toes and ankle joints with intact proprioception
Neuroimaging with MRI Brain and C-spine and metabolic lab work up was unremarkable. Given her family history and clinical presentation, genetic testing was pursued. Nucleotide repeat expansions were not detected. However based on whole exome capture (WEC), next generation sequencing (NGS) and targeted analysis of a comprehensive list of approximately 1000 genes currently associated with ataxia, a novel heterozygous variant in the same gene at exon 5; c.1453C>A (p.Gln485Lys) was detected

Conclusion: This case report expands the phenotypic spectrum of ataxia associated with GRM1 variants. Our patient had an older age of onset (previous descriptions mention 20-50 yrs) and had other features of hyper-reflexia, distal peripheral neuropathy and cognitive impairment. It also emphasizes the role of the metabotropic glutamate receptor(mGluR1) in cerebellar function which is encoded by GRM1 and offers avenues for exploration of therapies by manipulating glutamatergic signalling pathways

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-novel-grm1-variant-associated-with-autosomal-dominant-cerebellar-ataxia-adca/