Objective: We describe a patient with late-onset ataxia, cognitive impairment, and parkinsonism with a novel missense variant in FAT2, a gene implicated in spinocerebellar ataxia (SCA) 45.

Background: SCAs are heterogeneous autosomal dominant neurodegenerative disorders that manifest with cerebellar dysfunction, and in some cases, pyramidal tract signs, cognitive impairment, neuromuscular conditions, or movement disorders [1]. Of the 11 reported cases of SCA45 with FAT2 variants, six are classified as likely pathogenic, and most are associated with late-onset, pure cerebellar ataxia [2-6].

Method: Chart review was performed to identify relevant history, examination, diagnostic workup, and management.

Results: A 64-year-old man presented with two years of progressive gait instability, falls, and intermittent muscle twitching. Within one year, he exhibited cognitive decline. Comorbid diagnoses included diabetes, OSA on CPAP, HTN, and dyslipidemia. Family history was notable for similar symptoms in his mother, who was diagnosed clinically with Huntington’s disease (HD) in her 30s prior to the availability of genetic testing. Exam revealed slowed smooth pursuit and saccades, bradykinesia, limb myoclonus, and limb/gait ataxia. Work-up for toxic/metabolic, demyelinating, infectious, paraneoplastic, and autoimmune-related etiologies was negative. Genetic testing for HD and dentatorubropallidoluysian atrophy was negative. EMG/NCS were normal. MRI brain showed bilateral ventriculomegaly and hippocampal atrophy and a midbrain to pons ratio of 0.52. DaT scan was normal. FDG-PET scan showed diminished activity in the cerebellum. Neuropsychological testing confirmed multi-domain impairment. Genetic testing revealed a heterozygous missense mutation (c.9862T>A; p.Phe3288Ile) in the FAT2 gene. He was treated with carbidopa-levodopa with noticeable improvement in gait and balance and referred for physical therapy for evaluation and treatment.

Conclusion: Our patient presented with late-onset cerebellar ataxia, cognitive impairment, and parkinsonism, different from previously reported cases of SCA45. Genetic testing revealed a new variant in a cadherin-repeat domain of FAT2. Although classified as a variant of unknown significance, his family history raises the possibility of heredity and likely pathogenicity. This case adds to the body of knowledge regarding FAT2 mutations and hereditary cerebellar ataxia.

References: 1. Rossi M, Perez-Lloret S, Doldan L, Cerquetti D, Balej J, Millar Vernetti P, Hawkes H, Cammarota A, Merello M. Autosomal dominant cerebellar ataxias: a systematic review of clinical features. Eur J Neurol. 2014 Apr;21(4):607-15. doi: 10.1111/ene.12350. Epub 2014 Feb 12. PMID: 24765663.
2. Nibbeling EAR, Duarri A, Verschuuren-Bemelmans CC, et al. Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia. Brain 2017;140(11):2860–2878. https://doi.org/ 10.1093/brain/awx251.
3. Rafehi H, Szmulewicz DJ, Bennett MF, et al. Bioinformatics-based identification of expanded repeats: A non-reference Intronic Pentamer expansion in RFC1 causes CANVAS. The American Journal of Human Genetics 2019; 105(1):151–165. https://doi.org/10.1016/j.ajhg.2019.05.016.
4. Tonholo Silva TY, Rosa ABR, Quaio CR, Verbeek D, Pedroso JL, Barsottini O. Does SCA45 Cause Very Late-Onset Pure Cerebellar Ataxia? Neurol Genet. 2021 Mar 26;7(3):e581. doi: 10.1212/NXG.0000000000000581. PMID: 33884300; PMCID: PMC8054959.
5. Ganguly J, Mukherjee S, Basu P, Mondal B, Chatterjee K, Roy A, Pande P, Kumar H. Think of SCA45 in Late-Onset Familial Ataxias: The First Report from the Indian Subcontinent with a Novel Variant. Mov Disord Clin Pract. 2022 Oct 10;9(8):1140-1143. doi: 10.1002/mdc3.13580. PMID: 36339299; PMCID: PMC9631847.
6. Ameri A, Rosenbaum M, Kirby A. A Patient with Late-Onset Cerebellar Ataxia and a Novel FAT2 Gene Variant Concerning for Spinocerebellar Ataxia Type 45: A Case Report (P9-11.009). Neurology. 2023;100(17_supplement_2):2113.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/mixed-cerebellar-ataxia-in-a-patient-with-a-novel-fat2-gene-variant-associated-with-sca45/