To highlight the diagnostic complexity and importance of genetic testing in an SCA43 case. 

SCAs are genetically heterogeneous disorders with phenotypic variability. Along with cerebellar signs, SCAs may be associated with peripheral neuropathy, cognitive decline and pyramidal/extrapyramidal features. Genetic testing has become instrumental for diagnosis especially in overlapping clinical presentations. 

SCA43 is caused by a dominant mutation in membrane metalloendopeptidase gene (MME) which produces neprilysin, that maintains cellular homeostasis. It presents with late-onset, slowly progressive cerebellar ataxia, parkinsonian features, distal sensorimotor axonal polyneuropathy and cerebellar vermis atrophy on imaging. Recessive mutations in this gene cause Charcot-Marie-Tooth-Disease Type 2 without cerebellar symptoms. 

A 50-year-old man presented in 2020 with 2 years of progressive unsteady gait with misestimation of surroundings, impaired depth perception and dysautonomia. He reported co-existent balance problems, requiring use of a walker by 2022. This was associated with numbness, weakness in both legs (BLE), right hand (RUE) tremor and unexplained urinary retention. Exam showed muffled speech for certain syllables, abnormal eye movements with jerky pursuits and saccadic dysmetria, RUE mild resting and action tremor, bradykinesia, reduced proprioception and pinprick sensation in BLE, reduced RUE swing, wide-based gait with normal reflexes and cognition. Family history was unknown as patient was adopted. 

Preliminary workup for nutritional deficiencies, endocrinologic, rheumatologic and infectious etiologies was negative. MRI brain showed mild atrophy of cerebellar vermis without increased signal within middle cerebellar peduncles/pons. DaTscan and autonomic testing were negative. MRI spine was unremarkable. EMG showed mild sensorimotor axonal polyneuropathy in BLE. CSF studies including autoimmune encephalitis and dementia panels were unrevealing. GeneDx Ataxia Xpanded panel showed pathogenic variant in MME. Patient was eventually diagnosed with SCA43. 

Broader spectrum genetic testing should be considered in phenotypically complex cases where de-novo mutations/reduced penetrance are suspected, with negative/unknown family histories, or late-onset slowly progressive diseases with non-cerebellar symptoms.