The Neurodevelopmental and Motor Phenotype of SCA21 (ATX-TMEM240).

TitleThe Neurodevelopmental and Motor Phenotype of SCA21 (ATX-TMEM240).
Publication TypeJournal Article
Year of Publication2020
AuthorsBurdekin ED, Fogel BL, Jeste SS, Martinez J, Rexach JE, Distefano C, Hyde C, Safari T, Wilson RB
JournalJ Child Neurol
Date Published2020 12
KeywordsAdolescent, Brain, Child, Cognition, Communication, Female, Gait, Humans, Intellectual Disability, Magnetic Resonance Imaging, Male, Membrane Proteins, Motor Skills, Mutation, Phenotype, Spinocerebellar Degenerations, Symptom Assessment

Spinocerebellar ataxia type 21 (SCA21/ATX-TMEM240) is a rare form of cerebellar ataxia that commonly presents with motor, cognitive, and behavioral impairments. Although these features have been identified as part of the clinical manifestations of SCA21, the neurodevelopmental disorders associated with SCA21 have not been well studied or described. Here we present extensive phenotypic data for 3 subjects from an SCA21 family in the United States. Genetic testing demonstrated the c.196 G>A (p.Gly66Arg) variant to be a second recurrent mutation associated with the disorder. Standardized developmental assessment revealed significant deficits in cognition, adaptive function, motor skills, and social communication with 2 of the subjects having diagnoses of autism spectrum disorder, which has never been described in SCA21. Quantitative gait analysis showed markedly abnormal spatiotemporal gait variables indicative of poor gait control and cerebellar as well as noncerebellar dysfunction. Clinical evaluation also highlighted a striking variability in clinical symptoms, with greater ataxia correlating with greater severity of neurodevelopmental disorder diagnoses. Notably, neurodevelopmental outcomes have improved with intervention over time. Taken together, this case series identifies that the manifestation of neurodevelopmental disorders is a key feature of SCA21 and may precede the presence of motor abnormalities. Furthermore, the coexistence of ataxia and neurodevelopmental disorders in these subjects suggests a role for spinocerebellar pathways in both outcomes. The findings in this study highlight the importance of evaluation of neurodevelopmental concerns in the context of progressive motor abnormalities and the need for timely intervention to ultimately improve quality of life for individuals with SCA21.

Alternate JournalJ Child Neurol
PubMed ID32705938
PubMed Central IDPMC7674185
Grant ListK12 NS098482 / NS / NINDS NIH HHS / United States
K23 HD099275 / HD / NICHD NIH HHS / United States
U54 HD087101 / HD / NICHD NIH HHS / United States