2026 American Academy of Neurology Abstract Website

Objective:

Describe a three-generation family with proband and his mother with a novel heterozygous TGM6 c.538G>A (p.Gly180Arg) variant of uncertain significance whose clinical features strongly support pathogenicity and broadens the recognized variants associated with Spinocerebellar ataxia type 35 (SCA35).

Background:

A 30-year-old man developed right-hand dystonia, early appendicular ataxia, and intermittent myoclonic jerks at 28. Examination revealed writing dystonia, mild bradykinesia with fine coordination movements, dysdiadokokinesia, atypical tremor, in the right hand, with early mild cognitive decline on neuropsychiatric testing, and intermittent hallucinations. Genetic testing included negative mitochondrial DNA testing, with variants in the parkinsonism, dystonia panel which were not consistent with his phenotype. He had a heterozygous TGM6 variant of uncertain significance discovered on his cerebral palsy panel. His 52-year-old mother has the same variant and has truncal ataxia, widespread mild dystonia, myoclonic jerks, bradykinesia, mild dysarthria, and mild cognitive impairment with intermittent hallucinations. Maternal grandmother, not genetically tested, had experienced progressive gait instability, urinary incontinence, frequent falls, bradykinesia, cognitive decline, and appendicular ataxia with onset prior to the age of 30 and death at age 57.

Design/Methods:

N/A

Results:

Genomic Unity Movement Disorders Analysis reporting heterozygous TGM6 c.538G>A (p.Gly180Arg, rs371872705) variant of uncertain significance in both proband and affected mother of proband. Normal MRI Brain in both patients.

Conclusions:

SCA35 is a rare, autosomal dominant neurodegenerative disorder characterized by progressive cerebellar ataxia, most commonly presenting with gait and limb incoordination, dysarthria, tremors and rarely dystonia due to pathogenic variants in TGM6. This gene encodes transglutaminase 6 which is causative in SCA35. Age of onset can range from adolescence to fifth decade of life, typically with slow progression. We report a novel TGM6 c.538G>A (p.Gly180Arg) variant that we assert is likely pathogenic. Recognition expands the variants associated with SCA35 and underscores the importance of multigenerational genetic evaluation.