A Novel Gain-of-Function ITPR1 Variant Associated With a Movement Disorder Characterized by Tremor and Dystonia

ITPR1 gain-of-function variant — dysregulation of inositol 1,4,5-triphosphate receptor type 1 (distinct mechanism from cerebellar loss-of-function)

A novel gain-of-function ITPR1 variant is associated with a movement disorder characterized by tremor and dystonia — a phenotype distinct from the established loss-of-function spinocerebellar ataxia (SCA15/16). ITPR1 encodes the inositol 1,4,5-triphosphate receptor type 1, with dominant loss-of-function variants causing SCA15/16. This report introduces a gain-of-function mechanism producing a tremor-dystonia syndrome, fundamentally expanding the ITPR1 disease spectrum.

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Identifying a gain-of-function mechanism for ITPR1 has direct clinical implications: patients with unexplained tremor-dystonia do not fit the classic cerebellar ataxia phenotype and may not receive ITPR1 testing as a first step. This work highlights the need to include ITPR1 in movement disorder panels, not only ataxia panels.

Clinical impact : 2/3 · Evidence strength : 1/3 · Novelty : 2/2 · Sample size : 0/1 · Journal quality : 0/1 → Total : 5/10