SYNE1-related spastic-ataxia: A nuclear envelopathy beyond French Canadians

Abstract Spectrin Repeat Containing Nuclear Envelope Protein 1 ( SYNE1 ), one of the largest genes in the human genome, encodes the scaffold protein nesprin-1, a critical component of the linker of nucleoskeleton and cytoskeleton complex. Disorders associated with SYNE1 belong to a recently recognized group of conditions termed “nuclear envelopathies,” which arise from dysfunctions in proteins associated with the nuclear envelope. SYNE1-related ataxia (ATX-SYNE1) was initially described in the French Canadian population but has since been identified in diverse populations worldwide. The condition primarily presents as pure cerebellar ataxia, although it may also include a range of additional neurological or systemic features. To characterize the emerging phenotypic spectrum of ATX-SYNE1 and associated disorders, we conducted a narrative review. In addition, we report three newly identified patients of Indian ancestry with ATX-SYNE1, all exhibiting a spastic ataxia phenotype with variable age of onset, with or without lower motor neuron involvement, further highlighting the clinical heterogeneity of this condition.