Spinocerebellar ataxia type 48

Spinocerebellar ataxia type 48 (SCA48) is a rare, inherited neurodegenerative disorder caused by pathogenic variants in the STUB1 gene (also known as CHIP), which encodes the C-terminus of Hsp70-interacting protein, an E3 ubiquitin ligase and co-chaperone involved in protein quality control. SCA48 primarily affects the nervous system, particularly the cerebellum and its connections, leading to progressive cerebellar ataxia characterized by gait instability, limb incoordination, dysarthria (slurred speech), and oculomotor abnormalities. A distinguishing feature of SCA48 compared to many other spinocerebellar ataxias is the frequent presence of cognitive and psychiatric manifestations, including executive dysfunction, behavioral changes, depression, and in some cases frank cognitive decline or dementia. Cerebellar atrophy is typically observed on brain MRI. SCA48 was first described in the late 2010s and is increasingly recognized as a cause of both pure cerebellar ataxia and cerebellar cognitive affective syndrome. The age of onset is variable but most commonly occurs in adulthood, typically between the third and sixth decades of life, though earlier onset has been reported. The disease follows an autosomal dominant inheritance pattern when caused by heterozygous STUB1 mutations, though it is notable that biallelic (homozygous or compound heterozygous) STUB1 mutations cause a more severe autosomal recessive condition known as SCAR16 (spinocerebellar ataxia, autosomal recessive 16). There is currently no disease-modifying or curative treatment for SCA48. Management is supportive and symptomatic, including physical therapy, occupational therapy, speech therapy, and psychiatric or neuropsychological support as needed. Genetic counseling is recommended for affected individuals and their families.

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