Shape alterations in the striatum in chorea-acanthocytosis

Abstract

Objective Chorea-acanthocytosis (ChAc) is an uncommon autosomal recessive disorder due to mutations of the VPS13A gene, which encodes for the membrane protein chorein. ChAc presents with progressive limb and orobuccal chorea, but there is often a marked dysexecutive syndrome. ChAc may first present with neuropsychiatric disturbance such as obsessive-compulsive disorder (OCD), suggesting a particular role for disruption to striatal structures involved in non-motor frontostriatal loops, such as the head of the caudate nucleus. Two previous studies have suggested a marked reduction in volume in the caudate nucleus and putamen, but did not examine morphometric change. Methods We investigated morphometric change in 13 patients with genetically or biochemically confirmed ChAc and 26 age- and gender-matched controls. Subjects underwent magnetic resonance imaging and manual segmentation of the caudate nucleus and putamen, and shape analysis using a non-parametric spherical harmonic technique. Results Both structures showed significant and marked reductions in volume compared to controls, with reduction greatest in the caudate nucleus. Both structures showed significant shape differences, particularly in the head of the caudate nucleus. No significant correlation was shown between duration of illness and striatal volume or shape, suggesting that much structural change may have already taken place at the time of symptom onset. Conclusions Our results suggest that striatal neuron loss may occur early in the disease process, and follows a dorsal-ventral gradient that may correlate with early neuropsychiatric and cognitive presentations of the disease.

Lithium Sensitivity of Store Operated Ca2+ Entry and Survival of Fibroblasts Isolated from Chorea-Acanthocytosis Patients

“…Loss-of-function mutations of the chorein encoding gene VPS13A (vacuolar protein sorting-associated protein 13A) cause chorea-acanthocytosis (CA) [5-9], characterized by progressive hyperkinetic movement disorder, cognitive dysfunction, behavioural abnormalities, epilepsy, increased plasma creatine kinase concentration, and erythrocyte acanthocytosis [5, 10]. Gene targeted mice lacking functional chorein display erythrocyte shape changes [11], neuronal apoptosis [12] and altered behaviour [12]. …”

Neurons, Erythrocytes and Beyond –The Diverse Functions of Chorein

“…ChAc results in severe disability and early death of the affected patients [12]. Genetic knockout of chorein in mice leads to erythrocyte shape changes [24], neuronal apoptosis [29] and altered behavior [29]. In the striatum and hippocampus of those mice expression of the GABA(A) receptor-anchoring protein gephyrin and the GABA(A) receptor alpha1 (GABRA1) and gamma2 (GABRG2) subunits are increased [30].…”

Chorein Sensitive Orai1 Expression and Store Operated Ca2+ Entry in Rhabdomyosarcoma Cells

“…Loss-of-function mutations of the chorein encoding gene VPS13A (vacuolar protein sortingassociated protein 13A) account for chorea-acanthocytosis (ChAc), an autosomal recessive genetic disease [4][5][6][7][8][9] characterized by progressive hyperkinetic movement disorder, cognitive dysfunction, behavioral abnormalities, chronic hyperkalemia and variable acanthocytosis of red blood cells [5,10]. In mice, chorein knockout has been shown to result in erythrocyte shape changes [11], neuronal apoptosis [12] and behavioral abnormalities [12].…”