神経有棘赤血球症

BACKGROUND: VPS13A disease, historically known as chorea-acanthocytosis, is a rare autosomal recessive neurodegenerative disorder characterized by variable combinations of chorea, dystonia, orolingual involvement, cognitive or psychiatric changes, acanthocytosis, and peripheral neuromuscular abnormalities. Although phenotypic heterogeneity is well recognized, neuropathy-predominant onset may delay diagnostic recognition, particularly before typical hyperkinetic or orolingual features become apparent. CASE PRESENTATION: We describe two affected siblings from a consanguineous family who carried the same homozygous VPS13A missense variant and were followed for more than 10 years. The younger sister developed symptoms at 27 years of age with severe choreiform movements and prominent lingual/orofacial dystonia, which was partially relieved by placing a towel in the mouth and was considered consistent with a possible sensory trick. The older brother developed symptoms at 32 years of age with mild peripheral neuropathic symptoms and later developed facial/orofacial involuntary movements that progressed to more prominent choreiform and orofacial features in the later disease stage. Cognitive decline, acanthocytosis, and mild axonal peripheral neuropathy were documented in both siblings. Brain MRI in the younger sister showed findings suggestive of mild caudate atrophy. Genetic testing identified a homozygous VPS13A c.2964G > C [p.(Lys988Asn)] variant in both affected siblings, whereas family validation showed heterozygous carrier status in the parents. The variant was absent from the gnomAD East Asian population database and remained classified as a variant of uncertain significance by the reporting laboratories. CONCLUSIONS: This family illustrates that a VPS13A disease-like phenotype associated with a plausible candidate VPS13A variant may follow markedly different clinical trajectories even within the same sibship, including neuropathy-predominant onset and a hyperkinetic-dystonic presentation. The findings emphasize the need to reconsider VPS13A disease when peripheral neuropathy is accompanied or followed by progressive choreiform movements, orolingual dystonia, cognitive decline, acanthocytosis, or caudate atrophy. Although functional validation was unavailable, the characteristic phenotype, rarity of the variant, and segregation pattern support its clinical relevance as a plausible candidate variant associated with the phenotype, rather than as definitive proof of pathogenicity.

BACKGROUND: Chorea-acanthocytosis (ChA) clinically presents with motor and non-motor symptoms. Some features of the disease and their intercorrelations have remained insufficiently characterized. Thus, we aimed to perform a multidimensional assessment of ChA patients, focusing on motor, behavioral, cognitive and olfactory domains. METHODS: A cross-sectional clinical assessment of 23 genetically confirmed ChA patients was conducted from 2022 to 2024. Patients were evaluated using the Unified Huntington's Disease Rating Scale (UHDRS) and Mini-Mental State Examination. A case-control comparison of olfactory function was also performed between eligible patients (n = 20) and age-and gender-matched controls (n = 20) using the Sniffin' Sticks test. RESULTS: The mean age and disease duration were 38.57 ± 7.26 years and 7.86 ± 6.04 years, respectively. Chorea (91.3%), dystonia (82.6%) and oculomotor abnormalities (78.3%), particularly impaired vertical saccades and smooth pursuit, were frequent. All patients exhibited at least one behavioral disorder, most commonly anxiety, mood disorders (including sad mood and low self-esteem) and obsessive-compulsive features. Suicidal thoughts were found in 21.7% of the patients. Among patients with preserved cognition, 50% demonstrated hyposmia (sum of odor identification, discrimination and threshold scores [TDI] < 30.75), with significantly reduced odor discrimination, identification and TDI scores versus controls. Disease duration was negatively associated with olfactory function. Higher UHDRS motor scores were associated with poorer olfactory, cognitive and functional outcomes. CONCLUSION: These findings demonstrated the varied manifestations of ChA, identifying olfactory impairment as a prevalent, underrecognized non-motor symptom, with potential implications for clinical evaluation and management. Further multicenter studies with larger cohorts are required to confirm these observations and clarify their prognostic value.

BACKGROUND: Chorea is a hyperkinetic movement disorder with a broad differential diagnosis, ranging from acute symptomatic causes to slowly progressive neurogenetic diseases. While Huntington's disease (HD) remains the most prevalent hereditary form, numerous other genetic disorders may mimic its clinical presentation. A major diagnostic challenge arises in patients with a seemingly negative family history, which can obscure the suspicion of a genetic etiology. In patients with sporadic chorea, the potential contribution of genetic testing to the diagnostic process has not yet been systematically analyzed. METHODS: We conducted a retrospective analysis of 81 patients presenting with chorea as a prominent symptom at the movement disorders outpatient clinic between 2013 and 2024. Clinical data, family history, laboratory results, imaging, and genetic analyses were evaluated. Genetic testing included a chorea-related gene panel and, if unremarkable, whole-exome or whole-genome sequencing. RESULTS: Out of 81 patients, 44 presented with slowly progressive chorea and unremarkable family history of HD or chorea-related syndromes. After exclusion of secondary etiologies (n = 8), 36 patients remained, of whom 30 (83, 33%) received a confirmed genetic diagnosis. HD was the most frequent diagnosis (n = 20), followed by rare genetic disorders such as Spinocerebellar Ataxia Type 17 (n = 2), Wilson's Disease (n = 2), Ataxia with Oculomotor Apraxia Type 2 (n = 1), C9orf72-related Neurodegeneration (n = 1), Choreoacanthocytosis (n = 1), KMT2B-related Dystonia (n = 1), ERCC4-related Neurodegeneration (n = 1), and Glutaric Acidemia Type 1 (n = 1). DISCUSSION: These findings support the systematic use of genetic testing-even in apparently sporadic cases-and suggest that the prevalence of hereditary choreatic disorders, may be significantly underestimated.

The 12th International Meeting on Neuroacanthocytosis, Cohen Syndrome, and other VPS13-related Disorders was held on September 12th-14th, 2025, at the Jules Gonin Eye Hospital in Lausanne, Switzerland. This long-standing series of international symposia has traditionally focused on neuroacanthocytosis syndromes and associated disorders. The program further broadened its scope to include Cohen syndrome, reflecting the growing recognition of shared molecular features and common unsolved questions across VPS13-related disorders. The aim of the meeting was to present the latest updates in the field, from both clinical and basic science perspectives, and to facilitate collaboration and exchange of ideas among researchers, clinicians, and the patient community. An important aspect of these meetings is the active involvement of patients, their relatives and caregivers, who were invited to attend scientific sessions, in addition to participating in parallel patient-oriented sessions. A total of 20 oral communications were presented in eight scientific sessions accompanied by two keynote lectures, short talks by selected poster presenters, and the 2025 "Glenn Irvine Prize" award lecture.