Chorea, psychosis, acanthocytosis, and prolonged survival associated with ELAC2 mutations.
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ABSTRACT:
SUBMITTER: Paucar M
PROVIDER: S-EPMC6177277 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveTo perform a comprehensive characterization of a cohort of patients with chorea-acanthocytosis (ChAc) in Sweden.MethodsClinical assessments, targeted genetic studies, neuroimaging with MRI, [18F]-fluorodeoxyglucose (FDG) PET, and dopamine transporter with 123I FP-CIT (DaTscan) SPECT. One patient underwent magnetic resonance spectroscopy (MRS).ResultsFour patients living in Sweden but with different ethnical backgrounds were included. Their clinical features were variable. Biallelic VPS13A mutations were confirmed in all patients, including 3 novel mutations. All tested patients had either low or absent chorein levels. One patient had progressive caudate atrophy. Investigation using FDG-PET revealed severe bilateral striatal hypometabolism, and DaTscan SPECT displayed presynaptic dopaminergic deficiency in 3 patients. MRS demonstrated reduced N-acetylaspartate/creatine (Cr) ratio and mild elevation of both choline/Cr and combined glutamate and glutamine/Cr in the striatum in 1 case. One patient died during sleep, and another was treated with deep brain stimulation, which transiently attenuated feeding dystonia but not his gait disorder or chorea.ConclusionsLarger longitudinal neuroimaging studies with different modalities, particularly MRS, are needed to determine their potential role as biomarkers for ChAc.
| S-EPMC7217656 | biostudies-literature
Project description: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. 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. Both structures showed significant and marked reductions in volume compared with 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. 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.
| S-EPMC3324182 | biostudies-literature
Project description:BACKGROUND:Trunk flexion and axial extension are characteristic symptoms of chorea-acanthocytosis (ChAc). PHENOMENOLOGY SHOWN:A 41-year-old male with ChAc (confirmed by VPS13A mutations) reported that his involuntary axial movements were significantly ameliorated by either folding his arms over his chest or putting his hands behind his head. EDUCATIONAL VALUE:These apparent "sensory tricks" suggest a dystonic pathophysiology, and also merit further study to analyze their potential for symptom control in ChAc.
| S-EPMC5498799 | biostudies-literature
Project description:Chorea-Acanthocytosis (ChAc) is a devastating, little understood, and currently untreatable neurodegenerative disease caused by VPS13A mutations. Based on our recent demonstration that accumulation of activated Lyn tyrosine kinase is a key pathophysiological event in human ChAc cells, we took advantage of Vps13a-/- mice, which phenocopied human ChAc. Using proteomic approach, we found accumulation of active Lyn, γ-synuclein and phospho-tau proteins in Vps13a-/- basal ganglia secondary to impaired autophagy leading to neuroinflammation. Mice double knockout Vps13a-/- Lyn-/- showed normalization of red cell morphology and improvement of autophagy in basal ganglia. We then in vivo tested pharmacologic inhibitors of Lyn: dasatinib and nilotinib. Dasatinib failed to cross the mouse brain blood barrier (BBB), but the more specific Lyn kinase inhibitor nilotinib, crosses the BBB. Nilotinib ameliorates both Vps13a-/- hematological and neurological phenotypes, improving autophagy and preventing neuroinflammation. Our data support the proposal to repurpose nilotinib as new therapeutic option for ChAc patients.
| S-EPMC8091687 | biostudies-literature
Project description:Chorea-acanthocytosis (ChAc) is a rare autosomal recessive inherited syndrome characterized by hyperkinetic movements, seizures, cognitive impairment, neuropsychiatric symptoms, elevated serum biochemical indicators and acanthocytes detection in peripheral blood smear. Vacuolar protein sorting 13A (VPS13A) gene mutations have been proven to be genetically responsible for the pathogenesis of ChAc. Herein, based on the typical clinical symptoms and neuroimaging features, we present two suspected ChAc cases which are further genetically confirmed by four novel VPS13A gene mutations. Nevertheless, the sharp contrast between the population base and published ChAc reports implies that ChAc is considerably underdiagnosed in China. Therefore, we conclude several suggestive features and propose a diagnostic path of ChAc from a clinical, genetic and neuroimaging perspective, aiming to facilitate the diagnosis and management of ChAc in China.
| S-EPMC5388735 | biostudies-literature
Project description:To determine the molecular nature of the neurological disease in the seminal family reported by Critchley et al in the 1960s, characterized by a hyperkinetic movement disorder and the appearance of acanthocytosis on peripheral blood smear. The eponym Levine-Critchley syndrome, subsequently termed neuroacanthocytosis, has been applied to symptomatically similar, but genetically distinct, disorders, resulting in clinical and diagnostic confusion.DNA analysis.Molecular biology research laboratories.First- and second-degree relatives of the original Critchley et al proband from Kentucky.Mutations in the VPS13A gene.A mutation was identified in the VPS13A gene, responsible for autosomal recessive chorea-acanthocytosis. Haplotype reconstruction suggested that this mutation was homozygous in the proband.These findings strongly support the diagnosis of chorea-acanthocytosis as the disorder described in the original report.
| S-EPMC4615612 | biostudies-literature
Project description: Not available
| S-EPMC8370142 | biostudies-literature
Project description:BackgroundChorea-acanthocytosis (ChAc) is a neuroacanthocytosis syndrome presenting with severe movement disorders poorly responsive to drug therapy. Case reports suggest that bilateral deep brain stimulation (DBS) of the ventro-postero-lateral internal globus pallidus (GPi) may benefit these patients. To explore this issue, the present multicentre (n=12) retrospective study collected the short and long term outcome of 15 patients who underwent DBS.MethodsData were collected in a standardized way 2-6 months preoperatively, 1-5 months (early) and 6 months or more (late) after surgery at the last follow-up visit (mean follow-up: 29.5 months).ResultsMotor severity, assessed by the Unified Huntington's Disease Rating Scale-Motor Score, UHDRS-MS), was significantly reduced at both early and late post-surgery time points (mean improvement 54.3% and 44.1%, respectively). Functional capacity (UHDRS-Functional Capacity Score) was also significantly improved at both post-surgery time points (mean 75.5% and 73.3%, respectively), whereas incapacity (UHDRS-Independence Score) improvement reached significance at early post-surgery only (mean 37.3%). Long term significant improvement of motor symptom severity (? 20 % from baseline) was observed in 61.5 % of the patients. Chorea and dystonia improved, whereas effects on dysarthria and swallowing were variable. Parkinsonism did not improve. Linear regression analysis showed that preoperative motor severity predicted motor improvement at both post-surgery time points. The most serious adverse event was device infection and cerebral abscess, and one patient died suddenly of unclear cause, 4 years after surgery.ConclusionThis study shows that bilateral DBS of the GPi effectively reduces the severity of drug-resistant hyperkinetic movement disorders such as present in ChAc.
| S-EPMC3818425 | biostudies-literature
Project description:Objective:To determine a molecular diagnosis for a large multigenerational family of South Asian ancestry with seizures, hyperactivity, and episodes of tongue biting. Methods:Two affected individuals from the family were analyzed by whole-genome sequencing on the Illumina HiSeq X platform, and rare variants were prioritized for interpretation with respect to the phenotype. Results:A previously undescribed, 1-kb homozygous deletion was identified in both individuals sequenced, which spanned 2 exons of the VPS13A gene, and was found to segregate in other family members. Conclusions:VPS13A is associated with autosomal recessive chorea-acanthocytosis, a diagnosis consistent with the phenotype observed in this family. Whole-genome sequencing presents a comprehensive and agnostic approach for detecting diagnostic mutations in families with rare neurologic disorders.
| S-EPMC5961193 | biostudies-literature
Project description:Chorea-acanthocytosis (ChAc) is a rare autosomal recessive neurodegenerative disease due to mutation of the VPS13A gene encoding the protein chorein. ChAc is a slowly progressive disorder that typically presents in early adulthood, and whose clinical features include chorea and dystonia with involuntary lip, cheek, and tongue biting. Some patients also have seizures. Treatment for ChAc is symptomatic. A small number of ChAc patients have been treated with bilateral deep brain stimulation (DBS) of the globus pallidus interna (GPi), and we now present an additional case. Patient chart, functional measures, and laboratory findings were reviewed from the time of ChAc diagnosis until 6 months after DBS surgery. Here, we present a case of ChAc in a 31-year-old male positive for VPS13A gene mutations who presented with chorea, tongue biting, dysarthria, weight loss, and mild cognitive dysfunction. DBS using monopolar stimulation with placement slightly lateral to the GPi was associated with significant improvement in chorea and dysarthria. This case adds to the current state of knowledge regarding the efficacy and safety of bilateral GPi-DBS for symptomatic control of drug-resistant hyperkinetic movements seen in ChAc. Controlled trials are needed to better assess the impact and ideal target of DBS in ChAc.
| S-EPMC6738267 | biostudies-literature