Chorea-acanthocytosis: 3 New Families with Novel Genetic and Metabolic Findings.
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ABSTRACT:
SUBMITTER: Abbas MM
PROVIDER: S-EPMC8370142 | biostudies-literature | 2021 May-Jun
REPOSITORIES: biostudies-literature
Publications
Chorea-acanthocytosis: 3 New Families with Novel Genetic and Metabolic Findings.
Abbas Mirza Masoom MM Thenral S G SG Ramprasad Vedam L VL Walker Ruth H RH Kukkle Prashanth Lingappa PL
Annals of Indian Academy of Neurology 20210327 3
Similar Datasets
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
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| S-EPMC4629413 | 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: Not available
| S-EPMC4653107 | biostudies-literature
Project description:BackgroundTrunk flexion and axial extension are characteristic symptoms of chorea-acanthocytosis (ChAc).Phenomenology shownA 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 valueThese 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: Not available
| S-EPMC6353409 | 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:BackgroundMcLeod syndrome (MLS) and chorea-acanthocytosis (ChAc) are exceedingly rare diseases characterized by a variety of movement disorders including chorea, dystonia, and Parkinsonism. Genetic analysis plays a key role in early and accurate diagnosis, but relevant variants are still under investigation. This study aims to explore new pathogenic variants in Chinese patients with MLS and ChAc and to conduct a comprehensive analysis of the clinical heterogeneity among these patients.MethodsEighteen Chinese patients who presented with choreatic movements with negative HTT genetic testing were identified and underwent targeted next-generation sequencing, verified by Sanger sequencing.ResultsTwo novel XK variants (c.970A>T, c.422_423del) were identified in three index MLS patients and six novel VPS13A variants (c.9219C>A, c.3467T>A, c.4208dup, c.9243_9246del, c.5364del, c.556-290_697-483del) in five index ChAc patients. One copy number variant of VPS13A (g.79827595_79828762del/c.556-290_697-483del) was firstly described in Chinese population.ConclusionAs the currently largest descriptive study of MLS and ChAc patients in China, this study expands on the clinical and genetic spectrum of XK and VPS13A, contributing to the clinical diagnosis of MLS and ChAc.
| S-EPMC11425086 | biostudies-literature
Project description:Chorea-acanthocytosis (ChAc) is a rare, adult-onset disease usually characterized by, hence the name, a movement disorder and acanthocytosis in the blood. It is caused by mutations of the VPS13A gene with an autosomal recessive transmission. We report a consanguineous Turkish family with a different and informative clinical and diagnostic course. Three siblings developed seizures and the index patient had been diagnosed with bilateral temporal lobe epilepsy. A key finding, however, was the basal ganglia involvement in neuroimaging although no movement disorder was present. [18F]FDG-PET showed a prominent decline in striatal glucose metabolism at 31 years of age and [123I]FP-CIT-SPECT revealed a moderate loss of striatal dopamine transporter availability. The family was referred for genetic testing and exome sequencing detected a homozygous novel truncating mutation c.4326 T>A (p.Tyr1442*) in VPS13A in all affected siblings. With this case, we present autosomal recessive epilepsy as the predominant phenotype of ChAc with a new homozygous VPS13A mutation and provide pathological structural and molecular neuroimaging findings.
| S-EPMC6334619 | biostudies-literature
Project description:ObjectiveTo 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.DesignDNA analysis.SettingMolecular biology research laboratories.ParticipantsFirst- and second-degree relatives of the original Critchley et al proband from Kentucky.Main outcome measuresMutations in the VPS13A gene.ResultsA mutation was identified in the VPS13A gene, responsible for autosomal recessive chorea-acanthocytosis. Haplotype reconstruction suggested that this mutation was homozygous in the proband.ConclusionThese findings strongly support the diagnosis of chorea-acanthocytosis as the disorder described in the original report.
| S-EPMC4615612 | biostudies-literature