Disease relevance of VPS13A

• Chorea-acanthocytosis is a neurodegenerative disorder with peripheral red cell acanthocytosis [1].
• Involuntary movements in chorea-acanthocytosis: a comparison with Huntington's chorea [2].
• Peripheral neuropathy in amyotrophic chorea-acanthocytosis [3].
• RECENT FINDINGS: Advances in molecular medicine have enabled us to distinguish precisely among the disorders described under the label of neuroacanthocytosis, most notably between autosomal recessive chorea-acanthocytosis and the X-linked McLeod syndrome [4].
• It was concluded that neurogenic muscular atrophy should be included as one of the main pathological findings in chorea-acanthocytosis [5].

Psychiatry related information on VPS13A

• RESULTS: Trichotillomania, hypertrophic cardiomyopathy, and idiopathic hyperCKemia, in 1 patient each, preceded the development of the full clinical spectrum of CHAC by 2 to 20 years [6].
• Chorea-acanthocytosis is also an autosomal recessive condition and is characterised by chorea, orofaciolingual dyskinesia, dysphagia, dysarthria, areflexia, seizures and dementia [7].
• Self-mutilation in chorea-acanthocytosis: Manifestation of movement disorder or psychopathology [8]?

High impact information on VPS13A

• Linkage of chorea-acanthocytosis to chromosome 9q21 has been found [1].
• CHAC encodes an evolutionarily conserved protein that is probably involved in protein sorting [9].
• In the absence of cytogenetic rearrangements, we initiated a genomewide scan for linkage in 11 families, segregating for CHAC, who are of diverse geographical origin [10].
• Chorea-acanthocytosis: genetic linkage to chromosome 9q21 [10].
• However, chorein expression was absent or noticeably reduced in ChAc patient cells, but not McLeod syndrome and Huntington's disease cells [11].

Chemical compound and disease context of VPS13A

• A man, aged 52, is reported to show (1) adult onset, (2) progressive orofacial dyskinesia and choreic movements of the extremities, (3) tongue biting, (4) denervation of the peripheral nerves, (5) acanthocytosis, and (6) increased serum creatine kinase, which are characteristic of chorea-acanthocytosis [12].

Biological context of VPS13A

• We characterized the structure of three new genes encoding these CHAC-similar proteins, located on chromosomes 1p36, 8q22, and 15q21 [13].
• We reviewed their medical histories and performed molecular analysis by screening all 73 exons of VPS13A [6].
• Study of covalently (tightly) bound fatty acids in erythrocyte membrane proteins after alkaline hydrolysis, hitherto undescribed in chorea-acanthocytosis, revealed that palmitic acid (C16:0) was significantly increased and stearic acid (C18:0) was decreased in the patients with chorea-acanthocytosis [14].
• CONCLUSIONS: This family extends the genetic spectrum of chorea-acanthocytosis to include autosomal dominant inheritance, possibly due to expanded trinucleotide repeats [15].
• These findings are consistent with the human results reported elsewhere and indicate that the CHAC model mice showed a mild phenotype with late adult onset [16].

Anatomical context of VPS13A

• Chorea-acanthocytosis (CHAC, MIM 200150) is an autosomal recessive neurodegenerative disorder characterized by the gradual onset of hyperkinetic movements and abnormal erythrocyte morphology (acanthocytosis) [9].
• This autosomal recessive, neurodegenerative disorder with aberrant erythrocyte morphology (acanthocytosis) is caused by mutations in the VPS13A gene [17].
• All had heterozygous VPS13A mutations and degeneration of the basal ganglia on magnetic resonance imaging (MRI) typical of ChAc [17].
• Mutations in VPS13A or GNA14 or both may be associated with clinical features of temporal lobe epilepsy [18].
• Phospholipid class (phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, and phosphatidylserine) and peak profile of each phospholipid class from the erythrocyte membranes did not differ between the patients with chorea-acanthocytosis and the control subjects [14].

Associations of VPS13A with chemical compounds

• Analyses for total covalently bound fatty acids disclosed that palmitic and docosahexaenoic (C22:6) acids were increased and stearic acid was decreased in chorea-acanthocytosis [14].
• Of the loosely bound fatty acids, linoleic acid (C18:2) was significantly decreased in those with chorea-acanthocytosis, which seemed to be nonspecific [14].
• Autosomal dominant chorea-acanthocytosis with polyglutamine-containing neuronal inclusions [15].
• We studied cerebral perfusion and oxygen metabolism in three patients with chorea-acanthocytosis using positron-emission tomography and oxygen-15 labeled O2 and CO2 [19].
• Chorea-acanthocytosis with polyclonal antibodies to ganglioside GM1 [20].

Other interactions of VPS13A

• Both families shared a deletion of exons 70-73 of VPS13A, extending to exons 6-7 of GNA14 [18].
• The resemblance of McLeod syndrome with Huntington's disease and with autosomal recessive chorea-acanthocytosis suggests that the corresponding proteins--XK, huntingtin, and chorein--might belong to a common pathway, the dysfunction of which causes degeneration of the basal ganglia [21].
• RESULTS: The sulphate influx, the Ser/Thr phosphorylation level, and the membrane casein-kinase activity were increased in chorea-acanthocytosis compared with normal controls [22].
• Chorea-acanthocytosis (ChAc; OMIM 200150) is a rare autosomal recessive disease with dysfunction of the erythrocyte membrane, presenting with acanthocytes and neurological manifestations characterized by progressive hyperkinesias (chorea, dystonia) and neuropsychological impairment [23].
• Atypical McLeod syndrome manifested as X-linked chorea-acanthocytosis, neuromyopathy and dilated cardiomyopathy: report of a family [24].

Analytical, diagnostic and therapeutic context of VPS13A

• Phospholipid class, peak profile of each phospholipid class, loosely bound fatty acids, covalently (tightly) bound fatty acids of the erythrocyte membranes, and plasma fatty acids were investigated using high-performance liquid chromatography in six patients with chorea-acanthocytosis and 14 age- and sex-matched normal control subjects [14].
• Furthermore, immunohistochemistry demonstrated abnormal accumulation of tTGase products as well as proteinaceous bodies in CHAC muscles [25].
• Autopsy findings are reported from a patient with chorea-acanthocytosis treated for 2 years by deep brain stimulation (DBS) of the motor thalamus [26].
• In an attempt to cast light on the pathophysiology of CHAC, we used reverse-phase HPLC and immunohistochemistry to evaluate the role of tTGase in this disorder [25].
• Reduced cerebral perfusion and oxygen metabolism seem to be related to the intellectual and personality changes that occur in chorea-acanthocytosis [19].

References