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Ezekiel Watson
Ezekiel Watson

Acanthocytosis PORTABLE


Chorea-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.




acanthocytosis


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Funding: This study was supported by the ERA-net E-Rare consortium European Multidisciplinary Initiative on Neuroacanthocytosis (EMINA); www.e-rare.eu/node/474. Western blot analysis for chorein was performed with the financial support of the Neuroacanthocytosis Advocacy and the EMINA consortium (BMBF 01GM1003). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


Chorea-acanthocytosis (ChAc) is an autosomal recessive disease due to mutations of the VPS13A gene encoding for chorein [1]. It belongs to the neuroacanthocytosis syndromes, a heterogeneous group of genetically defined conditions, exhibiting neurological and neuropsychiatric disorders with red blood cell acanthocytosis [1,2]. ChAc is very rare, and typically presents as an adult-onset progressive disorder resembling Huntington's disease (HD) [1,2]. ChAc has however a slower progression, and displays some more or less specific clinical features such as tongue- and lip-biting, self-mutilations, seizures and neuromuscular manifestations but no specific neuropathological features besides prominent striatal degeneration [2,3].


Movement disorders and neurosurgical tertiary centres were identified and contacted on the basis of scientific publications (original research and review articles published between 1997 and November 2012) in Medline and PubMed databases (search terms: deep brain stimulation, DBS, high-frequency stimulation, pallidal stimulation, and neuroacanthocytosis, chorea, chorea-acanthocytosis, ChAc), as well as of meeting abstracts. The support association for neuroacanthocytosis patients (www.naadvocacy.org), and the diagnostic reference centre and database in Munich, Germany, also collaborated for patient identification, and announcements were published at the Movement Disorders Society (MDS) meeting 2011 and MDS website.


The authors would like to thank Ginger and Glenn Irvine and the Advocacy for Neuroacanthocytosis Patients (www.naadvocacy.org) for their help in identifying the patients, and Miss Adeline Cathala for statistical assistance. Western blot analysis for chorein was performed by Carol Dobson-Stone in the lab of Anthony Monaco at the Wellcome Trust Centre for Human Genetics, University of Oxford, UK, and by Benedikt Bader and Gertrud Kwiatkowski in the lab of Hans Kretzschmar at the Center for Neuropathology and Prion Research at Ludwig-Maximilians-Universität Munich, Germany.


Chorea-acanthocytosis (ChAc) is a form of neuroacanthocytosis (see this term) and is characterized clinically by a Huntington disease-like phenotype with progressive neurological symptoms including movement disorders, psychiatric manifestations and cognitive disturbances.


Diagnosis may be challenging. Presence of self-mutilating lip and tongue biting, or other self-mutilation is strongly suggestive of ChAc. Determination of acanthocytosis in peripheral blood smears may be negative and does not rule out the disorder. Serum CK is mostly elevated. Patients have absent chorein expression in erythrocytes on Western blot. Confirmatory DNA analysis of the VPS13A gene is difficult due to its size and heterogeneity of mutation sites. Electroneurography may demonstrate sensorimotor axonal neuropathy while electromyography shows neurogenic as well as myopathic changes. Electroencephalographic findings are not specific. Neuroradiologically, there is progressive striatal atrophy affecting especially the head of the caudate nucleus as well as impaired striatal glucose metabolism similar to that seen in HD.


The differential diagnoses depend on the presenting symptoms and include McLeod neuroacanthocytosis syndrome, Huntington's disease, Huntington-like disorders, juvenile Parkinson's disease and Tourette's syndrome (see these terms).


Acanthocytes have coarse, irregularly spaced, variably sized crenations, resembling many-pointed stars. They are seen on blood films in abetalipoproteinemia,[3] liver disease, chorea acanthocytosis, McLeod syndrome, and several inherited neurological and other disorders such as neuroacanthocytosis,[4] anorexia nervosa, infantile pyknocytosis, hypothyroidism, idiopathic neonatal hepatitis, alcoholism, congestive splenomegaly, Zieve syndrome, and chronic granulomatous disease.[5]


Acanthocytosis can refer generally to the presence of this type of crenated red blood cell, such as may be found in severe cirrhosis or pancreatitis,[6] but can refer specifically to abetalipoproteinemia, a clinical condition with acanthocytic red blood cells, neurologic problems and steatorrhea.[8] This particular cause of acanthocytosis (also known as abetalipoproteinemia, apolipoprotein B deficiency, and Bassen-Kornzweig syndrome) is a rare, genetically inherited, autosomal recessive condition due to the inability to fully digest dietary fats in the intestines as a result of various mutations of the microsomal triglyceride transfer protein (MTTP) gene.[9]


Acanthocytes arise from either alterations in membrane lipids or structural proteins. Alterations in membrane lipids are seen in abetalipoproteinemia and liver dysfunction. Alteration in membrane structural proteins are seen in neuroacanthocytosis and McLeod syndrome.


Chorea-acanthocytosis (ChAc), as the most common subtype of neuroacanthocytosis syndrome, is characterized by the presence of acanthocytes and neurological symptoms. It is thought to be caused by the VPS13A (vacuolar protein sorting-associated protein 13A) mutations. This article reports two confirmed cases of ChAc and summarizes some suggestive features, which provide direction for the diagnosis and treatment of acanthocytosis in the future.


Chorea-acanthocytosis (ChAc) is a rare genetic disease caused by loss-of-function-mutation of the vacuolar protein sorting-associated protein 13A (VPS13A) which is an encoding gene of the protein chorein [1, 2]. The ChAc mainly occurs in adulthood with an average age of about 35 years, and rarely occurs before the age of 20 years or after the age of 50 years [3]. Clinical manifestations of ChAc include progressive chorea, orofacial lingual dyskinesia, seizures, cognitive impairment, psychiatric symptoms, and neuromuscular manifestations with elevated serum biochemical indicators and increased acanthocytes in peripheral blood [1, 4, 5]. Neuroimaging showed atrophy of the caudate nucleus and decreased glucose uptake in the corpus striatum in the basal ganglia of the brain [6].


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.


There are currently no treatments to prevent or slow the progression of neuroacanthocytosis. Treatment is symptomatic and supportive. Medications may be prescribed to decrease the involuntary movements. Botulinum toxin injections usually improve symptoms of dystonia. A feeding tube may be needed for individuals with feeding difficulties. Seizures may be treated with a variety of anticonvulsants, and antidepressants may also be appropriate for some individuals. Speech, occupational, and physical therapy may also be beneficial.


Consider participating in a clinical trial so clinicians and scientists can learn more about neuroacanthocytosis and related disorders. Clinical research uses human volunteers to help researchers learn more about a disorder and perhaps find better ways to safely detect, treat, or prevent disease.


For information about participating in clinical research visit NIH Clinical Research Trials and You. Learn about clinical trials currently looking for people with neuroacanthocytosis at Clinicaltrials.gov.


In addition, the detection of spiculated red blood cells and hemolysis during the neonatal period shall raise the possibility of a hereditary disorder such as infantile pyknocytosis berfore considering an acquired causes of acanthocytosis. [4]


For maintenance of fluidity of RBC morphology, membrane fluidity is essential. This fluidity is, in turn, controlled by proportions of cholesterol, structural proteins, and phospholipids in the RBC membrane. Diseases such as abetalipoproteinemia, severe liver dysfunction, etc. and neuroacanthocytosis, etc. affect the cholesterol and protein content of the RBC membrane, respectively. Subsequently, the RBC membrane fluidity becomes altered, and the cells undergo morphologic changes leading to the formation of acanthocytes or spur cells. These structural modifications make them susceptible to splenic trapping and destruction, ultimately leading to hemolytic anemia. 041b061a72


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