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Adrian Danek - One of the best experts on this subject based on the ideXlab platform.

  • Neurofilament light chain in serum is significantly increased in chorea-acanthocytosis.
    Parkinsonism & Related Disorders, 2020
    Co-Authors: Kevin Peikert, Adrian Danek, Katja Akgün, Christian Beste, Tjalf Ziemssen, Carsten Buhmann, Andreas Hermann
    Abstract:

    Abstract Introduction Chorea-acanthocytosis (ChAc) is a rare hereditary neurodegenerative disease, characterized by hyper- and hypokinetic movement disorders, peripheral neuropathy and acanthocytosis. Biomarkers are not established; possible candidates include neurofilament reflecting neuroaxonal damage. Methods We studied serum neurofilament light chain (sNfL) of six ChAc patients compared to two healthy control cohorts (A, six age/sex matched and B, historical cohort of 59 healthy adult subjects) and in two patients with the very similar condition of McLeod syndrome (MLS), the second core syndrome of Neuroacanthocytosis. sNfL was quantified using single-molecule array analysis. Results sNfL concentration was significantly higher in the ChAc cohort (18.73 pg/ml; IQR 15.65–27.70) compared to both healthy control cohorts (A, 7.37 pg/ml; IQR 5.60–9.05; B, 3.10 pg/ml; IQR 2.43–3.98). In MLS patients, a similar sNfL increase was observed. Conclusions sNfL is significantly increased in ChAc and MLS and seems to reflect neuroaxonal damage in the peripheral as well as the central nervous system.

  • current state of knowledge in chorea acanthocytosis as core Neuroacanthocytosis syndrome
    European Journal of Medical Genetics, 2017
    Co-Authors: Kevin Peikert, Adrian Danek, Andreas Hermann
    Abstract:

    Abstract Neuroacanthocytosis (NA) syndromes are a group of rare diseases characterized by neurological disorders and misshaped spiky red blood cells (acanthocytes) including Chorea-Acanthocytosis (ChAc), McLeod syndrome (MLS), Huntington disease-like 2 (HDL 2), pantothenate kinase-associated neurodegeneration (PKAN), abeta- and hypobetalipoproteinemia and aceruloplasminemia. This clinically and genetically heterogeneous group of diseases shares main clinical features presenting most often as a hyperkinetic movement disorder. Even though these are long noted disease conditions, we still know only little on the underlying disease mechanisms. The current review focuses upon ChAc as the core entity of NA syndromes caused by mutations in the VPS13A gene. The support of patient organizations and the ERA-NET initiative yielded to different multidisciplinary efforts with significant progress on our understanding of ChAc. Disturbances in two pathways are currently considered to be significantly involved in the pathophysiology of ChAc, namely elevated Lyn kinase phosphorylation and decreased signaling via Phosphoinositide 3-kinase (PI3K). These recent developments may reveal potential drugable targets for causative therapies of ChAc.

  • Early Diagnosis of Chorea-Acanthocytosis: Orofacial Dyskinesia, Epileptic Seizures, and HyperCKemia
    Fortschritte der Neurologie-Psychiatrie, 2017
    Co-Authors: Christian Schneider, Adrian Danek, Arwed Hostmann, Gereon R Fink, Lothar Burghaus
    Abstract:

    Chorea-acanthocytosis is an uncommon neurodegenerative disorder. Early diagnosis is often challenging. The triad of orofacial dyskinesia, epileptic seizures, and hyperCKemia should alert neurologists of a Neuroacanthocytosis syndrome. The diagnosis can be confirmed by detection of chorein deficiency or through molecular genetics (VPS13A mutation).

  • eighth international chorea acanthocytosis symposium summary of workshop discussion and action points
    Tremor and other hyperkinetic movements (New York N.Y.), 2017
    Co-Authors: Samuel S Pappas, Adrian Danek, Lucia De Franceschi, Juan S Bonifacino, William T Dauer, Mithu De, Gilbert Dipaolo, Robert S Fuller, Volker Haucke, Andreas Hermann
    Abstract:

    Chorea-Acanthocytosis (ChAc) is a rare hereditary neurological disorder characterized by abnormal movements, red blood cell pathology, and progressive neurodegeneration. Little is understood of the pathogenesis of ChAc and related disorders (collectively Neuroacanthocytosis). The Eighth International Chorea-Acanthocytosis Symposium was held in May 2016 in Ann Arbor, MI, USA, and focused on molecular mechanisms driving ChAc pathophysiology. Accompanying the meeting, members of the Neuroacanthocytosis research community and other invited scientists met in a workshop to discuss the current understanding and next steps needed to better understand ChAc pathogenesis. These discussions identified several broad and critical needs for advancing ChAc research and patient care, and led to the definition of 18 specific action points related to functional and molecular studies, animal models, and clinical research. These action points, described below, represent tractable research goals to pursue for the next several years.

  • identification of phospho-tyrosine sub-networks related to acanthocyte generation in Neuroacanthocytosis. PLoS One 2012
    2016
    Co-Authors: Adrian Danek, Ruth H. Walker, Lucia De Franceschi, Hans H Jung, Giovanni Scardoni, Carlo Tomelleri, Antonella Pantaleo, Benedikt Bader
    Abstract:

    Acanthocytes, abnormal thorny red blood cells (RBC), are one of the biological hallmarks of Neuroacanthocytosis syndromes (NA), a group of rare hereditary neurodegenerative disorders. Since RBCs are easily accessible, the study of acanthocytes in NA may provide insights into potential mechanisms of neurodegeneration. Previous studies have shown that changes in RBC membrane protein phosphorylation state affect RBC membrane mechanical stability and morphology. Here, w

Ruth H. Walker - One of the best experts on this subject based on the ideXlab platform.

  • absence of acanthocytosis in huntington s disease like 2 a prospective comparison with huntington s disease
    Tremor and other hyperkinetic movements (New York N.Y.), 2017
    Co-Authors: David G. Anderson, Dobrila D. Rudnicki, Russell L. Margolis, Ruth H. Walker, Sergio Carmona, Kubendran Naidoo, Theresa L. Coetzer, Jonathan Carr, Amanda Krause
    Abstract:

    Background:  Huntington’s Disease-like 2 (HDL2) is classified as a Neuroacanthocytosis; however, this remains unverified. We aim to determine if acanthocytes are present in HDL2 and whether acanthocytes can differentiate HDL2 from Huntington’s disease (HD). Methods:  We prospectively compared 13 HD and 12 HDL2 cases against 21 unaffected controls in Johannesburg. Blood smears were prepared using international standards and reviewed by at least two blinded reviewers. An acanthocytosis rate of greater than 1.2% in the dry smear or greater than 3.7% in the wet smear was designated a priori as the threshold for clinical significance based on previously established standards. Flow cytometry was performed on all but four of the cases. Red cell membrane protein analysis was performed on all participants. Results:  There were 12 HDL2, 13 HD, and 21 controls enrolled. None of the HD or HDL2 participants had defined acanthocytosis or other morphological abnormalities. None of the HD or HDL2 cases had evidence of an abnormal band 3. Discussion:  Acanthocytosis was not identified in either HDL2 or HD in our patient population. Our results, based on the first prospective study of acanthocytes in HDL2 or HD, suggest that screening for acanthocytes will not help establish the diagnosis of HD or HDL2, nor differentiate between the two disorders and raises the question if HDL2 should be placed within the Neuroacanthocytosis syndromes.

  • identification of phospho-tyrosine sub-networks related to acanthocyte generation in Neuroacanthocytosis. PLoS One 2012
    2016
    Co-Authors: Adrian Danek, Ruth H. Walker, Lucia De Franceschi, Hans H Jung, Giovanni Scardoni, Carlo Tomelleri, Antonella Pantaleo, Benedikt Bader
    Abstract:

    Acanthocytes, abnormal thorny red blood cells (RBC), are one of the biological hallmarks of Neuroacanthocytosis syndromes (NA), a group of rare hereditary neurodegenerative disorders. Since RBCs are easily accessible, the study of acanthocytes in NA may provide insights into potential mechanisms of neurodegeneration. Previous studies have shown that changes in RBC membrane protein phosphorylation state affect RBC membrane mechanical stability and morphology. Here, w

  • identification of phospho-tyrosine sub-networks related to acanthocyte generation in Neuroacanthocytosis. PLoS One 2012
    2016
    Co-Authors: Lucia De Franceschi, Benedikt Bader, Adrian Danek, Ruth H. Walker, Hans H Jung, Maria Teresa Dotti, Giovanni Scardoni, Carlo Tomelleri, Sara Mazzucco, Angela Siciliano
    Abstract:

    Acanthocytes, abnormal thorny red blood cells (RBC), are one of the biological hallmarks of Neuroacanthocytosis syndromes (NA), a group of rare hereditary neurodegenerative disorders. Since RBCs are easily accessible, the study of acanthocytes in NA may provide insights into potential mechanisms of neurodegeneration. Previous studies have shown that changes in RBC membrane protein phosphorylation state affect RBC membrane mechanical stability and morphology. Here, we coupled tyrosine-phosphoproteomic analysis to topological network analysis. We aimed to predict signaling sub-networks possibly involved in the generation of acanthocytes in patients affected by the two core NA disorders, namely McLeod syndrome (MLS, XK-related, Xk protein) and chorea-acanthocytosis (ChAc, VPS13A-related, chorein protein). The experimentally determined phosphoproteomic data-sets allowed us to relate the subsequent network analysis to the pathogenetic background. To reduce the network complexity, we combined several algorithms of topological network analysis including cluster determination by shortest path analysis, protein categorization based on centrality indexes, along with annotation-based node filtering. We first identified XK- and VPS13A-related protein-protein interaction networks b

  • Reviews Management of Neuroacanthocytosis Syndromes
    2016
    Co-Authors: Ruth H. Walker
    Abstract:

    Background: The two core Neuroacanthocytosis (NA) syndromes, chorea-acanthocytosis (ChAc) and McLeod syndrome, are progressive neurodegenerative disorders that primarily affect the basal ganglia. The characteristic phenotype comprises a variety of movement disorders including chorea, dystonia, and parkinsonism, as well as psychiatric and cognitive symptoms attributable to basal ganglia dysfunction. These disorders are symptomatically managed on a case-by-case basis, with very few practitioners seeing more than a single case in their careers. Methods: A literature search was performed on PubMed utilizing the terms Neuroacanthocytosis, chorea-acanthocytosis, and McLeod syndrome, and articles were reviewed for mentions of therapies, successful or otherwise. Results: There have been no blinded, controlled trials and only one retrospective case series describing ChAc. The various therapies that have been used in patients with NA syndromes are summarized. Discussion: Management remains at present purely symptomatic, which is similar in principle to other more common basal ganglia neurodegenerative disorders such as Huntington’s disease (HD) and Parkinson’s disease (PD). However, there are some specific issues particular to NA syndromes that merit attention. A

  • Computational Identification of Phospho-Tyrosine Sub- Networks Related to Acanthocyte Generation in
    2016
    Co-Authors: Lucia De Franceschi, Benedikt Bader, Adrian Danek, Ruth H. Walker, Hans H Jung, Maria Teresa Dotti, Giovanni Scardoni, Carlo Tomelleri, Sara Mazzucco, Angela Siciliano
    Abstract:

    Acanthocytes, abnormal thorny red blood cells (RBC), are one of the biological hallmarks of Neuroacanthocytosis syndromes (NA), a group of rare hereditary neurodegenerative disorders. Since RBCs are easily accessible, the study of acanthocytes in NA may provide insights into potential mechanisms of neurodegeneration. Previous studies have shown that changes in RBC membrane protein phosphorylation state affect RBC membrane mechanical stability and morphology. Here, we coupled tyrosine-phosphoproteomic analysis to topological network analysis. We aimed to predict signaling sub-networks possibly involved in the generation of acanthocytes in patients affected by the two core NA disorders, namely McLeod syndrome (MLS, XK-related, Xk protein) and chorea-acanthocytosis (ChAc, VPS13A-related, chorein protein). The experimentally determined phosphoproteomic data-sets allowed us to relate the subsequent network analysis to the pathogenetic background. To reduce the network complexity, we combined several algorithms of topological network analysis including cluster determination by shortest path analysis, protein categorization based on centrality indexes, along with annotation-based node filtering. We first identified XK- and VPS13A-related protein-protein interaction networks b

Hans H Jung - One of the best experts on this subject based on the ideXlab platform.

  • molecular basis and clinical overview of mcleod syndrome compared with other Neuroacanthocytosis syndromes a review
    JAMA Neurology, 2018
    Co-Authors: Eileen Roulis, Hans H Jung, Catherine A Hyland, Robert L Flower, Christoph Gassner, Beat M Frey
    Abstract:

    Importance McLeod syndrome, encoded by the geneXK, is a rare and progressive disease that shares important similarities with Huntington disease but has widely varied neurologic, neuromuscular, and cardiologic manifestations. Patients with McLeod syndrome have a distinct hematologic presentation with specific transfusion requirements. Because of its X-linked location, loss of theXKgene or pathogenic variants in this gene are principally associated with the McLeod blood group phenotype in male patients. The clinical manifestation of McLeod syndrome results from allelic variants of theXKgene or as part of a contiguous gene deletion syndrome involvingXKand adjacent genes, including those for chronic granulomatous disease, Duchenne muscular dystrophy, and retinitis pigmentosa. McLeod syndrome typically manifests as neurologic and cardiologic symptoms that evolve in individuals beginning at approximately 40 years of age. Observations Diagnosis of McLeod syndrome encompasses a number of specialties, including neurology and transfusion medicine. However, information regarding the molecular basis of the syndrome is incomplete, and clinical information is difficult to find. The International Society of Blood Transfusion has recently compiled and curated a listing ofXKalleles associated with the McLeod phenotype. Of note, McLeod syndrome caused by structural variants as well as those cases diagnosed as part of a contiguous gene deletion syndrome were previously classified under a singular allele designation. Conclusions and Relevance This review discusses the clinical manifestations and molecular basis of McLeod syndrome and provides a comprehensive listing of alleles with involvement in the syndrome published to date. This review highlights the clinical diversity of McLeod syndrome and discusses the development of molecular tools to elucidate genetic causes of disease. A more precise and systematic genetic classification is the first step toward correlating and understanding the diverse phenotypic manifestations of McLeod syndrome and may guide clinical treatment of patients and support for affected and carrier family members. This review provides a knowledge base for neurologists, hematologists, and clinical geneticists on this rare and debilitating disease.

  • identification of phospho-tyrosine sub-networks related to acanthocyte generation in Neuroacanthocytosis. PLoS One 2012
    2016
    Co-Authors: Adrian Danek, Ruth H. Walker, Lucia De Franceschi, Hans H Jung, Giovanni Scardoni, Carlo Tomelleri, Antonella Pantaleo, Benedikt Bader
    Abstract:

    Acanthocytes, abnormal thorny red blood cells (RBC), are one of the biological hallmarks of Neuroacanthocytosis syndromes (NA), a group of rare hereditary neurodegenerative disorders. Since RBCs are easily accessible, the study of acanthocytes in NA may provide insights into potential mechanisms of neurodegeneration. Previous studies have shown that changes in RBC membrane protein phosphorylation state affect RBC membrane mechanical stability and morphology. Here, w

  • identification of phospho-tyrosine sub-networks related to acanthocyte generation in Neuroacanthocytosis. PLoS One 2012
    2016
    Co-Authors: Lucia De Franceschi, Benedikt Bader, Adrian Danek, Ruth H. Walker, Hans H Jung, Maria Teresa Dotti, Giovanni Scardoni, Carlo Tomelleri, Sara Mazzucco, Angela Siciliano
    Abstract:

    Acanthocytes, abnormal thorny red blood cells (RBC), are one of the biological hallmarks of Neuroacanthocytosis syndromes (NA), a group of rare hereditary neurodegenerative disorders. Since RBCs are easily accessible, the study of acanthocytes in NA may provide insights into potential mechanisms of neurodegeneration. Previous studies have shown that changes in RBC membrane protein phosphorylation state affect RBC membrane mechanical stability and morphology. Here, we coupled tyrosine-phosphoproteomic analysis to topological network analysis. We aimed to predict signaling sub-networks possibly involved in the generation of acanthocytes in patients affected by the two core NA disorders, namely McLeod syndrome (MLS, XK-related, Xk protein) and chorea-acanthocytosis (ChAc, VPS13A-related, chorein protein). The experimentally determined phosphoproteomic data-sets allowed us to relate the subsequent network analysis to the pathogenetic background. To reduce the network complexity, we combined several algorithms of topological network analysis including cluster determination by shortest path analysis, protein categorization based on centrality indexes, along with annotation-based node filtering. We first identified XK- and VPS13A-related protein-protein interaction networks b

  • Computational Identification of Phospho-Tyrosine Sub- Networks Related to Acanthocyte Generation in
    2016
    Co-Authors: Lucia De Franceschi, Benedikt Bader, Adrian Danek, Ruth H. Walker, Hans H Jung, Maria Teresa Dotti, Giovanni Scardoni, Carlo Tomelleri, Sara Mazzucco, Angela Siciliano
    Abstract:

    Acanthocytes, abnormal thorny red blood cells (RBC), are one of the biological hallmarks of Neuroacanthocytosis syndromes (NA), a group of rare hereditary neurodegenerative disorders. Since RBCs are easily accessible, the study of acanthocytes in NA may provide insights into potential mechanisms of neurodegeneration. Previous studies have shown that changes in RBC membrane protein phosphorylation state affect RBC membrane mechanical stability and morphology. Here, we coupled tyrosine-phosphoproteomic analysis to topological network analysis. We aimed to predict signaling sub-networks possibly involved in the generation of acanthocytes in patients affected by the two core NA disorders, namely McLeod syndrome (MLS, XK-related, Xk protein) and chorea-acanthocytosis (ChAc, VPS13A-related, chorein protein). The experimentally determined phosphoproteomic data-sets allowed us to relate the subsequent network analysis to the pathogenetic background. To reduce the network complexity, we combined several algorithms of topological network analysis including cluster determination by shortest path analysis, protein categorization based on centrality indexes, along with annotation-based node filtering. We first identified XK- and VPS13A-related protein-protein interaction networks b

  • REVIEW Open Access Neuroacanthocytosis Syndromes
    2015
    Co-Authors: Hans H Jung, Adrian Danek, Ruth H. Walker
    Abstract:

    Neuroacanthocytosis (NA) syndromes are a group of genetically defined diseases characterized by the association of red blood cell acanthocytosis and progressive degeneration of the basal ganglia. NA syndromes are exceptionally rare with an estimated prevalence of less than 1 to 5 per 1’000’000 inhabitants for each disorder. The core NA syndromes include autosomal recessive chorea-acanthocytosis and X-linked McLeod syndrome which have a Huntington´s disease-like phenotype consisting of a choreatic movement disorder, psychiatric manifestations and cognitive decline, and additional multi-system features including myopathy and axonal neuropathy. In addition, cardiomyopathy may occur in McLeod syndrome. Acanthocytes are also found in a proportion of patients with autosomal dominant Huntington’s disease-like 2, autosomal recessive pantothenate kinase-associated neurodegeneration and several inherited disorders of lipoprotein metabolism, namely abetalipoproteinemia (Bassen-Kornzweig syndrome) and hypobetalipoproteinemia leading to vitamin E malabsorption. The latter disorders are characterized by a peripheral neuropathy and sensory ataxia due to dorsal column degeneration, but movement disorders and cognitive impairment are not present. NA syndromes are caused by disease-specific genetic mutations. The mechanism by which these mutations cause neurodegeneration is not known. The association of the acanthocytic membrane abnormality with selective degeneration of the basa

Rh Walker - One of the best experts on this subject based on the ideXlab platform.

  • Clinical and genetic analysis of 29 Brazilian patients with Huntington's disease-like phenotype
    Brasil, 2015
    Co-Authors: Gr Rodrigues, Danek A, Bader B, Rh Walker, Brice A, Cazeneuve C, Russaouen O, Marques W
    Abstract:

    Huntington's disease (HD) is a neurodegenerative disorder characterized by chorea, behavioral disturbances and dementia, caused by a pathological expansion of the CAG trinucleotide in the HTT gene. Several patients have been recognized with the typical HD phenotype without the expected mutation. The objective of this study was to assess the occurrence of diseases such as Huntington's disease-like 2 (HDL2), spinocerebellar ataxia (SCA) 1, SCA2, SCA3, SCA7, dentatorubral-pallidoluysian atrophy (DRPLA) and choreaacanthocytosis (ChAc) among 29 Brazilian patients with a HD-like phenotype. In the group analyzed, we found 3 patients with HDL2 and 2 patients with ChAc. The diagnosis was not reached in 79.3% of the patients. HDL2 was the main cause of the HD-like phenotype in the group analyzed, and is attributable to the African ancestry of this population. However, the etiology of the disease remains undetermined in the majority of the HD negative patients with HD-like phenotype.693419423Bayerische ForschungsstiftungGerman Federal Ministry of ResearchManchner UniversitatsgesellschaftDeutsch-Franzosische HochschulstiftungAdvocacy for Neuroacanthocytosis Patient

  • Chorea-Acanthocytosis Genotype in the Original Critchley Kentucky Neuroacanthocytosis Kindred
    'American Medical Association (AMA)', 2011
    Co-Authors: Velayos-baeza A, Danek A, Bader B, Ap Monaco, Holinski-feder E, Critchley Emr, Neitzel B, Rh Walker
    Abstract:

    Objective: Todetermine the molecular nature of the neurological disease in the seminal family reported by Critchley et al inthe 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. Design: DNA analysis. Setting: Molecular biology research laboratories. Participants: First- and second-degree relatives of the original Critchley et al proband from Kentucky. Main Outcome Measures: Mutations in the VPS13A gene. Results: 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. Conclusion: These findings strongly support the diagnosis of chorea-acanthocytosis as the disorder described in the original report. ©2011 American Medical Association. All rights reserved

  • Chorea-acanthocytosis genotype in Critchley's original Kentucky Neuroacanthocytosis kindred
    'American Medical Association (AMA)', 2011
    Co-Authors: Velayos-baeza A, Danek A, Bader B, Ap Monaco, Holinski-feder E, Nietzl B, Critchley Emr, Rh Walker
    Abstract:

    Objective: Todetermine the molecular nature of the neurological disease in the seminal family reported by Critchley et al inthe 1960s, characterized by a hyperkineticmovement disorder and the appearance of acanthocytosis on peripheral blood smear. Theeponym Levine-Critchley syndrome, subsequently termed Neuroacanthocytosis, has been applied to symptomatically similar, but genetically distinct, disorders, resulting in clinical and diagnostic confusion. Design: DNA analysis. Setting: Molecular biology research laboratories. Participants: First- and second-degree relatives of the original Critchley et al proband from Kentucky. Main Outcome Measures: Mutations in the VPS13A gene. Results: 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. Conclusion: These findings strongly support the diagnosis of chorea-acanthocytosis as the disorder described in the original report

  • Functional imaging in Neuroacanthocytosis
    'Springer Fachmedien Wiesbaden GmbH', 2008
    Co-Authors: Leenders K L, Jung H H, Rh Walker, Saiki S, Danek A
    Abstract:

    The published functional neuroimaging results indicate that the major finding in Neuroacanthocytosis (NA) is severe striatal hypometabolism, either with or without atrophy. There is some evidence that the right side is more affected than the left. Cortical abnormalities are either not present or subtle, but if present appear to be particularly located in the frontal cortex. As with NA, an intriguing variety of devastating movement disorders may arise when specific striatal lesions occur. Due to the low prevalence of NA only a few patients have been investigated to date, and further studies are needed

Danek A - One of the best experts on this subject based on the ideXlab platform.

  • McLeod Neuroacanthocytosis Syndrome
    University of Washington, 2019
    Co-Authors: Jung, Hans H, Danek A, Walker R H, Frey B M, Gassner C
    Abstract:

    CLINICAL CHARACTERISTICS: McLeod Neuroacanthocytosis syndrome (designated as MLS throughout this review) is a multisystem disorder with central nervous system (CNS), neuromuscular, cardiovascular, and hematologic manifestations in males. CNS manifestations are a neurodegenerative basal ganglia disease including (1) movement disorders, (2) cognitive alterations, and (3) psychiatric symptoms. Neuromuscular manifestations include a (mostly subclinical) sensorimotor axonopathy and muscle weakness or atrophy of different degrees. Cardiac manifestations include dilated cardiomyopathy, atrial fibrillation, and tachyarrhythmia. Hematologically, MLS is defined as a specific blood group phenotype (named after the first proband, Hugh McLeod) that results from absent expression of the Kx erythrocyte antigen and weakened expression of Kell blood group antigens. The hematologic manifestations are red blood cell acanthocytosis and compensated hemolysis. Allo-antibodies in the Kell and Kx blood group system can cause strong reactions to transfusions of incompatible blood and severe anemia in affected male newborns of Kell-negative mothers. Females heterozygous for XK pathogenic variants have mosaicism for the Kell and Kx blood group antigens but usually lack CNS and neuromuscular manifestations; however, some heterozygous females may develop clinical manifestations including chorea or late-onset cognitive decline. DIAGNOSIS/TESTING: The diagnosis of MLS is established in a male proband with suggestive clinical, laboratory, and neuroimaging studies; a family history consistent with X-linked inheritance; and identification on molecular genetic testing of either a hemizygous XK pathogenic variant (90% of affected males) or a hemizygous deletion of Xp21.1 involving XK (10% of affected males). MANAGEMENT: Treatment of manifestations: Dopamine antagonists (e.g., tiapride, clozapine, quetiapine) and the dopamine depletory (tetrabenazine) to ameliorate chorea; treatment of psychiatric problems, cardiac abnormalities, and seizures is based on the clinical findings; long-term and continuous multidisciplinary psychosocial support is needed for affected individuals and their families. Agents/circumstances to avoid: Blood transfusions with Kx antigens should be avoided in males with MLS. Kx-negative blood or, if possible, banked autologous blood should be used. Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of any age in order to identify as early as possible those who would benefit from: (1) detailed blood compatibility information to prevent transfusion of Kx+ homologous blood products, and (2) possible prophylactic cryopreservation of autologous blood for use in future transfusions. Surveillance: Holter ECG and echocardiography every two to three years in those without known cardiac complications; consider placement of prophylactic cardiac pacemaker; monitor for seizures; monitor serum CK concentrations for evidence of rhabdomyolysis if excessive movement disorders are present or if neuroleptic medications are being used. GENETIC COUNSELING: MLS is inherited in an X-linked manner. If the mother of an affected male is heterozygous, the chance of transmitting the XK pathogenic variant in each pregnancy is 50%. Males who inherit the XK variant will be affected; females who inherit the XK variant will be heterozygous and will usually not be affected. Affected males pass the XK pathogenic variant to all of their daughters and none of their sons. Once the XK pathogenic variant has been identified in an affected family member, carrier testing for at-risk females, prenatal testing for a pregnancy at increased risk, and preimplantation genetic diagnosis are possible

  • Eighth International Chorea–Acanthocytosis Symposium: summary of workshop discussion and action Points
    'Columbia University Libraries Information Services', 2017
    Co-Authors: Ss Pappas, William T Dauer, De Franceschi L, Danek A, Bonifacino J, De M, Dipaolo G, Fuller R, Hermann A
    Abstract:

    Chorea-Acanthocytosis (ChAc) is a rare hereditary neurological disorder characterized by abnormal movements, red blood cell pathology, and progressive neurodegeneration. Little is understood of the pathogenesis of ChAc and related disorders (collectively Neuroacanthocytosis). The Eighth International Chorea-Acanthocytosis Symposium was held in May 2016 in Ann Arbor, MI, USA, and focused on molecular mechanisms driving ChAc pathophysiology. Accompanying the meeting, members of the Neuroacanthocytosis research community and other invited scientists met in a workshop to discuss the current understanding and next steps needed to better understand ChAc pathogenesis. These discussions identified several broad and critical needs for advancing ChAc research and patient care, and led to the definition of 18 specific action points related to functional and molecular studies, animal models, and clinical research. These action points, described below, represent tractable research goals to pursue for the next several years

  • CLINICS 2008;63(1):135 LETTER TO THE EDITOR
    2015
    Co-Authors: Dobson-stone C, Danek A
    Abstract:

    To the Editors; With great initial interest we read the report of brothers with a Neuroacanthocytosis syndrome1 but were later disap-pointed by the unmentioned fact that the details of the cases are identical to those of a previous publication by the sen-ior author2. Despite the time interval of 22 years since that original paper, the only significant additions in this dupli-cate publication are the color video stills and the figure of the brain MRI. Figure 1, of a peripheral blood smear with acanthocytes, was already made available to the public in an online medical resource3 (www.emedicine.com) and the connection with the present cases remains unclear. There is a hint that post mortem examination may have been per-formed as a further new fact. This, however, is mentioned only very briefly and could also be read as a reference to general knowledge about the neuropathological findings in Neuroacanthocytosis syndromes. The argument of keeping an open mind for differential diagnosis that may have driven Lakhan and Gross to discuss these cases again is somewhat trivial. Although the erythrocyte Kell antigen results mentione

  • Clinical and genetic analysis of 29 Brazilian patients with Huntington's disease-like phenotype
    Brasil, 2015
    Co-Authors: Gr Rodrigues, Danek A, Bader B, Rh Walker, Brice A, Cazeneuve C, Russaouen O, Marques W
    Abstract:

    Huntington's disease (HD) is a neurodegenerative disorder characterized by chorea, behavioral disturbances and dementia, caused by a pathological expansion of the CAG trinucleotide in the HTT gene. Several patients have been recognized with the typical HD phenotype without the expected mutation. The objective of this study was to assess the occurrence of diseases such as Huntington's disease-like 2 (HDL2), spinocerebellar ataxia (SCA) 1, SCA2, SCA3, SCA7, dentatorubral-pallidoluysian atrophy (DRPLA) and choreaacanthocytosis (ChAc) among 29 Brazilian patients with a HD-like phenotype. In the group analyzed, we found 3 patients with HDL2 and 2 patients with ChAc. The diagnosis was not reached in 79.3% of the patients. HDL2 was the main cause of the HD-like phenotype in the group analyzed, and is attributable to the African ancestry of this population. However, the etiology of the disease remains undetermined in the majority of the HD negative patients with HD-like phenotype.693419423Bayerische ForschungsstiftungGerman Federal Ministry of ResearchManchner UniversitatsgesellschaftDeutsch-Franzosische HochschulstiftungAdvocacy for Neuroacanthocytosis Patient

  • Computational identification of phospho-tyrosine sub-networks related to acanthocyte generation in Neuroacanthocytosis.
    'Public Library of Science (PLoS)', 2012
    Co-Authors: De Franceschi L, Scardoni G, Tomelleri C, Danek A, Bader B, Mazzucco S, Dotti M, Siciliano A
    Abstract:

    Abstract Acanthocytes, abnormal thorny red blood cells (RBC), are one of the biological hallmarks of Neuroacanthocytosis syndromes (NA), a group of rare hereditary neurodegenerative disorders. Since RBCs are easily accessible, the study of acanthocytes in NA may provide insights into potential mechanisms of neurodegeneration. Previous studies have shown that changes in RBC membrane protein phosphorylation state affect RBC membrane mechanical stability and morphology. Here, we coupled tyrosine-phosphoproteomic analysis to topological network analysis. We aimed to predict signaling sub-networks possibly involved in the generation of acanthocytes in patients affected by the two core NA disorders, namely McLeod syndrome (MLS, XK-related, Xk protein) and chorea-acanthocytosis (ChAc, VPS13A-related, chorein protein). The experimentally determined phosphoproteomic data-sets allowed us to relate the subsequent network analysis to the pathogenetic background. To reduce the network complexity, we combined several algorithms of topological network analysis including cluster determination by shortest path analysis, protein categorization based on centrality indexes, along with annotation-based node filtering. We first identified XK- and VPS13A-related protein-protein interaction networks by identifying all the interactomic shortest paths linking Xk and chorein to the corresponding set of proteins whose tyrosine phosphorylation was altered in patients. These networks include the most likely paths of functional influence of Xk and chorein on phosphorylated proteins. We further refined the analysis by extracting restricted sets of highly interacting signaling proteins representing a common molecular background bridging the generation of acanthocytes in MLS and ChAc. The final analysis pointed to a novel, very restricted, signaling module of 14 highly interconnected kinases, whose alteration is possibly involved in generation of acanthocytes in MLS and ChAc. PMID: 22355334 [PubMed - in process