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European Multidisciplinary Initiative on Neuroacanthocytosis

Neuroacanthocytosis Syndromes

The rare conditions collectively labelled as neuroacanthocytosis (NA) seriously disable young adults and place a heavy burden on them and their families. NA syndromes affect about 1 in 3 million individuals and present a variety of emotional, cognitive and movement disorders. They share considerable similarities with Huntington´s disease (HD). As in HD, the basal ganglia are preferentially affected by neurodegeneration but in contrast to HD a key to the understanding of underlying mechanisms may be found in easily accessible peripheral cells.

It is characteristic for NA that deformed erythrocytes with thorny protrusions are found in the patients´ blood. Although not detectable in every single case, these cells are the origin of the term neuroacanthocytosis, denoting the association of neurological findings and acanthocytes (“akantha”: Greek for thorn).

NA syndromes may be divided into those with lipid abnormalities and peripheral nervous system involvement (such as abetalipoproteinemia) and into the “core” NA syndromes with central nervous system involvement, including basal ganglia degeneration. Currently, the genetic basis is known for four of these conditions: McLeod syndrome (MLS, X-linked), chorea-acanthocytosis (ChAc, autosomal recessive), Huntington´s disease-like 2 (HDL2, autosomal dominant) and pantothenate kinase associated neurodegeneration (PKAN, autosomal recessive). Responsible genes are the Kell protein associated XK in MLS, VPS13A (vacuolar protein sorting 13 A, chorein) in ChAc, JPH3 (junctophilin 3) in HDL2 and PANK2 (pantothenate kinase 2) in PKAN. The recognition of PKAN as part of the NA spectrum creates a link to the NBIA group of syndromes (“neurodegeneration with brain iron accumulation”). NBIA syndromes are characterized by high brain iron with typical magnetic resonance imaging findings and the presence of axonal spheroids on histology. NBIA syndromes include some genetically still undefined conditions: PLA2G mutations were most recently added to the list of genes involved. At least 8% of PKAN patients show RBC acanthocytosis yet for other NBIA syndromes such analyses are currently not available

 

European Multidisciplinary Initiative on Neuroacanthocytosis (EMINA)

Little is known on the disease progression milestones and no treatment or cure of the debilitating disorders are available. Work with an international database should allow the development of scales for systematic treatment studies and the analysis of experience gained with procedures such as deep-brain stimulation (DBS) that is increasingly considered in the NA and NBIA syndromes.

Besides the actual mechanisms in neurodegeneration, the formation of the essentially unknown basis of the acanthocytic shape change is interesting to basic scientists. This implies alterations of membrane components of the outer and inner leaflet as compared to the disk shape of a normal RBC, the discocyte. These alterations imply a relative dilation of the outer membrane leaflet or a compression of the inner leaflet or a combination of both, outer leaflet dilatation and inner leaflet compression. Acanthocytic cells in NA blood appear to persist for longer. Thus, one may assume the existence of stable domains within these membranes, particularly in the “thorn” regions.

One interesting aspect concerning neurons as well as erythrocytes is the role of vesiculation and autophagy in the NA and NBIA syndromes. Chorein, the VPS13A protein, appears to be involved in such processes while terminal erythropoiesis and maintenance of (neural) cell viability are both connected to autophagy. A defect in the autophagic pathway could therefore account for both neuronal and RBC dysfunction and may be studied in vitro using patient RBC membranes. Post mortem analyses of nervous tissue in the NA and NBIA syndromes on a systematic basis, using case series, are similarly needed and require appropriate collection and preservation of tissue. Nervous tissue from ChAc cases is available in the Munich brain bank and examined neuropathologically.

The development of animal models for the various disease states has become possible, yet in comparison to HD the pace has been very slow. The few existing mouse models (for MLS, ChAc, HDL2 and PKAN, lacking variety in terms of gene mutations) have not yet been exhaustively analysed and the situation appears similar for C. elegans (MLS) and Tetrahymena thermophila (ChAc). For PKAN a drosophila model has recently become available. Development of animal models for NA and NBIA syndromes clearly is a major goal in EMINA.

 

EMINA Structure

Partners:

  • LMU - Ludwig-Maximilians-University, Neurologische Klinik und Poliklinik, Munich, Germany
  • MUV - Max F. Perutz Laboratories, Medical University of Vienna, Vienna, Austria
  • RUN - Radboud University Medical Center Nijmegen, Biochemistry, Nijmegen, The Netherlands
  • UMCG - University Medical Center Groningen, Groningen, Cell Biology, The Netherlands
  • CHUB - Centre Hospitalier Universitaire de Bordeaux, Service de Neurologie, Bordeaux, France
  • ITF - Istanbul Faculty of Medicine, Department of Neurology, Istanbul, Turkey

Diagnostic testing for ChAc is available at the University of Munich and is based on a Western blot of red blood cell (RBC) membranes. Instructions [PDF, 0,8 MB].

A dedicated databank was formed for this purpose through collaboration with the European Huntington´s Disease Network (Euro-HD) and is accessible through the internet. [...more]

 

EMINA aims and subprojects:

  1. Set up NA reference centre located in Munich (Partners involved: LMU, CHUB, ITF).
  2. Set up a diagnostic centre for ChAc located in Istanbul (Partners involved: LMU, ITF).
  3. Analyse NA red cell membranes composition (Partners involved: MUV, RUN).
  4. Analyse NA red cell proteoms and study localisation of NA relevant proteins in control cells and knock down effect on control cells (Partners involved: MUV, RUN).
  5. Elucidate the mechanism of vesicle formation in erythrocytes and acanthocytes of patients with various forms of NA (Partners involved: RUN).
  6. Develop Drosophila models for other NA syndromes in addition to the existing Drosophila PKAN model to identify underlying common mechanism of cell degeneration (Partners involved: UMCG).
  7. Create diagnostic guidelines and taxonomy for NA syndromes including collection of NA patients (Partners involved: LMU, CHUB, ITF)

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