Fourth International Symposium on Neuroacanthocytosis

Abstracts from the Fourth International Symposium on Neuroacanthocytosis

July 1-2, 2008
London and Oxford

Chairs: Prof. Kailash Bhatia, MD, FRCP, Institute of Neurology, University College London; Prof. Anthony P. Monaco, MD, PhD, Wellcome Trust Centre for Human Genetics, University of Oxford

Organizers: Antonio Velayos-Baeza, PhD; Susanne Schneider, MD; Glenn Irvine

6-1 The molecular basis of red cell membrane disorders
J. Delaunay
Hôpital de Bicêtre, Service d'Hématologie, Faculté de Médecine Paris-Sud, Le Kremlin-Bicêtre, France

Most genetic disorders of the red cell membrane are associated with a more or less pronounced hemolytic anemia and various shape abnormalities. Indeed, these disorders have been largely classified on the very change in erythrocyte morphology. The membrane is composed of a lipid bilayer and is studded with a variety of proteins spanning the bilayer and involved in transport functions. Specifically, there is, at the inner surface of the bilayer, a strong bidimensional skeleton tightly attached to the bilayer by anchoring proteins such as ankyrin-1, and playing a major role in red cell mechanical properties and morphology. Hereditary elliptocytosis (HE) and its aggravated form, hereditary poikilocytosis (HP), stem from mutations in the SPTA1, SPTB and the EPB41 genes that encode spectrin α-chain, spectrin β-chain and protein 4.1R, respectively. Mutations of both spectrin chains lie at or next to the site where αβ-spectrin dimers interact to form α2β2 tetramers or higher order oligomers. They loosen this site and generate an ellipsoid. A very common allele of the SPTA1 gene, allele αLELY, leads to an aggravation of elliptocytosis when it happens to stand in trans to an elliptocytogenic allele of this gene. The loosening is accentuated (through a subtle mechanism), resulting in the fragmentation of the red cell, that is, poikilocytosis. The Southeast Asian ovalocytosis is a unique condition due to a 27 nucleotide-deletion in the SLC4A1 gene that encodes the anion exchanger. The corresponding 9 amino acid loss lies at the very junction of the cytoplasmic and membrane domain of the anion exchanger. Hereditary spherocytosis (HS) is the most common genetic condition with an altered cell shape. Generally speaking, one of many possible proteins may be reduced or even absent (in the most severe cases): HS can be viewed as the result of quantitative defects. As a consequence, the lining of the inner surface of the membrane by the skeleton becomes more sparse. Microvesicles swarm out of the cell, diminishing its surface (normally in excess) and transforming the physiological biconcave disk into a spheroid. Mutations lie in at least five genes in HS: SPTA1 and SPTB (however the mutations in these genes are different from the ones seen above, and primarily lead to an isolated defect of spectrin), ANK1, that encodes ankyrin-1, SLC4A1 and EPB42, that encode the anion exchanger and protein 4.2, respectively. A huge collection of mutations have been gathered. Some of them, especially when they occur in the homozygous state, have proved very useful in the understanding of the supramolecular architecture and will be presented. Hereditary stomatocytoses (HSt) are now known to belong to the wider, ever diversifying group of genetic disorders of the passive leak of monovalent cations across the membrane. The shape abnormality (sometimes missing) relies on the conversion of the circular depression centering the normal red cells into a linear groove. The generation of this shape is ill-understood. These conditions are rare. The most frequent is dehydrated hereditary stomatocytosis (DHSt) which, very interestingly, is part of a pleiotropic syndrome including, in addition to anemia, a pseudohyperkalemia and perinatal fluid effusions. The involved genes are still unknown for most of this set of conditions. However, a dramatic example is accounted for by cryohydrocytosis. This condition, which is characterized by a cation leak enhanced by the cold, is due to mutations lying in the anion exchanger! Neuroacanthocytosis (NA) is an association of neurological manifestations and acanthocytosis. NA has been described as inherited as an autosomal recessive disorder, as an autosomal dominant disorder, and as part of an X-linked disorder called McLeod syndrome (MLS) and related to the Kell blood group system. The links between acanthocytosis and the other symptoms constitute a fascinating problem yet to be solved.