Abnormal red cell features associated with hereditary neurodegenerative disorders: the neuroacanthocytosis syndromes.

PURPOSE OF REVIEW: This review discusses the mechanisms involved in the generation of thorny red blood cells (RBCs), known as acanthocytes, in patients with neuroacanthocytosis, a heterogenous group of neurodegenerative hereditary disorders that include chorea-acanthocytosis (ChAc) and McLeod syndrome (MLS). RECENT FINDINGS: Although molecular defects associated with neuroacanthocytosis have been identified recently, their pathophysiology and the related RBC abnormalities are largely unknown. Studies in ChAc RBCs have shown an altered association between the cytoskeleton and the integral membrane protein compartment in the absence of major changes in RBC membrane composition. In ChAc RBCs, abnormal Lyn kinase activation in a Syk-independent fashion has been reported recently, resulting in increased band 3 tyrosine phosphorylation and perturbation of the stability of the multiprotein band 3-based complexes bridging the membrane to the spectrin-based membrane skeleton. Similarly, in MLS, the absence of XK-protein, which is associated with the spectrin-actin-4.1 junctional complex, is associated with an abnormal membrane protein phosphorylation state, with destabilization of the membrane skeletal network resulting in generation of acanthocytes. SUMMARY: A novel mechanism in generation of acanthocytes involving abnormal Lyn activation, identified in ChAc, expands the acanthocytosis phenomenon toward protein-protein interactions, controlled by phosphorylation-related abnormal signaling.

Acanthocytes of Stropharia rugosoannulata function as a nematode-attacking device.

Efficient killing of nematodes by Stropharia rugosoannulata Farlow ex Murrill cultures was observed. This fungus showed the ability to immobilize the free-living nematode Panagrellus redivivus Goodey within minutes and to immobilize the pine wilt nematode Bursaphelenchus xylophilus (Steiner & Buhrer) Nickle within hours on agar plates. Moreover, P. redivivus worms were completely degraded by the fungus within 24 to 48 h. The cultures of S. rugosoannulata studied shared the characteristic of abundantly producing cells with finger-like projections called acanthocytes. We showed that the nematode-attacking activity of this fungus is carried out by these spiny acanthocytes and that mechanical force is an important factor in the process. Furthermore, the growth and nematode-attacking activity of the fungus in soil were also determined, and our results suggest that acanthocytes are functional in soil.

Acanthocytosis and neurological disorders.

Acanthocytosis occurs because of ultrastructural abnormalities of the erythrocyte membranous skeleton resulting in reduced membrane fluidity. At least three hereditary neurological conditions are associated with it, although as yet the pathogenesis of the neurological features is unknown. In abetalipoproteinaemia, an autosomal recessive condition, vitamin E deficiency results in a progressive spinocerebellar syndrome associated with peripheral neuropathy and retinitis pigmentosa. Neuroacanthocytosis is also probably an autosomal recessive condition and is characterised by chorea, orofaciolingual dyskinesia, dysarthria, areflexia, seizures and dementia. McLeod syndrome is an X-linked recessive disorder usually presenting in males as a benign myopathy with areflexia, in association with a particular abnormality of expression of Kell blood group antigens. However, occasionally the neurological features are more severe and indistinguishable from those of neuroacanthocytosis. Recent advances in molecular genetics may assist better understanding of the disease mechanisms and the search for more effective treatments.

A novel point mutation in the McLeod syndrome gene in neuroacanthocytosis.

McLeod syndrome is an X-linked recessive disorder, characterized by neuromuscular and hematopoietic dysfunction. Two cases of McLeod syndrome were reported in a family with neuroacanthocytosis and, remarkably, 1 of them was female. Direct sequence analysis of the McLeod gene in 12 members of the family revealed a novel point mutation in exon 2 that creates a frameshift and results in premature termination of translation. There was marked skewing of X inactivation in the severely affected female.

Erythrocyte anion transporter and antibrain immunoreactivity in chorea-acanthocytosis. A contribution to etiology, genetics, and diagnosis.

Novel structural and functional alterations in the erythrocyte anion transporter band 3 are described in one patient with definite, and in two patients with symptoms compatible with chorea-acanthocytosis, but without acanthocytes. Immunoblotting analysis shows increased fragmentation of band 3, and sulfate flux measurements indicate that anion transport activity is reduced in the erythrocytes of these patients. These changes are similar, but not identical to those observed during normal erythrocyte aging. In addition, distinct antibrain immunoreactivity was present in the plasma of these patients. A family study indicates that abnormal erythrocyte band 3 structure and function and antibrain immunoreactivity may be phenotypes of two independent, genetically determined factors, that are part of the heterogenic defect of chorea-acanthocytosis. The findings in the patients without acanthocytes indicate that the biochemical abnormalities may be related to a chorea-acanthocytosis-like, amyotrophic extrapyramidal movement disorder with axonal neuropathy. Measurement of erythrocyte sulfate transport and plasma antibrain immunoreactivity could be of use in establishing the diagnosis and further unravelling the genetic background of chorea-acanthocytosis and related syndromes.

Erythrocyte membrane abnormalities in patients with amyotrophic chorea with acanthocytosis. Part 1. Spin labeling studies and lipid analyses.

Low fluidity was observed in the erythrocyte membranes of familial chorea-acanthocytosis by spin labeling with 12NS. The high content of the saturated fatty acids support the finding of low fluidity. Other lipid contents (cholesterol and phospholipids) and the cholesterol/phospholipid ratio were within normal ranges. The sharp decrease in the parameter, (h0/h-1)1/2, suggests phase separation deep inside the patients' erythrocyte membrane matrix. This distortion of the membrane matrix may be caused by membrane components other than the lipid components.

Acanthocytosis and cholesterol enrichment decrease lipid fluidity of only the outer human erythrocyte membrane leaflet.

The structure and functions of the human erythrocyte are influenced by the composition and organization of the membrane lipids. The outer (exofacial) and inner (endofacial) leaflets of the erythrocyte membrane differ in lipid composition, and recent studies using a group of membrane-impermeant pyrene fluorophores have demonstrated that the lipid fluidity of the outer leaflet exceeds that of the inner. Using one of these probes, pyrene butyryl hydrazide linked to the tetrasaccharide stachyose (SPBH), we have compared the lipid fluidity of the outer and inner leaflets in normal human erythrocytes treated experimentally to alter membrane cholesterol content and in acanthocytes, erythrocytes of altered morphology found in individuals with the genetic disorder abetalipoproteinaemia. The results, reported here, demonstrate that hemileaflet fluidity can be altered selectively: acanthocytosis and experimental cholesterol enrichment decrease the lipid fluidity of the outer but not the inner hemileaflet.

Decreased fluidity of red cell membrane lipids in abetalipoproteinemia.

Acanthocytic red cells in patients with abetalipoproteinemia are morphologically similar to the red cells in spur cell anemia. Fluidity of membrane lipids is decreased in spur cells due to their excess cholesterol content. Acanthocyte membranes have an increased content of sphingomyelin and a decreased content of lecithin. To assess the effect of this abnormality of acanthocyte membrane lipid composition on membrane fluidity, we studied red cells from five patients with abetalipoproteinemia and four obligate heterozygote family members. Membrane fluidity was measured in terms of microviscosity ( eta) at 37 degrees C, assessed by means of the fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene. It was increased from 3.2+/-0.1 poise in normals to 4.01-4.14 poise in acanthocytes. This was associated with an increase in the sphingomyelin/lecithin ratio from 0.84+/-0.08 in normals in 1.45-1.61 in acanthocytes. The eta of acanthocyte membranes was not influenced by the degree of vitamin E deficiency. Similar changes in eta were observed in liposomes prepared from red cell lipids. Heterozygotes had normal sphingomyelin/lecithin ratios and normal values for eta. The flow activation energy for viscosity, a measure of the degree of order in the hydrophobic portion of the membrane, was decreased from 8.3 kcal/mole in normal red cells to 7.2 kcal/mole in acanthocytes, indicating that acanthocyte membrane lipids are more ordered. Variations in the sphingomyelin/lecithin mole ratio of liposomes prepared from brain sphingomyelin and egg lecithin with equimolar cholesterol caused similar changes in both eta and activation energy. The deformability of acanthocytes, assessed by means of filtration through 3-mum filters, was decreased. These studies indicate that the increased sphingomyelin/lecithin ratio of acanthocytes is responsible for their decreased membrane fluidity. As in spur cells and in red cells enriched with cholesterol in vitro, this decrease in membrane fluidity occurs coincidentally with an abnormality in cell contour and an impairment in cell deformability.