Page 755 - Hematology_ Basic Principles and Practice ( PDFDrive )

642 Part V Red Blood Cells

by liver cells, caused either by aberrant posttranslational processing Neuroacanthocytosis Syndromes
or by defective aposecretion. In some patients this is because of
qualitative or quantitative defects in the microsomal triglyceride The neuroacanthocytosis syndromes are a group of degenerative
transfer protein, which catalyzes the transport of triglyceride, choles- neurologic disorders with phenotypic and genetic heterogeneity that
terol ester, and phospholipid from phospholipid surfaces. Microsomal share the feature of acanthocytes on peripheral blood smear. These
triglyceride transfer protein is the only tissue-specific component, disorders include chorea-acanthocytosis, the X-linked McLeod syn-
other than apolipoprotein B, required for secretion of apolipoprotein drome (see McLeod Phenotype), and several other neurodegenerative
B-containing lipoproteins. As a result, apoprotein B is absent in diseases, including Huntington disease-like 2 caused by mutations in
plasma, as are the individual lipoprotein fractions that contain this junctophilin-3 and pantothenate kinase-associated neurodegenera-
apoprotein. These lipoprotein fractions include chylomicrons and tion (formerly known as Hallervorden-Spatz syndrome and its allelic
very-low-density lipoproteins that transport triglycerides, as well as variant syndrome—hypobetalipoproteinemia, acanthocytosis, retini-
the low-density lipoproteins that are products of very-low-density tis pigmentosa, pallidal degeneration [HARP]) caused by mutations
lipoproteins and transport cholesterol. Consequently, preformed tri- in pantothenate kinase 2.
glycerides are not transported from the intestinal mucosa, and they Chorea-acanthocytosis syndrome is an autosomal recessive syn-
are nearly absent in the plasma. Plasma cholesterol and phospholipids drome of adult onset that is manifest by multiple neurologic abnor-
are markedly reduced, with a relative increase in sphingomyelin at malities, including limb chorea, progressive orofacial dyskinesia with
the expense of lecithin. tics, tongue-biting neurogenic muscle hypotonia, and atrophy. The
As is the case in acanthocytosis of liver disease, the acanthocytic hematologic manifestations are minimal and include a variable per-
lesion is acquired from the plasma. Erythrocyte precursors are of centage of acanthocytes on the peripheral blood film without anemia
normal shape, and the acanthocytic lesion develops as the cells mature and normal or only slightly decreased RBC survival. The mechanism
and age in the circulation. Normal cells acquire this shape when of acanthocytosis in this syndrome is unknown. Studies of plasma
transfused into the recipient. and RBC membrane lipids have revealed a high content of unsatu-
The most striking abnormality of RBC membrane lipids involves rated fatty acids, presumably accounting for reduced RBC membrane
a net increase in sphingomyelin. Because plasma lipids readily fluidity. Additional abnormalities of uncertain significance include an
exchange with the lipids of the RBC membrane, it is likely that this uneven distribution of intramembrane particles, impaired phos-
change simply mirrors the alterations in plasma lipid composition. phorylation of the erythrocyte actin-bundling protein dematin,
In contrast to RBCs in spur cell anemia of severe liver disease, abnormal accumulation of transglutaminase products, and altered
the content of membrane cholesterol is normal or only slightly function and structure of band 3.
increased. Mutations have been identified in the chorein gene (also known
The role of membrane lipids in the acanthocyte shape transforma- as CHAC or VPS13A—vacuolar protein sorting 13 homolog A) in
tion was first established by findings of restoration of biconcave shape many affected patients. Chorein does not belong to any known
after extraction of lipids from the cell membrane by detergents. The human gene family, and computer searches have not identified any
molecular basis of the acanthocytic shape is unknown, but several known structural motifs or domains. The function of the chorein
indirect observations suggest that it is related to an increase of the gene product remains unknown in either erythrocytes or the brain.
surface area of the outer hemileaflet of the lipid bilayer relative to the In yeast, a chorein homologue is involved in protein sorting and
inner leaflet. Several other abnormalities have been noted in abeta- transport and in regulation of levels of phosphatidylinositol-4-
lipoproteinemia, including a decrease in plasma lecithin cholesterol phosphate in cell membranes.
transferase activity and an increased susceptibility of membrane and
plasma lipids to oxidation as a result of malabsorption-induced
deficiency of vitamin E. The contributions of these abnormalities to MCLeod Phenotype
the acanthocyte red cell lesions are unknown.
The McLeod syndrome is characterized by a mild compensated
hemolytic anemia with a variable percentage of acanthocytes on the
Clinical Manifestations peripheral blood film and, in some patients, late-onset myopathy or
chorea. The McLeod blood group phenotype is an X-linked anomaly
This autosomal recessive disease can become evident in the first few of the Kell blood group system in which RBCs, white blood cells, or
months of life, manifested by fat malabsorption with normal absorp- both react poorly with Kell antisera. The affected cells lack Kx, the
tion of other nutrients. Intestinal biopsy is diagnostic, revealing product of the XK gene, which appears to be a membrane precursor
engorgement of mucosal cells with lipid droplets. Other features of the Kell antigens. The XK gene encodes a novel 444-amino acid
include retinitis pigmentosa and a progressive ataxia with intention integral membrane transporter. In most patients, pathogenic nonsense
tremors that usually develops at 5 to 10 years of age, progressing to or deletion mutations leading to absent or shortened XK protein
death in the second or third decade of life. The hematologic mani- that lacks the Kell protein binding site. Male hemizygotes who lack
festations are mild and include mild normocytic anemia with acan- Kx have variable acanthocytosis (8–85%) and mild, compensated
thocytosis (50–90%) and normal or slightly elevated reticulocyte hemolysis. Because of the RBC mosaicism predicted by the Lyon
counts. Occasional patients can have more severe anemia resulting hypothesis of X chromosome inactivation, female heterozygote car-
from the nutritional deficiencies (iron and folate) that accompany fat riers can have occasional acanthocytes on the peripheral blood film.
malabsorption. The treatment includes dietary restriction of triglyc- Lyonized women with more severe symptoms have been described.
erides and supplementation with the lipid-soluble vitamins A, K, D, Diagnosis may be challenging. CK levels are almost always elevated.
and E. Vitamin E can stabilize or even improve both the retinal and In affected males, erythrocytes demonstrate absent Kx antigen and
neuromuscular abnormalities. reduced Kell antigens. Because of the susceptibility to alloimmuniza-
Autosomal recessive abetalipoproteinemia should be distinguished tion, it is important to diagnose affected patients because if they
from the homozygous form of familial hypobetalipoproteinemia. are transfused, they can develop antibodies compatible only with
Although the clinical presentation of both disorders is similar, the McLeod red cells.
latter disorder is milder, and the parents have occasional acanthocytes The McLeod syndrome has been reported in association with
on the peripheral blood film, and their plasma low-density lipoprotein chronic granulomatous disease of childhood, retinitis pigmentosa,
levels are decreased. The molecular lesions in familial hypobetalipo- and Duchenne muscular dystrophy. This association is caused by the
proteinemia involve a variety of apoprotein B gene mutations, leading close proximity of the genetic loci for these disorders in the p21
to aberrant apoprotein B gene transcription or translation. region of the X chromosome (Xp21), suggesting the occurrence of
Varying degrees of acanthocytosis without anemia have also been various manifestations because of contiguous gene syndromes. This
described with isolated deficiency of apoprotein B100. may explain the occasional findings of either echinocytes or