There are 2 categories of neurologic disease associated with red blood cell acanthocytosis; one with a defect in the red cell lipid membrane (consisting of Bassen-Kornzweig disease and the disorder called HARP [hypobetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration] syndrome [see Chap. 36]); and a second group that lacks a lipid abnormality. The main syndrome, and the one to which the term neuroacanthocytosis had for a long time been applied, is caused by an autosomal recessive mutation. However, there are now 4 additional subtypes, one dominantly transmitted and another X-linked (McLeod type), which is discussed below. These are all in distinction to Bassen-Kornzweig disease that is caused by a defect in the lipid layer of the red cell membrane that leads to the red cell deformity (see further on).
In the series of 19 cases of typical neuroacanthocytosis reported by Hardie and colleagues, the manifestations included dystonia, tics, vocalizations, rigidity, and lip and tongue biting; more than half had cognitive impairment or psychiatric features. The average age of onset was 32 years; 7 of the 19 cases were sporadic. The disease has been linked in almost all families to chromosome 9q, where there is a mutation in the gene encoding a large (3,100-amino-acid) protein designated chorein that is involved in cellular protein sorting and trafficking (Rampoldi). Some of the families with dominantly inherited neuroacanthocytosis have mutations in the chorein gene. There is atrophy and gliosis of the caudate nuclei and putamens but no neuronal loss in the cerebral cortex or other parts of the brain.
According to Sakai and coworkers (1991), the acanthocytosis is the result of an abnormal composition of covalently (tightly) bound fatty acids in erythrocyte membrane proteins (palmitic and docosahexaenoic acids increased and stearic acid decreased). The red cells should be examined in a fresh preparation of blood in isotonic saline; it is likely to be overlooked in a conventional Wright stain from a hospital laboratory. More than 5 percent of the red cells have the characteristic structural abnormality in affected individuals. The acanthocytosis may also be detected by scanning electron microscopy. The latter may be necessary to undertake in cases of unexplained chorea that have the other features of this disease as genetic testing for the gene (see in the following text) is not widely available.
The second less common category of neuroacanthocytosis enters into the differential diagnosis of Huntington chorea or unexplained progressive choreas and has the following characteristics: (1) onset in adolescence or early adult life of generalized involuntary movements (described as chorea but including dystonia and tics), usually beginning as an orofacial dyskinesia and spreading to other parts of the body and to other neural systems; (2) mild to moderate mental deterioration with behavioral disturbance in some but not all cases; (3) decreased or absent tendon reflexes and evidence of chronic axonal neuropathy and denervation atrophy of muscles; and (4) the defining feature of acanthocytosis (thorny or spiky appearance of erythrocytes).
McLeod disease, another disorder with acanthocytosis and the gradual development of chorea in middle to late life, is characterized by degeneration of the caudate and putamen and a myopathy (elevated serum creatine phosphokinase [CPK]). These individuals have fewer facial tics and orofacial features than those with neuroacanthocytosis. McLeod syndrome arises from mutations in a gene on the X-chromosome that encodes the KX protein, which binds to surface Kell antigens on red cells. In addition to the primary KX gene mutations, these individuals show diminished Kell antigen expression on the red-cell surface.