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Neuroacanthocytosis

Background

Neuroacanthocytosis encompasses a group of genetically heterogenous disorders characterized by neurologic signs and symptoms associated with acanthocytosis, an abnormality of red blood cells.
Neurologic problems usually consist of either movement disorders or ataxia, personality changes, cognitive deterioration,
axonal neuropathy, and seizures
. At some point during the course of the disease, most patients manifest acanthocytosis on the peripheral blood smear, ie, a certain percentage of the patients’ erythrocytes (typically 10-30%) have an unusual starlike appearance with spiky- or thorny-appearing projections.

There has been, and there continues to be, considerable disagreement about which specific diseases should be included under the general term neuroacanthocytosis. This is the understandable result of gradually accumulating knowledge of the molecular and biological bases of these disorders.

The first form of neuroacanthocytosis to be well described in the medical literature is Bassen-Kornzweig disease, or abetalipoproteinemia (1950),
which is an autosomal recessive abnormality of lipoprotein metabolism resulting in ataxia combined with acanthocytosis. In the early descriptions, Bassen-Kornzweig disease was compared with a better known condition, Friedreich ataxia. The two are rather similar except that patients with Bassen-Kornzweig disease have acanthocytosis. In fact, the term acanthocyte was originated by the authors of the seminal Bassen-Kornsweig paper.

The second type of neuroacanthocytosis was described in 1960 by Levine
and later in 1968 by Critchley
. Just as Bassen-Kornsweig disease looks much like Friedreich ataxia, the Levine-Critchley syndrome, as it came to be called, resembles Huntington disease (HD) with prominent choreiform or choreoathetoid movements, progressive dementia, and, in the original descriptions, autosomal dominant inheritance.

One notable difference from HD is that Levine-Critchley syndrome manifests acanthocytosis. When it was originally described, it was also frequently compared with Bassen-Kornzweig disease in that both combined neurologic abnormalities with acanthocytosis, but the Levine-Critchley syndrome had normal lipoproteins as well as a later age of onset. What today is recognized as the Levine-Critchley syndrome is caused by a mutation in a specific gene called chorein (also called VPS13A). Interestingly, it is not clear that the original cases reported by Levine and Critchley had that mutation.

Most genetic diseases for which the term neuroacanthocytosis is appropriate exhibit phenotypes similar to either Bassen-Kornsweig disease or Levine-Critchley syndrome:

Bassen-Kornsweig disease or similar disorders, ie, hereditary lipoprotein disorders that cause a predominantly sensory ataxia involving the dorsal root ganglia and the ensuing spinocerebellar pathways and projections combined with acanthocytosis:

Bassen-Kornsweig disease (abetalipoproteinemia)

Familial hypobetalipoproteinemia

Other lipoprotein disorders of uncertain significance

Similar to Levine-Critchley syndrome, ie, a movement disorder with choreiform or Parkinsonlike features combined with dementia, various other neurologic abnormalities, and acanthocytosis:

Chorea-acanthocytosis (ChAc)

McLeod syndrome (MLS)

Huntington disease–like2 (HDL2)

Pantothenate kinase–associated neurodegeneration (PKAN)

A number of individual cases and families have been reported that do not seem to fit the existing genetic patterns and which may represent new genetic syndromes yet to be elucidated or perhaps are sporadic diseases.

As in many other diseases, there is considerable clinical heterogeneity in these syndromes, which may be caused by environmental interactions as well as the background of other genes and other diseases in the patient.

Finally, a number of systemic diseases (usually sporadic) exist in which the combination of neurologic findings and acanthocytosis may actually be incidental. Examples of this type of neuroacanthocytosis include case reports of patients with hepatic encephalopathy, myxedema, or certain types of vasculitis who at some point in their disease show choreiform features plus acanthocytosis. It is not known why such diseases show these features as an occasional manifestation and, in the authors’ opinion, it is not correct to call these diseases forms of neuroacanthocytosis per se. However, for the sake of completeness, diseases that have been known to occasionally exhibit features of neuroacanthocytosis are listed.

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