Neuroacanthocytosis

Updated: Oct 13, 2014
  • Author: Stephen A Berman, MD, PhD, MBA; Chief Editor: Selim R Benbadis, MD  more...
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Overview

Background

Neuroacanthocytosis encompasses a group of genetically heterogenous disorders characterized by neurologic signs and symptoms associated with acanthocytosis, an abnormality of red blood cells. [1, 2, 3] Neurologic problems usually consist of either movement disorders or ataxia, personality changes, cognitive deterioration, [4, 5] axonal neuropathy, and seizures [6] . 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. [7]

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), [1] 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 [8, 9] and later in 1968 by Critchley [10] . 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) [11, 12, 13, 14]
    • 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) [15]
    • McLeod syndrome (MLS) [16]
    • Huntington disease–like2 (HDL2) [17, 18]
    • Pantothenate kinase–associated neurodegeneration (PKAN) [19]
    • 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. [20, 21]

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. [22]

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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Pathophysiology

Multisystem pathology is evident, including severe atrophy of the caudate and putamen with loss of small- and medium-sized neurons and an associated astrocytic reaction. Less severe changes are seen in the pallidum.

Neuronal loss and mild gliosis can be seen in the thalamus, substantia nigra, and anterior horn of the spinal cord.

Acanthocytes are seen in peripheral blood smears. Creatine phosphokinase (CPK) level, and occasionally serum transaminases level, are elevated.

Serum vitamin E and lipoprotein levels typically are normal in the neuroacanthocytoses that do not involve abetalipoproteinemia or hypobetalipoproteinemia.

In the few cases for which neurochemical data are available, dopamine was decreased in almost the entire brain, norepinephrine levels were elevated in the putamen and globus pallidus, substance P levels were decreased in the striatum and substantia nigra, and serotonin levels were decreased in the caudate nucleus and substantia nigra. These findings are difficult to interpret because of severe caudate atrophy, concurrent medications, and small sample sizes. [23]

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Epidemiology

Frequency

United States

Neuroacanthocytosis is a rare disease for which insufficient epidemiological data are available to draw conclusions about frequency.

Mortality/Morbidity

Reported causes of death include the following:

  • Emaciation due to progressive weakness and dysphagia
  • Tracheobronchial aspiration
  • Suicide

Race

Neuroacanthocytosis has been reported in several races, but epidemiological data are insufficient to report prevalences.

Sex

Data are insufficient, but the condition may be more common in males than in females.

Age

Mean age of onset is 32 years (range, 8-62 y).

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