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:
-
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]
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.
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]
Epidemiology
Frequency
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
Demographics
Neuroacanthocytosis has been reported in several races, but epidemiological data are insufficient to report prevalences.
Data are insufficient, but the condition may be more common in males than in females.
Mean age of onset is 32 years (range, 8-62 y).
Tables
OMIM# |
Name |
Mode |
Gene, Locus, and Protein |
Onset age |
Description |
Pathology |
Autosomal recessive |
VPS13A 9q21 chorein [15] |
Adult onset; early to middle age (20-50 y) |
Features include choreoathetosis, dystonia, parkinsonism, orofacial dyskinesias, seizures, and neuropathy. Whether the original index cases (ie, Levine, 1960 and 1968; Critchley, 1967 and 1970) were part of the Levine-Critchley syndrome as understood genetically today remain unknown. [8, 9, 10] |
Atrophy of the caudate, putamen, globus pallidus, and substantia nigra |
||
MacLeod Syndrome or MLS [16] |
X-linked |
Kell blood group gene, XK Xp21 locus XK protein |
Adult onset middle to late age (40-70 y) |
Features include choreoathetosis, dystonia, parkinsonism, seizures, neuropathy, myopathy, and cardiomyopathy. |
Atrophy of the caudate, putamen, and globus pallidus; substantia nigra not involved |
|
Autosomal dominant (CAG repeat expansion) |
JPH3 16q24.3 Junctophilin-3 |
Onset earlier as repeat size increases (usually 30-40 y) |
Features include choreoathetosis, dystonia, parkinsonism, hyperreflexia, dementia, and weight loss. |
Atrophy of the caudate and putamen |
||
PKAN or PANK2 deficiency (previously termed Hallervorden-Spatz disease) [19] |
Autosomal recessive |
PANK2; 20p13 |
Childhood onset (by 4-6 y); adult onset subtypes exist |
Features include choreoathetosis, dystonia, dysarthria, rigidity, spasticity, and dementia. PKAN also includes the HARP (hypoprebeta-lipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration) subtype. |
Iron deposition in the globus pallidus (causes "eye-of-the-tiger" sign on MRIs |
|
Autosomal recessive |
MTP; 4q22- q24 |
Infancy / childhood |
Features include ataxia (sensory ataxia with some cerebellar features), visual loss, intellectual disability/dementia, low vitamin E level, high cholesterol level, and abnormal lipoprotein electrophoresis. |
Dorsal root ganglia, ascending sensory tracts, cuneate and gracile nuclei of cord, spinocere-bellar projections; possibly some direct cerebellar involvement; retinitis pigmentosa |
||
Autosomal recessive |
APOB; 2p24 |
Infancy / childhood |
Features include ataxia (sensory ataxia with some cerebellar features), visual loss, and intellectual disability/dementia. |
Dorsal root ganglia, ascending sensory tracts, cuneate and gracile nuclei of cord, spinocere-bellar projections; possibly some direct cerebellar involvement; retinitis pigmentosa. |
||
Possibly autosomal recessive |
3p22-p21.2 for some, for others linkage not known |
Infancy / childhood |
Features are same as for FHBL1. |
Same as FHBL1 |
OMIM |
Name |
Mode |
Locus |
Description |
Mitochondrial encephalopathy, lactic acidosis, and stroke (MELAS) with acanthocytosis [34] |
Mitochondrial for MELAS but this case is not proven |
Mitochondrial genome for MELAS but this case is not proven |
This is a single case. Typically, MELAS is an A3243G mutation. (Adenine is replaced by guanosine at position 3243 in the mitochondrial genome.) This single case report did not have mitochondrial genomic sequencing. Pathology reports showed abnormalities in Betz cells, brainstem neurons, and anterior horn cells. Muscle pathology results are compatible with MELAS. |
|
N/A |
Familial acanthocytosis with paroxysmal exertion-induced dyskinesias and epilepsy (FAPED) [35] |
Autosomal dominant (not certain; only one family) |
|
This is characterized by intermittent attacks of cramps and involuntary movements; attacks are myoclonic and atonic epilepsy. It has been described in one family. MRI showed mild basal ganglia degeneration. Positron emission tomography scanning showed decreased glucose metabolism in the thalamus. |
Anderson disease, now part of chylomicron retention disease (CMRD) |
Autosomal recessive |
Sar1B gene, 5q31.1 [36] |
Severe intestinal fat malabsorption with diarrhea, steatorrhea, hypobetalipoproteinemia, low cholesterol, triglyceride and phospholipid levels, and failure to secrete chylomicrons after a fatty meal. Typically lacks acanthocytes, retinitis pigmentosa, and ataxia. Rare cases may be associated with acanthocytes and some neurologic problems and so may be considered neuroacanthocytosis. A single mention of features of neuroacanthocytosis is found in book chapter [37] and reference to same chapter [38] . |
|
Atypical Wolman disease [39] |
Unknown (single case) |
Unknown (single case) |
In 1970, Eto and Kitagawa described a patient with lipid malabsorption, vomiting, growth failure, adrenal calcification, hypolipoproteinemia, and acanthocytosis and termed it Wolman disease (OMIM #278000) [39] . The patient had hepatosplenomegaly, steatorrhea, abdominal distention, and adrenal calcification that appeared in the first weeks of life, as well as widespread accumulation of cholesterol esters and triglycerides in the internal organs. Typically, Wolman disease is not associated with acanthocytes or neurologic problems. This single case has now been given its own number (OMIM #278100). Whether this case is truly Wolman disease is uncertain. |
