Neuroacanthocytosis

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.

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]

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).

See the list below:

• Involuntary movements

  • Chorea and dystonia, features of hyperkinetic movement disorders, are more frequent than tics and parkinsonism. Several of these disorders may be present simultaneously.

  • Parkinsonism eventually may replace the hyperkinetic state.

  • Orolingual dystonia causes eating problems, dysarthria, and dysphagia (ie, the tongue involuntarily pushes food out of the mouth).

• Personality changes occur, including impulsivity, antisocial personality, distractibility, anxiety, depression, apathy, loss of introspection, and compulsivity.[24, 25]

• A peculiar gait is characterized by lurching with long strides and quick, involuntary knee flexion.

• Seizures, generally tonic-clonic (ie, grand mal), occur in 30-40% of patients; they are infrequent and relatively easy to treat.

See the list below:

• The following signs are observed, in order of frequency: chorea, dystonia (including eating dystonia), other orolinguofacial dyskinesias (with lip biting[26] and dysarthria), vocal and/or motor tics, and parkinsonism.

• Subcortical dementia with executive skill problems of the frontal lobe has been reported.

  • Executive skill problems include perseverative errors, excessive vulnerability to external intrusion, and inability to inhibit immediate and inappropriate responses to stimuli.

  • Visuopraxic disorders, anomia, and verbal as well as nonverbal memory retrieval problems may be noted.

• Axonal neuropathy may present with the following signs:

  • Decreased or absent deep tendon reflexes

  • Muscle wasting (amyotrophy)

Each major type of neuroacanthocytosis appears to have its own basic etiology, ie, the specific gene in which a mutation is present. The known mutant genes are listed with their respective diseases below.

• The hereditary lipoprotein (typically betalipoprotein) disorders

  • Bassen-Kornsweig disease (abetalipoproteinemia) - Microsomal triglyceride transfer protein (MTP)[11, 12, 13, 14]

  • Familial hypobetalipoproteinemia (FHBL)

    • FHBL1 - Apolipoprotein B (APOB)[27, 28, 29, 30, 31]

    • FHBL2 - Gene not known[32, 33]

  • Other lipoprotein disorders of unknown etiology

• Hereditary movement disorders (choreiform or Parkinsonlike)

  • Chorea-acanthocytosis (ChAc)[15] - Chorein (VPS13A)

  • McLeod syndrome (MLS)[16] - Kell blood group protein, XK

  • Huntington disease–like2 (HDL2)[17, 18] - Junctophilin-3 (JPH3)

  • Pantothenate kinase–associated neurodegeneration (PKAN) - Pantothenatekinase 2 (PANK2)[19]

  • Other genetic and sporadic disorders - Genes not yet elucidated, or multigenetic, or due to sporadic conditions[21]

• Although the ultimate basic etiology of the genetic conditions that cause most of the cases of acanthocytosis is known, it is generally not known how the gene defect produces the pathophysiological abnormalities.

• The etiology is best understood for the betalipoprotein deficiencies. Lack of microsomal triglyceride transfer protein (MTP) or a direct mutation in the gene for betapolipoprotein leads to a decreased absorption of vitamin E as well as other vitamins and possibly other cofactors. This leads to damage to the dorsal root ganglia, spinocerebellar tracts, retina, and cerebellum. It also leads to a defect in the conformation and/or fluidity of the erythrocyte membrane. Band three of the membrane appears to be one of the components significantly involved.

• For the other genetic disorders, the connections between the gene defects and the pathophysiological changes are not known. Again, changes in erythrocyte membrane conformation and/or fluidity (possibly via band three) may be involved in the changes underlying the acanthocytosis. Despite the enormous progress in understanding the molecular biology of these syndromes, there are still cases that do not fit the present understand precisely. Much work remains to be done.[20, 21]

• To better understand the many different types of neuroacanthocytosis, the most common varieties have been organized into a table. The first column lists the Online Mendelian Inheritance in Man number (OMIM#). The Mendelian Inheritance in Man (MIM) catalog (not online) was developed by Dr. Victor McKusick and colleagues at Johns Hopkins University, and the OMIM is hosted by the US National Center for Biotechnology Information on what is essentially the same Web site as PubMed. Also provided in the table are the name, mode of inheritance, locus (including the chromosomal region and the names of the gene and protein if available), onset age, description of the condition, and the pathology.

Table 1. Most Common Neuroacanthocytosis Syndromes (Open Table in a new window)

See the list below:

• The diseases in the Table 2 are even rarer than those listed in the previous table. In some of these, the neuroacanthocytosis appears to represent an exception and possibly idiosyncratic reaction seen in some patients with concomitant diseases; however, the full range of acanthocytosis is not yet completely understood. What in current practice may appear to be an isolated idiosyncratic case may, in the future, stand as a part of a broader syndrome.

Table 2. Extremely Rare or Uncertain Causes of Neuroacanthocytosis (Open Table in a new window)

See the list below:

• Various systemic diseases may also be accompanied by acanthocytosis and neurologic findings, especially in severely ill patients. These include various cancers, thyroid disorders, patients who have had a splenectomy, cirrhosis of the liver and hepatic encephalopathy, psoriasis, and an obscure condition called Eales disease in which an idiopathic inflammatory venous occlusion primarily affects the peripheral retina in adults. In these conditions, the presentation as neuroacanthocytosis may be a coincidence in which some type of neurologic insult, such as a stroke due to vasculitis, coincides with bone marrow failure in a severely ill individual; alternatively, a more fundamental connection may be present that is not currently understood.

See the list below:

• Fresh blood smear for acanthocytes: Any level greater than 3% is abnormal; in neuroacanthocytosis, acanthocytes usually measure 10-30%. Liver disease, splenectomy, and hemolytic anemia must be excluded.

• Elevated creatine kinase level

• Serum lipoproteins: In addition to the abetalipoproteinemia and hypobetalipoproteinemia, a case report of a patient with aprebetalipoproteinemia has also been documented.[40] All the forms probably have not yet been discovered.

• Elevated liver enzyme levels

• Specific genetic tests

  • Bassen-Kornsweig disease (abetalipoproteinemia) -MTP gene

  • FHBL1 -APOB gene

  • ChAc - Chorein (VPS13A)

  • MLS - Kell blood group protein (XK)

  • HDL2 -JPH3 gene

  • PKAN -PANK2 gene

See the list below:

• Brain MRI - Caudate atrophy and increased signal in caudate and lentiform nuclei. In PKAN, a pallidal hypointensity with a central area of hyperintensity, named "eye of the tiger" sign, is observed. The hypointensity is due to iron deposition.

• Brain CT scanning - Caudate atrophy and ventricular dilatation (especially in the frontal horns of the lateral ventricles)

• Brain positron emission tomography - Hypometabolism in the neostriatum and the frontal cerebral cortical areas[41, 42]

• Brain single-photon emission computed tomography (SPECT) - Hypoperfusion in the neostriatum and frontal areas

See the list below:

• Electromyography (EMG) and nerve conduction study (NCS) findings are consistent with chronic denervation and a primarily axonal peripheral neuropathy.

The betalipoprotein disorders of abetalipoproteinemia and the hypobetalipoproteinemias cause a malabsorption of vitamins, especially vitamin E and also vitamins A and K. Treating the patient with high doses of these vitamins, especially vitamin E, ameliorates, but does not completely cure, these diseases.

For the choreiform/parkinsonian group, no specific treatment exists for the primary diseases. No attempts have yet been made to systematically collect observations regarding response to drugs. For choreiform and choreoathetoid movements (hyperkinesias), antipsychotics, such as haloperidol (Haldol), are still helpful. Second-generation antipsychotics may also be used as well as other medications such as tetrabenazine and tiapride.

Parkinsonian symptoms may respond to dopaminergic agents such as carbidopa-levodopa, ropinirole, and pramipexole. However, such agents tend to worsen chorea and could not be used unless a given patient had predominantly parkinsonian features (such as may occur in PKAN). Tremor may respond nonspecifically to either cholinergic agents such as benztropine (Cogentin) or trihexyphenidyl (Artane) or to medications used for essential tremor such as beta-blockers or primidone. One can consider botulinum toxin injection in treating both dystonias, choreoathetoid movements, and tremor. Some dyskinesias may respond to carbamazepine.[43]

For possible epileptic seizures, carbamazepine, oxcarbamazepine, and gabapentin are reasonable options.

The treatment is not based on a fundamental understanding of the diseases, but treatment that may work to suppress the symptoms without undue side effects is tried.

Deep brain stimulation was used to help two French patients with neuroacanthocytosis. One of them had a specific diagnosis of choreoacanthocytosis with an intronic mutation in the CHaC gene. The other had a diagnosis of McLeod syndrome (MLS) with weak Kell antigen expression and a mutation in the KX gene. Both had an extremely severe movement disorder with a combination of chorea and dystonia. One patient also had severe dysarthria, involuntary belching, and involuntary tongue biting. The other had hypotonia, postural instability, and cognitive deterioration. Both patients received bilateral globus pallidus stimulators. After extensive adjustment, blinded evaluation of "before" and "after" video by two independent movement disorder specialists showed significant improvement in each patient's chorea. The first patient also had an improvement in belching. However, the other aspects of their problems were not significantly improved.[44]

An earlier study of a single patient by a different group failed to show improvement in a patient with choreoacanthocytosis.[45] However, this was completed 6 years previously and technical knowledge of the details of positioning and regulating the stimulators has improved. The adjustments made in the two partially successful cases were very delicate, and small changes in stimulation parameters made major differences. Although these results are preliminary, they should be regarded as promising for future developments.

See the list below:

• Psychiatrist: Psychiatric evaluation is indicated to diagnose and treat depression and/or other psychiatric disorders.

• Consultations with rehabilitation specialists such as physiatrists, physical therapists, speech therapists, and occupational therapists are usually valuable.[46]

• Nutritionist

See the list below:

• Maintain a balanced diet.

• Consultation with a nutritionist may be appropriate.

• In advanced cases, a soft diet and/or a GI feeding tube may become necessary.

See the list below:

• Typically, no restriction in activity is required until more advanced stages of the disease.

• Fall and balance precautions should be observed.

• In patients with advanced disease, walkers and/or wheelchairs may be appropriate.

No effective treatment exists. However, symptomatic treatment can be attempted.

In one case describing a patient who presented with truncal tic as part of the symptoms of neuroacanthocytosis, the newly approved anticonvulsant, levetiracetam, was very helpful in controlling the tic. However, further studies are warranted to ensure that it is effective.[47]

Class Summary

These agents improve psychiatric symptoms and may improve chorea.

Haloperidol (Haldol)

Useful in treatment of irregular spasmodic movements of limbs or facial muscles.

Class Summary

This agent is effective in mandibular dystonia, thereby improving eating.

OnabotulinumtoxinA (BOTOX©)

Inject into mandibular muscles that are associated with dystonic movements. Treats excessive, abnormal contractions associated with blepharospasm. Binds to receptor sites on motor nerve terminals and inhibits release of ACh, which, in turn, inhibits transmission of impulses in neuromuscular tissue.

Reexamine patients 7-14 d after initial dose to assess response. Increase doses 2-fold over previous dose for patients experiencing incomplete paralysis of target muscle, but do not repeat injection for at least 1 mo.

See the list below:

• Disease progression is poorly understood, and no cure exists.