Neuroacanthocytosis Syndromes Clinical Presentation

Updated: Oct 16, 2018
  • Author: Kenneth B V Gross, MD; Chief Editor: Selim R Benbadis, MD  more...
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Presentation

History

The typical presentation of neuroacanthocytosis syndromes involves tic-like orofacial movements and gait instability beginning in young adulthood. In its classic form, NA is associated with orofacial tics, lingual dyskinesias, chorea, and leg buckling with ambulation. Dystonia, self-mutilating lip and tongue biting, and difficulty swallowing are also commonly seen. Occasionally, Parkinsonian features, belching, and violent truncal spasms associated with head banging can be noted.

As the disease progresses, increasing weakness and muscle wasting are often noted.

In some patients with NA, personality changes, particularly depression, appear early in the course of the disease.

Generalized tonic-clonic seizures and complex partial seizures have been reported. [21] The latter seizure type has featured déjà vu phenomena.

In the variant syndromes, the patient may present with gait imbalance as a prominent neurological symptom due to involvement of spinocerebellar pathways.

Some patients with variant syndromes may present with progressive dyspnea due to cardiomyopathy.

Some patients exhibit Tourettelike tics, which are thought to be due to hypersensitivity of dopamine receptors. As the disease progresses, the dopamine receptors may become hyporesponsive or decrease in number sufficiently to result in a parkinsonian syndrome.

Progressive cognitive disturbance is often a part of the symptomatic decline in NA syndromes.

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Diagnostic Considerations

Although chorea, reduced/absent reflexes, and acanthocytosis are extremely common in NA syndromes, all 3 of these signs may not be present in every patient with NA.

Features including orofacial tics, seizures, neuropsychiatric abnormalities, dysphagia, dysarthria, elevated CPK levels, and proximal muscle weakness and wasting are noted in varying combinations in a majority of the patients.

Occasional patients simply have acanthocytosis combined with one or more of the following:

  • Chorea/dyskinesia

  • Amyotrophy

  • CPK elevation

  • Parkinsonism or ataxia (rare)

Gilles de la Tourette syndrome

Orofacial tics are noted in both disorders, but acanthocytosis, high CPK level, and amyotrophy are not present in Tourette syndrome.

Huntington disease (HD)

In HD, limb chorea is more prominent and tics usually are not present. Early dementia commonly is associated with HD and not NA. No acanthocytosis or amyotrophy is noted in HD. The autosomal dominant pattern of inheritance in HD is helpful in making this diagnosis. Currently, definitive genetic testing for HD is available.

Hallervorden-Spatz disease (HS)

The classic basal ganglia iron distribution in the globus pallidus seen in HS usually is not seen in NA syndromes. In a young patient with HS, a syndrome of acanthocytosis, retinitis pigmentosa, low betalipoproteins, and a movement disorder that is consistent with NA has been described.

Wilson disease (WD)

Copper abnormalities or Kayser-Fleisher rings noted in WD do not occur in NA. The movement disorder in WD usually presents at a younger age (children or adolescents).

Polymyositis (PM)

Although patients with PM can show a high CPK level, an extrapyramidal system movement disorder is not part of the spectrum of PM. Both PM and NA can have a hemolytic anemia, the latter due to acanthocytosis. Acanthocytosis is not present in PM.

Bassen-Kornzweig syndrome (BK)

Abetalipoproteinemia, ataxia, and retinitis pigmentosa typically are seen in a child with acanthocytosis. Occasional NA syndromes have been reported in children, although these do not have all the BK features other than the acanthocytosis and decreased betalipoproteins.

McLeod syndrome

Acanthocytosis and high CPK level due to a benign skeletal myopathy can at times be complicated by a cardiomyopathy, involuntary movements, and/or dementia. This syndrome, found in children and adults with the Kell-null phenotype, is actually part of the NA variant syndrome family. Psychosis has also been described as a presenting feature.

Chorea-amyotrophy with chronic hemolytic anemia

This syndrome also has been described to include NA type dyskinesia. Lack of acanthocytosis and nonpallidal basal ganglia iron deposition distinguishes chorea-amyotrophy with chronic hemolytic anemia from HS.

Chorea-acanthocytosis presenting as motor neuron disease

As suggested by several researchers, including separate investigations by Bird and Gross, the amyotrophy of NA implicates features of motor neuron disease. [22, 23]

A recent report [24] cited a patient with a gait disturbance and dysarthria, with clinical and neurophysiological assessment disclosing upper and lower motor neuron signs suggestive of motor neuron disease. Involuntary movements were not present initially but later were observed. A novel mutation of chorein and acanthocytes were identified.

This is also extremely interesting in view of the identification of motor neuron disease, ie, amyotrophic lateral sclerosis plus frontotemporal dementia in the same patients [25] and related to a gene defect on chromosome 9, not far removed from the gene abnormality in NA. It would be worthwhile to check for morphologic red blood cell disorders in these patients in this regard and in view of the various links to red blood cell abnormalities in patients with degenerative disease of the nervous system.

MELAS syndrome

Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes in children (MELAS) have been reported with acanthocytosis.

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Physical

In patients with classic NA, multiple physical findings are observed.

Ticlike facial movements are noted in the context of tongue mutilation and dysarthric speech. Carbamazepine-sensitive paroxysmal kinesigenic dyskinesia and tongue protrusion dystonia have also been reported.

Truncal chorea can explain gait imbalance. However, gait ataxia can be explained on a cerebellar or spinocerebellar basis.

Classically, distal muscle wasting often is noted in the context of hand atrophy and a pes cavus deformity.

In variant syndromes, these features need not be present. In some variant cases, the patient eventually will be wheelchair bound because of both the chorea and the muscle wasting.

Cogwheel rigidity, resting tremor, and bradykinesia are late physical findings in patients with NA who have a parkinsonian syndrome.

Organic mental syndromes are common, including anxiety, depression, psychomotor agitation, obsessive-compulsive thinking, psychosis, paranoia, schizophrenialike features [26, 27] , cognitive dysfunction, and hallucinations.

Retinitis pigmentosa has been described in the HS variant of NA.

Generally, the acanthocytosis does not produce clinical symptoms or physical findings. In one NA variant syndrome, however, a child presented with acanthocytosis-related hemolytic anemia that included malaise and splenomegaly. Another variant case included attacks of jaundice that may have been related to the hemolysis.

Acanthocytosis (though not necessarily that related to NA) may be a predisposing factor for nonketotic hyperglycemia-induced chorea-ballism.

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Causes

NA syndromes can be related to, if not caused by, specific gene defects.

The gene defects may induce hypobetalipoproteinemia.

Since most patients with NA do not have abnormalities in betalipoproteins, the role of hypobetalipoproteinemia in the pathophysiology of NA syndromes is still in question.

Similarly, although membrane protein and ganglioside abnormalities have been noted in some patients with an NA syndrome, and others have serum antibodies against cell membrane components and evidence of sialic acid residues usually noted in active inflammation, none of these findings are known to be clearly causative of the disease in NA syndrome.

NA has been associated with a defect of the 4.1R membrane protein in erythrocytes. This might reflect the expression pattern in the central nervous system, especially the basal ganglia and might lead to dysfunction of AMPA-mediated glutamate transmission.

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