eMedicine Specialties > Neurology > Movement and Neurodegenerative Diseases

Neuroacanthocytosis Syndromes

Kenneth B Gross, MD, Founder, Owner, Fusion Clinical Multimedia, Inc, Division of Neurology, Fusion Clinical Multimedia Educational Center
Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants
Contributor Information and Disclosures

Updated: Dec 17, 2008

Introduction

Background

Neuroacanthocytosis (NA) syndromes include combined features of acanthocytosis (ie, spiked red blood cells), chorea, orofacial tics, amyotrophy often with hyperCKemia, and normobetalipoproteinemia. NA has been described as inherited as an autosomal recessive disorder, as an autosomal dominant disorder, and as part of an X-linked disorder called McLeod syndrome (MLS). The autosomal recessive type, usually called chorea-acanthocytosis, is most common and was originally described by Levine and Critchley in the 1960s.1, 2 In 2001, the gene for this recessive type was characterized on chromosome 9. Since that year, rarer autosomal dominant disease forms with variable penetrance with or without chromosome 9 abnormalities have also been described. In all types, the neurologic course is progressive. Degeneration of the basal ganglia is a consistent feature of this disorder.

All of the syndromes under the NA umbrella are distinguished from the Bassen-Kornzweig syndrome, an autosomal recessive disorder of childhood in which abetalipoproteinemia and acanthocytosis occur along with steatorrhea, retinitis pigmentosa, and cerebellar ataxia.

Acanthocytosis has also been associated with the rare hypobetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (HARP) syndrome, a disease of childhood akin to Hallervorden-Spatz disease and a defect in the gene for pantothenate kinase.

The array of clinical features in NA syndromes is complex. Not only are cases known in which neurologic features of classic adult and childhood acanthocytosis syndromes overlap, but adult forms have been well described in which lipid profiles more closely resemble those of Bassen-Kornzweig syndrome, as have adult forms that begin in childhood.

  • An adult NA syndrome due to an X-linked gene defect is known that largely excludes females.
  • NA syndromes that include parkinsonism, peripheral neuropathy, myopathy, and psychosis have been described.
  • Adult-type variants of NA have been associated with general medical disorders involving the heart and immune system.

In a detailed pathophysiological study, the well-described choreiform movement disorder of NA has been described coexisting with an associated peripheral neuropathy in a patient without acanthocytosis.

For related information, see Neuroacanthocytosis.

Pathophysiology

The precise pathophysiology is not understood. Clues to the pathogenesis of the disorder arise from the observation that both the neurological and hematological systems are affected.

In the classic form of the disorder, central nervous system pathologic features include atrophy of the caudate and putamen and, to a lesser extent, the globus pallidus and substantia nigra. A cell loss of 90% in the striatum with astrocytic gliosis has been reported. In contrast to Huntington disease (HD), the major inherited choreiform disorder of adults, the cerebral cortex and corpus callosum is relatively spared. Additionally, the presence of acanthocytosis distinguishes NA from HD.

  • Defects in such disparate systems (ie, basal ganglia and erythrocytes) have led to the suggestion that a common neurohematological membrane defect is involved.
  • In 2001, a deletion mutation in the gene localized to chromosome band 9q21 was identified as the site for the defect generating the autosomal recessive form of NA. This leads to a chorein protein deficiency or absence. In 2005, based upon research involving several large French-Canadian families that presented with temporal lobe epilepsy, an expanded conceptualization of the molecular genetics of the autosomal recessive form NA was attained. Of family members in this research who presented with epilepsy, 70-80% had large deletions in the NA gene, now known as VPS13A, on chromosome 9. Some family members with no epilepsy but with milder features, such as tics and dysphagia for example, may be representative of heterozygous expression of the deletion, suggesting that variations in the VPS13A gene may lead to a dominant pattern of inheritance.

    Japanese researchers support this latter point by positing that the disorder in several families studied with the chorein defect and no seizures may have a dominant form of NA with incomplete penetrance. Further genetic variability is derived from the work of Walker who found an autosomal dominant NA family with a Huntington disease–like syndrome (HDL2) characterized by a defect in the junctophilin-3 gene and not the chorein gene.3
  • To further induce pathophysiological consternation, the McLeod syndrome seen overwhelmingly in males has many features akin to the autosomal forms and is due to a completely separate abnormality featuring the following: (1) absent expression of Kx erythrocyte antigen, (2) weak expression of Kell glycoprotein antigens, (3) universally present hyperCKemia, and (4) X-linked inheritance. (Recently, the Kx protein has been shown to be neuronal, located mainly in intracellular compartments, suggesting a cell specific trafficking pattern.)
  • Variation in other systems in patients with NA syndromes reflects the possibility of genetic heterogeneity that is more wide ranging than what may be noted in the affected components of the red blood cell (RBCs) and striatum alone.

Other common sites of pathophysiological dysfunction are the spinal cord, muscles, and nerves.

  • Evidence of denervation with fasciculations has been noted intermittently on electromyography (EMG) and is consistent with motor neuron disease despite absence of anterior horn cell histopathology.
  • Neurogenic muscle atrophy on muscle biopsy is consistent with a possible insult affecting the anterior horn cells of the spinal cord or their axons, although a primary myopathy and even myositis also have been described.
  • The consistently noted increase in creatine phosphokinase (CPK) level may be due to a primary myopathy, neurogenic atrophy, or chorea.
  • Nerve biopsy has revealed loss of large myelinated axons consistent with a distal axonopathy.

Both RBC membrane protein and lipid abnormalities have been described, notably in the critical band 3 protein layer (most recently in the Walker family) and in an abnormal composition of covalently bound fatty acids.

Antibodies to the GM1 ganglioside component of peripheral nerves have been described. This GM1 ganglioside is also present in RBC membranes and in the central nervous system. Decreases in GM3 and sialoparagloboside components of RBC membranes have been noted. These gangliosides are also present throughout the nervous system.

Many of the patients with McLeod syndrome have cardiomyopathy or hemolytic anemia, features not as commonly noted in the autosomal cases.

Redman and Reid have commented on the complexity of the Kell blood group proteins whereby the Kell protein expressed via a gene on chromosome 7 interacts with the XK protein, strikingly absent in patients with McLeod syndrome.4 These proteins are preferentially expressed in erythroid tissue but are also present in lesser amounts in brain and skeletal and cardiac muscle. The Kell protein is essential in the activation of the endothelin system and is important in cell membrane integrity. The XK protein bound to it in a 2-protein complex may have a complementary role as a membrane transporter. Experimental evidence cited by van den Buuse and Webber suggests endothelins may be basal ganglia neurotransmitters.5 Thus, the implication exists for a neurochemical tie to the NA syndromes, so often highlighted by basal ganglia dysfunction.

In two recent reviews, Bosman and De Franceschi and Corrocher have also summarized several studies of non-McLeod NA that have shown abnormalities in the aforementioned band 3 region.6, 7 Changes in band 3 structure do not only lead to alterations in erythrocyte shape but also to altered anion transport characteristics and increased age-related autoimmunoreactivity, with anti-band 3 antibodies noted in patients with NA. Elaborating on this latter point, echinocytes are normally aging misshapen RBCs reported to have band 3 abnormalities as well.

Brain band 3 change is also tied to neuronal degeneration and has been linked generally to extrapyramidal movement disorders and axonal neuropathies.

These insights, though incompletely understood, suggest that the pathophysiology of all of the NA syndromes involves different gene abnormalities that can cause multisystem membrane defects. The common derangement is in the malformation of the RBC shape and the induction of various levels of central nervous system, neuromuscular, and cardiac dysfunction. Intriguingly is the prospect that some kind of accelerated senescence and autoimmune damage to both erythrocytes and nerve tissue holds a key in fully appreciating the triggering of acanthocytosis and neurodegeneration in NA syndromes.

Mindful that the neuroacanthocytotic McLeod syndrome and a recently described non-McLeod NA family with no typical autosomal recessive gene NA defect are not due to a specific chorein protein abnormalities, it is still extremely important to expand our knowledge of chorein, the protein specifically linked to most cases of NA. Dobson-Stone suggests the CHAC or chorein gene locus is abnormal in many ways to induce NA by either not producing gene product or yielding a truncated nonfunctional protein.8 However, beyond being involved in protein-protein trafficking, how this protein leads to malconfigured erythrocytes and the array of neuropathological and clinical signs of NA is not clear.

Many issues in NA and MLS are still unresolved, not the least of which is why these 2 disorders present syndromes that are so similar, despite showing distinct genetic defects. Why the genetic defects in NA and MLS induce hematologic, cardiac, and neurologic abnormalities is also not clear. In MLS, Walker and Danek note that different Kell mutations may have different effects on the Kell gene product and thus may account for the variable phenotype in patients with MLS. Indeed, this variable mutation phenomenon may explain the differing clinical presentations in the autosomal gene NA syndromes (non-MLS).9

Frequency

United States

NA syndromes have been described in consanguineous and nonconsanguineous families of English and Puerto Rican descent.

International

NA syndromes have been described in American (USA), Chinese, Japanese, Malaysian, South-African black, Mexican, British, Spanish, Australian, Indian, Italian, Chilean, German, Turkish, Scandinavian, French-Canadian, and French populations.

Mortality/Morbidity

  • NA syndromes are often fatal.
  • A common cause of death is aspiration pneumonia due to movement disorder-induced impairment in swallowing.
  • Other causes of death include complications of cardiomyopathy and suicide as a result of depression or psychosis.
  • Morbidity is related specifically to the progressive movement disorder and muscle wasting.
  • Malnutrition is very common in many of these neurological syndromes.
  • Although the acanthocytosis often is noted spectacularly on peripheral blood smear (approaching 50% of patients) it usually is not associated with hemolytic anemia or other life-threatening hematological problems. However, hemolysis has been described, which can carry significant morbidity.

Race

NA syndromes have been described in all races.

Sex

  • Overall, NA syndromes are more common in men (partly due to the McLeod syndrome types, which are X-linked and therefore almost exclusively found in men).
  • Presumed autosomal recessive NA is more common in males, with a male-to-female ratio as high as 70:30.

Age

The adult-type NA syndromes usually begin in mid life (age 20-50 y). However, they also have been reported to occur in childhood.

Clinical

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, 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 temporal lobe seizures can occur.
  • 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 Tourette-like 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.
    • Diagnostic considerations include the following:
      • 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.
      • 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.
      • MELAS syndrome: Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes in children (MELAS) have been reported with acanthocytosis.

Physical

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

  • Tic-like 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, 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.

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.

Contents

Overview: Neuroacanthocytosis Syndromes
Differential Diagnoses & Workup: Neuroacanthocytosis Syndromes
Treatment & Medication: Neuroacanthocytosis Syndromes
Follow-up: Neuroacanthocytosis Syndromes
[ CLOSE WINDOW ]

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Further Reading

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Keywords

acanthocytosis, spiked red blood cells, chorea, orofacial tics, amyotrophy, hyper-CKemia, normobetalipoproteinemia, chorea-acanthocytosis, degeneration of the basal ganglia, classic adult neuroacanthocytosis disorder, neuroacanthocytosis variant, NA, Bassen-Kornzweig syndrome, neuroacanthocytosis syndromes

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