Neuroacanthocytosis Syndromes 

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

Overview

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, 3] 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, seizures, 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. See the image below.

Patient with choreoacanthocytosis. A: Note self-mu Patient with choreoacanthocytosis. A: Note self-mutilation of the lips owing to orofacial dyskinesia. B: Peripheral blood smear exhibits acanthocytes (Wright-Giemsa, original magnification, >100). C: Coronal view of T1-weighted MRI shows atrophy of the caudate nuclei. Archives of Neurology 64(11):1661-1664 2007 Copyright © 2010 American Medical Association.

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 are 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 (now known as VPS13A) localized to chromosome band 9q21 was identified as the site for the defect generating the autosomal recessive form of NA. It has been determined that VPS13A encodes for a protein called chorein. Thus, patients with NA typically carrying this deletion mutation have a deficiency or even absence of chorein.

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.

VPS13A may be involved in the control of protein cycling through the trans-Golgi network. It is broadly expressed and found in the brain, heart, skeletal muscle, and kidney.

The chorein deficiency has been also linked to upregulation of gephyrin and GABA(A) receptors.

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.[4]

To further induce pathophysiological consternation, the McLeod syndrome (MLS) 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.

Indeed, Walker et al[5] noted in 2011 that in NA there exist several associated genetic loci in the 9q21 region. Many defects, including gene deletions and insertions, as well as missense, nonsense, and splicing, mutations, have been found spread over hundreds of kilobases of genomic DNA, making the authors' case for exome sequencing to help with the diagnosis and genetic counseling, including carrier detection.

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. Chorein deficiency in NA has been implicated in the cause of the myopathy.

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 MLS 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 MLS.[6] 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.[7] Thus, the implication exists for a neurochemical tie to the NA syndromes, so often highlighted by basal ganglia dysfunction.

Jung et al have noted that in MLS, known disease-causing XK gene mutations comprised deletions, nonsense, or splice-site mutations, predicting absent or truncated XK protein devoid of the Kell-protein–binding site, but they found 2 brothers who had XK missense mutation without hematologic, neuromuscular, or cerebral involvement. However, despite their having the McLeod phenotype, the mutated XK protein seemed to be largely functional.[8]

Meanwhile, speaking to the great variability in MLS disorders, Wiethoff, in 2013 described a 70-year-old man of Greek origin with choreatic movements of the tongue and face, lower limb muscle weakness, peripheral neuropathy, elevated creatine phosphokinase (CPK), acanthocytosis, and hemolysis in the absence of Kell RBC antigens with an additional factor IX deficiency. Genetic testing for mutations in the 3 exons of the XK gene revealed a previously unreported hemizygous single base-pair frameshift deletion at exon 1 (c.229delC, p.Leu80fs).[9]

Bosman and De Franceschi have also summarized several studies of non-McLeod NA that have shown abnormalities in the aforementioned band 3 region.[10, 11] 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 MLS 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. Chorein is normally present in man. 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.[12]

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. A patient has been described with chorein deficiency in red blood cells in the absence of acanthocytosis.[13] Further confounding the issue, deficiency of erythroid 4.1R protein has been described in patients with NA. This protein is distinct from chorein and essential for maintaining erythrocyte shape and mechanical properties of the membrane, such as deformability and stability.

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).[14]

In 2011, De Franceschi et al[15] published a report that indicated erythrocyte membrane changes of NA patients are the result of altered Lyn kinase (LYN) activity, which is involved in modulating band 3 function on the RBC membrane.[16]

In 2012, De Franceschi et al[17] went beyond the LYN identification and attributed NA acanthocyte genesis to a very restricted group of highly interconnected kinases, including LYN and ABL1, ABL2, AURKA, CDK5, EPHB2, EPHB4, FYN, MAP4K2, MAPK14, PDPK1, RPS6KA3, TGFBR1, and TTN, that regulate rho small GTPase-mediated signaling, cytoskeleton network, erythropoiesis, and neurogenesis. The authors maintain that this network may represent a shared regulatory cluster of kinases whose alteration is most likely involved in the generation of the abnormal red blood cells that characterize NA. They also believe these same kinases might be responsible for acanthocyte generation in MLS.

Epidemiology

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, Brazilian, British, Spanish, Portuguese, Australian, Indian, Italian, Chilean, German, Turkish, Scandinavian, French-Canadian, French, and Thai[18] populations.

MLS has been described in multiple nationalities and races, with a Chinese patient first described with it in 2013[19] and the first patients (a family) from India first described with the disorder in 2011.[20]

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.

 

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.

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.

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.

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.

 

DDx

 

Workup

Laboratory Studies

Several laboratory tests are essential for the diagnosis of neuroacanthocytosis (NA) and its variant syndromes.

Any adult with chorea and orofacial tics should have a complete blood count (CBC) and RBC morphology analysis for acanthocytes. Acanthocytes are usually present in fewer than 50% of the total RBC specimens in NA and its variants. At some point during the course of the disease, most patients with NA exhibit acanthocytosis on peripheral blood smear. This study may need to be repeated periodically to demonstrate this finding.

CPK levels should be checked in any adult with a midlife onset of a movement disorder. CPK levels in the range of 300-1000 IU/L are found in NA and its variants in the absence of a clear clinical myopathy and beyond what typically is noted in other choreiform disorders. However, Dotti has noted higher CK levels in patients with McLeod syndrome (reaching 3000) typically in association with the attendant myopathy.[28] Fractionation of CPK is reasonable if it is high, although usually the CPK is almost exclusively of the MM type.

Kell blood typing is required to rule out the NA-linked McLeod syndrome. The McLeod phenotype is characterized by weakened expression of antigens in the Kell blood group system and absence of Km and Kx antigens in addition to acanthocytosis. Suspicion is highest for the presence of the Kell null McLeod phenotype when only males in a given family have NA and cardiomyopathy is associated with the neurologic syndrome. Such patients may have a less severe movement disorder and more acanthocytosis-related hemolysis than what is noted in the more common form of NA, presumably due to a chromosome 9 defect.

Patients with a high CPK level and acanthocytes should also have Kell phenotyping done.

A lipid profile that includes lipoprotein analysis is reasonable in all patients with NA, particularly in young patients who have Bassen-Kornzweig features (eg, retinitis pigmentosa) along with more characteristic adult-onset NA features (eg, chorea). Normal lipid profile is of course most consistent with NA, but hypolipoproteinemia is common in NA variant syndromes.

Thyroid, prolactin, and growth hormone levels in adults with NA may be abnormal.

Genetic studies to rule out a gene abnormality in chromosome 9, the presumptive site for the most common (autosomal recessive) type of NA, may be useful in defining subclinical or variant cases. Low or absent levels of chorein protein via a blood assay are noted in patients with recessive NA. Rarely, NA can occur as a spontaneous mutation. Even in this group ruling out a chromosome 9 genetic defect or a Kell X chromosome anomaly may be helpful.

Imaging Studies

Brain MRI or CT scan is helpful in assessing caudate atrophy, which is characteristic of NA and its variants, including McLeod syndrome. Generalized mild cortical atrophy is also common, in addition to increased signal intensity lesions in the cerebral hemispheric white matter on MRI[29] . Hippocampal atrophy may be found in patients with temporal lobe seizures.

Neuroimaging typically shows basal ganglia atrophy, which correlates with disease duration.

Cerebellar atrophy on MRI has also been reported in a pair of siblings with NA.

MRI and CT scan are of greater value in looking for other causes of chorea in an adult, such as that due to cerebrovascular disease or a mass lesion.

MRI can demonstrate iron in the basal ganglia, typically noted in HS but not in NA.

In reports of the patients with autosomal forms of NA, brain single-photon emission computed tomography (SPECT) or positron emission tomography (PET) can confirm striatal hypometabolism, which on FDG-PET correlates with disease duration. In addition, striatal hypometabolism on FDG-PET has been reported in 2 unrelated patients with McLeod syndrome, even in the absence of chorea in one of those men.

Other Tests

Needle EMG and nerve conduction studies are indicated. Denervation atrophy with a distal motor axonal neuropathy is the typical finding in NA. However, a sensory axonal neuropathy also has been described. Patients with McLeod syndrome can show myopathic changes in addition to evidence of neurogenic atrophy and axonal neuropathy.

Echocardiography is recommended in patients with clinical evidence of NA and cardiac dysfunction. In these patients, cardiomyopathy should be ruled out. Mitral valve prolapse, concentric left ventricular hypertrophy, increased septal thickness, and generalized hypokinesia all have been described.

Patients with McLeod syndrome (who often have more dangerous cardiac problems than skeletal muscle difficulties) frequently have echocardiographic abnormalities including left ventricular hypertrophy. Cardiac biopsy in a recently described McLeod cardiomyopathy case revealed focal myocyte hypertrophy, slight variation of myofiber size, and patchy interstitial fibrosis.

EEG can be valuable because some patients will have seizures. A recent report documented a temporal lobe focus in a patient with NA and focal seizures.

Abnormalities in saccades and pursuits on neuro-ophthalmologic testing have been described. In addition, a high number of square wave jerks on eye movement evaluation has been reported, implicating brain stem dysfunction in patients with NA with VPS13A mutations.[30]

Procedures

Lumbar puncture can be of value to rule out an infectious etiology such as syphilis or AIDS or an autoimmune disease. Cerebrospinal fluid (CSF) in NA is typically normal.

If a patient has acanthocytosis and a high CPK level, performing a muscle biopsy is reasonable to rule out a component of the myopathy that can occur in patients with NA, either as a late manifestation of neurogenic disturbances in the muscle or as linked to the more characteristic myopathic disorder in McLeod syndrome. The main indication for muscle biopsy is to exclude the presence of a myositis that requires therapy. In some patients with hemolysis and a high CPK level, a muscle biopsy may be necessary to rule out polymyositis.

Sural nerve biopsy to rule out inflammatory changes may be valuable in any patient with NA and neurophysiological evidence of a neuropathy, particularly since anti-ganglioside antibody titers have been described in one NA variant with neuropathy.

Histologic Findings

Muscle biopsy changes in NA indicate neurogenic atrophy. Although a high percentage of central nucleation and longitudinal splitting indicated some degree of myopathy in a McLeod variant case, these are nonspecific myopathic findings. Even McLeod cases have high rates of neurogenic atrophy in skeletal muscle as opposed to a less common biopsy-proven primary skeletal myopathy.

Sural nerve biopsy shows varying degrees of myelinated fiber dropout, with selective reduction in the large-diameter myelinated fiber population. This is noted in most patients with NA, both classic and variant types. These findings are nonspecific.

Neuropathy is a major distinguishing factor differentiating (where neuropathy is present) HD from NA. With autopsy, the disorders are further distinguished. Although both disorders show prominent caudate atrophy, HD (where neuropathy is absent) may be associated with prominent cortical atrophy and low caudate levels of glutamic acid decarboxylase and choline acetyltransferase. These biochemical determinations are not part of routine neuropathologic autopsy protocols.

 

Treatment

Medical Care

Medical care for neuroacanthocytosis (NA) syndromes is symptomatic and supportive. No treatment is available for genetic defects per se.

In unusual patients with substantial cardiomyopathy, congestive heart failure must be treated by the appropriate specialist. Sudden death due to ventricular arrhythmia is possible and if it occurs also must be treated by the appropriate specialist.

Traditional drugs provide temporary relief of chorea and dyskinesia in some patients.

Judicious use of antidepressants and/or sedatives may be beneficial in some patients.

Splinting and botulinum toxin may be needed to help dystonia.

Mechanical protective devices may be needed for those with repeated falls or self-injurious behavior.

Surgical Care

Results for deep brain stimulation (DBS) have been mixed.[31] In one study by Volkmann, bilateral high-frequency stimulation of the globus pallidus (GPi) was not successful.[32] Burbaud has tried GPi stimulation on one patient with the recessive form of NA and another with McLeod syndrome.[33] In the first case, a marked decrease of belching, dyskinetic breathing, and tongue biting occurred. In both cases, a frequency-dependent response was noted with high-frequency stimulation (130 Hz), which worsened speech and distal chorea, but improved contralateral dystonia. Low-frequency stimulation (40 Hz) improved chorea but not dystonia. Burbaud also reported improvement in severe trunk spasms in a patient who received bilateral high-frequency stimulation of the motor thalamus.

Intrastriatal transplantation of fetal striatal neuroblasts has been reported to improve some motor and cognitive functions in patients with Huntington disease according to Beal.[34] Despite obvious disease parallels, whether such an approach for patients with NA is valuable is totally speculative at this time.

In later stages of the disease when dysphagia progresses, a feeding gastrostomy may be required for nutritionally compromised patients.

Tracheostomy may be needed in this same group of patients to decrease the risk of aspiration.

Consultations

A neurologist should lead the management team.

A cardiologist should evaluate for the presence of a cardiomyopathy, particularly when dyspnea and/or ECG abnormalities are noted.

A psychiatrist should be consulted when depression and/or behavioral disturbances are significant.

A hematologist should be consulted for RBC morphology analysis and evaluation of a possible hemolytic anemia.

A gastroenterologist should be consulted for the possible lipid abnormality or when nutritional disorders such as vitamin deficiency are noted. Malabsorption syndrome, particularly in young patients with hypobetalipoproteinemic NA, will need to be ruled out.

A physiatrist should coordinate the team working on gait improvement, speech therapy, and physical therapy. Patients with NA may benefit from orthotic devices for foot deformities, walking aids for advancing motor deficits, and alternate communication modalities for severe dysarthria.

Diet

As noted, nutritional support is an important issue, particularly later in the course of the disease.

Even in patients with only mild swallowing difficulties or in patients with mild lipid disorders, a multivitamin and supplementary vitamin E may be required.

Late in NA and its variant syndromes, the patient may be able to tolerate only a blended diet.

Solid foods can result in aspiration in patients in whom orofacial dyskinesia is prominent.

Activity

Truncal chorea impairs gait stability in many patients with NA. Gait activity should be limited and monitored in patients with severe truncal chorea, particularly those prone to the characteristic NA cataplexy such as leg buckling attacks.

Advancing amyotrophy also limits gait in some patients, although the myopathy usually does not cause ambulation failure.

In patients with severe chorea and/or amyotrophy, a wheelchair may be required.

 

Medication

Medication Summary

Medication for chorea and dyskinesia is usually inadequate but is worth trying.

Haloperidol, tetrabenazine, and diazepam have been used in high doses in selected patients with NA. Only modest temporary benefit can be expected. Levetiracetam and topiramate have shown some benefit in secondary choreas and may be considered in treating NA. Levetiracetam has also been shown to help a patient with truncal tic.

Rhabdomyolysis and the neuroleptic malignant syndrome are always concerns in patients with NA, particularly because compliance and swallowing problems may lead to undesired daily variations of the dopamine blocking agent blood levels.

Even when no dramatic haloperidol dosing changes could be documented, Robinson noted rhabdomyolysis in a patient with NA.[35] After treatment for the life-threatening condition, the patient was switched from haloperidol to a combination of molindone and divalproex to effectively reduce involuntary movements.

Epilepsy management is very individualized. Phenytoin has been used successfully. Carbamazepine and lamotrigine have been reported to worsen the involuntary movements.

Digitalis and diuretics have been used successfully for congestive heart failure in patients with NA and cardiomyopathy.

Anticonvulsant therapy with phenytoin has been successful in patients with generalized tonic-clonic seizures.

In view of potential anticholinergic problems in patients with cardiomyopathy, selective serotonin reuptake inhibitors (SSRIs) are probably a better choice than tricyclic antidepressants.

Citalopram was found to help a patient with NA and obsessive-compulsive disorder.[36]

Generally, if hemolytic anemia is noted owing to acanthocyte accumulation/degradation, it is mild and does not require treatment.

In a case report, electroconvulsive therapy helped only speech but not chorea and other progressive neurologic problems.[37]

New protocols similar to those for Huntington disease are worth discussing with the medical treatment team. Agents such as the atypical antipsychotics for chorea and anti-Parkinson disease drugs for patients with NA and Parkinson disease features may be of value. Newer antidepressant drugs may also have a role, particularly SSRIs.

Neuroprotective agents and gene therapy may also have key future roles.

Antipsychotic Agents

Class Summary

Chorea, tics, and other adventitious movements such as oral dyskinesia may respond to drugs that block dopamine receptors and facilitate GABA transmission.

Haloperidol (Haldol)

In general, can decrease chorea, tics, and dyskinesia through blockade of dopamine receptors of CNS.

Anxiolytic

Class Summary

An agent that can decrease anxiety, such as a benzodiazepine, can also decrease movement disorders often made worse by associated stress.

Diazepam (Valium)

Long-acting benzodiazepine that can decrease anxiety in patients with NA throughout the day.

 

Follow-up

Further Inpatient Care

Irrespective of whether the patient with neuroacanthocytosis (NA) is an outpatient or an inpatient in a general hospital, a rehabilitation center, or a nursing home, elevated CPK level may indicate fulminant neurological disease, particularly due to severe chorea, dyskinesia, or muscle dysfunction.

In some patients, a decrease in the movement disorder secondary to advancing muscle wasting will correlate with a fall in CPK level as the chorea/dyskinesia "burns out."

Complications

Complications include the following:

  • Sudden death due to cardiomyopathy-related arrhythmia

  • Congestive heart failure due to cardiomyopathy

  • Head trauma due to falls

  • Aspiration related to dysphagia

  • Muscle wasting partly due to poor nutrition

  • Rare hemolysis-related splenomegaly/jaundice

Prognosis

In the absence of an understanding of the cause of the disease and in view of the limited success in preventing disease progression, prognosis is, at best, guarded.

In patients with severe neurological disease, particularly those with severe orofacial dyskinesia (with secondary dysphagia), prognosis is poor in view of the high risk of aspiration.

A typical patient with severe NA syndrome that begins in adult life lives for an additional 5 to 10 years.

In patients who have NA and a cardiomyopathy, the prognosis is guarded in view of the risk for sudden cardiac death and congestive heart failure.

The prognosis for a normal life span is often good in some patients with no prominent neurological or cardiac sequelae, even in the presence of significant acanthocytosis.

Patient Education

Families and patients are encouraged to join The Advocacy for Neuroacanthocytosis Patients.

Family members of patients with NA syndrome should be screened for neurological disease, acanthocytosis, and CPK levels.

In the families of patients with NA who have hypobetalipoproteinemia or in families of teenagers who develop NA, family members should be screened for lipid abnormalities and clinical features of NA.

Kell blood group screening should be performed in family members in whom only males have evidence of NA.

In some families the McLeod or Kell null phenotype is the characteristic NA blood group feature.