Neuroacanthocytosis Clinical Presentation

Updated: Oct 16, 2018
  • Author: Stephen A Berman, MD, PhD, MBA; Chief Editor: Selim R Benbadis, MD  more...
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Presentation

History

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.

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Physical

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  • 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)

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Causes

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)

OMIM#

Name

Mode

Gene, Locus, and Protein

Onset age

Description

Pathology

#200150

ChAc or Levine-Critchley syndrome [8, 9, 10, 15]

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

+314850

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

#606438

Huntington's Disease-Like 2, HDL2 [17, 18]

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

#234200

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

#200100

Abeta-lipoprotein-emia [11, 12, 13, 14]

Autosomal recessive

MTP; 4q22- q24

Infancy / childhood

Features include ataxia (sensory ataxia with some cerebellar features), visual loss, mental retardation / 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

+107730

FHBL1 [27, 28, 29, 30, 31]

Autosomal recessive

APOB; 2p24

Infancy / childhood

Features include ataxia (sensory ataxia with some cerebellar features), visual loss, and mental retardation / dementia.

Dorsal root ganglia, ascending sensory tracts, cuneate and gracile nuclei of cord, spinocere-bellar projections; possibly some direct cerebellar involvement; retinitis pigmentosa.

%605019

FHBL2 [32, 33]

Possibly autosomal recessive

3p22-p21.2 for some, for others linkage not known

Infancy / childhood

Features are same as for FHBL1.

Same as FHBL1

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)

OMIM

Name

Mode

Locus

Description

#540000

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.

#246700

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] .

+278000 or 278100

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.

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  • 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.

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