Neuroacanthocytosis Syndromes Workup

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

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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.

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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]

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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.

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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.

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