Neuroacanthocytosis syndromes


Neuroacanthocytosis syndromes

Description, Causes and Risk Factors:

Neuroacanthocytosis syndromes are a group of genetically defined disorders leading to progressive neurodegeneration of the basal ganglia. The core NA syndromes include autosomal recessive chorea-acanthocytosis and X-linked McLeod syndrome. These disorders have a Huntington disease-like phenotype of a choreatic movement disorder, psychiatric manifestations and cognitive decline, but may have additional multi-system features including myopathy and axonal neuropathy. In addition, patients with McLeod syndrome may develop a cardiomyopathy. Acanthocytes are found in a proportion of patients with Huntington's disease-like 2 and pantothenate kinase-associated neurodegeneration. The association of the erythrocyte membrane abnormality resulting in acanthocytosis and selective neurodegeneration of the basal ganglia suggests a common pathogenic pathway, however, this has not yet been fully elucidated.

Major scienti?c developments since 2002 are the publication of a reference method for acanthocyte detection, the identi?cation of Huntington's disease-like 2 (HDL2) as one autosomal dominant form of NA, the discovery of an XK mutation without full MLS, the delineation of the conserved VPS13 gene family, the development of chorein antibodies and their potential use in a Western blot-based diagnostic assay, the identi?cation of a cluster of cases with a high incidence of seizures and genetic evidence of a founder effect, and ?nally an animal model, namely mice with the Ehime deletion of VPS13A. In addition, in the past few years, the differential diagnosis of chorea has been expanded, with molecular diagnosis facilitating the identi?cation of a wider spectrum of choreiform disorders. Autosomal dominantly inherited causes include the spinocerebellar ataxias (SCAs), SCA1, SCA2, SCA3, and SCA17; dentatorubropallidoluysian atrophy (DR-PLA); neuroferritinopathy; benign hereditary chorea; and Huntington disease-like disorders 1, 2, and 4. Of the latter group, only HDL2 has been reported to occur in more than a single family and HDL1 has been determined to be a prion disorder. Autosomal recessive causes include chorea-acanthocytosis (9q21), Wilson's disease, pantothenate kinase-associated neurodegeneration (PKAN; 20q12), HDL3 (4p15), aceruloplasminemia, ataxia-telangiectasia, and Friedreich's ataxia. Several autosomal recessively inherited metabolic conditions where choreo-dystonia may be a prominent feature include Lesch-Nyhan syndrome, glutaric academia type 1, propionic academia, and other organic or amino acidemias. X-linked disorders include MLS and Lubag dystonia-Parkinsonism.

In 2011, researchers 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. In 2012, researchers 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.

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.

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 populations.

Symptoms:

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.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 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.

Diagnosis:

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, researchers has noted higher CK levels in patients with McLeod syndrome (reaching 3000) typically in association with the attendant myopathy.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.

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. Hippocampal atrophy may be found in patients with temporal lobe seizures.

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.

Treatment:

To date treatment for the NA syndromes is purely symptomatic. As in other choreiform disorders, reduction of involuntary movements may be achieved in principle by reducing dopaminergic neurotransmission, using atypical antipsychotic agents or tetrabenazine. However, as in HD, this may not necessarily result in functional improvement. Anticonvulsants such as levetiracetam and topiramate can be beneficial in secondary choreas, and may be considered in NA. Levetiracetam has been reported as providing specific benefit to truncal tics in ChAc (choline acetyltransferase) yet anecdotal experience in a single case has not confirmed this effect. Carbamazepine and lamotrigine may worsen involuntary movements. Neuropsychiatric issues are often a major cause of morbidity and mortality, as suicide is not infrequent. Depression should be aggressively treated. Selective serotonin-reuptake inhibitors and tricyclic antidepressants may be useful for depression, in addition to mood-stabilizing medications such as anticonvulsants. The second-generation neuroleptics, especially clozapine and quetiapine, may improve both mood disorders and chorea. Classical neuroleptics should be avoided in order to avoid potential induction of tardive movement disorders.

NOTE: The above information is for processing purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.

DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.

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