Update on Neuroacanthocytosis Syndromes
By Guilherme Riccioppo Rodrigues, MD, MSc
School of Medicine of the Centro Universitário Barão de Mauá
São Paulo, Brazil
Special to The Movement Disorder Society
Neuroacanthocytosis designates a group of diseases that affects the nervous system in association with the presence of abnormally shaped erythrocytes, named acanthocytes. This term derives from the Greek word acantha, which means thorn, referring to the thorn-shaped protuberances on the erythrocyte surface (Danek et al., 2005). The main causes of NA are chorea-acanthocytosis (ChAc), McLeod syndrome (MLS), pantothenate kinase-associated neurodegeneration (see accompanying article by Kruer and Hayflick) and Huntington's disease-like 2 (Walker et al., 2007). This brief review will focus on the first two conditions.
ChAc is an autosomal recessive disorder characterized by chorea, epilepsy, and peripheral neuropathy, with symptom onset around 20-30 years. A prominent feature is severe oral dyskinesia, often leading to lip or tongue lacerations. In addition, there is a typical action-induced tongue protrusion dystonia, that impairs feeding early in the disease (Bader et al., 2010). Generalized chorea is the most common movement disorder, sometimes associated with tics or dystonia. In general, with the progression of the disease, the chorea disappears and the patients exhibit rigidity and bradykinesia. Interestingly, some patients have been reported with parkinsonism as the first clinical manifestation (Bostantjopoulou et al, 2000). Frequently, there is a prominent unsteadiness of gait, associated with episodes when the patient acutely bends forward, flexing the trunk, as if the patient wishes to touch the floor during walking. This involuntary movement, whose exact classification is unknown, is considered pathognomonic of ChAc by some authors (Schneider et al., 2010).
Seizures are found in approximately half of cases. Patients frequently present with symptoms of temporal lobe epilepsy, with aura characterized by epigastric discomfort, nausea, déjà vu or jamais vu, followed by loss of contact, automatisms, and sometimes secondary generalization. Interictal EEG often discloses temporal discharges. The diagnosis of epilepsy may precede the onset of movement disorders by several years (Al-Asmi et al., 2005; Scheid et al., 2009).
In addition to the presence of seizures, peripheral involvement is an important clue which distinguishes this disorder from Huntington's disease. Ankle areflexia is found in 90% of cases (Rampoldi et al., 2002), and muscle weakness is observed in more than half of patients, sometimes associated with evident muscle atrophy. In general, electroneuromyography is compatible with axonal neuropathy, although myopathic alterations may predominate in some cases (Rodrigues et al., 2008).
Psychiatric abnormalities are common and may precede the movement disorders by decades. (see accompanying article by Walterfang) Patients may present with depression, anxiety, auditory or visual hallucinations, persecutory delusions, and obsessive-compulsive behaviors, (Walterfang et al., 2008) which can be severe and refractory to treatment. Some patients may exhibit self-mutilation, which may be related to behavioral compulsion (Walker et al., 2006). Cognitive impairment is mainly characterized by executive dysfunction, with impairment in abstraction, concept formation, planning, and execution. Memory and visuoperceptual impairments have been reported and are probably secondary to frontosubcortical dementia (Danek et al., 2004).
Blood tests frequently reveal increased levels of creatine kinase (CK), lactate dehydrogenase and liver transaminases (Rampoldi et al., 2002), which can support this diagnosis even in the absence of acanthocytes. Neuroimaging studies demonstrate cerebral atrophy, predominantly in the caudate nucleus and putamen (Henkel et al., 2006), where MRI T2-hyperintensity can also frequently be observed. Positron emission tomography (PET) studies show striatal hypometabolism (Müller-Vahl et al., 2007).
ChAc is caused by mutations in the VPS13A gene (formerly CHAC), located at the 9q21 locus (Rampoldi et al. 2001; Ueno et al., 2001), which is related to the production of a ubiquitously expressed protein, whose function is unknown, named chorein (Dobson-Stone et al. 2004; Kurano et al., 2007). As there are over 100 different mutations described (Dobson-Stone et al., 2002), and the gene consists of 73 exons, complete gene sequencing for diagnosis is not feasible. To overcome this problem, Dobson-Stone et al. (2004) developed a Western blot method to detect the presence of chorein in the erythrocyte membrane. This method has become the procedure of choice for the diagnostic confirmation of ChAc. Information on this test is available at www.nefo.med.uni-muenchen.de/~adanek/Chorein_Blot.pdf.
There is no curative treatment for ChAc, and the basis of therapy consists of controlling epilepsy, movement disorders, speech and swallowing problems (see accompanying article by Giddens and Ramig) and psychiatric abnormalities. Orthoses may be useful in those patients with severe peripheral neuropathy and bite guards may be tried in patients with tongue or lip biting (Fontenelle and Leite, 2008). Percutaneous gastrostomy is indicated in those patients with severe dysphagia. Although some studies report benefit from surgical procedures (Guehl et al., 2007), more experience is necessary to establish the efficacy and safety of deep brain stimulation in the treatment of hyperkinetic movements in ChAc.
MLS is an X-linked form of neuroacanthocytosis caused by mutations (deletions, missense, nonsense or splice site) in the XK gene, located at Xp21.1. The XK protein forms a membrane complex with the Kell protein. Consequently, in MLS patients, there is a weak or no expression of Kx and Kell antigens on the erythrocyte surface (Lee et al., 2000). These hematological findings are known as the McLeod phenotype.
In the MLS, the neurological manifestations are attributed to the lack of XK protein expression in the brain (Russo et al., 2000). In general, clinical symptoms are similar to ChAc, thus acanthocytes, neuropsychiatric disorders, chorea and epilepsy are common findings. However, compared with ChAc, these patients tend to present with later onset of chorea, less marked oral dyskinesia (lip biting is uncommon), and more severe muscular involvement, with almost 80% of the patients manifesting weakness and muscle atrophy (Hewer et al., 2007). There is no clear phenotype-genotype correlation, and patients without neuromuscular involvement have been reported (Walker et al., 2007).
Systemic abnormalities such as hemolytic anemia, hepatomegaly, splenomegaly and cardiac disease are often observed (Danek et al., 2001). As MLS is X-linked, there is a strong male predominance, although female cases have been reported (Hardie et al., 1991). Neuroimaging studies reveal putaminal T2-hyperintensity and atrophy (Danek et al., 2001), which worsens with disease progression (Valko et al., 2010). Screening for absence of Kx and reduced expression of Kell antigens supports the diagnosis, and can usually be performed at regional blood centers; however, due to the frequent unavailability of the complete panel of Kell antibodies, definitive diagnosis requires further confirmation by sequencing of the XK gene.
In general, clinical management in MLS is similar to ChAc. Special care must be directed to cardiac abnormalities, which occur in two-thirds of the patients and can progress to cardiomyopathy and death (Malandrini et al., 1994; Danek et al., 2001). In addition, if MLS patients receive a transfusion with Kell-positive blood, they may produce anti-Kell antibodies, which can lead to hemolysis in subsequent transfusions. Thus, blood banks should have Kell-negative blood stored or patients should have their own blood stored, for possible autologous transfusion.
ChAc and MLS belong to the spectrum of neuroacanthocytosis syndromes and should be suspected in patients with neurodegenerative chorea and, at least one of the following findings: acanthocytes, high CK levels, epilepsy, or signs of peripheral nerve or muscle involvement, specially if an autosomal dominant history is lacking. Diagnostic confirmation can be performed by chorein detection (ChAc) or XK sequencing (MLS). To date, there is no specific treatment for ChAc or MLS and therapeutic management relies on controlling dyskinesia, epilepsy and neuropsychiatric problems.
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About Dr. Guilherme Riccioppo Rodrigues, MD, MSc
Dr. Guilherme Riccioppo Rodrigues, MD, MSc, obtained his medical degree from the Universidade Federal do Triângulo Mineiro, Brazil (2001), and completed his residency in clinical neurology at Ribeirão Preto School of Medicine, University of Sao Paulo (2004). There, he also concluded a movement disorders fellowship and received his Master's degree in Neurology studying patients with a Huntington's disease-like phenotype. At present, he is Assistant Professor of Neurology at the School of Medicine of the Centro Universitário Barão de Mauá and is a clinical neurologist with the Movement Disorders and Cognitive Neurology Group, Department of Neuroscience and Behavioral Sciences, Ribeirão Preto School of Medicine. His main interests are cognitive abnormalities associated with basal ganglia disorders. Dr. Riccioppo Rodrigues may be reached by e-mail at firstname.lastname@example.org.