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Neuroacanthocytosis denotes a group of uncommon heterogenous neurodegenerative disorders associated with acanthocytosis in the absence of any lipid abnormality. A variety of modes of inheritance have been proposed (X linked and autosomal recessive are clearly described, but a recent report of dominantly inherited chorea acanthocytosis1 appears to be caused by Huntington’s disease-like type 2 expansions in the junctophilin-3 gene2) and mutations in two genes have been identified, the XK gene (in the X linked McLeod phenotype) and the CHAC gene (9q21; autosomal recessive)3. A wide variety of clinical features including chorea, orofaciolingual dyskinesia, dysphagia, dysarthria, peripheral neuropathy, myopathy, seizures, and dementia has been described in these disorders.3
This patient was briefly described as case 19 in the report of Danek et al.4 He was a 61 year old white male who had been well until 3 years previously, when he took early retirement from teaching owing to "disillusionment". He subsequently developed a progressive dementing illness, associated with facial tics, grunting noises, dysarthria, and chorea over the subsequent 3 years. There was no family history of neurodegenerative disease. He first presented to a neurologist having had an isolated generalised tonic−clonic seizure. On examination, he had a frontal dementia (Mini Mental State Examination (MMSE) score of 27/30) with evidence of self neglect and choreiform movements in all four limbs, and a prominent facial tic. He had little insight into his current illness. All tendon reflexes were absent. Investigation demonstrated numerous acanthocytes on blood films. Creatine kinase was raised at 1125. Kell antigens were only weakly positive, which conformed to the McLeod phenotype. DNA analysis for Huntington’s disease was negative, but a R133X mutation in exon 2 of the XK gene was found.4 All other investigations were negative (full blood count, copper studies, lipid studies, protein electrophoresis, vasculitis screen (antinuclear antibody, antineutrophil cytoplasmic antibody, double stranded DNA antibodies) syphilis serology, CSF analysis, and urinary amino acids. An electroencelphalogram showed no evidence of seizure discharge, but excess generalised slow wave activity. Nerve conduction studies were within normal limits. An MRI scan of the head (fig 1A) showed widespread areas of increased signal within the white matter of both cerebral hemispheres, especially within the lentiform nucleus bilaterally, but also within the thalamus, cerebral peduncles, and pons, and involving the corpus callosum (white arrow, fig 1B).
This 56 year old Italian male developed chorea at the age of 42 years, and subsequently neuropsychological problems. The clinical aspects of this case have been reported previously.5 Numerous acanthocytes were seen on blood films, with weak Kell antigen. Analysis of the XK gene identified a R133X mutation. An MRI scan of the head showed mild increased signal within white matter on T2, proton density and fibre linked array image formatter (FLAIR) MRI sequences (fig 1C) in the posterior periventricular white matter.
A 32 year old Indian male, born of consanguineous parents, who presented with progressive disinhibition, altered personality and chorea over a 2 year period. His clinical details have not been reported previously. His family had noticed intermittent unusual head movements in which he would appear to be looking around the room into empty spaces while conversing. Although these movements were involuntary, he was able to stop them temporarily if asked to do so. His personality had become more volatile with emotional outbursts and frequent loss of temper. On examination, his MMSE was 27/30. There were continuous choreiform movements of head and neck, and of all four limbs. He was able to interrupt these temporarily if asked to do so. His speech was slightly dysarthric but there was no involuntary tongue protrusion or evidence of self mutilatory behaviour affecting the tongue or lips. The remainder of his neurological examination was normal. Numerous acanthocytes were seen on blood films (fig 1D). Kell serology was normal, with exclusion of the McLeod phenotype. All other investigations including Huntington’s mutational analysis, CSF, and white cell enzyme analysis were negative. Analysis of the CHAC locus is ongoing, but no mutations were identified in the XK gene. MRI head scan (fig 1E,F) demonstrated abnormally high signal in the periventricular white matter bilaterally, with involvement of the corpus callosum and cerebellar atrophy, but without contrast enhancement.
Both computed tomography and MRI have been reported to show caudate and more generalised cerebral atrophy in neuroacanthocytosis.4 Although increased signal on T2 weighted MRI in the caudate and putamen has been noted previously, the increased signal throughout the cerebral hemispheres (including the corpus callosum in cases 1 and 3) reported here has not been reported previously. Extensive investigation for alternative causes of white matter abnormalities (vasculitic screen, and analysis of CSF, very long chain fatty acids, mitochondria, white cell enzymes and plasma lysosomal enzymes) was negative and there was no history of hypertension. In view of the ages of cases 1 and 2 when these patients were initially assessed, not much weight had been given to their MRI appearances; it was in the assessment of case 3 (a normotensive young male who was being investigated for a possible leukodystrophy) that the significance of both his abnormal blood film and his MRI prompted us to review the previous two cases.
Until we have a better understanding of the functional basis of these rare neurogenetic disorders, it is difficult to speculate as to the mechanism via how such abnormalities appear. Although the appearances reported in these cases are not specific, they widen the spectrum of MRI abnormalities that have been reported in neuroacanthocytosis. Thus, clinicians need to be particularly aware of the possibility of neuroacanthocytosis in any patient presenting with unexplained chorea,3 as the MRI appearances are so variable.
We are grateful to the Dr J A Spillane and the late Professor S Bundey for their evaluation and referral of case 1.
Competing interests: none declared
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