JPH3 repeat expansions cause a progressive akinetic-rigid syndrome with severe dementia and putaminal rim in a five-generation African-American family
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We report the clinical, neuropsychological, genetic, and radiological features of a large five-generation African-American kindred from the southern USA presenting with a progressive akinetic-rigid syndrome and severe dementia, but clinically insignificant chorea, due to mutations in junctophillin 3 (JPH3). Overt disease onset was in the mid-20s to late 30s with cognitive decline, REM sleep disturbance, or psychiatric features, followed by development of a levodopa-unresponsive akinetic-rigid motor syndrome. Dystonia and myoclonus were present in some subjects. A bedridden, nonverbal severely akinetic-rigid state developed within 10 to 15 years after onset. CTG repeat expansions ranged from 47 to 53. Imaging revealed generalized cerebral atrophy with severe striatal involvement and putaminal rim hyperintensity. Analysis of our kindred indicates that JPH3 mutations should be considered in the differential diagnosis of early-onset dementia and hypokinetic-rigid syndromes in individuals of African descent. Moreover, chorea may not be overtly manifest at presentation or during significant parts of the disease course.
KeywordsDementia Parkinsonism Chorea Huntington's disease JPH3 Putaminal rim African-American
We thank the family for their participation; Professor Adolfo Bronstein, Imperial College London, for his opinion on the eye movements; and Dr. Amrish Mehta, Charing Cross Hospital, London, for evaluation of the MRI images.
None of the authors have a conflict of interest. Dr. LeDoux serves on the speakers' bureaus for Lundbeck, Merz, and Teva Neuroscience; serves as an advisor for Merz; serves on the Xenazine Advisory Board for Lundbeck, Inc., and the Botulinum Toxin Type A Advisory Board for Allergan; receives research support from the National Institutes of Health, Dystonia Medical Research Foundation, and Merz; and receives royalty payments for Animal Models of Movement Disorders (Elsevier).
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