The clinical triad of hereditary chorea syndromes includes (1) choreatiform involuntary movement disorder, (2) psychiatric symptoms, and (3) cognitive impairment. The most frequent hereditary chorea syndrome is Huntington’s disease (HD). There are several phenocopies of Huntington’s disease, such as the Huntington’s disease-like neurodegenerative
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The clinical triad of hereditary chorea syndromes includes (1) choreatiform involuntary movement disorder, (2) psychiatric symptoms, and (3) cognitive impairment. The most frequent hereditary chorea syndrome is Huntington’s disease (HD). There are several phenocopies of Huntington’s disease, such as the Huntington’s disease-like neurodegenerative disorders type 1 and type 2 (HDLD), benign hereditary chorea (BHC), dentato-rubro-pallido-Luysian atrophy (DRPLA), choreoacanthocytosis (CHAC), and McLeod syndrome (MLS). Huntington’s disease is caused by an instable CAG trinucleotide expansion in the Huntington disease gene, and onset age and severity of symptoms depend on the number of CAG repeats. The physiological function of the gene product Huntingtin and the disease mechanisms are not fully elucidated yet. However, experimental data strongly suggest that induction of apoptosis through a caspase (cysteine aspartate-specific proteases)- dependent mechanism might be an important factor for the development of the striatal neurodegeneration. The HDLDs are more or less exact phenocopies of Huntington’s disease. Two chromosomal localisations are described, and one responsible gene, Junctophilin-3, is identified. The BHC manifests as a pure chorea syndrome, without major psychiatric or cognitive impairment. The disease is located on chromosome 14, but the responsible gene has not yet been identified. Apart from the Huntington’s disease-like phenotype, DRPLA may manifest as a spinocerebellar ataxia, a progressive myoclonus epilepsy, or mixed phenotypes. DRPLA is caused by instable CAG expansions in Atrophin-1, whose physiological functions are not yet known. CHAC and MLS belong to the so-called neuroacanthocytosis syndromes.CHAC is an autosomalrecessive disorder characterised by a progressive chorea syndrome, perioral dyskinesias and mutilations, and – less frequently – an akinetic-rigid extrapyramidal syndrome and seizures. The responsible gene is located on chromosome 9, encoding chorein, a protein implicated in intracellular cell sorting. MLS is an X-linked multi-system disorder with haematological, neuromuscular, and CNS involvement. Haematologically, MLS is characterised by absent expression of the Kx erythrocyte antigen, weak expression of Kell antigens, acanthocytosis, and a compensated haemolytic state. Asymptomatic males have elevated serum creatine kinase levels, and are prone to develop neurological symptoms. Neuromuscular manifestations include myopathy, sensory-motor axonal neuropathy, and cardiomyopathy. CNS manifestations comprise a choreatiform movement disorder, neuropsychiatric abnormalities, and – less frequently – generalised seizures. MLS is caused by mutations of the XK gene encoding the XK protein, a putative membrane transport protein containing the Kx erythrocyte antigen. The XK protein is linked to the Kell glycoprotein by a single disulfide bond, probably forming a functional complex. The Kell protein is a member of the metalloproteinase family, and the XK protein has functional similarities to the CED-8 protein in nematodes, in which it controls the timing of apoptosis. These data strongly suggest an important role of the XK-Kell complex in striatal physiology. The advances in the molecular biology of hereditary chorea syndromes offer the possibility for a direct genetic analysis of affected individuals, and presymptomatic testing for individuals at risk. Although the genetic bases of some hereditary chorea syndromes are established, causal therapies are lacking. However, the rapidly accumulating knowledge will hopefully lead to the development of efficient therapies that might attenuate or even prevent these otherwise relentlessly progressive neurodegenerative disorders.
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