I searched Pub Med from 1965-2005 for the term “Huntington's Disease” cross referenced with the terms “apoptosis”, “axonal transport”, “mitochondria”, “animal model”, “proteosome”, “transcription”, “juvenile”, “suicide”, “neurotransmitters”, “age of onset”, “identical twins”, “neurodegeneration”, and “imaging”. I translated all non-English language publications that resulted from this search strategy. I mainly selected articles from the past five years, but did not exclude commonly
SeminarHuntington's disease
Section snippets
Clinical findings in Huntington's disease
Individuals with Huntington's disease can become symptomatic at any time between the ages of 1 and 80 years; before then, they are are healthy and have no detectable clinical abnormalities.9 This healthy period merges imperceptibly with a prediagnostic phase, when patients show subtle changes of personality, cognition, and motor control. Both the healthy and prediagnostic stages are sometimes called presymptomatic, but in fact the prediagnostic phase is associated with findings, even though
Differential diagnosis
Diagnosis of Huntington's disease is straightforward in patients with typical symptoms and a family history. However, dentatorubropallidoluysian atrophy,26 Huntington's disease-like 2 (frequent in black Americans and South Africans),27 and a few other familial disorders28, 29 are phenotypically indistinguishable from the disorder. Furthermore, about 8% of patients do not have a known affected family member.30, 31 Neuroacanthocytosis can also mimic Huntington's disease,32 but areflexia, raised
Neuropathology
Neuropathological changes in Huntington's disease are strikingly selective, with prominent cell loss and atrophy in the caudate and putamen.33, 34, 35 Striatal medium spiny neurons are the most vulnerable. Those that contain enkephalin and that project to the external globus pallidum are more involved than neurons that contain substance P and project to the internal globus pallidum.33, 34 Interneurons are generally spared. These findings accord with the hypothesis that chorea dominates early in
Imaging
Routine MRI and CT in moderate-to-severe Huntington's disease show a loss of striatal volume and increased size of the frontal horns of the lateral ventricles,56 but scans are usually unhelpful for diagnosis of early disorder. Data from PET and functional MRI studies have shown that changes take place in affected brains before symptom onset,57, 58, 59 and some MRI techniques can precisely measure cortex and striatum.60, 61 In fact, with these techniques, caudate atrophy becomes apparent as
Clinical genetics
The gene for Huntington's disease (HD) is located on the short arm of chromosome four and is associated with an expanded trinucleotide repeat. Normal alleles at this site contain CAG repeats, but when these repeats reach 41 or more the disease is fully penetrant.34, 63, 64 Incomplete penetrance happens with 36–40 repeats, and 35 or less are not associated with the disorder. The number of CAG repeats accounts for about 60% of the variation in age of onset, with the remainder represented by
Genetic testing and diagnosis of Huntington's disease
Despite early surveys that suggested a high amount of interest, fewer than 5% of individuals at risk for Huntington's disease choose to actually pursue predictive genetic testing.80 Those who undergo testing generally do so to assist in making career and family choices; others elect not to test because of the absence of effective treatment. Predictive testing for the disorder is not without risk. Suicide can follow a positive result,81, 82 and people who are misinformed about the nature of
Epidemiology and genetic fitness
Huntington's disease shows a stable prevalence in most populations of white people of about 5–7 affected individuals per 100 000. Exceptions can be seen in areas where the population can be traced back to a few founders, such as Tasmania92 and the area around Lake Maracaibo21 in Venezuela. In Japan, prevalence of the disorder is 0·5 per 100 000, about 10% of that recorded elsewhere, and the rate is much lower in most of Asia.93 African populations show a similarly reduced prevalence,2, 4, 94, 95
Huntingtin and pathogenesis of Huntington's disease
Huntingtin is expressed in all human and mammalian cells, with the highest concentrations in the brain and testes; moderate amounts are present in the liver, heart, and lungs.98 Recognisable orthologs of the protein are present in many species, including zebrafish, drosophila, and slime moulds.99, 100 The role of the wild-type protein is, as yet, poorly understood, as is the underlying pathogenesis of Huntington's disease.
One mechanism by which an autosomal-dominant disorder such as
Animal models of Huntington's disease
The earliest animal models of Huntington's disease were developed in the 1970s on the basis of selective vulnerability of striatal neurons to excitotoxic aminoacids.129 These neurons have many glutamate receptors because corticostriatal pathways use this excitatory aminoacid as a primary neurotransmitter. Striatal neurons have also proven to be selectively vulnerable to 3-nitroproprionic acid, a mitochondrial toxin, suggesting that Huntington's disease might affect energy metabolism in neurons.
Symptomatic treatment of Huntington's disease
Diagnosis of Huntington's disease usually happens when patients seek medical advice with respect to difficulties with work. In such situations, a diagnosis might be partly welcome because it helps to establish disability. People who are doubtful about having Huntington's disease, however, could benefit from a delay in diagnosis until a follow-up visit, when laboratory confirmation is available and they are supported by a family member. The visit at which a diagnosis of Huntington's disease is
Experimental treatments
Currently, several drugs for Huntington's disease are in clinical trials to slow the progression of the disease; a few agents have shown promise in work done in animal models.140, 141 The most intriguing research to date has been with coenzyme Q10, which has shown effectiveness in transgenic animal models of Huntington's disease and a possibility of improvement in a human trial.142 This substance is believed to work by enhancing mitochondrial function in Huntington's disease. A long-term
Future work
The best therapeutic option for Huntington's disease could entail starting treatment in the asymptomatic phase of the disorder. Currently, in several observational studies of at-risk individuals, the feasibility of using the onset of the clinical Huntington's disease phenotype or other biomarkers of disease (such as changes on imaging studies) is being investigated as a potential endpoint for future clinical trials.148 Successes in animal models, identification of possible surrogate markers,
Search strategy and selection criteria
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