Huntington disease is an autosomal dominantly inherited disease. It is a progressive neurodegenerative disorder with dementia and movement disorders. The salient features include a characteristic jerky movement, called chorea, affecting all parts of the body. These motor symptoms usually precede the dementia. Later disease may have Parkinsonism with bradykinesia and rigidity.
AGE RANGE-MEDIAN Onset usually 4-5th decade
PATHOGENESIS CHARACTERIZATION HD gene located on 4p16.3
Encodes for huntington protein (348kD mass)
In normal gene, there is 11-34 copies of a repeated sequence of CAG trinucleotide
Triple repeat mutation with larger number of repeats, the earlier onset of disease
Huntington has been hypothesized as a potential target for caspase 3, a protease associated with neuronal apoptosis
A worldwide study of the Huntington's disease mutation. The sensitivity and specificity of measuring CAG repeats.
Kremer B, Goldberg P, Andrew SE, Theilmann J, Telenius H, Zeisler J, Squitieri F, Lin B, Bassett A, Almqvist E, et al.
Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
N Engl J Med 1994 May 19;330(20):1401-6 Abstract quote
BACKGROUND. Huntington's disease is associated with an expanded sequence of CAG repeats in a gene on chromosome 4p16.3. However, neither the sensitivity of expanded CAG repeats in affected persons of different ethnic origins nor the specificity of such repeats for Huntington's disease as compared with other neuropsychiatric disorders has been determined.
METHODS. We studied 1007 patients with diagnosed Huntington's disease from 565 families and 43 national and ethnic groups. In addition, the length of the CAG repeat was determined in 113 control subjects with a family history of Alzheimer's disease (44 patients), schizophrenia (39), major depression (16), senile chorea (5), benign hereditary chorea (5), neuroacanthocytosis (2), and dentatorubropallidoluysian atrophy (2). The number of CAG repeats was also assessed in 1595 control chromosomes, with the size of adjacent polymorphic CCG trinucleotide repeats taken into account.
RESULTS. Of 1007 patients with signs and symptoms compatible with a diagnosis of Huntington's disease, 995 had an expanded CAG repeat that included from 36 to 121 repeats (median, 44) (sensitivity, 98.8 percent; 95 percent confidence interval, 97.7 to 99.4 percent). There were no significant differences among national and ethnic groups in the number of repeats. No CAG expansion was found in the 110 control subjects with other neuropsychiatric disorders (specificity, 100 percent; 95 percent confidence interval, 95.2 to 100 percent). In 1581 of the 1595 control chromosomes (99.1 percent), the number of CAG repeats ranged from 10 to 29 (median, 18). In 12 control chromosomes (0.75 percent), intermediate-sized CAG sequences with 30 to 35 repeats were found, and 2 normal chromosomes unexpectedly had expanded CAG sequences, of 39 and 37 repeats.
CONCLUSIONS. CAG trinucleotide expansion is the molecular basis of Huntington's disease worldwide and is a highly sensitive and specific marker for inheritance of the disease mutation.
Mutation analysis in patients with possible but apparently sporadic Huntington's disease.
Davis MB, Bateman D, Quinn NP, Marsden CD, Harding AE.
University Department of Clinical Neurology, Institute of Neurology, London, UK.
Lancet 1994 Sep 10;344(8924):714-7 Abstract quote
Until the advent of mutation analysis it was impossible to make a certain diagnosis of Huntington's disease (HD) in the absence of a positive family history, and sporadic cases of possible HD presented a substantial diagnostic dilemma.
We have looked for the characteristic expanded trinucleotide (CAG) repeat sequence in the HD gene in 44 patients with probable or possible HD who did not have similarly affected relatives. We used two methods, the traditional widely used method, which estimates both the CAG repeat and the flanking CCG repeat and gives the CAG length by subtraction, and the more precise CAG method, which estimates the repeat length directly. With the CAG method, the HD mutation was detected in 25 (89%) of 28 patients with the typical clinical features of HD and 5 (31%) of 16 in whom the diagnosis was more doubtful. The CAG-CCG method gave results in the borderline abnormal range of repeats for 13 of the 33 patients eventually shown to have an unequivocal repeat expansion by the CAG method. Most of these patients had late onset of symptoms. There was evidence of expansion of an intermediate-length paternal allele in 1 patient and of non-paternity in another.
The identification of the mutation causing HD means that it is now possible to confirm or exclude the diagnosis with confidence, even in the absence of a family history, by analysis of DNA from a blood sample. The precise method of measuring the CAG repeat, which is technically more difficult than the traditional method, may be needed to clarify results in a substantial proportion of such patients.
CHARACTERIZATION General Small brain with atrophy of the caudate nucleus and putamen
May have secondary atrophy of the globus pallidus
Lateral and third ventricles may be dilated
Atrophy may occur in the frontal lobe, parietal lobe, and occasionally entire cortex
HISTOLOGICAL TYPES CHARACTERIZATION General
Severe loss of striatal neurons, especially within the caudate nucleus, in tail and near the ventricle
Less severe changes in putamen
Changes occur in medial to lateral direction in caudate
Dorsal to ventral in putamen
Loss of small neurons precedes larger neurons with neurons utilizing GABA and enkephalin or GABA and substance P affected preferentially
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS Once the diagnosis is established, most will survive another 15 years TREATMENT
A controlled trial of remacemide hydrochloride in Huntington's disease.
Kieburtz K, Feigin A, McDermott M, Como P, Abwender D, Zimmerman C, Hickey C, Orme C, Claude K, Sotack J, Greenamyre JT, Dunn C, Shoulson I.
Department of Neurology, University of Rochester Medical Center, New York 14642, USA.
Mov Disord 1996 May;11(3):273-7 Abstract quote
We conducted a randomized, double-blind, placebo-controlled tolerability study of a N-methyl-D-aspartate (NMDA) glutamate receptor ion-channel blocker, remacemide hydrochloride, in 31 independently ambulatory patients (18 men, 13 women) with Huntington's disease (HD).
Subjects were randomized to receive either placebo or active remacemide at dosages of 200 mg/day or 600 mg/day. The primary outcome measure was the proportion of subjects able to complete the study with the assigned treatment. Remacemide was generally well tolerated, and no significant differences between the treatment arms were found in the primary outcome measure.
A trend toward improvement in chorea was observed among subjects administered remacemide 200 mg/day. Based on the tolerability and safety demonstrated during this short-term trial, remacemide warrants more extended controlled investigation in patients with HD.
A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington's disease.
The Huntington Study Group.
Neurology 2001 Aug 14;57(3):397-404 Abstract quote
BJECTIVES: To determine whether chronic treatment with coenzyme Q10 or remacemide hydrochloride slows the functional decline of early Huntington's disease (HD).
METHODS: The authors conducted a multicenter, parallel group, double-blind, 2 x 2 factorial, randomized clinical trial. Research participants with early HD (n = 347) were randomized to receive coenzyme Q10 300 mg twice daily, remacemide hydrochloride 200 mg three times daily, both, or neither treatment, and were evaluated every 4 to 5 months for a total of 30 months on assigned treatment. The prespecified primary measure of efficacy was the change in total functional capacity (TFC) between baseline and 30 months. Safety measures included the frequency of clinical adverse events.
RESULTS: Neither intervention significantly altered the decline in TFC. Patients treated with coenzyme Q10 showed a trend toward slowing in TFC decline (13%) over 30 months (2.40- versus 2.74-point decline, p = 0.15), as well as beneficial trends in some secondary measures. There was increased frequency of nausea, vomiting, and dizziness with remacemide and increased frequency of stomach upset with coenzyme Q10.
CONCLUSIONS: Neither remacemide nor coenzyme Q10, at the dosages studied, produced significant slowing in functional decline in early HD.
Riluzole in Huntington's disease (HD): an open label study with one year follow up.
Seppi K, Mueller J, Bodner T, Brandauer E, Benke T, Weirich-Schwaiger H, Poewe W, Wenning G K.
Department of Neurology, Innsbruck University Hospital, Austria.
J Neurol 2001 Oct;248(10):866-9 Abstract quote
In an open label study, we administered riluzole (50 mg twice a day) to nine patients with genetically confirmed Huntington's disease (HD) (clinical stages 1-3; mean age 46.4 (SD 9.3) years; mean disease duration 8 (SD 3.3) years).
The study was designed to evaluate (1) safety and tolerability of riluzole and (2) effects of riluzole on motor impairment, functional disability, cognitive impairment, and behavioral abnormalities using the Unified HD Rating Scale. Patients were evaluated at baseline and after three and twelve months of riluzole therapy. Laboratory tests (hematology and liver enzymes) were repeated monthly. All adverse experiences, reported spontaneously or observed directly by the investigator, were recorded. Riluzole was well tolerated. No increase of serum liver enzymes was seen throughout the study in all but one patient showing a mild elevation. At three months, mean total motor scale (TMS), mean TMS chorea subscore, and mean total functional capacity scale were significantly improved compared with baseline. At twelve months, however, this beneficial effect on motor status and overall function was not sustained. In contrast, severity and frequency of behavioral dysfunction as well as psychomotor speed assessed by the symbol digit modalities test were improved compared with baseline.
Our data suggest that there are transient antichoreatic effects and more sustained effects of riluzole on psychomotor speed and behavior in patients with HD.
A double-blind, placebo-controlled trial appears highly warranted to establish definitely the symptomatic versus neuroprotective actions of riluzole in HD.
Robbin's Pathologic Basis of Disease. 6th Edition. Cotran R. etal. WB Saunders. 1999.
Brain and Spinal Cord
Last Updated 8/17/2001
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