Editor—Huntington’s disease (HD) is an autosomal dominant disorder characterised by the association of choreic movements and cognitive/psychiatric changes. In 1993, the HD Collaborative Research Group reported the identification of the IT15 gene, which encodes a protein named huntingtin that carries an unstable and expanded CAG repeat in patients.1 Normal alleles are polymorphic with 11 to 35 CAG repeats, whereas expanded alleles in patients contain 36 or more repeats.

HD is thought to be a true dominant disorder, since homozygous carriers of the disease are no more severely affected than heterozygous carriers.2 However, precise clinical evaluations have not yet been reported in homozygous patients with known expansion sizes. We report here the clinical, neuropsychological, and molecular characterisation of such a patient in comparison to his heterozygous brother.

The patients underwent neurological examination, including the motor scale of HD,3 neuropsychological testing known to be sensitive to subcortical dementia.4 CAG repeats of the IT15 gene were sized by PCR using Hex labelled primer HD1 and HD2.5 PCR products were run on a 4% polyacrylamide gel and the CAG repeat was estimated using Genescan and the Genotyper software package.

Three HD patients (IV.4, IV.5, and IV.6) were born to parents who were first cousins (fig 1). The mother (III.2), who died at the age of 62, was known to be affected by history but age at onset could not be determined. The father (III.1, 20/41 CAG repeats), examined at the age of 68, had severe choreic movements (motor score 16/20), dysarthria, and cognitive changes with a Mini Mental State examination of 13/30, but was not aware of his symptoms and his age at onset could not be assessed. He died at the age of 70 of colon cancer. Patient IV.6 (42/46 CAG repeats) was referred by relatives at the age of 37 to the Hôpital de la Salpêtrière in Paris for evaluation of nocturnal agitation and increasing alcohol use. He had noticed, from the age of 33, some movement of his fingers. During the first examination at the age of 36, a few inconstant choreic movements of the hands and trunk were observed, which increased during tasks requiring concentration. His speech was slightly explosive, reflexes were increased in the lower limbs, and there was generalised hypotonia. Motor score was 4/20. There was no extrapyramidal rigidity, no bradykinesia or impassive facies, and no weakness or sensory deficit. MRI imaging was normal except for an isolated hyperdense signal in the right pallidum. Neuropsychological testing showed slight and selective impairment in executive functions, including decreased mental flexibility, decreased attentional control, but no memory impairment. The motor scale was 3/20 after one year of follow up and 1/20 after two years of follow up after taking 3 to 5 mg haloperidol some of the time. Neuropsychological testing showed worsening of attentional deficit, working memory impairment, and appearance of slowed thinking with normal memory efficiency (table1).

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Figure 1

Pedigree of the family with Huntington’s disease. Black symbols indicate patients. The numbers indicate the size of the CAG repeat on both chromosomes, the number in brackets the age at onset.

His affected brother (IV.4, 17/48 CAG repeats) was examined at the age of 37 after seven years of illness and showed a wide based gait, increased reflexes, axial rigidity, dysarthric speech, and marked chorea (motor score 10/20). Three years later the motor score had worsened to 16/20 and on examination he was unable to walk alone because of great instability, choreic movements were marked in all limbs, trunk, and face, and his speech largely incomprehensible. There was urinary incontinence. Neuropsychological testing showed typical features of subcortical dementia, including a severe memory and attentional deficit as part of global inertia (table 1).

This is the first report of a homozygous HD patient with characterisation of the mutation including the sizes of the CAG repeats and neuropsychological testing for subcortical dementia. Since the age at onset in patients with 46 CAG repeats ranges from 25 to 52 years in our series, onset at the age of 33 in homozygous patient IV.6 is within the range of values expected for heterozygous patients (data not shown). This extends previous reports of homozygous patients identified only by haplotype analysis.2 6 In addition, neurological and neuropsychological features were less severe in IV.6 than in his heterozygous brother IV.4. The fact that the disease duration was slightly longer in the heterozygous brother could partly explain the more severe clinical presentation in comparison to his homozygous brother after disease duration of six years. The worsening, however, was faster in the heterozygous brother, since during the three year follow up he gained 6 points on the motor score compared to the stable score of his homozygous brother. This result indicates that homozygosity for HD does not result in earlier onset, increased severity, or more rapid disease progression.

Most information on homozygosity in HD has come from the offspring of couples from a Venezuelan isolate in which both parents were affected. The largest of these sibships comprising 14 subjects has been presented elsewhere.1 The four sibs with proven homozygosity had no unusual clinical features; three of the four were too young (16 to 42 years) for a definite diagnosis of HD to be established. Myerset al 6 reported four probable homozygous sibs, determined by haplotype analysis, with ages at onset comparable to those of affected heterozygous sibs. In no case did the age at onset reflect an additive effect of the two mutations.

The expression of the mutation is similar in heterozygotes and homozygotes as observed in disorders with complete dominance like HD1 or Creutzfeldt-Jakob disease.7 The apparently complete dominance in HD, attested by the homozygous patient in this study, supports the hypothesis of a gain of function produced by the polyglutamine expansion in the corresponding protein that is expressed in a number of tissues. The gain of function hypothesis is also supported by the observation that knock-out HD mice are completely rescued by crossing with knock-in mice containing a 50 CAG repeat expansion.8 It is postulated that HD shares a common pathophysiological mechanism leading to neuronal degeneration with at least seven disorders, caused by unstable and expanded CAG repeats resulting in polyglutamine expansion, five types of spinocerebellar ataxia (SCA), dentatorubro-pallidoluysian atrophy (DRPLA), and spinal and bulbar muscular atrophy (SBMA). However, homozygotes for SCA3 or Machado-Joseph disease (65/69, 66/67, 67/68, 67/68 CAG repeats)9 10 and probably for DRLPA (57/57 CAG repeats),11 SCA1(45/54, 48/56, 44/50 CAG repeats),12 SCA2 (39/39 CAG repeats),13 and SCA6 (22/22 CAG repeats)14 present with earlier onset and more severe evolution than heterozygotes. This suggests aggravation of the phenotype by homozygosity in these diseases. In SCA3, the ages at onset in homozygous patients with similar expansions differed, as did severity of the disease,9 and this variability led the authors to hypothesise that the SCA3 mutation might act as a dominant negative, rather than a gain of function mutation. It is possible to reconcile these hypotheses, however, if long polyglutamine tracts produce a toxic gain of function in neuronal cells but also modify to variable degrees the normal function of the protein. This may or may not contribute to the phenotype, depending on the nature of the normal function. Since the functions of huntingtin and most of the ataxins are still unknown, it cannot be determined whether this hypothesis explains the difference between the complete dominance observed in HD and the apparent gene dosage effect in the dominant ataxias and DRPLA. In favour of this hypothesis, however, is the observation in spinal and bulbar muscular atrophy where the polyglutamine expansion produces specific motor neurone degeneration, but also some degree of hypogonadism, reflecting a loss of function, found to a greater extent in patients carrying point mutations in the same gene.