Final Diagnosis -- Juvenile-onset Huntinton's Disease


Molecular Testing

The 5' region of the Huntington's disease (HD) gene on the short arm of chromosome 4, which contains a polymorphic trinucleotide (CAG) repeat, was amplified by polymerase chain reaction (PCR) and the sizes of the two alleles were measured by denaturing polyacrylamide electrophoresis against M13mp18 as size standard (5). The results are shown in Figure on the right. The patient in this case report has one normal-sized allele and one abnormally expanded allele with 68 CAG repeats. In contrast, a normal control has two alleles in the normal size range (<36 CAG repeats). Approximately 99% of patients with a clinical diagnosis of Huntington's disease have an expanded allele with 36 or more CAG repeats (7).


Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor, cognitive and behavioral dysfunction. The hallmark of the disorder is involuntary choreiform and athetotic movements, hence it is also known as Huntington's chorea. Within the last four years, great advances have been made in understanding the molecular genetics of HD. In 1993, a novel gene containing a polymorphic CAG trinucleotide repeat was cloned and HD patients were found to have expansions of this CAG repeat (6). Normal individuals have alleles with up to 35 CAG repeats, while affected HD patients almost always have an allele with 40 or more CAG repeats. Alleles containing from 36 to 39 repeats showed "reduced penetrance," meaning that only some individuals with such alleles will show clinical symptoms within their expected lifespans (8, 9).

The presented case describes onset of HD before the third decade of life. Such juvenile-onset cases of HD are differentiated from classic adult-onset HD cases by a number of clinical, pathological and genetic features. Juvenile HD patients typically do not present with chorea, but instead with rigidity or seizures (2). With progression of disease, classic uncontrolled, choreoathetotic movements do develop. Behavioral, cognitive or psychiatric difficulties are prominent, as seen in this patient, who presented with a decline in school performance and is currently being treated for psychosis. Although degeneration and atrophy in the caudate and putamen are seen in juvenile HD patients as in adult-onset HD patients, a more widespread pattern of neurodegeneration is usually seen both radiologically and neuropathologically. Neuronal loss in the Purkinje and granule cells of the cerebellum is common, as is atrophy of the dentate nucleus, globus pallidus, hippocampus and neocortex (3).

An interesting genetic feature of HD is anticipation, which may be defined as worsening disease severity in successive generations. Thus, in some cases offspring of affected HD patients have been found to present at an earlier age than their affected parent and to have their disease progress more rapidly than that of the affected parent. For HD, a strong parental bias for this effect has been shown, with paternal transmission of the HD gene mutation found to be statistically more likely to produce anticipation (1). The molecular explanation for anticipation lies in the instability of the causal CAG repeat expansion. Research has shown that there is a correlation between the length of the mutant CAG repeat expansion and the age of onset and age of death in HD (4, 10). Further expansion of the CAG repeat occurs much more frequently with paternal transmission than maternal transmission of the HD CAG repeat mutation. Thus, this increased tendency to further expansion upon paternal transmission accounts for the observation that about 90% of juvenile HD patients have inherited their disease repeat from an affected father. The presented case, which shows paternal transmission of HD, exemplifies this, with the patient inheriting a 68 CAG repeat allele - an increase of 11 from the father's 57 CAG repeats.


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Contributed by Wolfgang T. Hofgärtner MD, Albert R. La Spada, MD, PhD, and Jonathan F. Tait, MD, PhD.


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