Huntington disease

Huntington disease is a progressive disease of
the brain. Within 5–10 years, it leads to
complete loss of motor control and intellectual
abilities (1). It usually begins around age 40–50
with uncoordinated movements (chorea, St.
Vitus’ dance), excitation, hallucinations, and
psychological changes. The disease is transmitted
by autosomal dominant inheritance and
shows complete penetrance. It presents an affected
family with two difficult problems: (i)
due to its late onset, carriers of the mutation
have usually completed their family planning
before the disease is manifest, and (ii) children
of affected persons first learn as young adults
that they are at a 50% risk of developing the disease
later in life. Thus, the introduction of a
direct predictive DNA diagnostic procedure is
very important. However, before such a genetic
test is carried out, it must be established
through genetic counseling that the persons at
risk have decided for themselves whether they
want to have the test performed. The gene is located
on the distal short arm of chromosome 4
(2). It spans 210 kb and codes for a protein
(called huntingtin) of important function. The
5! end of the gene contains numerous copies of
a trinucleotide sequence consisting of cytosine,
adenine, and guanine (CAG), a codon for the
amino acid glutamine. Normally the gene has
10–34 CAG repeats; in patients there are
42–100. The diagnostic test (3) demonstrates
that affected individuals (here, individuals 1, 2,
and 4) have enlarged DNA fragments due to expanded
CAG repeats. (Findings of the Institut
für Humangenetik of the Universität Göttingen
with kind permission by Prof.W. Engel; Zühlke
et al., Hum. Mol. Genet. 2:1467–1469, 1993).