Keywords
juvenile Huntington's disease -
HTT gene - CAG repeat expansion
Introduction
Huntington disease (HD) is an autosomal dominant progressive disease caused by a Cytosine-Adenine-Guanine
(CAG) repeat expansion in the huntingtin (HTT) gene, characterized by the triad of choreic abnormal movements, cognitive decline,
and psychiatric disturbances such as depression.[1] The juvenile variant of HD (JHD), with onset ≤ 20 years, accounts from 4.81 to 9.95%
of all cases of HD and only approximately 20% of JHD have childhood-onset HD with
onset of symptoms before 10 years of age (Westphal variant, W-HD).[2] This clinical triad is also observed in JHD but with a different clinical presentation,
with bradykinesia, dystonia, and parkinsonian features being predominant over chorea,
associated to neuropsychiatric manifestations and myoclonus and epilepsy in nearly
half of patients with JHD.[3]
Case Report
A 14-year-old girl was referred to our neuropediatric clinic because of a 7-year history
of frequent falls by progressive postural instability. During the past 2 years, she
developed clumsiness, limb stiffness, dysarthria, hearing impairment, marked emotional
lability with periods of agitation and anxiety, and rapidly declining school performance.
Her early developmental milestones and cognitive function were normal. Her father
suffered from a progressive neurological disorder, characterized by chorea and dementia
at the age of 45, and her paternal grandmother, uncles, aunts, and a cousin presented
a similar clinical picture ([Fig. 1]).
Fig. 1 Family pedigree. Filled boxes indicate symptomatic participants. Arrow points to
the proband object of this report.
General examination was otherwise normal. Neurologic examination showed slurred speech,
abstraction, and calculation impairment; assessment of cranial nerves was unremarkable.
We found generalized hyperreflexia and hypertonia, cogwheel rigidity, marked left
hemibody dystonic posture with gait limitation and bradykinesia. Sensory examination
was unremarkable. No ataxia was observed.
Brain magnetic resonance imaging (MRI) showed bilaterally caudate and putamen atrophy
([Fig. 2]). Routine blood tests were normal. Molecular analysis of HTT showed an abnormally expanded 79 CAG repeats allele in exon 1 consistent with a molecular
diagnosis of HD.
Fig. 2 Axial T2-weighted FLAIR image showing bilateral putaminal hyperintensities (black
arrows) and atrophy of the head of caudate nuclei (white arrows). FLAIR, fluid attenuation
inversion recovery.
Tetrabenazine was started at 12.5 mg/d and increased up to 100 mg/d with a slight
improvement of abnormal dystonic posture and dysarthria. Genetic counseling was given
to the family for prenatal guidance.
Discussion
The described patient had dystonia, gait impairment, rigidity, and neuropsychiatric
symptoms that started at the age of 7 years, which is characteristic of the W-HD.
This form differs from that in adults, as it has prominent parkinsonism features.[4] It is proposed that these clinical manifestations are the result of a degeneration
of the direct inhibitory striatopallidal projection, which results in increased inhibition
of the ventrolateral thalamus.[5] In the largest study to date, only seven children (1.92%) had onset of symptoms
before the age of 10 years.[1]
Molecular analysis in our patient showed an abnormally expanded 79 CAG repeats in
HTT. Patients with early age onset carry large CAG expansions on the HD gene[6] and most of them, as well as other CAG expansion diseases, show anticipation when
the disease is inherited from their father.[7] An inverse correlation has been described between the number of CAG repeats and
the age of onset of HD,[8] with patients with JHD carrying usually over 60 repeats. There is also a direct
correlation between the CAG repeats and the rate of motor and cognitive progression.[9] Thus, W-HD shows more similarities with an advanced form of adult-onset HD, although
other modifier genes might alter the phenotype.[10]
As a predictive test, genetic testing should not be done if the child presents neuropsychiatric
symptoms suggestive of HD and the responsible health professional is concerned about
the information being harmful to the patient.[11] Presymptomatic testing is not indicated in children unless there is a clinical intervention
appropriate in childhood; thus, parents should defer knowing their child's genotype.[12] In HD, an early diagnosis or detection will not give a cure nor will it improve
the prognosis. Furthermore, testing positive for HD can generate social stigma, insurance
discrimination, and affect patients' development.[13]
Treatment is essentially supportive. Tetrabenazine has been approved by the United
States Food and Drug Administration for chorea, but its effect in W-HD is limited.
Haloperidol or risperidone have been helpful for behavioral problems, and antidepressants
of mood stabilizing medications have been used for neuropsychiatric manifestations.
Physical, speech, and occupational therapies are important for maximizing functionality,
particularly as the disease progresses.[4]
[5]
Even though infrequent, W-HD should be suspected when parkinsonism and cognitive decline
present in a child with family history of movement disorder and dementia.
