Childhood-onset (Juvenile) Huntington's disease: A rare case report.

Huntington's disease (HD) is a rare dominantly inherited neurodegenerative disorder characterized clinically by a combination of abnormal involuntary (choreic) movements, neuropsychiatric manifestations, and dementia. It is caused by an unstable CAG repeat expansion in the gene IT15 which encodes a Huntingtin protein. We present a case of a 9 year old boy who had developmental regression starting from the age of 8 years of age along with resistant seizures and signs of cerebellar involvement with absence of chorea and is on anticonvulsants, baclofen, and tetrabenzine. As is expected in a case of childhood-onset HD, our patient is rapidly deteriorating and is currently in the terminal phase of his illness along with resistant convulsions.

Introduction

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder characterized clinically by a combination of abnormal involuntary (choreic) movements, neuropsychiatric manifestations, and dementia.[1] Its prevalence in various areas of the world ranges from 5 to 10 per 100,000.[1]

The onset of disease <20 years of age is classified as Juvenile HD (JHD) and those with disease onset <10 years are described as having “Childhood-onset HD.”[2]

The disease is caused by an unstable CAG repeat expansion in the gene IT15, which encodes a protein of unknown function known as Huntingtin.[1]

The characteristics of JHD differ from those of adult-onset HD, as chorea does not occur in JHD although bradykinesia, dystonia, and signs of cerebellar disorder such as rigidity are present frequently in association with convulsive episodes and psychotic manifestation.[3]

Case Report

Our patient is a 9-year-old male child, first by birth order, born of nonconsanguineous marriage who was developmentally normal till 8 years of age when he suddenly developed episodes of frequent falls, ataxic gait and bradykinesia following which one day he had generalized tonic-clonic seizures which were refractory to anticonvulsants. Over the period of few months the parents noticed a loss of achieved developmental milestones to a current developmental age of 1.5–2 years. There is also regression of language milestones to a current status of just monosyllable speech. Inspite of multiple anticonvulsants the child still has persistent seizures. There was no history of any abnormal movements, psychiatric manifestations, and no other members are affected in the family.

On examination, the child had ataxic gait, bradykinesia, oculomotor apraxia, rigidity, and signs of cerebellar involvement. Fundus examination was normal. However, there was no chorea, microcephaly, facial dysmorphism, or hepatosplenomegaly.

On investigation, electroencephalography (EEG) was normal. Magnetic resonance imaging (MRI) brain showed hyperintensity involving caudate nucleus and putamen on both sides with atrophy and volume loss suggestive of JHD [Figure 1]. Positron emission tomography (PET) scan showed severe hypometabolism in bilateral striatum suggestive of JHD. DNA polymerase chain reaction showed 83 expanded trinucleotide CAG repeat sequences.

Figure 1

T2 axial image showing bliateral symmetrical hyperintensity in the caudate (C) and putamen (P) with volume loss and mild atrophy

The patient is currently on three anticonvulsants (sodium valproate, levetiracetam, and topiratmate), a muscle relaxant (baclofen) and tetrabenzine. But, inspite of this the patient has frequent seizures and has a rapid deteriorating course and is bedridden at present.

Discussion

In 1872 George Huntington in his original article described HD[1] and also stated that he does not know even a single case that has shown any marked signs of chorea before the age of 30 or 40 years.[14] But in retrospect, it became known that in 1863, that is, 9 years before Huntington's report, Lyon published the first case of childhood HD.[15] Onset of HD in children younger than 10 years was first described by Harbinson in 1880.[16]

Any patient with HD will experience a mixture of problems with both voluntary and involuntary movements. Classically, patients with adult HD will demonstrate signs of chorea early in the course of illness whereas in JHD, the pattern tends to be that of bradykinesia, dystonia and Parkinsonian features which are prominent at an early stage while chorea, if present, is less prominent.[27] Our patient has a similar presentation.

Diagnostic criteria for childhood-onset HD (≤10 years).[28]

A family history of HD (usually in the father) and two or more of:

Declining school performance

Seizures

Oral-motor dysfunction

Rigidity

Gait disturbance.

Our patient had seizures, oral-motor dysfunction, rigidity, and gait disturbance, but there was no history of declining school performance and neither a family history of HD. Speech and language problems may occur early in the course of illness and can be a pointer toward the diagnosis[2] which is there in our case.

Summary of HD symptoms that require treatment:

Movement disorder

Involuntary movements

Incoordination of voluntary movements

Rigidity/dystonia

Oral-motor dysfunction.

Cognitive disorder

Progressive cognitive dysfunction (treated by repeated testing, and creation of appropriate school or vocational programs and goals).

Psychological/behavioral disorder

Depression

Anxiety

Obsessiveness

Inattention/ADHD

Apathy

Impulsiveness

Irritability.

Family issues

Caregiver stress

School placement

Work placement.

Other

Weight loss

Poor oral hygiene

Aspiration pneumonia (late).

The course of childhood-onset HD is a rapid downhill course[1] as is in our patient.

Three phase of childhood-onset HD have been described:

An initial phase of behavioral disorder, learning difficulty, gait disturbance, and mild chorea

A florid phase with signs of mental deterioration, rigidity, speech disturbance, and seizures

A terminal phase of bed confinement, hypotonia and increasing seizures.[1]

In general the younger the age at onset, the shorter the survival.[1]

On genetic analysis, CAG repeat lengths >60 suggests JHD.[2] Our patient had 83 CAG repeats.

In the majority of JHD cases, the transmitting parent is the father[2] because of instability in the CAG repeat length during spermatogenesis which increases if the father has a longer CAG repeat length,[2] but in our case none of family members were affected.

MRI findings seen in HD include changes in the volume of the striate and other cerebral regions such as the thalamus, hippocampus, amygdala, hypothalamus, cerebellum, and frontal and insular cortex as well as atrophy of the caudate and putamen.[3] In our case, the patient had bilaterally symmetrical hyperintensity in the caudate and putamen with volume loss and mild atrophy as shown in the adjoining Figure 1.

PET scans are more sensitive and specific of JHD amd include marked hypometabolism in the caudate and putamen nuclei and posterior thalamic nuclei.[1910111213] In our patient, we had hypometabolism in bilateral striatum suggestive of JHD.

Currently, EEG is usually less useful in JHD and shows paroxysmal features.[1]

Treatment

At present, there is no definitive treatment for HD.[31415] However, we started with antiepileptics (sodium valproate, levetiracetam, and topiramate) for resistant seizures, baclofen for muscle relaxation and tetrabenzine as a symptomatic treatment for our patient.

The following drugs could be given although questions remain regarding their safety. Typical antipsychotics (haloperidol and pimozide) improve chorea at the expense of deteriorating voluntary movements. NMDA receptors antagonists (riluzole and amantadine) have been used experimentally for the treatment of motor disorders. Also, combination of haloperidol and lithium carbonate may control irritability and impulsivity better than monotherapy and risperidone has been shown to improve abnormal involuntary movements and psychotic clinical manifestations. Olanzapine appears to be a good alternative particularly for the control of psychiatric manifestations.[3]

Noteworthy experimental therapies include drugs that prevent aggregation of Huntingtin protein (drosophila),[316] gene therapy (intracellular antibodies[317] and RNAi[318] ), neurotrophic[319] and neuroprotective factors such as coenzyme Q10[32021] and transplantation of striate fetal cells with the aim of delaying or reversing HD.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.