Huntington Disease

Dpt. Aamir Memon 8/26/2013

Huntington Disease

Introduction: Huntington disease (chorea) is a rare, degenerative disease of the basal ganglia and

cerebral cortex. It is passed genetically as an autosomal-dominant disorder,

apparently caused by expansion of a repeating codon located on chromosome 4.

Atrophy and loss of striatal neurons in caudate, putamen, and globus

pallidus.

Age of Onset: Onset of the disease typically occurs between 35 and 45 years of age.

Pathophysiology: → This autosomal dominant disorder causing a movement disorder and psychiatric

and cognitive dysfunction most often results from a defect in the coding region of

the gene encoding huntingtin (IT15) on the short arm of chromosome 4, namely an

expansion of a CAG trinucleotide, hence a trinucelotide repeat disease.

→ With degeneration of the basal ganglia and cerebral cortex, several different

neurotransmitters are lost. Many complications of the disease result from the loss

of the inhibitory neurotransmitter GABA. There also appear to be gross

abnormalities in energy production by the neuronal cell mitochondria.

→ Deletion of the huntingtin gene by telomeric rearrangement on chromosome 4p

results in the Wolf–Hirschhorn syndrome or chromosome 4p syndrome, the

clinical phenotype of which bears no relation to Huntington’s disease.

Clinical features:

→ Personality change: irritability, apathy, depression, slowly progressing dementia

or schizophrenia-like features.

→ Movement disorder: chorea (involuntary jerking movements), initially transient,

often progresses to continuous athetotic and dystonic movement.

Juvenile cases may present with parkinsonism (Westphal variant) and

may show cortical myoclonus.

→ Cognitive disorder: subcortical type dementia leading to a global dementia with

time.

→ Hypothalamic changes may occur early in the disease course with disturbances in

sleep and weight loss.

→ Family history of movement disorder, dementia, suicide, may be suggestive of

diagnosis.

Diagnostic Tools:

→ Neurogenetic testing for CAG trinucleotide repeat expansion in the IT15 gene is

the diagnostic test, but requires pretest counseling about implications.

→ Neuroimaging (CT/MRI) may demonstrate caudate atrophy in late disease, with

dilatation of frontal horns of lateral ventricles (box-like appearance of ventricles).

Decreased signal may be seen in globus pallidus and putamen on T2-

weighted MR scans.

→ SPECT/PET may show hypometabolism i.e. decreased caudate/striatal perfusion

and glucose metabolism.

→ Neuropathology: brain atrophy, particularly marked in striatum and caudate

nucleus. Loss of spiny neurones in the basal ganglia.

Brain intranuclear aggregates suggest that abnormal protein handling

is a feature of the disease, whether pathogenetic or epiphenomenal.

→ EEG is normal early on; low voltage with poorly developed or absent alpha

rhythm may be seen in symptomatic cases.

Differential diagnosis:

→ Huntington disease-like 1 (HDL1): due to eight extra octapeptide repeats in the

PRNP gene.

→ Huntington disease-like 2 (HDL2): due to CAG/CTG repeat in the junctophilin-3

(JPH3) gene.

→ Huntington disease-like 3 (HDL3): linked to chromosome 4p15.3.

→ Huntington disease-like 4 (HDL4): spinocerebellar ataxia type 17 (SCA17) due to

trinucleotide repeat encoding glutamine (CAG or CAA) in the TATA box-binding

protein (TBP).

→ The choreiform disorder is often characteristic, but other causes of chorea may

have to be excluded (e.g., neuroacanthocytosis, dentatorubral-pallidoluysian

atrophy (DRPLA)); ditto young onset parkinsonism.

→ Benign hereditary chorea is also autosomal dominant but the absence of dementia

means it is unlikely to be mistaken for HD.

→ Familial dementias (e.g., familial Alzheimer’s disease, FTLD) may be considered,

but neuropsychological profile is different and movement disorder absent.

Treatment:

→ No specific treatment is currently available. The possibility of gene and cell

transplantation is being investigated.

→ Symptomatic treatment for the movement disorders may include olanzapine,

sulpiride, or tetrabenazine.

→ Cognitive and behavioral deficits are difficult to manage; the latter may mandate

the use of olanzapine or antiepileptic medication.

→ Depression may be treated with SSRIs. Genetic counseling is important in affected

families.

→ Support may also be obtained from patient organizations.

Prognosis:

→ Prognosis from onset to death is around 15–20 years.

→ In some patients there is a risk of suicide, and this is typically seen early on in the

disease course.

→ In advancing cases of HD, consideration needs to be given for PEG feeding and

advanced directives.