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 WolfHirschhorn syndrome or chromosome 4p syndrome, the clinical phenotype of which bears no relation to Huntingtons 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 T2weighted 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 Alzheimers 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 1520 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.