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Huntington Disease – Causes, Symptoms, Diagnosis And Treatment

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Huntington Disease

Huntington disease or chronic chorea is a degenerative disease, with genetic determination, transmitted autosomal dominant with complete penetrance. Genetic defect is located on chromosome 4 and is represented by the gene that encodes huntigtin, a cytomplasmatic protein with unknown function, but the central nervous system cells suffer when the levels of this protein are increased. Huntington disease was first described in 1872 by George Huntington and is an incurable disease that occurs in adults, being characterized by involuntary movements, behavioral changes and dementia that develop gradually.

Huntington disease becomes clinically symptomatic at the age of 35-40 years and until now there is no diagnostic test which can detect the disease in the asymptomatic stage. Family history is the main identifiable risk factor.

Neurological changes in Huntington disease are represented by neostriatum atrophy (caudate nucleus and putamen), frontal cortex and temporal cortex atrophy accompanied by neuronal loss and astrogliosis. Other brain structures including the globus pallidus, thalamus, subthalamic nucleus, substantia nigra, and cerebellum may present varying degrees of atrophy.

Huntington Disease Causes

Huntington disease is a genetic condition in which the main modification is represented by the expansion of a cysteine-adenosine-guanine (CAG) repeat encoding a polyglutamine tract in the N-terminus of the protein product called huntingtin. The exact role of huntingtin is not known, but it was observed that this cytoplasmatic protein is found in cellular organelles such as mitochondria, microtubules, transport vesicles and synaptic vesicles. N-terminal fragments of abnormal huntingtin accumulate in the central nervous system cells and form inclusions.

Huntington Disease Causes

Huntington Disease Causes

It is estimated that frequency of Huntington’s disease in European countries is 2-10 cases per 100,000 inhabitants, but there is great variability in the frequency of disease worldwide. In USA the disease frequency is estimated at 4.1-8.4 cases per 100,000 inhabitants. High prevalence of Huntington disease were recorded in countries such as Venezuela, 700 cases per 100,000 inhabitants, Tasmania, 17.4 cases per 100,000 inhabitants and in South Africa, 46 cases per 100,000 inhabitants. In Finland and Japan, Huntington disease prevalence is less than 1 case per 100,000 inhabitants.

Mean age of disease onset is between 35-40 years. Have been reported cases in which Huntington disease debuts around the age of 2 years, but onset before the age of 10 years is very rare. Huntington disease does not affect gender with a particular predilection.

Huntington Disease Symptoms

Huntington disease is characterized by involuntary movements, cognitive impairment and behavioral changes that may have different intensities and any of these events can represent the first symptom of the disease. At the onset, choreiform movements can be discrete, occur distal to the fingers or may be represented by grimacing. Choreiform movements are represented by spontaneous movements, irregularly timed, randomly distributed, and abrupt. Severity of choreiform movements may vary  from mild intermittent gesture and expression exaggeration, abnormal hand movements and unstable dancelike gait with kept balance, to disabling violent movements.

Huntington Disease

Huntington Disease

Other involuntary movements are represented by parakinesia (unnatural movements into apparently purposeful gestures), ballism (large amplitude, usually proximal, flinging movements of a limb or a body part) and athetosis (slower, distal, writhing, sinuous movements ) which are considered to appear in sever forms of Huntington disease.

Bradykinesia, akinesia and dystonia (sustained muscle contractions) are features of Huntington disease which appear in evolution of the disease and may represent a major source of voluntary movements impairments, causing twisting or repetitive movements and abnormal postures. In terminal stages of the illness, patients  may present akinesia and rigidity or other signs characteristic for Parkinson disease such as postural instability and extrapyramidal hypertonicity.

In Huntington disease evolution, eye movement abnormalities such as saccadic slow and uncoordinated eye movements may occur. In very advanced forms of the disease, choreiform movements become minimal and may be  replaced by tics or myoclonus. Anxiety and stress can aggravate the symptoms. During the state of disease, dysarthria and dysphagia may be present.

It is described a juvenile form of Huntington disease (Westphal variant) with onset around the age of 20 years, or before puberty.  In this form of the disease motor degradation is much faster. In Westphal variant muscle stiffness is predominant and cognitive function deterioration is associated with cerebellar ataxia, bradykinesia and dystonia. Choreiform movements are minor or absent.

Behavioral changes may be present with several years before manifestation of choreiform movements. Personality changes, such as irritability, impulsive, paranoid and antisocial behavior. Drug and alcohol addiction is common and depression and suicide attempts are characteristic for Huntington disease.

Dementia syndrome has a progressive development, cognitive disorders appear later in disease evolution and are represented by behavioral and intellectual impairments, memory problems, reduction of verbal fluency and attention disorders. Other behavioral changes are represented by bipolar disorder, obsessive-compulsive, sexual and sleep disorders.

Huntington Disease

Huntington Disease

Huntington Disease Diagnosis

Huntington disease diagnosis is manly based on symptoms in characteristic forms of the disease. Imaging studies such as CT or MRI are not sufficient for Huntington disease diagnosis, but enlargement of bicaudate diameter (the distance between the heads of the 2 caudate nuclei) may represent a marker for diagnosis. Genetic testing it is available and should be performed in patients with suggestive clinical symptoms but with a negative family history, in order to confirm or exclude Huntington disease.

Huntington Disease Treatment

Huntington disease benefit only from symptomatic treatment of Huntington disease and is aiming to improve life quality and prevent disease complications.

Anticonvulsant medications (valproic acid and carbamazepine) have proven effective in reducing choreiform movements. Other drugs such as dopamine blockers (haloperidol, pimozide and clozapine) and depletion dopamine agents  (tetrabenazine and reserpine) are useful in choreiform movements control, but present adverse effects such as dizziness, akathisia and dyskinesia.

Selective serotonin reuptake inhibitors are useful in cases of Huntington disease that present depression. Other antidepressants such as bupropion, venlafaxine, nefazodone and tricyclic antidepressants are useful.

In patients with Huntington disease that present hallucinations, delusions or schizophrenia-like symptoms, antipsychotic medications is useful. Quetiapine, clozapine, olanzapine and risperidone, drugs that represent newer antipsychotic agents, are preferred to older agents because have a lower rate of adverse effects.