Huntington's Disease: Causes and History

• Huntington's disease (HD) is an autosomal-dominant, progressive neurodegenerative disorder.
• Symptoms manifest in middle-age after the affected have children, but can emerge in infancy or senescence.
• Huntington's disease is characterized by chorea and dystonia, incoordination, cognitive decline, and behavioral difficulties

Genetic cause

• Expanded CAG repeat in the huntingtin gene leads to a polyglutamine strand at the N-terminus.
• The polyglutamine tail confers a toxic gain of function.
• Precise mechanisms of HD are not well understood.
• Research using animal models is helping to determine factors and potential treatments.

Historical context

• Hereditary nature of chorea was noted in the 17th century by Thomas Sydenham and others.
• George Huntington offered a vivid description of the disease in the 19th century, leading to the designation of the disease as Huntington's.
• The discovery of the causal HD gene has lead to a focus on molecular mechanisms.

Clinical Presentation

• Individuals can become symptomatic from ages 1 to 80, with a preceding healthy period.
• Subtle changes in personality, cognition, and motor control mark the prediagnostic phase.
• Irritability, disinhibition, forgetfulness, anxiety, restlessness, and fidgeting are some symptoms of the prediagnostic phase.
• The diagnostic phase involves distinct chorea, incoordination, motor impersistence, and slowed saccadic eye movements.
• Cognitive dysfunction usually spares long-term memory but impairs executive functions.
• Psychiatric and behavioral symptoms occur with varying frequency.
• Depression is common and suicide risk estimated to be 5 to 10 times higher than in the general population.
• Suicidal ideation is frequent in at-risk individuals and recent diagnoses
• Motor impersistence contributes to restlessness.
• Patients have difficulty maintaining voluntary muscle contraction at a constant level.
• The "milkmaid's grip" is a characteristic inability to apply steady pressure during a handshake.
• As motor and cognitive deficits progress, patients may experience falls, inanition, dysphagia, or aspiration and usually die 20 years post-diagnosis
• Motor skill decline and school performance issues manifest in juvenile Huntington's disease cases
• Individuals can display rigidity in the absence of chorea

Differential Diagnosis

• Huntington's disease diagnosis is straightforward with typical symptoms and family history.
• Dentatorubropallidoluysiatrophy and Huntington's disease-like 2 are phenotypically indistinguishable from HD.
• Other conditions to consider include tardive dyskinesia, chorea gravidarum, hyperthyroidism, Sydenham's chorea, and antiphospholipid antibodies relating to chorea.

Neuropathology

• Selective cell loss and atrophy occurs in the caudate and putamen
• Medium spiny neurons are most vulnerable

Clinical Genetics

• The HD gene is located on chromosome four and involves an expanded trinucleotide repeat.
• Normal alleles have <28 CAG repeats, fully penetrant alleles have >41 CAG repeats.
• Incomplete penetrance occurs with 36-40 repeats.
• The number of CAG repeats accounts for about 60% of the variation in age of onset.
• Trinucleotide CAG repeats that exceed 28 show instability on replication, more likely to expand.
• Instability is greater in spermatogenesis, causing new-onset cases to stem from expansion of the allele.
• Somatic instability of CAG repeats also happens in transgenic mouse models.
• Huntington's disease is often linked to familial inheritance, but those with no family history can carry it

Imaging

• Routine MRI and CT scans in moderate-to-severe Huntington's disease show loss of striatal volume and increased size of frontal horns of lateral ventricles.
• PET and fMRI studies indicate changes happening before symptom onset.
• Caudate atrophy can become apparent as early as 11 years before estimations.

Genetic fitness and Epidemiology

• Huntington's disease has a stable prevalence, impacting around 5-7/100,000 people.
• Populations with a traceable history to a few founders will be likely to have the disease.
• Differing results in race may come from the amount the populations intermarry.
• Genetic fitness reveals no consistent increase or decrease in the number of children that have the disease.

Huntingtin Protein

• Huntington's is expressed in all human and mammalian tissues with the highest concentrations in the brain and testicles
• The protein is expressed in low amounts with the liver heart and lungs as well.
• It is not believed that this disease affects the patient regarding cell function or inadequate production of a protein.

Mutant Huntington

• Mutant proteins have a toxic gain of function by leading to other human genetic disorders.
• The length of the gene indicates the severity of the disease, which is found to be the longest within juvenile patients.
• Research suggests there may be a faster rate of progression with longer CAG repeats for juvenile-onset cases.

Molecular Biology

• Findings suggest that aggregation rates increase along with the number of glutamine residues.
• Disease usually arises with 36 or more repeats, findings show a minimum of 37 consecutive residues
• The expressed proteins likely affect aggregation and their characteristics
• Huntington begins with polyglutamine
• It is not elucidated on how aggregation leads to selective neuronal dysfunction, but several key processes have been identified.
• Higher rates of proteolysis are shown with aggregate proteins
• Mutant huntingtin prevents cell degradation

Animal Models and Treatments

• Mutant huntingtin effects other mechanism and nuclear production, with cytoplasmic proteins to trigger primary neurotransmitters
• Many models are not directly related and are more specific to mitochondria

Treating Symptoms

• Seeking treatment is usually welcome because that means more support is available.
• Even though many will not show symptoms until the disease has progressed, people will delay their recognition until necessary for laboratory confirmation.
• Diagnosing should always be conducted with bedside manner for the best results.
• Research has not lead to much success in medical treatments.
• The ability to treat and treat the correct medications can help slow down the decline with movement disorders.
• All family should be available to seek comfort with counseling methods