Structural Biochemistry/Huntington's Disease

Overview

Huntington's disease is an autosomal dominantly inherited disease characterized by slowly progressive neurodegeneration associate with abnormal and involuntary movements. It also affects muscle coordination and ultimately leads to cognitive decline and psychiatric problems. This disease tend to be more common in Western European people than Asian or African people. Any child of an affected person has a 50% change of inheriting the disease.

File:Huntington brain.jpeg

A brain affected by Huntington's disease compared to a healthy brain

Cause

Huntington's disease occurs when there is a mutation leading to unnecessary repeats of three nucleotides, also called trinucleotide repeats. The trinucleotide is the sequence CAG, and is caused by a specific genetic defect on chromosome 4. The trinucleotide sequence repeats many more times than necessary, ranging from 36-120 times. A normal individual unaffected by the disease only has repeats the trinucleotide 10-28 times. The accumulation of the trinucleotide repeats cause Huntington's because the polyglutamine stretches become increasingly prone to aggregation as their lengths increase.

Genetics

All humans have two copies of the Huntingtin gene (HTT or HD). This gene codes for the protein Huntingtin (Htt). Huntington's Disease is caused by the expansion of a CAG trinucleotide repeat in the first exon of the HTT. The HTT is composed of 67 exons and generates two mRNAs that differ in the length of their 3' untranslated regions. When the length of this repeated section reaches a certain point, it produces an altered from of the protein called mutant Hungtingtin protein (mHtt). When an individual inherits one copy of the gene with an expanded trinucleotide repeat from an affected parent, he or she will also be affected by the Huntington's Disease. Each offspring has a 50% change of inheriting the mutant allele. In some cases when both parents have the mutant gene, the possibility increases to 75%. When one parent had bas both the mutant gene, there is a 100% chance of the offspring to inherit the mHtt.

There are two forms of Huntington's disease:

Adult-onset Huntington’s disease(most common), individuals with this form usually develop symptoms in their mid 30s to 40s

Early-onset: form of Huntington disease where symptoms begin in childhood or adolescence – it is found that there are only a small number of cases of this form.

Mechanism

The Htt gene is expressed in all mammalian cells especially in the brain and testes. The function of Htt in humans is unclear. the Htt interacts with proteins that are involves in transcription, cell signaling and intracellular transporting. In animals, Htt is importnat for embryonic development. Without the Htt, embryos tend to die.. Htt also acts as an anti apoptotic agent and prevents cell death. In addition, there are cellular changes through which the toxic function of mHtt produces the Huntington's Disease pathology. During the modification of mHtt, cleavage of the protein can leave shorter fragments of the polyglutamine expansion. Because glutamine is polar, it causes interactions with other proteins when overabundant in Htt proteins. therefore, the mHtt molecules form hydrogen bonds with each other, resulting in a aggregate protein.

Symptoms

Behavioral changes may occur, usually before movement problems. These include behavioral disturbances, irritability, hallucinations, moodiness, restlessness or fidgeting, psychosis and or paranoia.

Abnormal and unusual movements such as: facial movements (i.e. grimaces), head turning to shift eye position, sudden jerking movement of limbs, face and other body parts, slow, uncontrolled movements, and or unsteady gait.

Those affected by Huntington's disease may also develop dementia. Once symptoms of dementia develops it will slowly get worse and an individual will gain disorientation or confusion, loss of judgement, loss of memory, personality changes and speech changes.

Additional symptoms may also occur that may be associated with Huntington's such as: anxiety, stress, tension, difficultly swallowing and speech impairment.

Other symptoms may occur more frequently in children such as rigidity, slow movements, and tremors.

Diagnosis

Genetic testing can be used to confirm a physical diagnosis if there is no family history of Huntington's Disease. The genetic test can confirm if an individual or embryo carriesan extended copy of the trinucleotide repeat in the HTT gene. Because Huntington's Disease is an autosomal dominantly inherited disease, medical professionalists strongly recommend individuals who are at risk to seek a diagnosis. The genetic test consists of a blood test which counts the number of CAG repears. Excessive unintentional movemnts in any part of the body are often why people seek medical consultation. Cognitive and psychiatric symptoms are rarely the first diagnosed. they are usually only recognized when the disease develops further. CT and MRI can show the atrophy of caudate nuclei in the disease. A pre-symptomatic test can be a very personal decision. Over 95% of individuals at irisk of inheriting Huntington's Disease do not test because there is no treatment for this disease. Some take the test because of the anxiety of not knowing, but the risk of suicide is procen to be higher after a positive test result. Some who found out that they have not inherited the disorder experience survivor guilt regards to family members who are affected.

Management

Currently, there is no cure for Huntington's Disease. There are treatments to reduce the severity of the symptoms. As the disease progress, the ability to care for oneself declines and a caregiver becomes necessary. There has been some usefulness in physical, occupational, and speech therapy. The involuntary movements, or chorea, is treated by tetrabenazine. Although it helps reduce chorea, many drugs are still under investigation. Psychiatric symproms are treated with medications that are used in the general population. Depression medications and long term neuropsychiatric treatments are combined to treat these symptoms. Life expectancy in Huntington's Disease is about twenty years after the visible symptoms. Most life-threatening complications come from muscle coordination and decline in cognitive function. Pneumonia, heart disease and suicide are some big causes of death in those with the disorder.

References

1. http://themedicalbiochemistrypage.org/huntingtondisease.php
2. PubMed Health: Huntington's disease. 2011. <http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001775/>
3. http://commons.wikimedia.org/wiki/File:Huntington_brain.jpeg
4. Berg, Jeremy M.; Tymoczko, John L.; Stryer, Lubert. Biochemistry. 7th ed. W.H. Freeman and Company: New York, 2012.