HTT & Its CAG Repeats

The scenario:  You are faced with a genetic dilemma. Your maternal grandfather died at age 65 of a known, inherited neurodegenerative disease. The HTT gene, that when

containing extra CAG repeats, encodes this disease. Currently, there is no cure for this disease. Presence of the repeat is easily detected by genetic testing. You have 3 other siblings: a brother who is 30, a brother who is 15, and a sister who is 18. What should one do? What are the basics one should know of the HTT gene and its incurable disease? 

Upon finding out that my maternal grandfather died at the age of 65 of a known, inherited neurodegenerative disease, I would inform my siblings that he died from Huntington’s disease that is caused by CAG expanded repeats in the exon 1 region of the HTT gene. This region encodes for a polyglutamine tract that starts from the N-terminus, which is located 17 residues away (Kraub 2013).

The Huntington Disease and Patient Counseling

The HD is a neuro degenerative genetic disease. It is characterized by lack of coordination and involuntary movements. Cognitive problems appear in later stages of disease and patients’ quality of life deteriorates up to the point where they need 24 hour assistance. Depression is common among people suffering from the disease. 

The Genetic Disorder and Mechanisms of Disease

This genetic defect on chromosome 4 causes excessive CAG repeats. Usually this repeat occurs 10 to 28 times, however those with this defect causes CAG to be repeated 36 to 120 times. (URAC 2013) This disease is characterized by progressive neuronal cell death. It progresses over time becoming fatal which lead to his death. It is a disorder passed down through families in which parts of the brain degenerate. (URAC 2013)

HD is inherited as a dominate trait so those who inherit homozygous HTT have similar signs as with those who are heterozygote for HTT including the symptoms, signs, or age of onset. (Kraub 2013)

Although in most cases the age of onset is 35 to 50, it is inversely correlated with the length of CAG expanded repeats. The CAG repeats bind to translation regulatory protein complex containing MID1, protein phosphatase 2A and 40S ribosomal S6 kinase. These repeats are translated into elongated polyQ stretches (Tobin 2000).

The size of the CAG repeat grows when MID1 binds to protein phosphatase 2A protein complex. This also stimulates the translation of the CAG expansion, protein phosphatase 2A and mammalian target of rapamycin- dependent manner. The MID1 complex may serve as a therapeutic target for the treatment of CAG repeat expansion. (Tobin 2000)

The higher the repeat numbers the lower the ages of onset for individuals. Those with 35 repeats of HTT or fewer do not develop HD. Individuals with 35 to 39 repeats may or may not develop Huntington’s disease. Repeats of 40 to 60 develop into HD when the individual reaches adulthood. In more severe cases, people who have 60 or greater repeats have onset before 20 years of age. (Kraub 2013)

Symptoms of those living with HD show altered energy metabolism in brain and muscle. (Kraub 2013).

Clinical symptoms and Quality of Life

Huntington’s disease causes motor, cognitive, and behavioral dysfunction. Choreatic movements are usually the first sign of Huntington’s disease. These are irregular, unpredictable, purposeless, rapid movements that flow randomly from one body part to another. The first signs also include motor dysfunction of the toes, fingers, and face. Eye movement abnormalities soon follow with slow saccades. (Tobin 2000)

It is relentlessly progressive where death occurs 15-20 years after symptom onset. Juvenile onset includes symptoms such as seizers, and rapidly progressive dementia. (Tobin 2000)

Diagnosis and Treatment

The treatment of HD consists mainly in treating and alleviating the symptoms and trying to preserve the quality of life as long as possible. The goal is to slow down the symptoms and help the person function and live a normal life. Supervision and treatment (such as DOPA blockers which aid in decreasing abnormal behaviors and movements) might be needed since depression and suicide are very common among person with HD. (URAC 2013)

Epidemiology and Prevention

The risk of getting HD from one parent suffering from HD is 50 percent. Inheriting the HTT gene from a parent will guarantee that the child will develop the disease at some point in their lives which will be passed on to their children. (URAC 2013)

Although there is no cure or no way to stop the disease from getting worse, it is crucial for family members to have their DNA tested for HD because as the gene is passed down through family generations, the number of repeats get larger and the risks of developing HD symptoms at a younger age increases. (URAC 2013)

For my brother that is 30 years of age, will develop symptoms in his mid 30s and 40s. This is the most common form of HD which is in adult onset. (URAC 2013)

For my 18 year old brother and 15 year old sister, it will be less likely that they will develop early onset form of HD there are only a small number of cases that begins in childhood or 

adolescence. (URAC 2013)

Once I have informed my siblings of our grandfather’s disease, I would encourage them to get tested and screened for risk of developing HD.

If any of my siblings were to have high risk or have the disease I would encourage them to get supportive counseling after the DNA testing whether or not they are symptomatic.

It is difficult to take the right steps in the pathogenic pathways of HD since there is no cure for the disease, as of yet. There are however, therapeutic interventions that target early steps in a pathogenic chain of events of those with HD. I would make sure that they are well informed and supported throughout the process.

Kraub, Syllibe, Susann Schweiger, Erich Wanker, Stephanie Dorne, Rainer Schneider, Nadine Griesche, Ewa Jastrzebwa, Desiree Rutschow, and Changwei Chen. "Translation of HTT MRNA with Expanded CAG Repeats Is Regulated by the MID1–PP2A Protein Complex." Translation of HTT MRNA with Expanded CAG Repeats Is Regulated by the MID1–PP2A Protein Complex (2013): 1723-2041. Nature. 26 Feb. 2013. Web. 10 Oct. 2013.

Tobin, Allan J., and Ethan R. Signer. "Trends in Cell Biology - Huntington's Disease: The Challenge for Cell Biologists." Huntington's Disease: The Challenge for Cell Biologists 10.12 (2000): 531-36. Trends in Cell Biology - Huntington's Disease: The Challenge for Cell Biologists. Web. 9 Oct. 2013.

URAC. "Huntington's Disease: MedlinePlus Medical Encyclopedia." Huntington's Disease (n.d.): n. pag. Medline Plus. U.S. National Library of Medicine, 22 Mar. 2013. Web. 11 Oct. 2013.

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