Legacy of Huntington’s

Huntington’s Disease, or for short HD, is a subject that is discussed in my family with a great deal of trepidation. It is a family legacy, which has plagued generations, and for the most part was feared. 

Some background

I can vividly remember seeing my mother sitting in our dining room in total despair, overly tired and totally dejected, still grieving the death of my grandfather, barely managing the farm and caring for my grandmother. This was early 1980. My grandmother at the age of 58 needed fulltime care. Doctors were at a loss as to a diagnosis, but agreed that she was becoming a danger to herself. She sustained heavy burns, when she “forgot” to add cold water to the dish washing water; had to be strapped in when transported because she would randomly attempt to get out of the fast moving car seemingly completely unaware of the dangers of doing so at high speed and sustained various serious bruises from bumping into things. After being hospitalized for tests, she one night climbed out of the second story window of the hospital (miraculously she did not sustain any serious injuries), and was found wandering the hospital garden completely unaware of her whereabouts or her less than desirable attire, the doctors finally understood the need for serious action. Up to that point her symptoms were coming and going unpredictably, which made it hard for the doctors to understand the extent and seriousness. Uncharacteristic to the normal progression of the disease, she did not exhibit chorea until much later. At first, her symptoms resembled those of Alzheimer’s and one doctor suspected a problem in the hippocampal area. She was placed in a psychiatric facility for observation. There she was finally diagnosed with HD. It was a huge relief to the family to finally having a name for the disorder. She was transferred to a 24-hour care facility specifically for elderly patients with Parkinson’s, HD, dementia, etc. where she stayed the final 10 years of her short life. Her suffering and slow decline was hard to witness. Mercifully, the last few years she was believed to be unaware of herself, her suffering or her surroundings. She was not much more than an empty shell. Although it was merciful for her not to be aware, it did not make the witnessing of the decline or her death any easier on the family. Without a living will, her death was a long drawn-out process lasting weeks and involving several resuscitations.

What is HD

HD is an uncurable, fatal neurodegenerative disorder, which is caused by a mutated Huntingtin gene found on the short arm of chromosome 4. The mutated Huntingtin gene contains an extended repeat (longer than 36 repeats) of the trinucleotide combination cytosine-adenine-guanine (CAG), which results in the production of the altered form of the Huntingtin protein.

 HD that is autosomal dominant. This means that a child of a person with the mutated Huntingtin gene has a 50% change to inherit the gene. If the number of CAG repeats are between 27 and 35, the person won’t be affected by HD, but offspring may inherit the gene and since CAG repeats may increase from generation to generation, is still at risk to develop symptoms of HD (called genetic anticipation). This risk of developing HD is less than 50%. Persons with 36 to 39 CAG repeats show reduced penetrance HD, and may or may not develop HD symptoms. Offspring of the persons with reduced penetrance have a 50% chance to inherit the mutant Huntingtin gene and to develop symptoms of HD. More than 40 CAG repeats are associated with full penetrance HD (development of symptoms are certain).

Higher CAG repeats are associated with earlier onset of symptoms (under the age of 20), more severe symptoms and faster deterioration.

Huntingtin protein’s functions and effects of the mutated protein

 The Huntingtin’s protein interacts with more than 100 other proteins, many found in the brain. The Huntingtin’s protein concentration is the highest in the brain and testes, but also found in moderate amounts in the heart, lungs and liver. It is believed that the Huntingtin’s protein is involved in transcription, cell signaling and intracellular transportation. 

The mutated Huntingtin’s protein is toxic to cells, especially specific types of neurons or neurons found in specific brain areas. So even though the whole brain is affected certain areas are more sensitive. The mutated Huntingtin’s proteins tend to clump together (protein aggregation) to form inclusion bodies within neurons. These inclusion bodies e.g. mechanically stop the release of neurotransmitters by blocking the vesicles containing the neurotransmitters, which results in less and less neurotransmitters are released over time.

In the striatum (in the basal ganglia) the mutated Huntingtin’s protein interacts with the Rhes protein, which enhances the cytotoxic effects of the mutated Huntingtin’s protein.

In the mutated Huntingtin’s protein makes the mitochondria (powerhouse of neurons) of striatal neurons more sensitive to glutamine. Excessive amounts of glutamine are excitotoxic. Even though there is no increase of glutamine in HD, the increased sensitivity to glutamine mimics the effects of excess glutamine. 

Specific brain effects of HD

The spiny striatal neurons are the most vulnerable to the toxic effects of the mutated protein. Thus, one of the first brain areas to be affected by HD is the striatum in the basal ganglia. This damage and atrophy in the basal ganglia leads to uninhibited, random and uncontrollable movements (called chorea, which means “dance”). At first this may appear as general restlessness, lack of coordination and slow saccadic eye movements, but progress to severe motor dysfunction including writhing and abnormal posturing. The damage to the basal ganglia together with the cerebellum and layer 5 of the cortex leads to pervasive motor difficulties. The damage to the purkinje cells in the cerebellum leads to the characteristic high stepping gait, intention tremors (not to be confused with the resting tremors found in Parkinson’s), difficulty with judging distance and space (thus bumping into or tripping over things) and the lack of the menace eye reflexes. The motor difficulties also effects facial expressions, swallowing and speaking. Swallowing and coordinated eating may become so affected that malnutrition is a common consequence of HD. 

Other brain areas affected include the hypothalamus. The main symptoms seen as a result of the damage and atrophy of neurons in the hypothalamus are disturbed sleeping patterns, problems with breathing, and urination. Because the mutated protein is also toxic to the cells in the lungs, many HD patients suffer and eventually die from respiratory illnesses. The same is true for heart and liver cells.

Damage and atrophy of neurons in the hippocampus leads to memory loss and decreased spatial navigation. This is referred to subcortical dementia to differentiate it from Alzheimer’s. Patients can often recall more reinforced episodic memories, but have trouble with more recent less reinforced episodic memories and semantic memories. Working memory seem to remain intact to some extent, but transfer of information from working memory to declarative memory is usually affected.

HD also affected the thalamus and the cortex (layers 3, 5 and 6). This leads to problems with executive functions, such as concentration, re-directing attention and rule acquisition. Patients struggle to follow or focus their attention on any one thing for longer than a few seconds, and have trouble with abstract thinking.

Genetic testing

Genetic testing brought a freedom of choice to my family. We had a choice to find out whether we are likely to develop HD or not. Testing also brought a heavy burden. Do you want to know that somewhere in the age range of 45-55 you will slowly develop an absolutely devastating neurological disease for which there is no cure and no relief until you finally pass away from lung  disease, malnutrition or heart failure 10-15 years later? For me my choice was simple: my chances of testing positive was low, because my mother is asymptomatic and only a carrier of the gene mutation at its very least penetrative. I knew it does not rule out that I might become symptomatic due to genetic anticipation. But I am not at risk to develop full-blown HD.

 As I sat waiting for my results, in a near panic (why, I knew the odds beforehand?), I could not help to think about my cousins whom already experienced direct family members develop full penetrative HD. Would they want to know? As it turns out 50% did want to do the genetic testing and 50% did not. The most interesting about their choices were that my cousins living in countries/areas where euthanasia/assisted suicide are legally practiced all got tested, and those that don’t all didn’t want to know.

Euthanasia or assisted suicide is an ethical dilemma I feel no human being, medical professional or not, wants to face. On the one hand there is the argument that why do we treat animals more humanely than humans. But there are also many counter arguments. Does any human have the right to take the life of another human (with or without their consent)? There are many religious arguments. There are many emotional and social factors for those left behind to take into consideration. I been trying to put myself in the shoes of someone facing HD or another debilitating neurocognitive disease and wondering would I choose euthanasia, if it was available to me? I really don’t know. I can only hope I would have the humanity to respect the choices others make.

I would love to hear opinions from others on these matters.

Caution: These are my personal opinions and does in no way reflect those of any organisation I am affiliated with.