Title of article: Huntington’s Disease
Author: Omar AL Khateeb
Editor: Ethar Hazaimeh
Keywords: Chorea, tremor, dementia, congenital, depression, movement.

Overview

The name Huntington was coined for a great share of aspects, however, it also refers to a “crippling” disease, “no pun intended”.
Huntington’s disease (HD) is a rare, genetic condition that causes nerve cells in the brain to break down (degenerate) over time. This disease usually disrupts the patient’s life with physical and mental disorders. Huntington’s disease (HD) is named after George Huntington, who described it as hereditary chorea among residents of East Hampton, Long Island in 1872 [2]. It eventually causes jerky or uncontrollable movements, medically known as chorea. It progressively worsens over time and is fatal after up to 20 years. Usually, it appears at ages between 30 and 50. If appearing at lower ages, then we would refer to it as Juvenile Huntington’s disease. Even though Huntington’s is treatable, the treatments will not prevent the decline of mental, physical, and behavioral symptoms associated with this disease, Figure (1).

 

Etiology and epidemiology

A mutation in the gene for the protein huntingtin causes Huntington’s disease. The deficiency causes the DNA building units cytosine, adenine, and guanine (CAG) to repeat several times more than they should [4]. Since it’s an autosomal dominant disorder, a person would need only one copy of the defected gene to develop the disorder. “The defect causes the cytosine, adenine, and guanine (CAG) building blocks of DNA to repeat many more times than is normal” [4]. Moreover, the mutation is caused on a gene on the 4th chromosome. The more the CAG repeats, the sooner the onset and the greater is the phenotype. The clinical picture seen in cases with HD can be explained by selective neuronal malfunction and subsequent death of neurons in the striatum, cerebral cortex, and other areas of the brain [5].

The involvement of local cortical and striatal microcircuits still remains greatly unexplored. Moreover, when the father passes the mutation down through the generations, the number of CAG repeats might grow, leading to increasingly severe phenotypes within a family (called anticipation) [1]. Figure(2).

 

Unfortunately, precise estimates of HD are not available, yet it varies from one county to the other. A founder effect appears to have resulted in an extremely high frequency of HD in a few isolated groups of western European heritage [5]. “These include the Lake Maracaibo region in Venezuela (700 per 100,000 people) [12], the island of Mauritius off the South African coast (46 per 100,000 people), and Tasmania (17.4 per 100,000 people). The prevalence in most European countries ranges from 1.63-9.95 per 100,000 people. The prevalence of HD in Finland and Japan is less than 1 per 100,000 people [5]. The majority of studies reveal that the average age of onset is between 35 and 44 years old. However, the age range is wide, ranging from 2 years to over 80 years. It is uncommon for symptoms to appear in people less than 10 years old or older than 70 years old. When compared to Americans (37.47 years) and Canadians (34.35 years), Venezuelan relatives have a younger mean age of onset (34.35 years) (40.36 years). In these distinct populations, changing genes and environmental factors are hypothesized to alter the age of onset[5].

Symptoms and signs

The onset of symptoms varies from person to person. Some people experience depression first and then changes in motor skills. Mood swings and abnormal behavior are common early signs[6]. As we said, symptoms can appear at any age. Some of the key symptoms are:

•  Mood and personality changes
•  Depression
•  Memory, thinking, and judgment problems
•  Difficulty in swallowing and speaking
•  Loss of coordination and control over movements [6].

Sadly, if none of the family members haven’t been previously diagnosed, doctors may not be able to recognize the early symptoms of Huntington’s disease.

Early signs and symptoms include:

• Slight uncontrollable movements and stumbling
• Small changes in coordination
• Slight emotional changes
• Difficulty focusing
• Lapses in short term memory
• Depression
• Irritability
• Losing motivation and focus
• Lethargic

One of the common signs is forgetting common information or people’s names. Yes, this is a common appearance in many healthy people, but it appears more severe in patients with HD [6]. In later stages of the disease, we can notice more physical, emotional, and cognitive changes.

Physical changes:

•  Slurring and problems with finding words
•  Weakness and weight loss
•  Difficulty with eating and swallowing and risk of choking (mouth and diaphragm muscles lose function).
•  Uncontrollable movements such as jerking of the head and face
•  Fidgety movements of arms, legs, and body
•  Rigid muscles
•  Stumbling [6].

Emotional changes:

• Aggression
• Antisocial
• Apathy
• Mania
• Frustration
• Lack of emotion
• Moodiness
• Low organizational skills and difficulty focusing
• Can’t multitask

According to the Huntington’s Disease Society of America (HDSA), cognitive abnormalities such as disinhibition and impulsivity raise the likelihood of suicide in people with Huntington’s by up to ten times the national average. It is suggested that loved ones and caregivers of people with the disease be aware of the warning signals of suicidal ideation [6]. As we can notice, the farther we progress, the more the patient loses his ability to move. Alas, in later stages, patients will lose the ability to move or talk and will probably need a full-time nurse. However, they will still be able to hear and understand their loved ones to some extent.

Investigations: 

A neurologist will have to rule out other illnesses that cause similar symptoms and confirm that the patient has Huntington’s. The following tests are blood testing, genetic testing, neuroimaging like MRI [8].

• Blood Testing:

Thanks to the continuous and extensive medical research on Huntington’s disease, a simple blood test developed by University College London (UCL) and University College London Hospitals (UCLH) researchers can detect early physiological abnormalities induced by Huntington’s disease. The researchers developed a toolkit that can evaluate two early biomarkers of Huntington’s disease in blood and brain fluid during the most recent investigation, which involved 40 participants [13]. According to Ed Wild, a consultant neurologist at UCLH, the biomarkers are the neurofilament light (NFL) which is a protein associated with nerve damage, and the disease-causing mutant huntigton (mHTT). He added that the blood test can detect the prodromal stage of Huntington even before imaging does [13]. The prodromal stage refers to the earliest symptoms of Huntington, which are changes in mood and coordination. Though the blood test still needs more research, it would be a key to developing a drug that cures Huntington’s.

• Genetic Testing:

There are a couple of genetic tests done to diagnose Huntington’s disease. They include diagnostic, prenatal, and predictive or pre-symptomatic investigations. The latter is usually done if Huntington’s disease runs through the family. All these tests are usually ordered by a genetic counselor.

The genetic test identifies the number of CAG repeats in the HTT gene. A normal HTT gene has 26 or less CAG repeats and is not linked to the development of Huntington’s disease. The number of CAG repeats in a HTT gene is classified into 3 subtypes. “Full penetrance or HTT positive” means that the patient has 40 or more CAG repeats. Alas, Huntington’s disease is quite likely to strike the individual at some point in their lives. The longer the CAG repeat region, the earlier the illness manifests itself. “Reduced penetrance” shows the patient having 36 to 39 CAG repeats. In this case, it is impossible to determine whether or not the individual would get Huntington’s disease. Lastly, “Intermediate” describes an HTT gene with 27 to 35 CAG repeats. The person will not get Huntington’s disease in this situation. An HTT gene with an intermediate number of CAG repeats, on the other hand, is unstable, and the number of repeats may rise as the gene is passed down through the generations. As a result, there’s a chance that the condition will spread to future generations [14].

Prenatal testing may be recommended for a woman who has Huntington’s disease or has a family history of the disease. It is also divided into 3 different tests: chronic villus sampling, amniocentesis, and pre-implantation genetic diagnosis. Chronic villus sampling is possible to be done between the 10th and 14th weeks of pregnancy. A little sample of the chorion, the uterine lining that subsequently develops into the placenta, is taken for this test. Amniocentesis is done during the 15th to 20th week of pregnancy. For the test, a little sample of amniotic fluid is obtained. Pre-implantation genetic diagnosis is a sort of prenatal testing that involves the genetic testing of embryos created through in vitro fertilization before they are put into the uterus [14].

• Neuroimaging

The caudate, putamen, and globus pallidus show bilateral atrophy on MRI. This is especially noticeable in the caudate nucleus, which is the most commonly affected area of the brain. The combination results in enlargement of the frontal horns, often giving them a “box” like configuration.

• Frontal horn width to intercaudate distance ratio (FH/CC)
• Intercaudate distance to inner table width ratio (CC/IT)

Both of these ratios are useful in younger patients with suspected Huntington’s disease and become abnormal before the caudates appear abnormal to visual inspection alone (16).

 

Management 

There is still no cure for Huntington’s disease, nor is there any method to prevent it from progressing. However, treatment and support can help to alleviate some of the issues brought on by the illness. Medicines can help alleviate some of the symptoms of Huntington’s disease, but they do not cure or delay the disease [10].

Firstly, Tetrabenazine (Xenazine) and deutetrabenazine (Austedo) are two drugs that have been licensed by the Food and Drug Administration to treat uncontrollable jerking and writhing motions (chorea) associated with Huntington’s disease.

Secondly, Antipsychotic medications including haloperidol (Haldol) and fluphenazine inhibit mobility as a side effect. As a result, they may be useful in the treatment of chorea. Treatment for psychiatric disorders can vary depending on the symptoms. However, doctors usually prescribe antidepressants, antipsychotics, and mood-stabilizing drugs.

Also, a psychotherapist can help with behavioral issues, coping methods, managing expectations as the disease progresses, and facilitating good communication among family members through talk therapy. Speech, physical p, and occupational therapies can be used to improve the life of a Huntington patient[1].

Complications

The complications are severely dangerous. HD has endless symptoms, but ultimately they don’t cause death. The complications do! Two of the leading causes of death are pneumonia and suicide, respectively. Twenty-five percent of patients make an attempt to take their own lives. Also, complications of immobility, such as pneumonia, heart problems, or infection, are frequently the cause of mortality. Larger amplitude chorea might result in damage and poor placement. Fractures and head injuries are other possible outcomes. Behavioral problems can be extremely debilitating, generating stress not just for the patient but also for their family and carers [12].

References...