This paper presents a multi-part case study of Huntington's disease (HD), a dominantly inherited neurodegenerative disorder caused by CAG trinucleotide repeat expansion in the HTT gene. Beginning with a clinical case presentation of a 45-year-old nurse with a familial HD history, the paper examines global prevalence and incidence, FDA pharmaceutical policy, genetic and chromosomal analysis, the single-gene autosomal dominant inheritance pattern, and implications for genomic health policy. Subsequent sections address nutritional challenges unique to HD patients — including weight loss, dysphagia, and caloric needs — along with nutritional assessment and counseling strategies. The paper also explores ethical issues surrounding presymptomatic genetic testing, advance directives, and family involvement in care decisions, and concludes with a framework for educating colleagues and patients about this progressive, currently incurable disease.
As Harper et al. (2000) note, "Huntington's disease (HD) was the first autosomal dominant disorder for which genetic prediction became possible" (p. 567). HD is a disease that occurs due to an inherited disorder leading to the death of brain cells. A diagnosis of HD is accomplished through genetic testing, which can be implemented at any age regardless of whether symptoms have manifested. Although the specific symptoms vary between individuals, they typically begin between the ages of 35 and 45, and can emerge even earlier in some cases. The disease may affect successive generations if health interventions are not implemented (Mandel, 2016).
Additionally, "the cause of HD is due to a dominant mutation of autosomal form of the gene called Huntingtin, which means that a child born to an affected person has a 50% chance of developing or inheriting the disease" (Liou, 2010, para. 2). Huntingtin genes manifest from genetic information, and the expansion of cytosine-adenine-guanine (CAG) in the Huntingtin protein leads to an abnormal protein that gradually damages the brain through a mechanism that is not yet fully understood (Liou, 2010).
Marilyn is a forty-five-year-old nurse whose father was diagnosed with HD at the age of forty-two. She had been experiencing subtle difficulties with mental abilities and mood, but did not consider these significant until she began having problems with jerky movements while writing. Recognizing that HD is a hereditary genetic disorder — and that "if a parent has the gene, each son or daughter has a one in two (50/50) chance of inheriting HD" (Liou, 2010, para. 2) — Marilyn became concerned about a possible familial connection to HD through her father. She must now find a way to discuss this with her daughter.
A review of HD reveals that its prevalence varies considerably across the world. Prevalence is very low among Black people in South Africa, at 0.5 per 100,000, and 1.84 per 100,000 among people in Zimbabwe. By contrast, HD prevalence is higher in North America, at 6.37 per 100,000 among African Americans and 4.9 per 100,000 among white populations. A low percentage of HD prevalence has been recorded in Japan, Hong Kong, and Taiwan, which is partly attributed to inadequate diagnosis of the disease (Rawlins, Wexler, Wexler et al., 2016).
Existing prevalence for HD in Asia is 0.42 per 100,000, and in Western Europe (excluding the UK) the rate is 0.53 per 100,000. The prevalence rate is comparatively high among Caucasian populations in the UK and Australia, at 9.71 per 100,000 (Rawlins et al., 2016). A reduced mutation rate among East Asian people has been identified as responsible for their lower prevalence. Notably, the prevalence rate in the United Kingdom more than doubled between 1990 and 2010, and there has been a 15–20% increase in HD prevalence in Australia, North America, and Western Europe between 1930 and 2012 (Rawlins et al., 2016).
The rise in HD prevalence in North America, Australia, Western Europe, and the United Kingdom has been attributed to higher rates of diagnosis, as physicians have developed greater knowledge of the disease, leading to increased diagnosis among older adults. Pringsheim et al. (2012) support this view, noting that HD is less common among Asians compared to people in North America and Western Europe. Furthermore, "although there is an unusually rare juvenile form of the condition, HD usually presents in early middle life with abnormal movements (particularly chorea) together with psychiatric symptoms including psychosis, depression, and obsessive-compulsive disorder, along with progressive cognitive impairment" (Rawlins et al., 2016, p. 144).
Recent estimates place the incidence of HD at approximately one in every 10,000 individuals in the United States, meaning that roughly 30,000 people suffer from the disease in this country today (Swierzewski, 2015).
Chromosomal analysis is indicated for the confirmation of diagnosis and for addressing issues related to the patient's children and grandchildren. Huntington's disease (HD; MIM 143100) is a dominantly inherited, gradually progressive neurodegenerative disorder caused by a mutation that leads to expansion of the CAG polymorphic trinucleotide tract in the HTT gene. In ordinary individuals, the size of the CAG repeat normally falls between 17 and 20 repeats. In HD patients, one or two duplicate genes carry an expanded CAG tract of at least 36 repeats (Kremer et al., 1994).
The size of the polymorphic trinucleotide tract can be unstable and is more likely to expand, particularly when transmitted through a male germline. Initially, the new mutation rate for Huntington's disease was estimated to be extremely low, and the illness was believed to affect only families with a known history of HD. Current estimates have shown that expansion of CAG into the disease range is more common than previously predicted, with the new mutation rate estimated to be at least 10% (Warby et al., 2009).
Many factors are believed to contribute to CAG instability, including CAG tract size, interruptions within the CAG tract, the age and sex of the transmitting parent, environmental factors, and genetic trans-factors and cis-elements. A larger CAG tract and transmission via a male germline are clearly associated with greater CAG instability. Trans-factors such as DNA mismatch repair machinery have also been identified as major contributing factors. For example, CAG instability in transgenic HD mice was reduced after crossing with mice lacking MSH2 (MIM 609309), a mismatch repair enzyme, or OGG1 (MIM 601982), a base excision repair enzyme. Although cis-elements are believed to modify CAG instability in different genes, prior evidence suggests that cis-elements do not play a role in CAG instability in HTT (Warby et al., 2009).
Multiple studies have examined the origins of HD by constructing haplotypes for the HTT region in specific tribal populations. Most of these studies identified positive associations between disease chromosomes and specific markers, and concluded that HD mutation shares common descent but does not necessarily originate from a single founder (Warby et al., 2009).
HD is an autosomal dominantly inherited disease caused by an elongated CAG repeat found on the short arm of chromosome 4p16.3, within the Huntingtin gene. This gene contains Huntingtin protein codes and carries CAG tracts in exon 1. In wild-type individuals, the CAG repeat encodes a polyglutamine stretch of between 6 and 16 residues in the available protein. The disease is associated with at least 36 repeats.
Definite clinical appearance occurs when repeats exceed 40. A range of 36–39 causes incomplete penetrance of Huntington's disease or leads to late onset. At 29–35 repeats, intermediate alleles are unstable and likely to change during reproduction, with elongation occurring more frequently than shortening. This process occurs predominantly in male reproduction (Roos, 2010).
The lifespan of a Huntington's disease patient can be categorized into three phases: at-risk, Stage A (preclinical), and Stage B (clinical). The at-risk phase ends once it is established whether the patient carries the expanded CAG repeat on the fourth chromosome. If the patient carries the gene, they will progress through Stages A and B until the end of life (Roos, 2010).
HD is caused by a single abnormal allele transmitted from a carrier parent to a child in an autosomal dominant pattern (Swierzewski, 2015). Research examining the relationship between symptomatology (chorea vs. rigidity) and age of onset in HD used data gathered from the Huntington's Disease Victims and Families Research Roster. The research found that age of onset differs among families and between maternal and paternal transmission. Rigidity was specifically associated with very early onset, paternal transmission, young parental onset age, and marked anticipation. It has been suggested that age of onset depends on the methylation state of the disease locus, which differs among familial traits — a phenomenon attributed to genomic imprinting that varies by parental transmission. Early familial onset age and male parental imprinting can interact to produce a substantial change in gene expression, resulting in the rigid or early-onset variant (Ridley, Frith, Farrer, & Conneally, 1991).
Genomic methylation differences have been proposed as a cause of the variation in onset age observed in HD cases, depending on which parent transmitted the HD allele. Genomic imprinting differences may also contribute to differences in symptomatology. The later HD onset age observed in the offspring of affected mothers, compared with affected fathers, has been associated with a protective maternal factor. While some researchers have suggested this factor may reside in the mother's mitochondrial DNA, maternal genomic imprinting may also contain it (Ridley et al., 1991).
The HTT (Huntingtin) gene (NM_002111.6; NG_009378.1), previously designated IT15, is located on chromosome 4p16.3, contains 67 exons, and spans approximately 180 kb. The Huntingtin gene is broadly expressed and is required for normal human development. It is expressed in two alternatively polyadenylated forms that show differing relative abundance across adult and fetal tissues. The larger transcript is approximately 13.7 kb and is predominantly expressed in the fetal and adult brain, while the smaller transcript of approximately 10.3 kb is expressed more widely (Losekoot, Belzen, Seneca, Stenhouse, & Barton, 2013).
HD is brought about by the expansion of an unstable polymorphic CAG trinucleotide in exon 1 of the HTT gene, leading to a polyglutamine tract extension within the protein. Alleles containing more than 27 CAG repeats are considered normal, while those with 36 or more repeats are found in HD patients. Currently, the fewest CAG repeats reported in patients with confirmed clinical HD features is 36. Alleles containing between 27 and 35 repeats (intermediate or mutable normal alleles) are not associated with disease symptoms, but can expand into the pathogenic range following predominantly paternal germline transmission, thereby causing HD in offspring. CAG repeats between 36 and 39 are partially penetrant and can be observed in both affected individuals and those who remain asymptomatic until old age (≥70–80 years). The number of CAG repeats inversely correlates with the average age of symptom onset: individuals with longer CAG repeats generally have earlier onset. People with very large CAG repeats (≥60) tend to develop juvenile HD, while those with shorter repeats (36–39) may remain asymptomatic for many years. Nonetheless, repeat length accounts for only approximately 70% of variance in onset age, meaning that not every case of juvenile HD involves ≥60 CAG repeats (Losekoot et al., 2013).
Although the precise mechanism by which the HTT gene mutation affects protein function is not fully understood, HD is clearly an inherited genetic disease caused by a mutation transmitted from a carrier parent. Research by Saey (2010) also suggests that while HTT mutations are the primary driver of HD onset, other genes may contribute to disease onset and progression. Ongoing research continues to examine how gene mutations in DNA cause HD and other diseases such as sickle-cell anemia and cystic fibrosis.
"FDA drug policy, research grants, and family caregiving"
"Weight loss, dietary needs, and nutritional counseling for HD"
"Presymptomatic testing ethics, privacy, and genomic policy"
"Current treatments, advance directives, and patient education"
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