Huntington’s Disease – A Condensed Overview

Medium Spiny Neurons

Huntington’s disease is a rare neurodegenerative disorder that plagues families. The culprit responsible for Huntington’s is a trinucleotide (CAG) repeat expansion within the huntingtin (HTT) gene [ii]. A trinucleotide repeat expansion is when the machinery responsible for DNA replication slips while writing which leads to repetitive DNA sequences. If the machinery slips while its writing an exon portion of the DNA, which are the coding regions, a disease will occur [i]. In the case of Huntington’s, the slippage occurred with the HTT gene resulting in several CAG repeats within this gene. CAG codes for glutamine which is one of most versatile amino acids. It is used in a wide range of metabolic functions and is an energy source for the nervous system [iv]. Due to mistake happening in an important part of the genes, this disease is autosomal dominant and it becomes a 50/50 chance for future family members to inherit Huntington’s with just a few repeats. This can be determined with genetic tests and can be done prenatally for high risk families [i].

The pathogenesis of Huntington’s is dependent on two components [iii]. The onset of Huntington’s is determined, in part, by the length of the inherited CAG repeat. The longer the length of these expansions, the earlier the age of onset for motor symptoms [v]. The second component involved in the pathogenesis are the modifier genes involved with DNA maintenance. If this component is affected, it will lead to more cellular damage. However, if the modifier is not affected, then it will never allow the CAG length to exceed the threshold, therefore resulting in no damage occurring to the patient during their lifetime [iii].

Patients affected with Huntington’s show signs of involuntary movements in the distal extremities first, such as the fingers, toes, and small facial muscles. Their walking will become unstable and eventually they will experience choreatic movements constantly while awake. Chorea is a movement disorder that results in involuntary and irregular muscle movements. This diagnosis itself is not life threatening however it can be a sign of a neurological disease, in this case, Huntington’s [vii]. In the late stages of this disease, the patient has difficulty swallowing and talking, sometimes leading them to become completely mute. In hand with chorea, affected individuals will experience hypokinesia which is diminished motor activity. The balance between chorea and hypokinesia depends on the individual. Cognitive defects start to occur and their memory is severely impaired, including psychomotor processes [i].

There is currently no cure for Huntington’s disease. The treatment regimen currently involves managing the individual symptoms, such as chorea, hypokinesia, swallowing disorders and so on. For example, the first line of treatment for chorea could be tetrabenazine or second generation neuroleptics if the patient has behavioral disorders [vi]. Finding a cure for Huntington’s has proven difficult because the exact pathophysiology that occurs is not known. The few things that are certain is the degeneration of striatal gray matter. There have been studies done on the white matter changes that occurs in affected individuals leading to a theory about the oligodendrocytes malfunctioning. In addition, the relationship of grey matter degenerating and white matter loss could be due to some form of Wallerian degeneration. If the demyelination hypothesis is considered, then it could be assumed that the mutation of the huntingtin gene could lead to a premature breakdown of the myelin [viii]. However, it is still unclear. On the bright side, there are better diagnostic tools that researchers can use coming out over the years and perhaps one day scientists will have figured out exactly how Huntington’s manifests. Hopefully stem cell therapy or being able to replace neurons, specifically the striatal medium spiny neuron in this case, will have promise in the future for individuals affected by this horrible disease and several other neurological diseases [ix].

[i] Roos RA. Huntington’s disease: a clinical review. Orphanet J Rare Dis. 2010;5:40. Published 2010 Dec 20. doi:10.1186/1750-1172-5-40

[ii] Schulte J, Littleton JT. The biological function of the Huntingtin protein and its relevance to Huntington’s Disease pathology. Curr Trends Neurol. 2011;5:65-78.

[iii] Hong, Eun Pyo et al. ‘Huntington’s Disease Pathogenesis: Two Sequential Components’. 1 Jan. 2021 : 35 – 51.

[iv] Albrecht J, Sonnewald U, Waagepetersen HS, Schousboe A. Glutamine in the central nervous system: function and dysfunction. Front Biosci. 2007;12:332-343. Published 2007 Jan 1. doi:10.2741/2067

[v] PhD MF. Age of onset in Huntington’s linked to property of CAG repeat… Huntington’s Disease News. Published September 17, 2019. Accessed December 26, 2021.

[vi] Bachoud-Lévi A-C, Ferreira J, Massart R, et al. International guidelines for the treatment of Huntington’s disease. Frontiers. Published January 1, 1AD. Accessed December 25, 2021.

[vii] Chorea: Risk factors, causes, symptoms & treatment. Cleveland Clinic. Accessed December 25, 2021.

[viii] Casella C, Lipp I, Rosser A, Jones DK, Metzler-Baddeley C. A critical review of white matter changes in Huntington’s disease. International Parkinson and Movement Disorder Society. Published June 15, 2020. Accessed December 25, 2021.

[ix] Bachoud‐Lévi A, Massart R, Rosser A. Cell therapy in Huntington’s disease: Taking stock of past studies to move the field forward. STEM CELLS. 2020;39(2):144-155. doi:10.1002/stem.3300

Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s