In 1872, the 22-year-old George Huntington presented a paper describing an elaborately outlined inheritance pattern of a disease, which during the time was referred to as "chorea." In his paper, which was presented at the Meigs and Mason Academy of Medicine at Ohio, George described all the features of the adult-onset form of the disorder and outlined the disease’s autosomal-dominant pattern of inheritance. Although the mechanism underlying the inheritance pattern of the disease was not understood until the rediscovery of Mendel’s works, his paper was so comprehensive that George Huntington quickly became widely acclaimed. In fact, he gained international recognition that the disease featured on his paper became the Huntington disease (Bates, 2005).
Symptoms and Disease Development
Today, we now know that Huntington's disease is a neurodegenerative disorder characterized by chorea, progressive cognitive dysfunction, mood changes and depression. The disease develops more commonly during mid-adult, but cases suggest that the disease may develop starting from the age of 2 until 80 years or more. At the beginning of the development of the disease, the symptoms would seem light, such as mood swings and sudden peculiar behavior. Eventually, the disease progresses from lighter symptoms to more intense symptoms, such as depression, uncontrollable movements, cognitive impairment, and psychiatric symptoms. Most known patients develop the symptoms starting at ages 35 to 55 years, and surviving from the disease is highly improbable. An average patient would have his symptoms worsen within the span of 10 to 20 years, which will then be followed by his inevitable death (Nordqvist, 2016).
The slow progression of the disease starting from mild symptoms make Huntington’s disease difficult to diagnose at the start of onset due to its similarities with other neurological disorders. As the disease progresses, the patient develops chorea, a neurological condition characterized by uncontrollable, jerky movements. In fact, one distinguishing feature of Huntington’s disease is the development and progression of chorea (Bates, 2005).
Genetic Nature of Huntington’s disease
When George Huntington presented his paper in 1872, the most notable feature of the disease is its high probability of being inherited from the parents. In fact, modern genetics has recognized Huntington’s disease as one of the autosomal dominant disorders, which means that the tendency of a person to have Huntington’s disease is 50% when one of his parents has the disease. To understand clearly, let us elaborate on the phrase “autosomal dominant.”
Basic understanding of Mendelian genetics states that a certain genotype has a corresponding phenotype, and that a specific phenotype consists of two alleles, one inherited from each of the parents. Furthermore, a specific locus can have different alleles, and the expressed character depends on the combination of these alleles. For instance, the trait “having the Huntington’s disease” is the dominant trait (H), while the trait “not having the Huntington’s disease” is the recessive trait (h). In this case, the phenotype “not having the Huntington’s disease” will only be expressed when the genotype of the organism consists of two recessive alleles (hh) inherited from each of the parents. In fact, Huntington’s disease easily transferable to the next generation due to the fact that the trait “having the Huntington’s disease” is the dominant trait.
More notably, the advancement in genetics has identified the specific genes that are responsible for Huntington's disease. Indeed, Huntington’s disease was fully mapped genetically in 1983, and the gene that is expressed to be the Huntington's disease is found on chromosome number 4. In this chromosome, a normal gene, termed as the HD gene, produces huntingtin, a variable chain of amino acids. However, the Huntington's disease will develop when there is a presence of a single mutation of this gene, which produces a larger huntingtin. To be specific, Huntington’s disease is genetically distinct due to its single mutation of the HD gene, causing an elongation of the trinucleotide CAG repeats. Note that exceeding a number of trinucleotide CAG repeats produces the dangerous larger form of huntingtin (Walker, 2007).
Normally, the HD gene has at most 26 CAG repeats. However, mutations causing CAG repeats of more than 40 are associated with the expression of Huntington’s disease. Note that the normal HD gene produces the protein huntingtin, a polyglutamine chain, due to the fact that the CAG gene corresponds to the glutamine amino acid. As effect, the mutant HD gene produces a larger huntingtin which interacts differently with cells involved with normal huntingtin. For instance, the sensitivity of the brain cells to larger forms of huntingtin causes apoptosis of brain cells (Myers, 2004).
In fact, scientists have proposed theories on the role of polyglutamines in Huntington's disease. The most convincing theory states that 38 or more consecutive glutamine residues aggregate by forming dimers, trimers, and oligomers. Note that this process have a variable abeyance, which may explain the delayed onset of Huntington's disease. Moreover, the rate of this process depends on the number of glutamine repeats, which may explain that the longer CAG repeats corresponds to shorter onset (Walker, 2007).
Diagnosis and Treatment
Up to this day, the definitive and conclusive way of diagnosing Huntington’s disease is through genetic testing. Although physicians and medical doctors may inquire about family history and environmental factors, genetic testing confirms whether the patient has a Huntington’s disease or not. Moreover, genetic testing can also be performed to check for genetic risks of inheriting Huntington’s disease and other disorders.
Unfortunately, Huntington’s disease is still incurable. However, there are medications that are recommended to alleviate the symptoms of Huntington’s disease. For instance, tetrabenazine is an FDA approved treatment for chorea associated with Huntington’s disease. However, tetrabenazine has side effects, and is not recommended to be taken by patients diagnosed with depression. Similarly, other medications can be taken to control chorea, such as clonazepan, haloperidol, and clozapine. On the other hand, speech and muscle therapy can be taken by patients to improve speech control and muscle movements (Nordqvist, 2016).
Summary
In summary, Huntington’s disease is a rare autosomal dominant disorder characterized by chorea, progressive cognitive dysfunction, mood changes and depression. The HD gene was identified to be responsible for the disorder, and is found on chromosome four. The mutant HD gene produces a larger huntingtin, a protein consisting of a long chain of glutamines. Several theories suggest that the larger huntingtin aggregates within a variable abeyance, which then interacts and damages brain cells, presumably those responsible for motor skills.
References
Bates, Gillian P. (2005). The molecular genetics of Huntington disease – a history. Nature, 6: 766-773.
Myers, Richard H. (2004). Huntington’s Disease Genetics. The Journal of the American Society for Experimental NeuroTherapeutics, 1: 255-262.
Nordqvist, Christian. (2016). “Huntington's disease: Causes, Symptoms and Treatments.” MNT.com. 22 July 2016. Accessed from <http://www.medicalnewstoday.com/articles/159552.php>
Walker, Francis O. (2007). Huntington’s disease. The Lancelet, 369: 218-228.
