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Huntington's disease (HD) is also known as "hereditary chorea" and "chronic progressive chorea" [1]. Huntington's disease is a hereditary neurodegenerative disease caused by an autosomal dominant mutation that causes the gradual depletion (degeneration) of nerve cells in the brain. Huntington's disease has a wide range of effects on a person's function and ability, often leading to motor, thinking (cognitive) and mental disorders.
In 1841, Charles Oscar Waters first described the disease. In 1872, the doctor George Huntington described the disease in more detail and named it after him. In 1993, the International Huntington Disease Collaborative Research Group cloned the disease-causing gene IT15, also known as the Huntington gene. The gene is located on the short arm of chromosome 4 and its metabolite is Huntingtin. Huntingtin may be involved in nervous system development, endocytosis and secretion, and inhibition of apoptosis.
The main differences between Parkinson's and Huntington's are as follows:
Table 1 Differences between Parkinson's disease and Huntington's disease
| Differences | Parkinson's Disease | Huntington's Disease |
|---|---|---|
| Pathogeny | It is caused by degeneration of neurons in the substantia nigra | It is caused by mutations in the HTT gene |
| Age of onset | After age 50 | 30 to 40 years old |
| Symptom | Tremor, stiffness, tardiness, and gait disturbance | Higher functional abnormalities, such as thinking and reasoning problems, accompanied by idiopathic chorea |
| Treatment | Levodopa, dopamine agonists and other dopamine-enhancing drug therapy | There is no effective treatment for HD, and the main treatment is supportive therapy |
| Daily life | It has no effect on life expectancy however, it reduces the quality of life | HD patients live 15-20 years after the first symptom |
Huntington's disease is a family dominant hereditary disease. It is caused by a family genetic or genetic mutation. CAG trinucleotide repeat amplification in the huntingtin gene on the short arm of chromosome 4 is the leading cause of the disease [2]. The mutant gene is the Huntington's gene, also known as IT15 (" interesting transcript 15 "), which encodes an abnormal Huntington's protein many repetitive glutamines.
Figure 1 The production process of abnormal Huntington's protein
This mutant protein can enter the nucleus and alter gene transcription [3]. This protein can also affect cell metabolism, especially mitochondrial function, which may lead to the production of metabolites and oxidative stress markers [4]. Abnormal Huntington's protein adhesion and aggregation, causing damage to brain cells, leading to the gradual degradation of the patient's nervous system.
Figure 2 The inheritance of Huntington's disease
The average clinical onset age of HD was about 45 years old, which was affected by the length of CAG trinucleotide amplification in HTT gene [5], and was inversely proportional to the number of polyglutamine repeat sequences. Younger diagnosed patients tend to have longer repeat lengths [6] [7]. The effect of CAG repetition length on the rate of disease progression was not obvious, but still significant [8].
There is no gender difference in the disease. The incidence of Huntington's disease is related to human race, with the highest incidence in European and American caucasians (5-7/10 thousand). Asian and African populations are the lowest.
HD mainly affects the basal ganglia, which are a collection of nerve cells located deep in the brain. The main components are shown in the figure below.
Figure 3 Composition and location of basal ganglia
The basal ganglia help smooth out muscle movements and coordinate changes in posture. Huntington's disease is caused by the gradual degeneration of small parts of the basal ganglia called the caudate nucleus and striatum.
The onset time of Huntington's disease is defined as the presence of an unexplained extrapyramidal dyskinesia (eg, chorea, dystonia, bradykinesia, stiffness) in people with expansion of CAG (cytosine-adenine-guanine) triplet repeats in the gene HTT. [9].The symptoms of HD have some similarities with amyotrophic lateral sclerosis (ALS), Parkinson's disease, and Alzheimer's disease.
Although the symptoms of HD vary from person to person, the progress of the disease can be roughly divided into three stages.
Huntington's disease (HD) can cause a wide range of brain lesions, which are characterized by motor, cognitive and mental symptoms [10]. Impaired hippocampal synaptic plasticity is one of the major causes of cognitive impairment in Huntington's disease (HD). In addition, a hallmark of the disease is unconscious weight loss [11] [12].
Other mental illnesses include: Obsessive-compulsive disorder and bipolar disorder.
HD also affects children or adolescents. The symptoms of juvenile HD (JHD) are different from those of adult-onset HD. The progression of JHD is generally faster, manifested as transient chorea, stiffness, epilepsy, accompanied by progressive cognitive and memory impairment, eventually lead to dementia.
Life expectancy after onset is about 10 to 20 years, according to the Huntington's chorea society. The earlier the onset, the faster the progression.
Clinical depression is associated with Huntington's disease and may increase the risk of suicide.
Other common complications that cause death:
Huntington's disease is a dominant inherited neurodegenerative disease, which is clinically diagnosed on the basis of positive family history, typical dancing-like motor symptoms, mental disorders and progressive dementia, and positive results of genetic testing.
Standardized examination: the unified HD score scale (UHDRS) is currently the most commonly used clinical and research tool for HD assessment. The scale includes components of movement, cognition, behavior, emotion and function.
Brain imaging tests are used to assess the structure or function of the brain. The main techniques include magnetic resonance imaging (MRI) or computed tomography (CT).
Typical imaging features: bilateral caudate nucleus atrophy. Magnetic resonance imaging (MRI) has shown extensive brain atrophy in HD studies, most notably in the striatum [13].
SPECT examination showed a significant decrease in blood flow in the caudate nucleus and the lenticular nucleus, and decreased blood flow in the frontal and parietal lobe.
PET examination showed that the glucose metabolism in caudate nucleus decreased in patients with subclinical status, which can be used for super early diagnosis.
It is an important means of diagnosis. The number of repeated copies of CAG in Huntington's gene (TT15) was detected by PCR. Normal people had no more than 38 copies, and patients had more than 39 copies.
Genetic testing can be diagnostic or predictive. If the patient has typical characteristics of Huntington's disease, the most effective confirmatory diagnostic test is the cag-repeat test [14].
In symptomatic Huntington's disease, levodopa can aggravate choreography. Therefore, it can be used for early diagnosis, but the test has a certain false negative reaction.
Studies have shown that qEEG may also serve as a biomarker for HD to help monitor the efficacy of intervention studies [15].
In addition, inflammation may act as a biomarkers of Huntington's disease [16].
The latest study found that blood tests can detect the earliest changes caused by Huntington's disease, even before the scan can detect any signs in the brain.
The study of pathogenic molecules in cerebrospinal fluid (CSF) is also one of the ways to find biomarkers [17].
Like most neurodegenerative diseases, Huntington's disease lacks specific treatment methods, and symptomatic treatment is mainly used at present.
With proper medication, the symptoms of motor and mental disorders can be alleviated, and the quality of life of patients can be improved and complications can be prevented.
In mice model, the researchers found that a bile acid was effective in reducing damage to nerve cells in the brain. If future studies prove that bile acid therapy works in humans and can prevent the death of nerve cells in the brain at an early age, it may be possible to prevent Huntington's disease for life.
In addition, Congo red can prevents the accumulation of abnormal proteins in the brain and prevents Huntington's disease. The findings provide new insights into the treatment of Huntington's disease, but further research is needed before the method can be used clinically.
In addition to medical treatment, psychotherapy, language therapy, physical therapy and occupational therapy are also commonly used treatments, which can improve basic symptoms to some extent.
Psychotherapists can help patients deal with behavioral problems, develop strategies, and promote effective communication between family members.
A speech therapist can help you improve your ability to express yourself clearly or teach you how to use communication tools. Speech therapists can also help with eating and swallowing muscle problems.
Exercise properly and safely to increase strength, flexibility, balance and coordination.
Occupational therapists can help patients with Huntington's disease use assistive devices that improve their functioning.
It is often difficult for Huntington's chorea to maintain a healthy weight. In order to get enough nutrition, it may be necessary to have more than three meals a day or to use dietary supplements.
When dining, choose foods that are easy to eat. Use instruments designed for people with limited motor skills (cups with straws or water outlets).
The treatment of Huntington's disease by cell transplantation is still under exploration. Brain cell transplantation can alleviate Huntington's disease to some extent, but this method is controversial.
The method of RNAi can reduce the HD protein level of mice and effectively improve the related motor and neurological abnormalities caused by HD in mice.
Autophagy is the primary pathway leading to the clearance of aggregated proteins in Huntington's disease, and autophagy induction prevents HD-mediated neurotoxicity [18]. mTOR inhibitors and rapamycin-induced autophagy speed up the removal of these toxic substrates. Mammalian cell, fly and zebrafish models provide a theoretical proof for the therapeutic relevance of Huntington's disease [19].
Mutant HTT (mHTT) will undergo a series of post-translational modifications, such as ubiquitination and phosphorylation [20] [21]. Deubiquitinase Usp12 plays a non-catalytic autophagy and neuroprotective role in Huntington's chorea model [22].
IGF-1/Akt pathway plays a neuroprotective role in Huntington's chorea, and Akt phosphorylation of huntingtin is crucial for the neuroprotective role of IGF-1 [21].
Based on these findings, new therapeutic strategies can be developed.
In addition, a new CRISPR cas9-based gene editing method for Huntington's disease can inactivate HTT alleles associated with HD-related mutations without affecting normal alleles.
If safety is demonstrated in animal models and humans, it will have broad application prospects.
For more information, Huntington's disease organizations and some websites related to Huntington's disease can help you:
Huntington's Disease Society of America: https://hdsa.org/
The Huntington's Disease Youth Organization: https://en.hdyo.org/
Huntington's Disease Association: https://www.hda.org.uk/contact-us/branches-and-support-groups
References
[1]Harper B. Huntington disease [J]. Journal of the Royal Society of Medicine, 2005, 98(12): 550.
[2]Listed N A. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes [J]. Cell, 1993, 72(6): 971-83.
[3]Seredenina T, Luthicarter R. What have we learned from gene expression profiles in Huntington's disease? [J]. Neurobiology of Disease, 2012, 45(1): 83-98.
[4]Browne S E, Bowling A C, Macgarvey U, et al. Oxidative damage and metabolic dysfunction in Huntington's disease: selective vulnerability of the basal ganglia [J]. Annals of Neurology, 2010, 41(5): 646-653.
[5] Langbehn D R, Hayden M R, Paulsen J S. CAG-repeat length and the age of onset in Huntington disease (HD): a review and validation study of statistical approaches [J]. Am J Med Genet B Neuropsychiatr Genet, 2010, 153B (2): 397-408.
[6]Gusella JF, MacDonald ME. Huntington's disease: CAG genetics expands neurobiology [J]. Curr Opin Neurobiol 1995, 5: 656–62.
[7]Paulson HL, Fischbeck KH. Trinucleotide repeats in neurogenetic disorders [J]. Annu Rev Neurosci 1996, 19: 79–107.
[8]Rosenblatt A, Kumar B V, Mo A, et al. Age, CAG repeat length, and clinical progression in Huntington's disease [J]. Movement Disorders, 2012, 27(2): 272-276.
[9]Hogarth P, Kayson E, Kieburtz K, et al. Interrater agreement in the assessment of motor manifestations of Huntington's disease [J]. 2005, 20(3): 293-297.
[10]Bates G P, Dorsey R, Gusella J F, et al. Huntington disease [J]. Nature Reviews Disease Primers, 2015, 1: 15005.
[11]Aziz N A, Burg J M M V D, Landwehrmeyer G B, et al. Weight loss in Huntington disease increases with higher CAG repeat number [J]. Neurology, 2009, 73(7): 1506.
[12]Burg J M M V D, Bacos K, Wood N I, et al. Increased metabolism in the R6/2 mouse model of Huntington's disease [J]. Neurobiology of Disease, 2008, 29(1): 41-51.
[13]Hadzi T C, Hendricks A E, Latourelle J C, et al. Assessment of cortical and striatal involvement in 523 Huntington disease brains [J]. Neurology, 2012, 79(16): 1708-1715.
[14]Craufurd D, Macleod R, Frontali M, et al. Diagnostic genetic testing for Huntington's disease [J]. Practical Neurology, 2015, 15(1): 80-84.
[15] Odish Omar F F, Johnsen Kristinn, van Someren Paul, et al. EEG may serve as a biomarker in Huntington's disease using machine learning automatic classification [J]. Sci Rep, 2018, 8: 16090.
[16]Björkqvist M, Wild E J, Thiele J, et al. A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease [J]. Journal of Experimental Medicine, 2008, 205(8): 1869-1877.
[17]Borowsky B, Warner J, Leavitt B R, et al. 8OHdG is not a biomarker for Huntington disease state or progression [J]. Neurology, 2013, 80(21): 1934.
[18]Ravikumar B, Vacher C, Berger Z, et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease [J]. Nature Genetics, 2004, 36(6): 585-595.
[19]Williams A, Sarkar S, Cuddon P, et al. Novel targets for Huntington's disease in an mTOR-independent autophagy pathway [J]. Nature Chemical Biology, 2008, 4(5): 295-305.
[20]Bhat K P, Yan S, Wang C E, et al. Differential ubiquitination and degradation of huntingtin fragments modulated by ubiquitin-protein ligase E3A [J]. Proceedings of the National Academy of Sciences, 2014, 111(15): 5706-5711.
[21]Humbert S, et al. The IGF-1/Akt Pathway Is Neuroprotective in Huntington's Disease and Involves Huntingtin Phosphorylation by Akt [J]. Developmental Cell, 2002, 2(6): 831-837.
[22]Aron Rebecca, Pellegrini Pasquale, Green Edward W, et al. Deubiquitinase Usp12 functions noncatalytically to induce autophagy and confer neuroprotection in models of Huntington's disease [J]. Nat Commun, 2018,9: 3191.
