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Huntington’s disease; Chorea; Neurodegeneration; Psychotropic drugs

Introduction

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease that affects approximately 5 to 10 people per 100,000 people. People often experience motor and cognitive impairments, loss of identity and spatial awareness, depression, dementia, and increased anxiety within the 10 to 20 years before death. Today, treatment is limited to stopping the chorea, discomfort, and frequent movements in the arms and legs that accompany HD, and there is no treatment method against the changes in the disease [1]. HD is a devastating autosomal dominant genetic disease that is clinically characterized by motor, behavioural, cognitive and neuropsychiatric symptoms. The average age of onset (AO) is 35 to 44 years [2]. The disease is characterized by a triad of physical, cognitive, and psychiatric symptoms that are medically dependent on striatal spinouts neurons, the first neurons to emerge due to poor performance. This then spreads to other parts of the brain, including the cortex [3]. Huntington Society and World Federation of Neurological Research Groups 1994 International Huntington's Disease Guidelines and 2013 posits that neurological examinations (if possible) are considered important to establish a baseline evaluation of each person [4]. However, as the disease progresses neurons in the direct pathway are also affected, which is thought to explain the increasing bradykinesia and rigidity observed in advanced-stage HD patients [5]. Cognitive deficits in HD generally manifest as a decline in executive function, with patients frequently having increasing difficulty with attention, concentration, multi-tasking, and decision making. Depression and loss of memory and insight are also commonly observed [6-8].

History of Huntington’s disease

Huntington's disease is a neurodegenerative genetic disease that affects movement, cognition and development and is fatal. Although it had different names before, it took its name after George Huntington described the clinical appearance of the disease in detail in 1872. Although it has been referred to as Huntington's disease for nearly a century, it is now referred to as Huntington's disease. HD is an autosomal dominant disease with complete penetrance such that all carriers of the defective gene develop the disease. In 1993, Dr. When Nancy Wexler (Columbia University) and colleagues discovered the genetic mutation that causes Huntington's disease (HD), it turned out that there were changes in the CAG (encoding glutamine) repeat in a previously unknown stretch of the short arm of chromosome 4 a serious, incurable neurodegenerative disease. Its prevalence is also very high (5-10/100 000) in Western European countries, Venezuela, the United States, Canada and Oceania, but low (0.1-0.5/100 000) in Asia and most of Africa. . So, although this disease affects a small number of victims, the risks are higher in number; this highlights the need to find new treatments to reduce symptoms and improve quality of life in HD patients [9].

Clinical sign and symptoms

The clinical symptoms of HD are classically defined as occurring in three domains: motor, cognitive, and psychiatric. The motor symptoms are progressive and early in the disease are mostly hyperkinetic with involuntary movements of chorea. These movements generally begin distally and are of small degree, then become more axial and are of greater amplitude. Movements are often incorporated into natural voluntary movements and, thus, early on may appear as simple restlessness. Although the early stages of motor symptoms are hyperkinetic, in later stages of the disease, motor symptoms tend to be hypokinetic with bradykinesia and dystonia [10] (Figure 1).

Figure 1: Clinical Symptoms of Huntington’s disease.

Etiology

Increased CAG trinucleotide repeats of the Huntingtin gene on chromosome 4 cause Huntington's disease, an autosomal dominant genetic disorder. The result is an unusual predator protein with an extended polyglutamine sequence. If a person has more than 39 CAG repeats, the disease will develop, but between repeats 36 and 39, penetration is minimal. Parents with longer CAG repeats in the middle of the range will have children with longer transmission; It is required when the gene is passed on to the father. This is because sperm cells are more differentiated and larger in size than normal tissue [11].

Epidemiology

In European communities, the prevalence of Huntington's disease ranges from 10 to 13 per 100,000 people. With a frequency of 1-7 per million, Huntington's disease is substantially less frequent in East Asia. Black inhabitants in South Africa have lower rates than white and mixed communities. The genetic variations in the huntingtin (HTT) gene are attributable to differences in illness frequency among ethnic communities. Typical CAG repeat length is longer in communities having increasing incidence levels [12].

Molecular pathogenesis

Several pathways are involved in the dysfunction and neuron death caused by huntingtin mutations. Direct effects of site-one mutant Huntingtin (mHTT) fragments include the propensity of mHTT to form abnormal fragments and its effects on cellular homeostasis, neuronal transport, transcription, translation, mitochondrial function and synaptic function. The striatal medium spiny neurons are particularly susceptible to the adverse effects of that. Striatal pathology progresses in two phases. The first phase is marked by the loss of medium spiny neurons (MSNs) of the indirect pathway, which causes a hyperkinetic phenotype, and the second phase is characterized by the loss of medium spiny neurons of the direct path, which causes a hypokinetic trait [13]. Unknown factors may lead to a biased pathway in the selection of negative MSNs, but D2 dopamine receptors may play a role as they are involved in Huntington's disease pathogenesis and are deposited indirectly, if not directly, on MSNs [14]. Other hypotheses include depletion of brain-derived neurotrophic components, presumed glutamate excitotoxicity in the corticostriatal body, and deleterious effects of associated non-ATG translation proteins [15] (Figure 2).

Figure 2: Huntington’s disease pathogenetic cellular mechanisms.

Clinical management Huntington’s disease

Various disease-modifying methods have been investigated in HD, including anti-oligonucleotide therapy, but to date none have been shown to slow disease progression [16]. Therefore, current treatment focuses on symptom management, psychological and social support, and effectiveness. aims to improve life. A set of recommendations for treating the many symptoms of Huntington's disease was recently published by the European Huntington's Disease Network. [17]. It is important to have a good treatment method and to have many ways to help patients even if there is no cure for the disease. Perhaps the most important aspect of management is the collaboration of various groups, including psychiatrists, geneticists, psychiatrists, psychologists, nutritionists, speech and language therapists, physiotherapists and occupational therapists, social workers, specialist nurses and doctors. Patient support groups (such as the HD Association of England and Wales, the American HD Association and the Canadian Huntington's Society) are important; some of these provide funding for local counsellors to work with family influence in the community. Lack of visibility means that patients are sometimes reluctant to accept help, and information from family and carers can sometimes provide a good indication that the patient's problems are being met. Advance treatment planning discussions are important before the onset of severe mental illness, particularly regarding pre-nutrition assistance (e.g., percutaneous endoscopic gastrostomy placement), access, and care. There is little evidence for treating symptoms with medication, and the choice of medication mostly depends on the doctor's experience. It is important to consider all side effects for the patient when deciding which drug to use, because the treatment used for some diseases may affect others (for example, tetrabenazine is effective in treating chorea but may aggravate neuropsychiatric symptoms) [18].

Treatment

Many agents have been tested to reduce choreatic movements including, for example, neuroleptics, monoamine depleting agents, benzodiazepines, antiepileptic, acetyl cholinesterase inhibitors, and glutamate antagonists. Nevertheless, there is not enough evidence to propose longterm guidelines for the symptomatic treatment of HDrelated motor symptoms, and double-blinded controlled treatment trials are needed urgently [19].

Tetrabenazine

The monoamine depletor tetrabenazine (TBZ) has been shown to effectively reduce chorea in HD and is therefore recommended by American and European guidelines [20]. In contrast to typical or atypical neuroleptics, TBZ carries a less severe risk of developing tardive dyskinesia. In general, TBZ is well tolerated and serves as a good candidate to start medical treatment of choreatic movements even in early stages. Possible side effects include depression, parkinsonism, insomnia, akathisia, and sedation. Starting with 12.5 mg per day, the dosage of TBZ can be increased weekly in 12.5-mg steps distributed three times per day. The maximum dose is discussed controversially, but usually limited to 100 mg per day. If comedication includes strong cytochrome P450 2D6 (CYP2D6) inhibitors eg, selective serotonin reuptake inhibitors (SSRIs) such as paroxetine, fluoxetine, or other antidepressants such as, eg, bupropion, or the subject turns out to be a CYP2D6 slow metabolizer by genotyping, the maximum dose should be restricted to half, although no distinguishing features have been found in patients exhibiting various CYP2D6 activities. Notably, despite uncountable beneficial effects on chorea, certain cognitive functions can worsen under medication with TBZ [21].

Neuroleptics

If both chorea and psychiatric symptoms like agitation and psychosis are predominant features, neuroleptics, which act by blocking the dopamine transmission, could be chosen preferentially. Although atypical neuroleptics should be favoured with respect to their better profile of adverse effects, is a special responsibility, which requires recognition of disease-related symptoms at the earliest and, if needed, installation of an adequate therapy [22].

Benzodiazepines

Chorea is known to worsen in psychologically demanding situations or under stress. Therefore, low dosages of benzodiazepines can be added to the medication transitionally to cushion these emotional effects. The risk of drug abuse and dependency, however, has to be respected.

Amantadine

The usefulness of amantadine (recommended dose: 300–400 mg/ day) in the treatment of chorea is discussed controversially, since results of the present trials are not concordant the usefulness of amantadine (recommended dose: 300-400 mg/day) in the treatment of chorea is discussed controversially, since results of the present trials are not concordant [23].

Riluzole

The initially high expectations in using Riluzole for the treatment of chorea in HD have diminished since results of randomized controlled trials did not show the expected improvements. Besides, notable side effects were reported, but restricted to high doses of 200 mg/day. In conclusion, a time- and dose-dependent positive effect of Riluzole in the treatment of chorea is discussed, but no generalized recommendation can be given for the use of this drug.18 Thus, in our experience Riluzole does not serve as first-line medication in the treatment of chorea in early symptomatic HD patients, although it is recommended in third position for treating chorea in HD by the American Academy of Neurology guidelines [24].

Anti-glutamatergics

There has also been some research into the role that glutamate excitotoxicity plays in HD-associated chorea. Hence, medications such as amantadine and Riluzole have been trailed as antiglutamatergics to reduce chorea symptoms. [25].

Mood stabilizing medications

HD patients with behavioural symptoms can also present with symptoms such as OCD, aggression and bipolar disorder. To stabilize these mood disorders, patients can be prescribed a range of anticonvulsants such as sodium valproate, lamtringine and carbamazepine [26].

Non-invasive strategies and life-style adaptations

The overall treatment of HD requires a holistic approach to health, involving a range of health professionals. Non-invasive strategies and life-style adaptations can also play a vital role in the patient’s management of HD. Chorea is the primary symptom that can severely impair balance and gait. Physiotherapists can support patients by extending the proper function of these actions as well as assessing when walking aids or wheelchairs are required similarly, occupational therapists can assist HD patients through completing home assessments and installing bathroom adaptions or handrails so patients can prolong living in the comfort of their own home.

Conclusion

HD is the first trinucleotide disease that was described and the first autosomal dominant disease with a possible diagnosis prior to the manifestation of symptoms. Since 1983 and the localization of the gene, knowledge of the disorder has markedly increased, which is necessary in order to improve the quality of life of patients and improve therapeutic strategies by discovering novel molecular targets. In order to address the challenges posed by movement disorders, depression, anxiety, and psychosis, which have a substantial negative impact on the overall well-being of patients, the use of Pharmacogenetics data may be employed to enhance the effectiveness of HD anticholinergic, antidepressant, and antipsychotic medications.

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