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Huntington’s disease

Huntington’s disease (HD) is a rare, familial, monogenetic, neurodegenerative disorder marked by the progressive development of psychiatric symptoms, cognitive impairment, and involuntary jerky movements called chorea. It was first identified by the American physician George Huntington in 1872. HD is an inherited autosomal dominant disorder, which means that a person needs only one copy of the defective gene to develop this disorder. It is caused by the cytosine-adenine-guanine (CAG) trinucleotide repeat expansion on the 5’ end of the Huntingtin (HTT) gene which codes for the HTT protein.

The HTT protein plays an important role in nerve cells (neurons) in the brain and is essential for normal post-embryonic development before birth. This mutation leads to an abnormally long version of the HTT protein that is cut into smaller, toxic fragments which bind together and accumulates in neurons, disrupting the normal functions of these cells and leading to neurodegeneration. HD commonly affects patients between the ages of 30 to 50 years. HD is not equally prevalent across the world and has a worldwide prevalence of only 2.7 per 100,000. It is most prevalent in the West as compared to Asian countries.

This variation is attributed to the difference in length of the HTT gene among different ethnicities. Males and females have almost the same risk of getting HD. If the onset of HD symptoms is in childhood, it is called juvenile HD. In the late-onset of HD, symptoms appear in the seventh or eighth decade of life.

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Symptoms

The signs and symptoms classically consist of motor, cognitive, and psychiatric disturbances. Other less common symptoms include weight loss, sleep disturbances, and autonomic nervous system dysfunction.

Motor disturbances are:

  • Involuntary jerking or writhing movements (chorea)

  • Muscle problems, such as rigidity or muscle contracture (dystonia) lead to abnormal posturing such as torticollis and can be the first sign of motor involvement in HD.

  • Slow or abnormal eye movements

  • Impaired gait, posture, and balance

  • Difficulty with speech (dysarthria) or swallowing (dysphagia)

  • Other involuntary features include tics and cerebellar signs such as ataxia

 

The motor disturbance in daily activities progresses over time and can lead to difficulties in walking, standing, and frequent falls. This may have a greater impact on a person's ability to work, perform daily activities, communicate and remain independent.

Behavioral and psychiatric symptoms are:

  • Initial presentation of poor attention, impulsivity, and irritability leading to outbursts of anger and aggression.

  • Emotional blandness with prominent apathy, loss of intuition, and creativity.

  • Depression (most common).

  • Social withdrawal

  • Insomnia

  • Frequent thoughts of death, dying, or suicide

  • Psychosis can appear in later stages, which goes hand in hand with cognitive decline.

 

Cognitive disturbances are:

  • Patients find difficulty in organizing, multitasking, and planning.

  • Dementia.

  • Psychomotor processes severely slow down.

Diagnosis

Diagnosis of HD can be based on one or more of the following three factors including family history, the onset of motor symptoms, and genetic testing. In the presence of motor symptoms, family history is first evaluated. Finally, genetic testing provides an unambiguous indication of the presence of HD based on the CAG repeat length in a person’s genome.

Genetic testing can also predict whether a person is going to incur HD decades before the onset of even the subtle motor symptoms. Motor symptoms are evaluated using a score from 0 to 4. Unified HD Rating Scale (UHDRS) and the Problem Behaviours Assessment (PBA) are the commonly used rating scales to evaluate the frequency and severity of symptoms in HD patients. Biomarkers and MRI are used to rule out the possibility of other neurodegenerative disorders particularly if family history is not available as well as to determine the prognosis of the disease and to evaluate the effectiveness of treatment.

Management

HD is one of the best-studied and most understood neurological diseases however, there is still no cure for this disease. All of the currently available therapeutic options are mainly pharmacological, which treat signs and symptoms to improve the quality of life. The following are the symptomatic interventions for disease management:

  • Suppression of chorea - drugs that act on the dopaminergic pathway such as tetrabenazine (TBZ), amantadine, and riluzole are used.

  • Managing behavioral and psychiatric disturbances - selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors can be used to manage anxiety and depression.

  • Non-medical interventions - psychotherapy and cognitive behavioral therapy are considered primary management options for depression in HD before prescribing anti-depressants. Community-based yoga can be effective in managing deficits in posture, range of motion, breath control, and multitasking.

  • Gene therapy - the silencing of mutant HTT (mHTT) gene responsible for HD, by various techniques like CRISPR/Cas9, antisense oligonucleotides, microRNA, or zinc-finger nucleases (ZFN) is the upcoming therapeutic option.

  • Clearance of mHTT - mHTT may be cleared from the cell through its degradation through macro-autophagy by the use of drugs like rapamycin, autophagosome-tethering compound (ATTEC), as well as selisistat.

 

Records of family history and subsequent genetic testing are the fundamental factors in HD diagnosis, which can help in the early management of patients in their life.

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