HUNTINGTON’S DISEASE

Introduction

The human brain is made up of billions of neurons involved in the conduction and processing of sensory as well as motor information. Higher cognitive functions like thinking, making a judgment, and storing information in the memory are also performed by the neurons in the brain. It controls almost all the functions performed by the body. Some of them are under conscious control while others are controlled unconsciously. These highly essential functions of the brain can be affected by several disorders including Huntington’s disease.

Network Brain Structure Brain Cells Neurons Brain

Huntington’s disease is an inherited disorder of the brain that causes progressive deterioration of the nerve cells in different regions of the brain. The patients present with different motor symptoms based on the area of the brain affected. Different environmental factors can play a role in the progression of diseases.

The early symptoms in Huntington’s disease are lack of some mental abilities, unsteady gait, and lack of coordination. A progressive decline in the mental and physical abilities of the patient is seen with time. In this article, we will be discussing the signs and symptoms of the disease, its genetic as well as environmental causes, diagnosis, and management.

Signs and Symptoms

In most of the cases, the symptoms start appearing in the middle age. However, early age patients can also be seen. Mild symptoms are seen in the early stages of the disease. These symptoms become worse as the disease progresses. Physical symptoms are first to be noticed followed by cognitive decline and dementia. A brief detail of these symptoms is mentioned below.

Physical Symptoms

The physical symptoms of Huntington’s disease are defined as Huntington’s chorea. These are the random and jerky movements of different body parts that are not controlled by the brain.

Chorea first presents as mild symptoms as minor unintentional movements, uncoordinated eye movements, and lack of motor coordination. The choreiform movements are first seen in the extremities of the upper and lower limb.

As the disease progress, more motor abnormalities are observed such as rigidity, writhing movements of hands, abnormal posture, etc. Facial grimacing is also seen due to the twitching of facial muscles.

As the more muscle groups are involved, the patients become immobile. They have abnormal facial expressions, physical instability, and feel difficulties in performing activities that require fine motor control such as speaking, writing, swallowing, or chewing, etc.

Cognitive Impairments

Cognitive decline is seen in the late stage of the disease. Higher cognitive functions such as learning, planning, thinking, and judgment are more severely affected. Dementia and memory impairments are seen as the disease progresses further. Short-term as well as long-term memories are affected. Deficits are seen in the procedural, episodic, and working memories of the patients.

Cognitive decline ultimately leads to dementia. This pattern of dementia is called subcortical dementia. It can be distinguished from dementia seen in Alzheimer’s disease for differential diagnosis.

Psychiatric Symptoms

Psychiatric manifestations are also seen along with dementia in the later stages of Huntington’s disease. Important symptoms include anxiety, depression, and aggression. They cannot properly display their emotions. They are often aggressive and egocentric.

Compulsive behavior also develops in such patients. If the patient is already addicted to alcohol or some drugs, the addictions may also get worse in Huntington’s disease.

These people have less awareness of the disease state. They are also unable to recognize the emotions of others.

Genetics and Inheritance

Huntington’s disease is an autosomal dominant disease caused by a trinucleotide repeat expansion mutation. The gene for Huntington’s disease, HTT, is located on chromosome 4. Two copies of this gene are located in an individual. It encodes for huntingtin protein.

Recall that genes contain introns and exons. The first exon of the HTT gene contains the CAG nucleotide repeat sequence. It codes for the polyglutamine region located near the N-terminal of the huntingtin protein.

The normal HTT gene contains six to 35 copies of CAG nucleotide repeats. If the number of nucleotide repeats increases this limit, it causes Huntington’s disease.

An inverse relationship is seen between the number of CAG repeats and the disease onset. The greater the number of nucleotide repeats, the earlier the disease onset.

This repeat expansion occurs during the process of spermatogenesis.

As mentioned earlier, Huntington’s disease follows the autosomal dominant inheritance pattern. It means that if a person inherits only one copy of the mutant gene, he gets the disease. The offsprings of the affected individual have 50% chance of getting the disease. Both males and females have an equal probability of getting the disease.

Pathophysiology

The pathology of the disease is associated with polyglutamine repeats in the huntingtin protein. The biologic function of the huntingtin protein is not known. However, the triple repeat mutation causes a gain of function to the huntingtin protein. Although the altered huntingtin protein is found in all the cells of the body, the deleterious effects of mutant protein are seen only in the central nervous system.

The mutant huntingtin protein can be aggregated in the brain cells. The mutant protein is cleaved by the enzymes to generate polyglutamine fragments. These fragments undergo misfolding and are aggregated into the cells.

The polyglutamine aggregates resemble the properties of beta-amyloid aggregates seen in Alzheimer’s disease. These aggregates accumulate to form inclusion bodies within the cytoplasm as well as the nucleus of neurons. The neuronal inclusions interfere with the normal functioning of neurons.

The mutant protein can cause cell death in the following ways.

  • The mutation interferes with the function of chaperone proteins, the proteins involved in removing the misfolded polypeptide fragments.
  • Caspases are involved in the removal of affected cells.
  • Glutamine has toxic effects on brain cells.
  • The mutant huntingtin protein also impairs energy production inside the neurons.
  • It also affects the expression of other genes in neurons.

The mutant huntingtin protein is also involved in causing mitochondrial damage to the neurons in the striatum. The disruption of the mitochondrial electron transport chain increases the oxidative stress in the neurons. The increased amount of reactive oxygen species thus formed can be a cause of cell death causing dementia.

Another hypothesis explains that the abnormal huntingtin protein interacts with other proteins and makes the cell vulnerable to damage by glutamine. Even the normal glutamine levels in the neurons can cause damage to cellular structures.

Morphological Changes

Several morphologic changes are caused by Huntington’s disease in different regions of the brain. The appearance of inclusion bodies in the neurons is the earliest sign of the disease. The morphological changes can be divided into gross changes and microscopic changes.

Gross Changes

In Huntington’s disease, the brain usually becomes small due to atrophy of different areas.

In the early stages, marked atrophy can be seen in the caudate nucleus. The putamen nucleus also shows atrophy to some extent.

In the secondary stages, globus pallidus develops atrophy. The third and fourth ventricles undergo dilation.

As far as the cortex is concerned, atrophy is more frequently seen in the frontal lobe. In some cases, the parietal lobe also undergoes atrophy. The atrophy of the entire cortex is very likely to be seen in Huntington’s disease.

Microscopic Changes

A profound loss of striatal neurons is seen upon microscopic examination. More severe changes are noticed in the tail and ventricular regions of the caudate nucleus. Nucleus accumbens is the only part of striatum that is best preserved in this disease.

The pattern of pathological changes is different in caudate and putamen nuclei. In the caudate nucleus, the pathologic changes start appearing first in the medial portions and then progress towards the lateral side. On the other hand, in the case of the putamen, pathologic changes occur from dorsal to ventral side.

The neuronal destruction of both small and large neurons is seen in this disease. The medium-sized neurons that use GABA as a neurotransmitter bear the most severe damage. The loss of neurons in the striatum is directly associated with the worsening clinical symptoms of the disease.

Protein aggregates containing polyglutamate are found in the neurons of the striatum as well as the cerebral cortex.

Neuronal loss causes the fibrous astrocytes to extend their processes in an attempt to repair the damaged neurons. This causes scarring known as fibrous gliosis. Extensive fibrous gliosis can be seen in the later stages of the disease.

Diagnosis

The diagnosis of Huntington’s disease is based on typical symptoms of the disease as well as family history. The diagnosis is confirmed by genetic testing for the mutant HTT gene.

The clinical diagnosis of Huntington’s disease can be made after the appearance of physical symptoms such as random movements and lack of coordination. In addition to clinical diagnosis, genetic and prenatal testing is also done to check for the probability of Huntington’s disease in the offsprings. Different types of diagnostic techniques applied in Huntington’s disease are as follows.

Clinical Diagnosis

The clinical diagnosis involves a physical examination of the patient as well as imaging studies.

Physical examination of the patient is done to check for the physical symptoms. The unintentional and random movement of body parts indicates the onset of disease.

A psychological examination can also be performed to assess cognitive impairments. However, cognitive symptoms do not appear early in the disease process.

A unified Huntington’s disease rating scale has been designed to provide an insight into the overall body state based on motor and cognitive assessments.

Medical imaging of the brain is done to establish a definitive diagnosis. Atrophy of the caudate and putamen nuclei can be revealed by the MRI or CT-scan of the brain in the early stages of life. Cerebral atrophy can also be viewed using medical imaging techniques.

PET-scan can also be performed to find out the activity of neurons in the brain.

Genetic Testing

Genetic studies are performed to find out the probability of the disease in the individuals who are already at risk. Genetic testing is based on the blood tests that are performed to find the number of CAG repeats in the individual cells.

Genetic testing performed before the onset of symptoms can prove to be a life-changing event for those who are at risk. It greatly helps in choosing a better career. Counseling is also provided to individuals who are willing to undergo genetic testing. In the USA, the patients are required to undergo three counseling sessions about Huntington’s disease before genetic testing.

People who have a family history of Huntington’s disease are encouraged to undergo genetic testing.

Preimplantation Testing

This diagnostic technique is used in the case of in-vitro fertilization. Embryos that are formed as a result of in-vitro fertilization are tested for Huntington’s disease before implantation. In this technique, one or two cells are removed from an embryo and genetic testing is done to check for genetic abnormalities.

Using these techniques, it can be assured that embryos having CAG repeats are not implanted so that any offspring does not get the disease in any stage of life.

 Although encouraged by medical professionals, this technique is considered ethically wrong in some communities.

Prenatal Diagnosis

Prenatal diagnosis of a fetus can be done using amniocentesis or chronic villus sampling techniques. The fetal cells acquired by using these diagnostic techniques are subjected to genetic studies to find out the mutations in HTT genes.

Fetal testing can be done in the case if one of the parents is a known patient of Huntington’s disease. It is also advised in the cases when the disease runs in the family. Parents who are at the risk of getting the disease can also be counseled to go for prenatal testing during pregnancy.

Management

Huntington’s disease begins as mild motor symptoms and minor changes in behavior. However, the disease progresses over the course of years and can effectively reduce the quality of life of patients. In the late stage, the patients are unable to live on their own and are dependent on caregivers. Although no proper care exists for the diseases, different therapeutic and medical interventions can lessen the severity of symptoms and improve the quality of life.

Nutrition Management

Dysphagia or difficulty in swallowing seen in the late stage of the disease can result in severe weight loss. Nutrition management can help prevent weight loss. Patients should be advised to eat slowly and in small pieces. Different thickening agents should be used to help the swallowing process.

Physical Therapy

Physical symptoms can be managed by physical therapy. It can help gain some motor control. Different physical devices may be used to aid walking. Rehabilitation programs are designed to prevent physical symptoms.

Palliative Care

In the advanced stage of the disease, patients cannot live on their own. They need the help of caregivers to perform daily life activities. A good quality palliative care can help in the treatment of some symptoms. It also helps in stress management thus improving the quality of life.

Medical Treatment

Benzodiazepines and other drugs are used to treat the chorea and associated symptoms. Bradykinesia and jerky movements can be prevented using drugs like valproic acid. Depression, anxiety, and aggression can be treated by selective serotonin reuptake inhibitors (SSRIs) like escitalopram, etc. Atypical antipsychotic drugs can be used to treat behavior problems.

In addition to these therapeutic interventions, family and close friends should be educated to take proper care of patients. Genetic counseling should be done for individuals who are at risk of developing the disease.

Summary

Huntington’s disease is an inherited disorder that causes the progressive deterioration of neurons in the brain. The disease begins with mild physical symptoms and can progress to dementia in the advanced stage.

Physical symptoms are first to appear in the early stages of the disease. These include random jerky movements of hands and feet, loss of coordination, and unintentional motion. Difficulty in fine motor tasks in also seen.

Cognitive decline is seen in the later stages. The person suffers from memory impairments and behavior problems. He is unable to perform complex tasks.

Psychiatric problems such as aggression, anxiety, and depression are also seen.

The disease occurs due to a trinucleotide repeat mutation in the HTT gene on chromosome 4. The mutant protein has a polyglutamate region that is toxic to cells.

The polyglutamine fragments in the mutant protein are cleaved and aggregated in the neurons. These protein aggregates can interfere with neuronal functions in several ways and can cause cell death.

The inclusion bodies formed by the aggregated protein fragments are the first morphological signs to be noticed in the disease. Atrophy in the striatum is also an early morphologic sign.

Clinical diagnosis is based on physical symptoms and is confirmed by imaging techniques.

Genetic testing can be performed for early diagnosis.

Different diagnostic techniques can be used to diagnose the mutant HTT gene in the fetus before birth.

Management of the disease involves medical therapy, food therapy, physical therapy, and rehabilitation.

Reference

  1. Lawrence, David M. (2009). Huntington’s Disease. Infobase Publishing. p. 21. ISBN 9780791095867.
  2. Dayalu P, Albin RL (February 2015). “Huntington disease: pathogenesis and treatment”. Neurologic Clinics. 33 (1): 101–14. doi:10.1016/j.ncl.2014.09.003PMID 25432725.
  3. Caron NS, Wright GE, Hayden MR (2014). Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, Amemiya A (eds.). “Huntington Disease”. GeneReviews. PMID 20301482.
  4. Frank S (January 2014). “Treatment of Huntington’s disease”. Neurotherapeutics. 11 (1): 153–60. doi:10.1007/s13311-013-0244-zPMC 3899480PMID 24366610.
  5. “Huntington’s Disease Information Page: National Institute of Neurological Disorders and Stroke (NINDS)”. NINDS. 28 January 2016. Archived from the original on 27 July 2016. Retrieved 19 July 2016.
  6. Durr A, Gargiulo M, Feingold J (November 2012). “The presymptomatic phase of Huntington disease”. Revue Neurologique. 168 (11): 806–8. doi:10.1016/j.neurol.2012.07.003PMID 22902173.
  7. Ferri, Fred F. (2010). Ferri’s differential diagnosis : a practical guide to the differential diagnosis of symptoms, signs, and clinical disorders (2nd ed.). Philadelphia, PA: Elsevier/Mosby. p. Chapter H. ISBN 978-0323076999.

Image sources

  1. https://www.maxpixel.net/Network-Brain-Structure-Brain-Cells-Neurons-Brain-1739997
  2. https://commons.wikimedia.org/wiki/File:Huntington%27s_disease_(5880985560).jpg