Huntington disease (HD), a neurodegenerative autosomal dominant disorder, is characterized by involuntary choreatic movements with cognitive and behavioral disturbances. It occurs as a result of cytosine, adenine, and guanine (CAG) trinucleotide repeats on the short arm of chromosome 4p16.3 in the Huntingtin (HTT) gene. This mutation leads to an abnormally long expansion of the polyglutamine in the HTT protein, which leads to neurodegeneration. The expansion also causes the HTT protein to be more prone to aggregation and accumulation that mitigates protein folding. HD commonly affects patients between the ages of 30 to 50 years. However, the longer the CAG repeats, the earlier the onset of symptoms. The term juvenile HD refers to the onset of illness before the age of 20 and is characterized by learning difficulties as well as behavioral disturbances at school.
Diagnosis can be made clinically in a patient with motor and or cognitive and behavioral disturbances with a parent diagnosed with HD and can be confirmed by DNA determination. In those patients who are at-risk for the disease, pre-manifest diagnosis can determine if they carry the gene. There is no cure for the disease, and affected patients tend to be entirely dependent on their caregiver as the disease progresses. Therefore, treatment is aimed at improving the quality of life and decreasing complications. Pneumonia is a common cause of death, followed by suicide.
Huntington disease is an autosomal dominant disorder caused by the elongation of CAG repeats on the short arm of chromosome 4p16.3 in the HTT gene. The gene encodes for the HTT protein, which plays a role in the synaptic function and also plays a crucial role in the post-embryonic period. It is thought to have anti-apoptotic functions as well as protect against the toxic mutant HTT. There is some evidence that the mutant protein leads to both an addition as well as a loss of function. Intranuclear and intracytoplasmic inclusions are found in several areas of the brain. It is, however, unknown if the inclusions themselves play a role in the pathogenesis or if they are pathogenic themselves. The brain atrophy, particularly in the striatum with associated extensive neuronal loss, is well known.
Patients commonly have the HTT allele with CAG repeats in the range of 36 to 55. Those with juvenile-onset of the disease usually have CAG repeats greater than 60. Patients with alleles in the range of 27 to 35 do not show the disease phenotype but are, however, prone to repeat instability. There is an inverse correlation between the length of the repeats and the age of onset, which is determined by the onset of the first motor manifestation. The length of the repeats also determines 70% of the variation in the age of onset. The anticipation phenomenon is seen in the paternal line of inheritance, which arises due to the instability of the CAG repeats during spermatogenesis. Anticipation leads to a phenomenon that is common in HD, where an affected offspring of a patient with the condition will develop the disorder at a younger age than the relative who passed on that gene.
Studies have found three significant categories of risk factors for the onset of the disease. The CAG repeat lengths in the HTT gene, instability of CAG, and genetic modifiers were identified as risk factors. Among these, the most critical risk factor was found to be CAG repeat lengths. Genetic factors play an essential role in the progression of the disease. CAG length is also a significant factor for the progression of the disease, especially in cognitive, motor, and neurological disturbances.
HD is a rare neurodegenerative disorder with a worldwide prevalence of 2.7 per 100,000. The prevalence varies amongst geographical locations by more than ten-folds; this can be attributed to differences in approach to case-ascertainment as well as diagnostic criteria. Due to the adult onset of the disease, patients may show expanded CAG repeats rather than manifest the disease. There is also an incomplete penetrance at the lower end of the CAG repeats. Therefore, the frequency of expanded repeats might be higher in the general population than previously assumed. A lower prevalence in the Asian population has been seen consistently together with higher prevalence in Europe, North America, and Australia. This could be due to the HTT gene haplotypes.
The primary feature is the degeneration of neurons in the putamen, caudate as well as the cerebral cortex. The preferential degeneration of the enkephalin-containing medium spiny neurons in the basal ganglia in the indirect pathway provides the basis for chorea. Additional loss of substance-P containing medium spiny neurons in the direct pathway results in the development of dystonia and akinesia. The region-specific pattern of loss of neurons in the cortex and basal ganglia in the affected patients could explain the phenotypic variability.
There are multiple theories in the pathogenesis of HD, and more than one process can occur at the same time:
The disease tends to affect patients between the ages of 30 to 50. The signs and symptoms classically consist of motor, cognitive, and psychiatric disturbances. Other less common features include weight loss, sleep disturbances, and autonomic nervous system dysfunction.
Other secondary symptoms include:
Clinical course and classification:
1) Presymptomatic HD (if genetically confirmed and clinically at risk if not confirmed): there are no signs or symptoms of motor or cognitive disturbances. These patients might exhibit changes in imaging. Generally, no symptomatic treatment is indicated.
2) Prodromal HD (if genetically confirmed and clinically prodromal HD if not confirmed): Patients start to exhibit subtle motor and cognitive disturbance. Behavioral changes, such as apathy and depression, might be present. The changes in imaging are seen. Patients may require symptomatic treatment. Initiating disease-modifying treatments may be appropriate.
3) Manifest HD (if patients are genetically confirmed and clinically manifest HD if they are not genetically confirmed): Prominent motor and/or cognitive disturbances that interfere with the quality of life are seen. Start symptomatic and disease-modifying treatments.
Overall, the mean age of onset is approximately 45 years. Patients who often present with neurological symptoms also exhibit psychiatric changes. Early in the course of the disease following diagnosis, symptoms such as changes in eye movements, mental planning, depressed or irritable mood as well as mild involuntary movements can be observed. The affected patients are generally able to perform their daily activities. Eventually, chorea progresses, and it becomes increasingly difficult to perform voluntary activities. There are intermittent bursts of aggressive behavior and social disinhibitions. Although patients can maintain some degree of independence, most depend on their caregiver for help. In the later stages of the disease, severe motor disability is noted, and patients are completely dependent on caregivers. The median survival after the onset of the disease is 15 to 18 years. In around 25% of patients, a delayed onset is seen, and these patients exhibit symptoms after the age of 50 and some after the age of 70. Chorea and disturbances in gait are noted on them and often exhibit a benign and more prolonged course than typical patients.
Juvenile Huntington disease:
The onset of symptoms is before the age of 20 years. The length of CAG repeats is more than 55. Motor, cognitive and psychiatric disturbances exhibited in adult HD are also seen in the juvenile form, but the clinical presentation is different. Most often, behavioral disturbances and learning difficulties are the first signs which are noticed in school. Motor disturbances include hypokinesia and bradykinesia with dystonic components. Chorea is rarely seen in the first decade, and commonly appears in the second decade of life. Epileptic fits are commonly observed. Severe mental deterioration, as well as cerebellar symptoms associate with motor, speech, and language delay, are characteristics of juvenile HD. In teenagers, the manifestation of the disease is similar to adult HD, where chorea and severe behavioral disturbances are often the initial presentations.
Once the diagnosis of the disease is delivered to the patient, both short-and long-term responses to living with HD will occur. Recognizing the state of psychological response is crucial prior to delivering the diagnosis. In a minority of patients, this psychological readiness lags behind symptomatology and could result in significant adverse events. Therefore, understanding of the stages provides a framework for evaluating their state of mind and determining the readiness to receive the diagnoses.
The diagnosis is made on clinical signs and symptoms in a patient with a parent with proven HD. The presence of motor symptoms with or without psychiatric and cognitive disturbances or usually a combination of all three in the presence of positive family history is normally sufficient for a diagnosis. The sequence of the motor, psychiatric, and cognitive disturbances are variable and can lead to a delay in diagnosis or misdiagnosis.
Basic investigations should be performed before genetic testing is done. Lab testing becomes particularly useful to differentiate HD from other progressive hereditary HD-like syndromes. An increase in creatine kinase and liver enzymes are frequently seen in chorea-acanthocytosis and McLeod syndrome. Patients with pantothenate kinase-associated neurodegeneration might show abnormal lipoprotein electrophoresis.
Magnetic resonance imaging (MRI) is useful for the diagnosis. MRI findings are present before overt clinical manifestation; brain volume and brain connections show changes several years before the onset of clinical manifestation. Adult-onset of HD is typically characterized by early striatal atrophy in the caudate. Cerebellar and cortical atrophy is seen later in the disease. MRI is important to help differentiate HD from all forms of spinocerebellar ataxia and can be used to aid in the diagnosis of juvenile HD from other metal accumulation disorders such as Wilson’s disease and aceruloplasminemia. However, several progressive HD-like syndromes are indistinguishable based on MRI findings. Both chorea-acanthocytosis and McLeod’s syndrome show caudate atrophy accompanied by the dilatation of the anterior horns of the lateral ventricle.
The gold standard for evaluation is genetic testing. This includes targeted testing of the CAG repeat size. A patient with 26 or fewer repeats is not associated with the HD phenotype. Allele sizes of 27-35 are not common and have not been associated with the HD phenotype. However, due to the instability of CAG, they may be at risk of having a child with an allele in the disease-causing range. Allele sizes of 36 to 39, also known as reduced penetrance HD-causing alleles, are at risk for developing HD but may not be symptomatic. It is common to find asymptomatic elderly patients with CAG repeats in this range. Allele size of 40 or more repeats is associated with the development of the disease.
Prenatal diagnosis is made with chorionic villi sampling, which is performed between the 10th to 12th week of pregnancy and amniocentesis between the 15th to 17th week, where DNA-testing can be carried out. The procedure is only done if the parents are already aware of their own genetic status. Preimplantation diagnosis is also offered in several countries during the last decade where a cell from the embryo in its eight-cell stage is removed for genetic testing. Analysis of monogenic disorders can be done by a polymerase chain reaction to amplify the DNA and to detect the repeat sizes of each chromosome. The eggs are harvested, fertilized in vitro, tested, and the embryo without the CAG repeats is then placed back in the mother’s womb for normal pregnancy to develop.
There is no cure for HD. However, many therapeutic options exist for treating signs and symptoms with the aim of improving the quality of life. Treatment is mainly pharmacological as well as supportive. Surgical management does not play an important role. There are many therapeutic and surgical options that have been evaluated for their efficacy in suppressing chorea, including dopamine antagonists, benzodiazepines, acetylcholinesterase, lithium, deep brain stimulation, and glutamate antagonists. These measures typically address the hyperkinetic movement disorders associated with HD, such as chorea, dystonia, and myoclonus. Adjunctive therapies, as well as behavioral plans and cognitive interventions, may also play a role and should be considered. It is important to consider the negative impact of the agent of the psychiatric disturbances associated with HD, such as depression, mania, irritability, or apathy.
In patients with the Westphal variant (bradykinesia and rigidity), antiparkinsonian medications can be considered, such as levodopa, dopamine agonists as well as amantadine. Botulinum injections can be considered for focal dystonia.
Behavioral and Psychiatric disturbances:
There is a wide range of behavioral and psychiatric issues in HD, such as aggression, depression, irritability, apathy, mania, and psychosis. Although selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants are commonly used in HD for the treatment of depression, anxiety, and obsessive-compulsive disorders, there is no convincing evidence of their use in HD. Non-pharmacological treatment should also be considered when possible, including environmental changes and therapy.
Supportive care with attention to diet, nursing, and special equipment is recommended. Smoking and alcohol use is discouraged.
Emotional support, as well as counseling, can provide relief to patients living with HD and their families.
New therapies under investigation:
The European Huntington disease network developed an international task force to provide evidence-based recommendations in the treatment of HD. This is to provide a standardized medical, surgical, and non-pharmacological treatment to improve the care and quality of life of patients. Their recommendations are summarized below.
Global motor capacities:
Language and communication:
Reduced lung function and respiratory muscle strength:
Huntington disease falls into a differential diagnosis for dementia, chorea, and psychiatric disturbances.
Non inherited conditions:
2) McLeod syndrome:
3) Pantothenate kinase-associated neurodegeneration:
4) Wilson disease:
5) Huntington disease-like 1:
6)Huntington disease-like 2:
7) Spinocerebellar ataxia type 17:
8) Dentatorubral-pallidoluysian atrophy:
Huntington disease is a neurodegenerative disease with no cure. The course of the disease commonly lasts 15 to 20 years. The CAG repeats not only provide information on the age of clinical onset but also predict the age of death. The larger the CAG repeat sizes, the greater is the rate of deterioration of motor, cognitive, and functional measures. The progression of the behavioral symptoms is not related to the size of CAG repeats. Homozygotes for fully penetrant HD have a similar age of onset to those that are heterozygotes but may show an accelerated rate of progression of the disease. The progression of the disease leads to a complete dependency in everyday life, ultimately resulting in full-time care and, finally, death. Pneumonia is the most frequent cause of death, which is followed by suicide.
There are numerous complications of Huntington disease.
Genetic counseling and predictive testing can be done for asymptomatic adults who are at risk of developing HD. This helps patients to make informed decisions with respect to the caregiver, finance, and reproduction. This also makes them eligible to participate in clinical trials. The optimal time to determine the genetic risk as well as discuss prenatal testing is before pregnancy. DNA banking, which is the storage of DNA, can also be done for possible future use. Psychiatric and psychological help is advised as the patients need to cope with the stressful situation of living with HD.
Patients with HD commonly have an affected parent.
Family history is negative if:
There is a 50% chance for each offspring of a patient with HD to develop the disease. Each child homozygous for the repeat will inherit an HD causing allele. An offspring of a patient with an intermediate allele are at risk of developing HD due to the instability of the repeats.
The risk of the child inheriting repeats greater than 35, depends on:
The management of HD is challenging and complex. While once the domain of the neurologist, today, it is realized that treatment may also require the expertise of a psychologist, psychiatrist, physiatrist, internist, family practitioner, and social worker. Periodic evaluations should be made to address the severity of chorea, gait problems, rigidity, behavioral changes, and cognitive decline. To improve outcomes, the European Huntington disease network provided evidence-based recommendations in the treatment of HD (See: treatment and management). They provide a standardized medical, surgical, and non-pharmacological treatment to improve the care and quality of life of patients.
The roles of the nurse, social worker, and pharmacist are critical. The nurses will assist the team by monitoring the patient for pain, atelectasis, and deep vein thrombosis. The social worker will provide the patient and the caregiver all the necessary help and equipment to improve the quality of life. The pharmacist will be involved in the multiple medication therapies needed for these patients to improve the symptoms. The need for meticulous planning and discussion with other professionals involved in the management of the patient is highly recommended to lower the morbidity and improve outcomes.
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