Continuing Education Activity
Huntington disease (HD), a neurodegenerative autosomal dominant disorder, is characterized by involuntary choreatic movements with cognitive and behavioral disturbances. This activity outlines an overview of Huntington disease with emphasis on etiology, pathophysiology, clinical features, and the differential diagnosis as well the role of the interprofessional team in the evaluation and treatment options in patients with Huntington disease.
- Identify the etiology of Huntington disease.
- Overview the evaluation of patients with Huntington disease.
- Outline the management options for Huntington disease.
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:
- Neuronal aggregates: Intracytoplasmic and intranuclear inclusions containing the mutant HTT are components of the proteolytic pathway in HD. Accumulation of these mutant protein aggregates could lead to an impairment of the ubiquitin-proteosome pathway.
- Transcriptional dysregulation.
- Excitotoxicity: This is due to a combination of increased glutamate as well as glutamate agonist release from the cortical afferents.
- Mitochondrial dysfunction and altered energy metabolism.
- Changes in axonal transport and synaptic dysfunction.
History and Physical
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.
- Motor disturbances: These include the characteristic unwanted involuntary movements which initially begins in the distal extremities and are of a smaller degree but could go on to affect the facial muscles as well. The movements then spread gradually to the more proximal and axial muscles and are of greater amplitude. Motor symptoms tend to be progressive. Early in the disease, they are mostly hyperkinetic with involuntary chorea. In later stages, however, hypokinesia with bradykinesia and dystonia predominate. The balance between chorea and hypokinesia varies from patient to patient and ranges from overwhelming rigidity in the younger patients, also known as the Westphal variant to older patients being severely affected in the later stages of the disease with rigidity and contractures in the extremities leading them to be bedridden. Dysarthria and dysphagia develop during the course of the disease, which could lead to aspiration in patients, with pneumonia being a common cause of death. Dystonia, characterized by increased muscle tone with slower movements, leads to abnormal posturing such as torticollis and can be the first sign of motor involvement in HD. Other involuntary features include tics and cerebellar signs such as ataxia. Pyramidal signs such as the Babinski sign are present. The motor disturbance on daily activities progresses over time and can lead to difficulties in walking, standing, and frequent falls.
- Behavioral and psychiatric symptoms: These are present very early in the disease, often even prior to the onset of motor symptoms. Behavioral and psychiatric symptoms are often consistent with frontal lobe dysfunction. Initially, patients may present with poor attention, impulsivity, and irritability. The irritability is often severe and leads to outbursts of anger and aggression. Later on in the disease, there is an emotional blandness with prominent apathy, loss of intuition, and creativity. The frontal lobe symptoms are likely due to the frontostriatal degeneration. The most common feature of the disease is apathy, which is progressive and manifests alongside progressive motor disturbances and cognitive decline. Depression is also commonly reported, but it is unclear whether these are due to the manifestation of the disease or underlying neural pathology. Suicide may occur between the time of gene testing and when a patient's dependence starts to increase. Psychosis can appear in later stages, which goes hand in hand with cognitive decline. Another prominent feature is the lack of insight into the nature of the symptoms they are experiencing. This includes a lack of awareness of all three domains of the disease (motor, cognitive, and psychiatric). Therefore, family members become a crucial source of information and should be involved in decision making and assessment.
- Cognitive disturbances: Cognitive decline is one of the main features of HD and could also be present before the onset of motor disturbances. The cognitive changes are more prominent for executive functions with patients finding difficulty in organizing, multitasking, and planning. These symptoms then progress with more cognitive deficits leading to dementia. Dementia in HD is subcortical in nature, and the memory loss originates from an inefficient search of memory rather than a deficient memory, and features such as apraxia and aphasia, which is common in cortical dementia are spared in HD. Psychomotor processes become severely slowed.
Other secondary symptoms include:
- Ataxia: Rarely occurs. Patients might exhibit mild degrees of cerebellar atrophy, and the presence of more severe cerebella dysfunction is suggestive of an alternate diagnosis.
- Gait abnormalities
- Eye movement abnormalities: Patients exhibit slow and hypometric gaze with a superimposed dysfunctional gaze. A mild form of oculomotor apraxia can also be seen.
- Seizures: these are only present in the juvenile variant, occurring in 30 to 50% of patients before the age of 10.
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.
Treatment / Management
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.
- The American Academy of Neurology guidelines recommends the use of tetrabenazine (TBZ), amantadine, or riluzole in managing chorea. TBZ reversibly inhibits the central monoamine transporter type 2, thereby selectively depleting dopamine than norepinephrine.
- The highest binding sites for TBZ are in the putamen, caudate nucleus, and the nucleus accumbens, which are known to be the most affected in HD.
- Potential side effects include depression, fatigue, akathisia, insomnia, and somnolence during titration of the drug. Depression is common in HD and can be exacerbated by using TBZ. Therefore, all patients need to be monitored for signs of depression as well as suicide ideation.
- Other medications that are commonly prescribed include dopamine antagonists, benzodiazepines as well as glutamate antagonists. Dopamine antagonists are considered in the management of chorea and psychosis. Apathy, as well as akathisia, are adverse effects of dopamine receptor blockers and therefore, can be problematic in patients with HD. Compounds containing L-Dopa might increase chorea.
- Due to their improved tolerability, atypical neuroleptics have been evaluated in the management. Olanzapine has been used in small studies to treat the motor symptoms. There are reports of risperidone in the treatment of chorea with tolerable adverse effects. Quetiapine has been tried in multiple trials with success on both the motor as well as psychiatric symptoms. Aripiprazole has been found to be of benefit in the treatment of chorea, equivalent to that of TBZ, However, similar to other typical and atypical neuroleptic agents, and it is associated with akathisia as well as tardive dyskinesia.
- Amantadine, an N-methyl D-aspartate antagonist, has been shown to significantly reduce chorea. However, a dose of 400 mg/day or higher is needed for symptomatic relief.
- Riluzole inhibits the striatal glutamate release, and its neuroprotective effects are being studied in large trials.
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.
- Gene therapy provides exciting and promising advances in the prevention of HD.
- The silencing of mutant genes provides an opportunity for treatment.
- This could either restore function by returning to normal neuronal circuits that are dysfunctional but not dead or could be neuroprotective with a lack of manifestation of the disease. Quantitative measures of brain regions such as striatum are good biomarkers for disease progression and are useful in the upcoming gene therapy studies.
New therapies under investigation:
- Pharmacological agents that are being studied include those that inhibit apoptosis, excitotoxicity, HTT aggregation as well as HTT proteolysis and phosphorylation, and oxidative damage. Compounds that modulate transcription, mitochondrial activity, and chaperone activity are also being investigated.
- Treatment options that have shown improvements in preclinical animal models and that have advanced to clinical trials include the following: minocycline, memantine, sodium butyrate, phosphodiesterase 10a inhibitor.
- Experimental therapies include pridopidine, laquinimod as well as a semaphorin-4D neutralizing antibody that are still in development.
- Gene silencing to target the cause of HD has been shown to be safe in preclinical animal studies. These aim to either silence all HTT expression non-selectively or selectively for the mutated HTT allele.
- Cell transplantation has shown variable results and safety, as well as the efficacy of intravenously injecting mesenchymal stem cells, is being tested. Recent studies suggest that the mutated HTT gene can spread into the allografted neural tissue.
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.
- Tetrabenazine (TBZ) is usually the first line [Level 1] of treatment unless the patient suffers from uncontrolled depression or suicidal ideation.
- In the case of depression or personality or behavioral changes, second-generation neuroleptics are the preferred line of treatment. [Level 2]
- Monotherapy is generally preferred as combination therapy greatly increased the risk of adverse effects.
- Active and passive physiotherapy is recommended to maintain the range of joint motion as well as limit the postural and musculoskeletal deformities and also prevent the development of contractures. [Llevel 3]
- Botulinum injections can be used to treat focal dystonia.
- The rigidity can be increased or induced with the use of neuroleptics or TBZ. A reduced dose or withdrawal should be considered in the overall benefit of the chorea/behavioral symptoms vs. the severity of rigidity.
- Levodopa can provide temporary relief, especially in juvenile cases. [Level 3] The daily dose is lower than that in Parkinson’s disease.
- Physiotherapy is recommended to prevent the development of contractures and joint deformity as well as maintain mobility. [Level 3]
- TBZ as well as neuroleptics and SSRI can induce akathisia, and reducing the dose or withdrawal may be of benefit. [Level 3]
- A referral to speech and language therapists is recommended at the onset of the disease. [Level 3]
- For severe disorders, the use of a percutaneous endoscopic gastrostomy may be considered.
- Treatment with sodium valproate or clonazepam, either alone or in combination, is recommended if functional capacity is impaired. [Level 3] Levetiracetam is an alternative. Benzodiazepines can be used with caution.
- Piracetam can be used in the case of myoclonus of cortical origin, not associated with epilepsy. [Level 3]
- Physiotherapy [Level 2], as well as the implementation of falls prevention programs, core stability, and balance interventions, are recommended. [Level 3]
- Pharmaceutical management of chorea aids in walking and therefore help in balance. [Level 3] However, they should be used with caution as the adverse effects can also aggravate walking disorders.
- The use of assistive walking devices such as a four-wheeled walker is recommended by physiotherapy or occupational therapist. [Level 2]
- Botulin toxin into masseter muscle is usually the first line of management. [Level 3]
- Customizes mouth guards can also be used, mostly in early-stage patients.
- Bruxism can also occur as a side effect of using neuroleptics or SSRI, and reducing their dose should be considered. [Level 3]
- The use of neuroleptics and TBZ may be beneficial but may aggravate bradykinesia. [Level 3]
- Physiotherapy and occupational therapy can be useful. [Level 2]
Global motor capacities:
- Physiotherapy is beneficial to the overall functional ability as well as independence and motor function in HD in combination with pharmacological options. [Level 2]
- No pharmacological management is recommended.
- Rehabilitation strategies such as speech therapy, occupational therapy can improve and stabilize cognitive functions.[Level 2]
- Treating anxiety and depression may improve executive functions. Rehabilitation helps with initiation and planning and improve cognitive stimulation. [Level 3]
- Neuroleptics and sedatives need to be monitored carefully.
- Cognitive stimulation is beneficial for the slowing down of processing of cognitive information and a prolongation in reaction time.
Language and communication:
- A referral to speech and language therapists early on is recommended. [Level 3]
- Communication techniques and strategies also include voice therapy, reduction of environmental distractions as well as allowing time for communication. Simple techniques, such as gestures or tools such as pens, can also be used.
- Establishing a daily routine may be of help.Speech therapy, as well as neuropsychology, may also be beneficial.
- Sedative drugs, neuroleptics, and TBZ may negatively impact memory.
- Keeping the environment safe with the use of padding furniture may be useful to minimize falls and shocks.
- Cognitive therapy and acceptance and commitment therapy may be of use.
- Psychotherapy and cognitive behavioral therapy are beneficial.
- Use of antidepressants such as selective SSRI or a serotonin noradrenaline reuptake inhibitor (SNRI). [Level 2]
- A psychiatrist should be consulted in patients with resistant depression or those with associated psychosis.
- Severe cases with resistance to oral medication, electroconvulsive therapy may be tried (level 3)
- Suicidal risk needs to be assessed in patients irrespective of the stage of the disease. Close attention should be made, especially from the time of diagnosis to when daily life is affected.
- Underlying risk factors such as depression, impulsiveness, and social isolation needs to be addressed.
- Behavioral strategies should be implemented.
- SSRI is the first line. [Level 3] If SSRI is ineffective, then a combination with Mirtazapine may be beneficial.
- Neuroleptics are recommended for patients with aggression. [Level 3]
- In the presence of overt aggression in association with depression, sedative antidepressants should be considered.
- Cognitive stimulation, as well as daily routines and programs with structured activities, is recommended.
- SSRI should be initiated in the presence of depression.
- The first line of treatment is SSRI or SNRI, especially when depression is present.
- Neuroleptics are alternatives in case of failure. [Level 3]
- SSRI may be used, especially in the presence of anxiety. [Level 3]
- Olanzapine and risperidone are also valuable. [Level 3]
- Second-generation neuroleptics are generally the first line. [Level 3]
- Clozapine is the first line in akinetic forms with Parkinsonian symptoms.
- Electroconvulsive therapy can be used in the failure of pharmacological therapies. [Level 3]
- If lifestyle modifications are ineffective, hypnotic agents can be used for short periods. Mirtazapine can be used.
- Carbamazepine may be of use in those with sudden bladder emptying without the presence of an urge.
- Antimuscarinic can be used in cases with an overactive bladder.
- A multidisciplinary approach is advised with dietitians to avoid cariogenic food. [Level 3]
- Instructions on good oral hygiene should be given to both patients as well as caregivers. [Level 3]
- Assessment by a dietitian is recommended. Factors such as mood, behavior as well as swallowing ability need to be considered as causes of weight loss. [Level 3]
- In cases of weight loss, high calorie, and protein supplements should be prescribed. [Level 3]
Reduced lung function and respiratory muscle strength:
- Home-based respiratory muscle training can be initiated. [Level 2]
Huntington disease falls into a differential diagnosis for dementia, chorea, and psychiatric disturbances.
Non inherited conditions:
- Tardive dyskinesia
- Cerebral lupus
- Levodopa-induced dyskinesia
- Group A beta-hemolytic streptococcus.
- Autosomal recessive.
- Due to mutations in the VPS13A gene, that codes for chorein, a protein involved in intracellular protein sorting.
- Clinical features include facio-bucco-linguo-masticatory chorea, dystonia, and dyskinesia that are aggravated by feeding, accompanied by tongue protrusion and self-mutilating tongue. Patients might also present with violent neck spasms with sudden flexion/extension.
- The progressive movement disorder, along with cognitive and behavioral changes are similar to HD. However, unlike HD, the presence of myopathy, acanthocytosis, as well as the mean age of onset of 30 years, are differentiating features
2) McLeod syndrome:
- X-linked recessive.
- It is caused by mutations in the XK gene.
- It affects the basal ganglia, muscles, myocardium, and peripheral nerves. Chorea may involve the facio-buccal region, but tongue or lip biting, dysphagia, or parkinsonism is rarely seen.
- Cognitive and psychiatric disturbances overlap with HD while the presence of acanthocytosis, compensated hemolysis, as well as McLeod blood group phenotype (absence of expression of Kell antigen on erythrocytes) help to distinguish it from HD.
3) Pantothenate kinase-associated neurodegeneration:
- Autosomal recessive.
- It is caused by mutations of the PANK2 gene, that codes for pantothenate kinase. This enzyme plays a role in the synthesis of coenzyme A from vitamin B5 and is associated with lipid metabolism.
- The age of onset is before 6 years and presents with generalized dystonia with bucco-facial and lingual involvement. Parkinsonism, choreoathetosis, and pyramidal signs might also be observed. A later onset of symptoms with lesser severe presentation might also be seen with rigidity, focal arm dystonia, or cognitive and behavioral problems.
4) Wilson disease:
- Presents with orofacial dystonia associated with parkinsonism in the setting of generalized dystonia that could pose a diagnostic challenge.
5) Huntington disease-like 1:
- Autosomal dominant.
- Range of clinical features that overlap with Huntington disease.
- Earlier onset of action, as well as slower progression, can be used as differentiating features.
6)Huntington disease-like 2:
- Autosomal dominant.
- These are clinically indistinguishable from HD.
- Prevalence is highest among and exclusive to patients of African descent
7) Spinocerebellar ataxia type 17:
- Autosomal dominant.
- Overlapping features with HD include chorea, dementia, and psychiatric disturbances. Cerebellar ataxia is a prominent movement disorder.
8) Dentatorubral-pallidoluysian atrophy:
- Autosomal dominant.
- Also presents with progressive movement disorders and dementia, psychiatric disturbances are common.
- Ataxia and myoclonus are more prominent movement disorders.
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.
- Patients with dystonia, as well as swallowing difficulties, might experience accelerated complications and, therefore, a shorter life span.
- Chorea with larger amplitude can lead to injury and poor positioning. It can also lead to fractures and head trauma.
- The cause of death is usually related to complications arising from immobility such as pneumonia, cardiac disease, or infection.
- Twenty-five percent of the patients attempt suicide.
- Behavioral issues can be severely disabling, causing distress not only to the patient but to the family and caregivers.
Deterrence and Patient Education
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.
Pearls and Other Issues
Patients with HD commonly have an affected parent.
Family history is negative if:
- Failure to recognize the disease.
- The early death of a parent.
- Presence of intermediate allele (27 to 35 CAG repeat) with reduced penetrance.
- Late-onset of disease in the parent.
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:
- Size of the CAG allele, larger the size, more is the chance for expansion.
- Intermediate alleles that are inherited paternally are more prone to CAG expansions.
- Repeats that are interrupted by CAA and CCG are more stable.
Enhancing Healthcare Team Outcomes
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.