Huntington Disease

Etiology

Huntington disease is an autosomal dominant inherited neurodegenerative 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 crucial role in synaptic function in the postembryonic period. The HTT protein is thought to have antiapoptotic functions and protect against the toxic mutant HTT. Limited evidence has demonstrated that the mutant protein leads to both a toxic gain of function and a mutant loss of function. Intranuclear and intracytoplasmic inclusions are found in several areas of the brain. However, whether the inclusions themselves play a role in the pathogenesis or if they are pathogenic is unknown. Brain atrophy, particularly in the striatum with associated extensive neuronal loss, is well-known pathologically.

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. A repeat length of 26 or less is normal. Patients with alleles in the range of 27 to 35 do not show the disease phenotype but are prone to repeat instability and may expand into the disease-causing range with transmission. An inverse correlation between the length of the repeats and the age of onset of clinical manifestation has been established. A repeat length of 36 to 39 may result in the development of Huntington disease, yet not in all cases, ie, reduced penetrance. A repeat length of ≥40 is almost always completely penetrant and will result in Huntington disease symptomatology.[1] Similar to other trinucleotide (triplet) repeat inherited disorders, a phenomenon of anticipation occurs. In Huntington disease, the anticipation phenomenon is seen mainly in the paternal line of inheritance, which arises due to the instability of the CAG repeats during spermatogenesis.[2][4] Anticipation leads to longer triplet repeats and earlier clinical manifestations in subsequent generations. 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 3 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.[5]

Epidemiology

Huntington disease is a rare neurodegenerative disorder with a worldwide prevalence of 2.7 per 100,000. A high prevalence of 10.6 to 13.7 per 100,000 is observed among populations of Caucasian descent. The prevalence is much lower for Asian and African nations. The prevalence varies amongst geographical locations by more than 10-fold. These differences are largely attributed to ethnic differences in the CAG repeat length. An average CAG repeat length of 18.4 to 18.7 in people of Caucasian descent versus 17.5 to 17.7 in people of East Asian descent has been noted. Over the past decades, the overall prevalence also increased due to longer lifespans and more accurate genetic tests.[6][7][8]

Pathophysiology

Huntington disease is a classical monogenic autosomal dominant inherited disease with complete penetrance. However, the pathogenic mechanisms are still relatively unknown, mainly due to the ubiquitous expression of the HTT protein across most tissue types and its varied roles in multiple molecular pathways. Genetic modifiers may alter the age of onset. Current proposed mechanisms focus on either a toxic gain of function of the mutant HTT (mHTT) or a dominant loss of the wild-type HTT protein. 

The primary feature is the degeneration of neurons of the striatum, ie, the putamen and the caudate. Pathologically, the striatum's medium spiny neurons (MSN) are most affected in patients with Huntington disease. About 95% of the MSN in the striatum are GABAergic projecting into the globus pallidus external. Throughout Huntington disease, over 90% of these GABAergic neurons degenerate, whereas the remaining 5% of the striatal interneurons are relatively spared.[9]

Huntington disease is largely characterized pathologically by the degeneration of MSN in the striatum; neurodegeneration and cell death are also seen in other brain areas, especially throughout the cerebral cortex. Loss of pyramidal cortical neurons may result in predominant motor symptoms of Huntington disease. The involvement of the cingulate gyrus is associated with emotion and mood disturbances. Other affected brain regions may include the globus pallidus, cerebellum, amygdala, and hippocampus.[10][11][12]

Multiple theories in the pathogenesis of Huntington disease exist, and more than one process can occur at the same time, including:

• Neuronal aggregates
  • Intracytoplasmic and intranuclear inclusions containing the mutant HTT are components of the proteolytic pathway in Huntington disease.
  • 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 and glutamate agonist release from the cortical afferents.
• Mitochondrial dysfunction and altered energy metabolism
• Neuroinflammation
• Changes in axonal transport and synaptic dysfunction [4][1][6][4]

History and Physical

The disease tends to affect patients between the ages of 30 to 50. The signs and symptoms classically consist of the triad of motor, cognitive, and psychiatric disturbances. Other less common features include weight loss, sleep disturbances, and autonomic nervous system dysfunction.[6]

Clinical Features of Huntington Disease

Motor disturbances

These include the characteristic unwanted involuntary movement of chorea, which initially begins in the distal extremities and is 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 primarily hyperkinetic with involuntary chorea. In later stages, however, hypokinesia with bradykinesia and dystonia may predominate. The balance between chorea and hypokinesia varies from patient to patient. These motor disturbances range 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 (eg,  torticollis) and can be the first sign of motor involvement in Huntington disease. Other involuntary features include tics and cerebellar signs of ataxia. Pyramidal signs (eg, the Babinski sign) are present. The motor disturbance in daily activities progresses over time, leading to difficulties in walking, standing, and frequent falls.

Behavioral and psychiatric symptoms

Behavioral and psychiatric symptoms are present very early in the disease, often even before the onset of motor manifestations. Behavioral and psychiatric symptoms are usually 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 in the disease, an emotional blandness with prominent apathy, loss of intuition, and creativity is demonstrated. The frontal lobe symptoms are likely due to frontostriatal degeneration.[11] 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 this is 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 3 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 Huntington disease and could also be present before the onset of motor disturbances. The cognitive changes are more prominent for executive functions, with patients having difficulty organizing, multitasking, and planning. These symptoms then progress with more cognitive deficits, leading to dementia. Dementia in Huntington disease is subcortical, and memory loss originates from an inefficient search of memory rather than a deficient memory. Features such as apraxia and aphasia, which are common in cortical dementia, are spared in Huntington disease. Psychomotor processes become severely slowed.[11]

Other secondary symptoms include:

• Ataxia: This symptom is rare; however, patients might exhibit mild degrees of cerebellar atrophy. More severe cerebella dysfunction suggests 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 and occur in 30% to 50% of patients before age 10.

Clinical Course and Classification

Overall, clinical features of Huntington disease have a mean age of onset of 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. Affected patients are generally able to perform their daily activities. Eventually, the chorea progresses, making performing voluntary activities increasingly difficult. Intermittent bursts of aggressive behavior and social disinhibition may be noted. Although patients can maintain some degree of independence, most depend on their caregivers for help.

In the later stages of the disease, severe motor disability is noted, and patients are entirely 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 in them, and they often exhibit a benign and more prolonged course than typical patients.[4] The following classification is used for Huntington's disease:

• Presymptomatic Huntington disease
  • The disease is genetically confirmed, or clinical risk is present for patients with unconfirmed disease.
  • No signs or symptoms of motor or cognitive disturbances are noted.
  • Patients may have changes noted on neuroimaging.
  • Generally, no symptomatic treatment is indicated.
• Prodromal Huntington disease
  • The disease is genetically confirmed, or clinical prodromes are present for patients with unconfirmed disease.
  • Patients exhibit subtle motor and cognitive disturbances.
  • Behavioral changes, such as apathy and depression, might be present.
  • Changes on imaging studies are seen.
  • Patients may require symptomatic treatment. 
• Manifestation of Huntington disease
  • The disease is genetically confirmed, or clinical manifestations are present in patients with unconfirmed disease.
  • Prominent motor and cognitive disturbances that interfere with the quality of life are seen.
  • Symptomatic and disease-modifying treatments should be initiated.

Juvenile Huntington disease

In patients with juvenile Huntington disease, symptom onset occurs before the age of 20. The length of CAG repeats is more than 55. Motor, cognitive, and psychiatric disturbances exhibited in adult Huntington disease are also seen in the juvenile form, but the clinical presentation is different. Most often, behavioral disturbances and learning difficulties are the first signs 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 seizures are commonly observed. Severe mental deterioration, as well as cerebellar symptoms associated with motor, speech, and language delay, are characteristics of juvenile Huntington disease. In teenagers, the manifestation of the disease is similar to adult Huntington disease, where chorea and severe behavioral disturbances are often the initial presentations.[2][13][14]

Evaluation

The diagnosis is made on clinical features in a patient with a parent diagnosed with Huntington disease. The presence of motor symptoms with or without psychiatric and cognitive disturbances or usually a combination of all 3 in the presence of a positive family history is normally sufficient for a diagnosis. 

Laboratory Studies

Basic investigations should be performed before genetic testing is performed. Laboratory testing becomes particularly useful to differentiate Huntington disease from other progressive hereditary Huntington disease-like syndromes. An increase in creatine kinase and liver enzymes is frequently seen in chorea-acanthocytosis and McLeod syndrome. Patients with pantothenate kinase-associated neurodegeneration might show abnormal lipoprotein electrophoresis.

Imaging Studies

Magnetic resonance imaging (MRI) is useful for the diagnosis of Huntington disease. 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 Huntington disease is typically characterized by early striatal atrophy in the caudate. Cerebellar and cortical atrophy is seen later in the disease.

Additionally, MRI is necessary to help differentiate Huntington disease from all forms of spinocerebellar ataxia and can be used to help diagnose juvenile Huntington disease from other metal accumulation disorders, eg, Wilson’s disease and aceruloplasminemia. However, several progressive Huntington disease-like syndromes are indistinguishable based on MRI findings. Both chorea-acanthocytosis and McLeod syndrome show caudate atrophy accompanied by the dilatation of the anterior horns of the lateral ventricle.[15] Regular MRI imaging may show changes, especially with striatal atrophy, before clinical manifestations of Huntington disease. Diffusion MRI may be useful to identify and track the progression of microstructural anomalies and organization deficits in Huntington disease decades before clinical disease onset.[16]

Genetic Testing

The gold standard for evaluation is genetic testing, which is targeted testing of the CAG repeat size. A patient with 26 or fewer repeats is not associated with the Huntington disease phenotype. Allele sizes of 27 to 35 are also not associated with the Huntington disease 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 Huntington disease-causing alleles, are at risk for developing Huntington disease but may not be symptomatic. Finding asymptomatic elderly patients with CAG repeats in this range is common. An allele size of ≥40 repeats is associated with the clinical development of the disease.

Prenatal diagnosis is made with chorionic villi sampling, which is performed between 10 and 12 weeks gestation pregnancy, and amniocentesis between 15 and 17 weeks gestation, where DNA testing can be carried out. The procedure is only performed if the parents know their genetic status. Preimplantation diagnosis has also been offered in several countries during the last decade, where a cell from the embryo in its 8-cell stage is removed for genetic testing. A polymerase chain reaction can analyze monogenic disorders to amplify the DNA and detect the repeat sizes of each chromosome. The eggs are harvested, fertilized in vitro, and tested, and the embryo without the CAG repeats is then placed back in the mother’s womb for normal pregnancy to develop.[2][13][17][18][19]

Treatment / Management

Huntington disease has no known curative treatment, and clinical trials in humans have been unsuccessful in altering the course of the disease. The problems are related to variability in clinical phenotypes, lack of reliable clinical endpoints, and the late onset of clinical symptoms. Furthermore, given its late onset of symptoms, cell death and neurodegeneration that are too advanced have occurred before treatments can be delivered and accessed.

The European Huntington Disease Network (EHDN) commissioned an international task force to provide global evidence-based recommendations for everyday clinical practice for managing patients with Huntington disease to provide a standardized medical, surgical, and nonpharmacological treatment to improve patients' care and quality of life.[20] Current Huntington disease treatments are therefore targeted mainly towards the major symptoms, including vesicular monoamine transporter (VMAT2) inhibitors and antipsychotics for abnormal movements, NMDA receptor antagonists for cognitive impairment, antioxidants against mitochondrial dysfunction, and autophagy inducers to remove toxic mHTT protein.[6][21] Unfortunately, no effective medication has been consistently found for patients with Huntington disease except those for treating their abnormal motor symptoms or movements.

Abnormal Movement Therapies

Chorea and other motor symptoms

Medications to treat chorea and other motor symptoms mainly target the dopaminergic pathways. The most commonly used and FDA-approved medications are the VMAT2 inhibitors. These medications decrease dopamine's bioavailability in the synapses and dopamine effects and include tetrabenazine, deutetrabenazine, and valbenazine. These medications effectively improve motor functions, especially in reducing dyskinetic movements of chorea. Potential adverse effects include depression, fatigue, akathisia, insomnia, and somnolence during titration of the drug. Depression is common in Huntington disease and can be exacerbated by using these VMAT2 inhibitors. Therefore, all patients need to be monitored for signs of depression as well as suicide ideation.

Antipsychotics are commonly prescribed off-label for chorea, psychiatric symptoms, sleep disturbances, and weight loss, yet evidence to support their therapeutic use is inconsistent. Atypical neuroleptics are more commonly used due to their improved tolerability. Olanzapine has been used in small studies to treat motor symptoms. The use of risperidone in the treatment of chorea has been reported with tolerable adverse effects. Quetiapine has been tried in multiple trials with success on both the motor as well as psychiatric symptoms. Aripiprazole is beneficial in the treatment of chorea, equivalent to tetrabenazine. However, similar to other neuroleptics, their use is associated with extrapyramidal adverse effects, including akathisia and tardive dyskinesia.[22]

Parkinsonism

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.

Treatments Targeting Excitotoxicity and Cognitive Impairment

NMDA receptor antagonists such as memantine have been tried with no concluding efficacy.[23] Riluzole and amantadine also showed limited efficacy. No pharmacological agent is effective or indicated for cognitive impairment in Huntington disease.(B3)

Behavioral and Psychiatric Disturbances

A wide range of behavioral and psychiatric issues are present in Huntington disease, including aggression, depression, irritability, apathy, mania, and psychosis. Although selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants are commonly used in Huntington disease for the treatment of depression, anxiety, and obsessive-compulsive disorders, no convincing evidence of their use in Huntington disease has been documented. Nonpharmacological treatment, including environmental changes and therapy, should also be considered when possible.

Supportive Management

Supportive care with attention to diet, nursing, and special equipment is recommended in the treatment of Huntington disease. Furthermore, smoking and alcohol use is discouraged. Emotional support, as well as counseling, can provide relief to patients living with Huntington disease and their families.

Therapies Under Investigation

Pharmacological agents being studied include those that inhibit apoptosis, excitotoxicity, HTT aggregation, 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 have advanced to clinical trials include minocycline, memantine, sodium butyrate, and a phosphodiesterase 10a inhibitor. Experimental therapies still in development include pridopidine, laquinimod, and a semaphorin-4D neutralizing antibody.

Gene silencing to target the cause of Huntington disease has been shown to be safe in preclinical animal studies. These aim to silence all HTT expression nonselectively or selectively for the mutated HTT allele. Cell transplantation has shown variable results and safety, and 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.[4]

Differential Diagnosis

The clinical diagnosis of Huntington disease is generally very straightforward when a positive family history is noted and the presence of motor features of choreiform movements. Any combination of the clinical triad of motor, behavioral, and cognitive dysfunction among adult patients but not elderly onset should prompt the diagnosis. When the diagnosis is suspected clinically, genetic testing will confirm the diagnosis. As a consequence, not many differential diagnoses need to be considered. The essential diagnoses to exclude include the following inherited motor or basal ganglia disorders:

• Chorea-acanthocytosis (autosomal recessive)
  • Chorea-acanthocytosis occurs 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, is similar to Huntington disease. However, unlike Huntington disease, the presence of myopathy and acanthocytosis and the mean age of onset of 30 years are differentiating features.
• McLeod syndrome (X-linked recessive)
  • Mutations in the XK gene cause this syndrome.
  • McLeod syndrome affects the basal ganglia, muscles, myocardium, and peripheral nerves. Chorea may involve the facial-buccal region, but tongue or lip biting, dysphagia, or parkinsonism are rarely seen.
  • Cognitive and psychiatric disturbances overlap with Huntington disease, while acanthocytosis, compensated hemolysis, and the McLeod blood group phenotype (absence of expression of Kell antigen on erythrocytes) help distinguish it from Huntington disease.
• Pantothenate kinase-associated neurodegeneration (autosomal recessive)
  • This disorder is caused by mutations of the PANK2 gene that codes for pantothenate kinase. This enzyme plays a role in synthesizing coenzyme A from vitamin B5 and is associated with lipid metabolism.
  • Onset typically occurs before the age of 6 years, and the patient presents with generalized dystonia with buccal-facial and lingual involvement. Parkinsonism, choreoathetosis, and pyramidal signs might also be observed. A later onset of symptoms with a less severe presentation might also be seen with rigidity, focal arm dystonia, or cognitive and behavioral problems.
• Wilson disease: Presents with orofacial dystonia associated with parkinsonism in the setting of generalized dystonia that could pose a diagnostic challenge.
• Spinocerebellar ataxia syndromes (mostly autosomal dominant): Overlapping features with Huntington disease include chorea, dementia, and psychiatric disturbances. Cerebellar ataxia is a prominent movement disorder.[4][13]

Prognosis

Huntington disease is a neurodegenerative disease with no cure. The course of the disease commonly lasts 15 to 20 years. The CAG repeats provide information on the age of clinical onset and predict the age of death. The larger the CAG repeat sizes, the greater the rate of deterioration of motor, cognitive, and functional measures. The progression of behavioral symptoms is unrelated to the size of CAG repeats. Homozygotes for fully penetrant Huntington disease 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 patients who are completely dependent in everyday life, ultimately resulting in full-time care and, finally, death. Aspiration pneumonia is the most frequent cause of death, which is followed by suicide.[2][4]

Complications

Complications of Huntington disease include:

• 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, eg, pneumonia, cardiac disease, or infection.
• Approximately 25% of the patients attempt suicide.
• Behavioral issues can be severely disabling, causing distress not only to the patient but to the family and caregivers.[24]