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Huntington Disease

Huntington disease (HD) is a progressive neurodegenerative disorder with an autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance mode of inheritance and poor prognosis Prognosis A prediction of the probable outcome of a disease based on a individual's condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas. It is caused by cytosine Cytosine A pyrimidine base that is a fundamental unit of nucleic acids. Nucleic Acids- adenine Adenine A purine base and a fundamental unit of adenine nucleotides. Nucleic Acids- guanine Guanine Nucleic Acids (CAG) trinucleotide repeats in the huntingtin gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics (HTT). The most common clinical presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor in adulthood is a movement disorder known as chorea: abrupt, involuntary movements of the face, trunk, and limbs. Psychiatric and cognitive features are also characteristic, and patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with HD are at an increased risk for suicide Suicide Suicide is one of the leading causes of death worldwide. Patients with chronic medical conditions or psychiatric disorders are at increased risk of suicidal ideation, attempt, and/or completion. The patient assessment of suicide risk is very important as it may help to prevent a serious suicide attempt, which may result in death. Suicide throughout the course of the disease. The diagnosis is primarily clinical, often with a positive family history Family History Adult Health Maintenance followed by genetic confirmation. Management by an interdisciplinary team is supportive, with the goal of maintaining quality Quality Activities and programs intended to assure or improve the quality of care in either a defined medical setting or a program. The concept includes the assessment or evaluation of the quality of care; identification of problems or shortcomings in the delivery of care; designing activities to overcome these deficiencies; and follow-up monitoring to ensure effectiveness of corrective steps. Quality Measurement and Improvement of life. Treatment of depression, agitation Agitation A feeling of restlessness associated with increased motor activity. This may occur as a manifestation of nervous system drug toxicity or other conditions. St. Louis Encephalitis Virus, and psychosis is the 1st priority for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with Huntington disease over the treatment of chorea.

Last updated: 29 Nov, 2021

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Definition

Huntington disease (HD) is an inherited and progressive neurodegenerative disorder that causes a choreiform movement disorder, unsteady gait Gait Manner or style of walking. Neurological Examination, and depression.

Epidemiology

  • Age of onset is between 20 and 50 years, with an average of 40 years.
  • Worldwide prevalence Prevalence The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. Measures of Disease Frequency is 2.7 cases per 100,000 people.
  • No gender Gender Gender Dysphoria predominance
  • Affects all races and ethnic groups
  • Juvenile HD can present before age 20.
  • Tendency for paternal transmission: 70%–88% of children with juvenile HD inherit the gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics from their father.

Etiology

Huntington disease is caused by an autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance genetic alteration in the huntingtin gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics (HTT) present on chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 4p.

  • Every child of a parent with HD has a 50/50 chance of inheriting the expanded gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics.
  • Expansion of the cytosine Cytosine A pyrimidine base that is a fundamental unit of nucleic acids. Nucleic Acids adenine Adenine A purine base and a fundamental unit of adenine nucleotides. Nucleic Acids guanine Guanine Nucleic Acids (CAG) repeat number over successive generations → HD presents earlier and becomes more severe

Pathophysiology

HD is caused by CAG trinucleotide repeats in the HTT gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics

Normal physiology 

  • In the basal ganglia Basal Ganglia Basal ganglia are a group of subcortical nuclear agglomerations involved in movement, and are located deep to the cerebral hemispheres. Basal ganglia include the striatum (caudate nucleus and putamen), globus pallidus, substantia nigra, and subthalamic nucleus. Basal Ganglia: Anatomy: Equilibrium Equilibrium Occurs when tumor cells survive the initial elimination attempt These cells are not able to progress, being maintained in a state of dormancy by the adaptive immune system. In this phase, tumor immunogenicity is edited, where T cells keep selectively attacking highly immunogenic tumor cells.This attack leaves other cells with less immunogenicity to potentially develop resistance to the immune response. Cancer Immunotherapy is maintained between direct and indirect pathways to facilitate normal motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology movements.
    • Direct pathway: dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS → excitatory connections with the thalamic neurons Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. Nervous System: Histology → activate the motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology cortex → facilitates movement
    • Indirect pathway: dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS → inhibitory effect → inhibits thalamic neurons Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. Nervous System: Histology → inhibits motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology cortex → inhibits movement
  • In the striatum Striatum Striped gray matter and white matter consisting of the neostriatum and paleostriatum (globus pallidus). It is located in front of and lateral to the thalamus in each cerebral hemisphere. The gray substance is made up of the caudate nucleus and the lentiform nucleus (the latter consisting of the globus pallidus and putamen). The white matter is the internal capsule. Basal Ganglia: Anatomy: degeneration → loss of GABAergic neurons Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. Nervous System: Histology → imbalance between dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS and GABA GABA The most common inhibitory neurotransmitter in the central nervous system. Receptors and Neurotransmitters of the CNS → abnormal movements

Pathophysiology

  • The huntingtin protein is physiologically expressed throughout the body tissues and brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification; its function remains unexplained. Pathophysiology in HD is limited to the CNS.
  • CAG triplet repeats on chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 4—normally encode the protein huntingtin
    • Normal CAG repeats are 27 or less in the HTT gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics.
    • The threshold Threshold Minimum voltage necessary to generate an action potential (an all-or-none response) Skeletal Muscle Contraction for developing HD is 36 repeats.
    • The length of the CAG repeats correlates with the severity of the disease symptoms.
  • Mechanism of anticipation is unique to HD: increases in the number of repeats → earlier age of onset in subsequent generations → increased severity of disease
  • Toxic gain-of-function mechanism:
    • The mutant form of the protein gains a deleterious function, which leads to clinical HD.
    • Abnormal HTT protein fragments undergo misfolding and aggregation Aggregation The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin; collagen) and is part of the mechanism leading to the formation of a thrombus. Coagulation Studies.
      • Fibrillar aggregates → form neuronal inclusion bodies 
      • Neurodegeneration → begins in caudate, putamen of basal ganglia Basal Ganglia Basal ganglia are a group of subcortical nuclear agglomerations involved in movement, and are located deep to the cerebral hemispheres. Basal ganglia include the striatum (caudate nucleus and putamen), globus pallidus, substantia nigra, and subthalamic nucleus. Basal Ganglia: Anatomy, and cortex → eventually involves the whole brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification → neuronal death
  • Heightened susceptibility in the striatum Striatum Striped gray matter and white matter consisting of the neostriatum and paleostriatum (globus pallidus). It is located in front of and lateral to the thalamus in each cerebral hemisphere. The gray substance is made up of the caudate nucleus and the lentiform nucleus (the latter consisting of the globus pallidus and putamen). The white matter is the internal capsule. Basal Ganglia: Anatomy to the abnormal protein causes symptoms of abnormal movements.
Huntington disease genetics

Cytosine Cytosine A pyrimidine base that is a fundamental unit of nucleic acids. Nucleic Acids adenine Adenine A purine base and a fundamental unit of adenine nucleotides. Nucleic Acids guanine Guanine Nucleic Acids (CAG) repeat expansion in the huntingtin gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics (HTT) resulting in Huntington disease

Image: “Huntington’s disease patient” by National Institute of Standards and Technology. License: Public Domain

Clinical Presentation and Diagnosis

Huntington disease affects generations of family members and typically spans several decades. The symptoms can be motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology, cognitive, and behavioral.

Clinical presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor

  • Motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology manifestations:
    • Huntington’s chorea = the cardinal feature of HD
      • Abrupt, involuntary, “dance-like” movements involving the face, trunk, and extremities
      • Later involves diaphragm Diaphragm The diaphragm is a large, dome-shaped muscle that separates the thoracic cavity from the abdominal cavity. The diaphragm consists of muscle fibers and a large central tendon, which is divided into right and left parts. As the primary muscle of inspiration, the diaphragm contributes 75% of the total inspiratory muscle force. Diaphragm: Anatomy, larynx Larynx The larynx, also commonly called the voice box, is a cylindrical space located in the neck at the level of the C3-C6 vertebrae. The major structures forming the framework of the larynx are the thyroid cartilage, cricoid cartilage, and epiglottis. The larynx serves to produce sound (phonation), conducts air to the trachea, and prevents large molecules from reaching the lungs. Larynx: Anatomy, and pharynx Pharynx The pharynx is a component of the digestive system that lies posterior to the nasal cavity, oral cavity, and larynx. The pharynx can be divided into the oropharynx, nasopharynx, and laryngopharynx. Pharyngeal muscles play an integral role in vital processes such as breathing, swallowing, and speaking. Pharynx: Anatomy dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming “stuck.” Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia and dysarthria Dysarthria Disorders of speech articulation caused by imperfect coordination of pharynx, larynx, tongue, or face muscles. This may result from cranial nerve diseases; neuromuscular diseases; cerebellar diseases; basal ganglia diseases; brain stem diseases; or diseases of the corticobulbar tracts. The cortical language centers are intact in this condition. Wilson’s Disease
    • Athetosis: involuntary writhing movements involving hands, fingers
    • Signs on physical exam:
      • Nystagmus Nystagmus Involuntary movements of the eye that are divided into two types, jerk and pendular. Jerk nystagmus has a slow phase in one direction followed by a corrective fast phase in the opposite direction, and is usually caused by central or peripheral vestibular dysfunction. Pendular nystagmus features oscillations that are of equal velocity in both directions and this condition is often associated with visual loss early in life. Albinism
      • Reduction in velocity of saccadic eye movements Saccadic Eye Movements Internuclear Ophthalmoplegia
      • Hyperreflexia
      • Rigidity Rigidity Continuous involuntary sustained muscle contraction which is often a manifestation of basal ganglia diseases. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity. Megacolon
      • Dystonia Dystonia Dystonia is a hyperkinetic movement disorder characterized by the involuntary contraction of muscles, resulting in abnormal postures or twisting and repetitive movements. Dystonia can present in various ways as may affect many different skeletal muscle groups. Dystonia
      • Tics Tics Habitual, repeated, rapid contraction of certain muscles, resulting in stereotyped individualized actions that can be voluntarily suppressed for only brief periods. They often involve the face, vocal cords, neck, and less often the extremities. Examples include repetitive throat clearing, vocalizations, sniffing, pursing the lips, and excessive blinking. Tics tend to be aggravated by emotional stress. When frequent they may interfere with speech and interpersonal relations. Conditions which feature frequent and prominent tics as a primary manifestation of disease are referred to as tic disorders. Tics and Tourette Syndrome
  • Cognitive/behavioral symptoms: present early in the course of the illness 
    • Memory Memory Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. Psychiatric Assessment deficits
    • Diminished decision-making ability
    • Affective disturbances
      • Personality changes
      • Irritability
    • Mood disturbances
      • Depression is common.
      • Suicidal ideation Suicidal ideation A risk factor for suicide attempts and completions, it is the most common of all suicidal behavior, but only a minority of ideators engage in overt self-harm. Suicide is a major concern.
    • Dementia Dementia Major neurocognitive disorders (NCD), also known as dementia, are a group of diseases characterized by decline in a person’s memory and executive function. These disorders are progressive and persistent diseases that are the leading cause of disability among elderly people worldwide. Major Neurocognitive Disorders/psychosis
    • Aggression Aggression Behavior which may be manifested by destructive and attacking action which is verbal or physical, by covert attitudes of hostility or by obstructionism. Oppositional Defiant Disorder/ impulsivity Impulsivity Attention Deficit Hyperactivity Disorder
    • Apathy Apathy Lack of emotion or emotional expression; a disorder of motivation that persists over time. Wernicke Encephalopathy and Korsakoff Syndrome
  • Atypical neurologic symptoms:
    • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
    • Ataxic gait Gait Manner or style of walking. Neurological Examination
    • Dystonia Dystonia Dystonia is a hyperkinetic movement disorder characterized by the involuntary contraction of muscles, resulting in abnormal postures or twisting and repetitive movements. Dystonia can present in various ways as may affect many different skeletal muscle groups. Dystonia
    • Parkinsonism Parkinsonism West Nile Virus
  • Other symptoms:
  • Juvenile-onset HD
    • Minimal or no chorea
    • May have myoclonus Myoclonus Involuntary shock-like contractions, irregular in rhythm and amplitude, followed by relaxation, of a muscle or a group of muscles. This condition may be a feature of some central nervous system diseases; (e.g., epilepsy-myoclonic). Nocturnal myoclonus is the principal feature of the nocturnal myoclonus syndrome. Neurological Examination and seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
    • Children have a more rapidly progressive disease.

Diagnosis

  • Based on clinical history and pattern of movement disorders exhibited by the patient 
  • Family history Family History Adult Health Maintenance: highly significant in diagnosing HD
  • Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies:
    • > 36 CAG repeats in genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies of the HTT gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics confirm the diagnosis.
    • 99% sensitive and 100% specific for HD
    • Indicated for symptomatic patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with or without a positive family history Family History Adult Health Maintenance
  • Imaging with MRI/CT scan:
    • Caudate atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation correlates with changes in cognitive function.
    • Hydrocephalus Hydrocephalus Excessive accumulation of cerebrospinal fluid within the cranium which may be associated with dilation of cerebral ventricles, intracranial. Subarachnoid Hemorrhage ex vacuo = compensatory enlargement of the lateral ventricles Lateral ventricles Cavity in each of the cerebral hemispheres derived from the cavity of the embryonic neural tube. They are separated from each other by the septum pellucidum, and each communicates with the third ventricle by the foramen of monro, through which also the choroid plexuses (choroid plexus) of the lateral ventricles become continuous with that of the third ventricle. Ventricular System: Anatomy

Progression

  • Slow and continual deterioration:
    • Early stage:
      • Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship are generally functional and independent.
      • Able to drive
    • Middle stage: 
      • Lose the ability to work, drive, or manage their own finances
      • Most patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship need help with activities of daily living.
      • Impairments in balance and walking → falls
    • Late stage: 
      • Can last a decade or more
      • Severe loss of motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology and cognitive function
      • Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship require 24-hour care.
  • Average length of survival is 10–20 years from the onset of HD but may be longer.

Management

Management of HD includes medical and psychological support to manage symptoms and maintain quality Quality Activities and programs intended to assure or improve the quality of care in either a defined medical setting or a program. The concept includes the assessment or evaluation of the quality of care; identification of problems or shortcomings in the delivery of care; designing activities to overcome these deficiencies; and follow-up monitoring to ensure effectiveness of corrective steps. Quality Measurement and Improvement of life. Treatment of depression, agitation Agitation A feeling of restlessness associated with increased motor activity. This may occur as a manifestation of nervous system drug toxicity or other conditions. St. Louis Encephalitis Virus, and psychosis is the 1st priority for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with HD over the treatment of chorea.

Treatment

  • Multidisciplinary approach:
  • Medications for chorea/hyperkinetic movements in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship without depression:
    • Vesicular monoamine transporter 2 (VMAT2) inhibitors:
      • Tetrabenazine or deutetrabenazine
      • The precise mechanism is unknown but believed to be related to its effect as a reversible depletor of monoamines (e.g., dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS, serotonin Serotonin A biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Receptors and Neurotransmitters of the CNS, norepinephrine Norepinephrine Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus. Receptors and Neurotransmitters of the CNS, and histamine) from nerve terminals.
      • Can increase the risk of depression and suicidal thoughts and behavior in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with HD
      • Must balance the risks of depression and suicidality with the clinical need for control of chorea
    • 2nd-generation antipsychotics: risperidone Risperidone A selective blocker of dopamine D2 receptors and serotonin 5-HT2 receptors that acts as an atypical antipsychotic agent. It has been shown to improve both positive and negative symptoms in the treatment of schizophrenia. Second-Generation Antipsychotics, olanzapine Olanzapine A benzodiazepine derivative that binds serotonin receptors; muscarinic receptors; histamine h1 receptors; adrenergic alpha-1 receptors; and dopamine receptors. It is an antipsychotic agent used in the treatment of schizophrenia; bipolar disorder; and major depressive disorder; it may also reduce nausea and vomiting in patients undergoing chemotherapy. Second-Generation Antipsychotics, and aripiprazole Aripiprazole A piperazine and quinolone derivative that is used primarily as an antipsychotic agent. It is a partial agonist of serotonin receptor, 5-HT1a and dopamine D2 receptors, where it also functions as a postsynaptic antagonist, and an antagonist of serotonin receptor, 5-HT2a. It is used for the treatment of schizophrenia and bipolar disorder, and as an adjunct therapy for the treatment of depression. Second-Generation Antipsychotics
      • If VMAT2 inhibitors fail to control symptoms
      • Block dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS transmission
    • 1st-generation antipsychotics if severe symptoms
      • Haloperidol Haloperidol A phenyl-piperidinyl-butyrophenone that is used primarily to treat schizophrenia and other psychoses. It is also used in schizoaffective disorder, delusional disorders, ballism, and tourette syndrome (a drug of choice) and occasionally as adjunctive therapy in intellectual disability and the chorea of huntington disease. It is a potent antiemetic and is used in the treatment of intractable hiccups. First-Generation Antipsychotics
      • Chlorpromazine Chlorpromazine The prototypical phenothiazine antipsychotic drug. Like the other drugs in this class chlorpromazine’s antipsychotic actions are thought to be due to long-term adaptation by the brain to blocking dopamine receptors. Chlorpromazine has several other actions and therapeutic uses, including as an antiemetic and in the treatment of intractable hiccup. First-Generation Antipsychotics
    • Benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines for short-term control of chorea
  • Treat concomitant depression: Up to 25% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with HD attempt suicide Suicide Suicide is one of the leading causes of death worldwide. Patients with chronic medical conditions or psychiatric disorders are at increased risk of suicidal ideation, attempt, and/or completion. The patient assessment of suicide risk is very important as it may help to prevent a serious suicide attempt, which may result in death. Suicide.
    • Selective serotonin Serotonin A biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity. Receptors and Neurotransmitters of the CNS reuptake inhibitors ( SSRIs SSRIs Serotonin Reuptake Inhibitors and Similar Antidepressants)
    • Tricyclic antidepressants Tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications used in the management of mood disorders, primarily depression. These agents, named after their 3-ring chemical structure, act via reuptake inhibition of neurotransmitters (particularly norepinephrine and serotonin) in the brain. Tricyclic Antidepressants
    • 2nd-generation antipsychotics for psychosis or severe behavioral symptoms
  • Medications for dystonia Dystonia Dystonia is a hyperkinetic movement disorder characterized by the involuntary contraction of muscles, resulting in abnormal postures or twisting and repetitive movements. Dystonia can present in various ways as may affect many different skeletal muscle groups. Dystonia:
    • Benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines
    • Baclofen Baclofen A gamma-aminobutyric acid derivative that is a specific agonist of gaba-b receptors. It is used in the treatment of muscle spasticity, especially that due to spinal cord injuries. Its therapeutic effects result from actions at spinal and supraspinal sites, generally the reduction of excitatory transmission. Spasmolytics
    • Botulinum toxin Botulinum toxin Toxic proteins produced from the species Clostridium botulinum. The toxins are synthesized as a single peptide chain which is processed into a mature protein consisting of a heavy chain and light chain joined via a disulfide bond. The botulinum toxin light chain is a zinc-dependent protease which is released from the heavy chain upon endocytosis into presynaptic nerve endings. Once inside the cell the botulinum toxin light chain cleaves specific snare proteins which are essential for secretion of acetylcholine by synaptic vesicles. This inhibition of acetylcholine release results in muscular paralysis. Botulism for focal dystonia Focal Dystonia Dystonia
  • Disease-modifying treatment is not yet available, but pharmacologic and genetic approaches are being studied.
  • Advance care planning 
    • Palliative care 
    • Hospice

Complications

  • Pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways 
    • May develop contractures Contractures Prolonged shortening of the muscle or other soft tissue around a joint, preventing movement of the joint. Wound Healing or musculoskeletal injuries
    • Simple analgesics Simple Analgesics Primary vs Secondary Headaches may be helpful.
    • Low-dose opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics in late-stage HD
  • Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
  • Urinary retention Urinary retention Inability to empty the urinary bladder with voiding (urination). Delirium
  • Pressure sores
  • For severe dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming “stuck.” Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia → palliative care
  • Causes of death are related to the motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology impairments seen with HD:
    • Pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia (85% due to aspiration)
    • Dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming “stuck.” Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia

Differential Diagnosis

  • Tourette syndrome Tourette Syndrome A neuropsychological disorder related to alterations in dopamine metabolism and neurotransmission involving frontal-subcortical neuronal circuits. Both multiple motor and one or more vocal tics need to be present with tics occurring many times a day, nearly daily, over a period of more than one year. The onset is before age 18 and the disturbance is not due to direct physiological effects of a substance or another medical condition. The disturbance causes marked distress or significant impairment in social, occupational, or other important areas of functioning. Tics and Tourette Syndrome (TS): a severe form of tic disorder in children ages 2 to 15, involving both motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology and vocal tics Tics Habitual, repeated, rapid contraction of certain muscles, resulting in stereotyped individualized actions that can be voluntarily suppressed for only brief periods. They often involve the face, vocal cords, neck, and less often the extremities. Examples include repetitive throat clearing, vocalizations, sniffing, pursing the lips, and excessive blinking. Tics tend to be aggravated by emotional stress. When frequent they may interfere with speech and interpersonal relations. Conditions which feature frequent and prominent tics as a primary manifestation of disease are referred to as tic disorders. Tics and Tourette Syndrome. Although there is no definite cause of TS, the condition has genetic and environmental factors that contribute to disease development. The disease is clinically diagnosed. Treatment involves behavioral therapy, antipsychotics, and treatment of comorbid conditions.
  • Sydenham chorea Sydenham Chorea Rheumatic Fever: a movement disorder that can be seen with rheumatic fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever several weeks to months after a Group A streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus (GAS) infection. The disorder manifests clinically with rapid, irregular, and involuntary movements (chorea), as well as neuropsychiatric symptoms. Diagnosis is made clinically. The management includes antibiotics, symptomatic treatment with antipsychotic Antipsychotic Antipsychotics, also called neuroleptics, are used to treat psychotic disorders and alleviate agitation, mania, and aggression. Antipsychotics are notable for their use in treating schizophrenia and bipolar disorder and are divided into 1st-generation antipsychotics (FGAs) and atypical or 2nd-generation antipsychotics. First-Generation Antipsychotics and anticonvulsant Anticonvulsant Anticonvulsant drugs are pharmacological agents used to achieve seizure control and/or prevent seizure episodes. Anticonvulsants encompass various drugs with different mechanisms of action including ion-channel (Na+ and Ca+2) blocking and GABA reuptake inhibition. First-Generation Anticonvulsant Drugs medications, and possibly steroids Steroids A group of polycyclic compounds closely related biochemically to terpenes. They include cholesterol, numerous hormones, precursors of certain vitamins, bile acids, alcohols (sterols), and certain natural drugs and poisons. Steroids have a common nucleus, a fused, reduced 17-carbon atom ring system, cyclopentanoperhydrophenanthrene. Most steroids also have two methyl groups and an aliphatic side-chain attached to the nucleus. Benign Liver Tumors.
  • Drug-induced movement disorders: include tardive dyskinesia, a serious side effect of 1st-generation antipsychotics or metoclopramide Metoclopramide A dopamine d2 antagonist that is used as an antiemetic. Antiemetics, which can last for up to a month after discontinuing the causative agent; and dystonia Dystonia Dystonia is a hyperkinetic movement disorder characterized by the involuntary contraction of muscles, resulting in abnormal postures or twisting and repetitive movements. Dystonia can present in various ways as may affect many different skeletal muscle groups. Dystonia, seen following treatment with an antihistamine or anticholinergic Anticholinergic Anticholinergic drugs block the effect of the neurotransmitter acetylcholine at the muscarinic receptors in the central and peripheral nervous systems. Anticholinergic agents inhibit the parasympathetic nervous system, resulting in effects on the smooth muscle in the respiratory tract, vascular system, urinary tract, GI tract, and pupils of the eyes. Anticholinergic Drugs. Frequent early monitoring is necessary for patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship taking these medications. The symptoms include smacking of the lips Lips The lips are the soft and movable most external parts of the oral cavity. The blood supply of the lips originates from the external carotid artery, and the innervation is through cranial nerves. Lips and Tongue: Anatomy, twisting of the tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Lips and Tongue: Anatomy, speech problems, headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess, and seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures. Diagnosis is clinical, and management includes avoiding future use of the causative agent. Treatment with a VMAT2 inhibitor, such as deutetrabenazine or valbenazine, may be helpful. 
  • Wilson disease (WD): can manifest with unexplained dystonia Dystonia Dystonia is a hyperkinetic movement disorder characterized by the involuntary contraction of muscles, resulting in abnormal postures or twisting and repetitive movements. Dystonia can present in various ways as may affect many different skeletal muscle groups. Dystonia, tremor Tremor Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of parkinson disease. Myotonic Dystrophies, chorea, or other neurologic symptoms, and this diagnosis should be considered in younger patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with no known family history Family History Adult Health Maintenance of HD. Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship often present in adolescence or young adulthood (though WD can be diagnosed later in life as well) with a combination of elevated liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy function tests and neurologic and psychiatric symptoms. Diagnosis is by clinical features and lab testing for liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy abnormalities, anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types, and copper Copper A heavy metal trace element with the atomic symbol cu, atomic number 29, and atomic weight 63. 55. Trace Elements overload. Treatment is with lifelong therapy to remove excess copper Copper A heavy metal trace element with the atomic symbol cu, atomic number 29, and atomic weight 63. 55. Trace Elements with a chelating agent and maintain proper copper Copper A heavy metal trace element with the atomic symbol cu, atomic number 29, and atomic weight 63. 55. Trace Elements balance.
  • Schizophrenia Schizophrenia Schizophrenia is a chronic mental health disorder characterized by the presence of psychotic symptoms such as delusions or hallucinations. The signs and symptoms of schizophrenia are traditionally separated into 2 groups: positive (delusions, hallucinations, and disorganized speech or behavior) and negative (flat affect, avolition, anhedonia, poor attention, and alogia). Schizophrenia: a serious psychiatric disorder characterized by relapsing episodes of psychosis. The disorder is due to alterations in the level of dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS in different neural circuits of the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification. Symptoms include hallucinations Hallucinations Subjectively experienced sensations in the absence of an appropriate stimulus, but which are regarded by the individual as real. They may be of organic origin or associated with mental disorders. Schizophrenia (mainly auditory) and delusions. Schizophrenia Schizophrenia Schizophrenia is a chronic mental health disorder characterized by the presence of psychotic symptoms such as delusions or hallucinations. The signs and symptoms of schizophrenia are traditionally separated into 2 groups: positive (delusions, hallucinations, and disorganized speech or behavior) and negative (flat affect, avolition, anhedonia, poor attention, and alogia). Schizophrenia causes social impairment due to disorganized speech and behavior. Antipsychotics and CBT are treatments of choice.

References

  1. Ghosh, R, & Tabrizi, SJ. (2018). Huntington disease. Handbook of Clinical Neurology, 147, 255– 278. https://doi.org/10.1016/B978-0-444-63233-3.00017-8
  2. Suchowersky, O. (2021).Huntington disease: Management. UpToDate. Retrieved June 23, 2021, from https://www.uptodate.com/contents/huntington-disease-management
  3. Ha, A. (2021). Huntington Disease and Other Genetic Causes of Choreas. DeckerMed Medicine. Retrieved July 31, 2021. https://doi.org/10.1016/j.ncl.2009.04.001
  4. Suchowersky, O. (2021). Huntington disease: Clinical features and diagnosis. UpToDate. Retrieved August 4, 2021, from https://www.uptodate.com/contents/huntington-disease-management
  5. Zoghbi, HY, & Orr, HT. (2020). Huntington disease: Genetics and pathogenesis. UpToDate. Retrieved August 4, 2021, from https://www.uptodate.com/contents/huntington-disease-genetics-and-pathogenesis

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