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Huntington's Disease

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Huntington disease (Huntington's chorea) is an incurable, neurodegenerative, autosomal dominant inherited disorder caused by an elongated CAG repeat on the short arm of chromosome 4p16.3 in the Huntingtine gene. The signs and symptoms of the disease consist of motor, cognitive and psychiatric disturbances.


Presentation

The salient clinical features of Huntington’s disease are listed below:

  • Chorea: Patients with Huntington’s disease present with are continuous, involuntary, jerky and dyskinetic movements. This is referred to as chorea. In case of Huntington’s disease, chorea is often generalized and involves the face, head, neck, tongue and extremities.
  • Impaired memory and cognition: Progressive loss of memory is a key feature of Huntington’s disease [5]. Initially, there is a loss of short-term memory. Later on, cognitive functions such as speech, reasoning and comprehension are also impaired. [6][7] In most cases, severe dementia occurs by the age of 50 years.
  • Altered behavior: A variety of behavioral abnormalities are also present in Huntington’s disease. Depression is the most common abnormality. As a result, suicidal tendency is often present in the patients suffering from this disease. Other disorders include personality changes, irritability, antisocial behavior, psychosis and obsessive-compulsive features [8].
  • Gait abnormalities: Gait abnormalities start developing in the intermediate stage of the disease. The gait is irregular and unsteady. In the later stage, features similar to Parkinsonism (bradykinesia and rigidity) also develop.
Difficulty Walking
  • He had depression, poor cognitive function, choreiform movements, difficulty pronouncing words, and difficulty walking. His symptoms had worsened markedly over several months.[ncbi.nlm.nih.gov]
  • Symptoms may appear at any age and include uncontrolled movements, clumsiness, balance problems, difficulty walking, talking, or swallowing.[icd9data.com]
  • walking trouble swallowing and speaking confusion memory loss personality changes speech changes decline in cognitive abilities Early Onset This type of Huntington’s disease is less common.[healthline.com]
  • ., infections) Falls and difficulty walking requiring the use of assist devices such as wheelchairs Children with juvenile-onset HD have rigidity, slow movements, and tremors that are similar to symptoms of Parkinson disease.[labtestsonline.org]
Muscle Rigidity
  • Juvenile HD (also called Westphal variant or akinetic-rigid HD) develops before the age of 20, progresses rapidly, and produces muscle rigidity in which the patient moves little, if at all (akinesia).[healthcommunities.com]
  • Other movement problems include figidty movements, tics, difficulty swallowing, balance problems and falls, and muscle rigidity and/or tightness. Cognition problems generally occur slowly over time.[ucdmc.ucdavis.edu]
  • Muscle rigidity and involuntary muscle contractions can be treated with diazepam. Depression and other psychiatric symptoms can be treated with antidepressants and mood-stabilizing drugs.[healthline.com]
  • Markus HS, Cox M, Tomkins AM (1992) Raised resting energy expenditure in Parkinson’s disease and its relationship to muscle rigidity. Clin Sci (Lond) 83(2):199–204 PubMed Google Scholar 53.[doi.org]
Abnormal Eye Movement
  • Abnormal eye movements may be seen early in the disease. Other movement disorders, such as tics and myoclonus, may be seen in patients with HD.[emedicine.medscape.com]
  • Characteristics and Symptoms of Huntington's Disease Personality changes, depression, anxiety, irritable or aggressive behavior, apathy, hallucinations, delusions or mood swings Unsteady gait, dance-like movements, rigidity, abnormal eye movements, problems[health.ucsd.edu]
  • Dysarthria, dysphagia and abnormal eye movements are common. There may also be other movement disorders - eg, tics and myoclonus.[patient.info]
  • eye movements Impaired gait, posture and balance Difficulty with the physical production of speech or swallowing Impairments in voluntary movements — rather than the involuntary movements — may have a greater impact on a person's ability to work, perform[mayoclinic.org]
Facial Grimacing
  • Typical features include a bizarre, puppet-like gait, facial grimacing, inability to intentionally move the eyes quickly without blinking or head thrusting (oculomotor apraxia), and inability to sustain a motor act (motor impersistence), such as tongue[merckmanuals.com]
Psychiatric Manifestation
  • Huntington's disease (HD) is an autosomal dominant and progressive neurodegenerative syndrome characterized by motor, cognitive and psychiatric manifestations.[ncbi.nlm.nih.gov]
  • Although noncompliance to oral antipsychotic drugs can be a practical problem, especially when significant psychiatric manifestations of HD are present, the effect of depot antipsychotic medication in HD remains largely unknown.[ncbi.nlm.nih.gov]
  • Specific psychiatric manifestations among preclinical Huntington disease mutation carriers.[web.archive.org]
  • In this study, to reduce the chances of bias from age at onset, we obtained detailed longitudinal data on our patients’ clinical presentations and could evaluate separately the age of onset for motor and psychiatric manifestations.[dx.doi.org]
  • Specific psychiatric manifestations among preclinical Huntington disease mutation carriers. Arch Neurol. 2007; 64 :116–21. [ PubMed : 17210818 ] Martino D, Stamelou M, Bhatia KP.[ncbi.nlm.nih.gov]
Withdrawn
  • The shoulders are shrugged, and the feet and legs kept in perpetual motion; the toes are turned in, and then everted; one foot is thrown across the other, and then suddenly withdrawn, and, in short, every conceivable attitude and expression is assumed[en.wikisource.org]
Emotional Lability
  • Presentation is typically with progressive rigidity, choreoathetosis, dementia, psychosis and emotional lability 2 . The juvenile form has a different presentation, with cerebellar symptoms, rigidity and hypokinesia being prominent.[radiopaedia.org]
Chorea
  • chorea Chronic progressive non-hereditary chorea Dementia due to Huntington chorea Dementia due to Huntington chorea with altered behavior Dementia due to Huntingtons chorea w behavior changes Dementia due to Huntingtons disease Dementia from huntingtons[icd9data.com]
  • This occurrence of rheumatic chorea in a family with Huntington's disease highlights the importance of the differential diagnosis for the different forms of chorea.[ncbi.nlm.nih.gov]
  • […] by unwanted choreatic movements, behavioral and psychiatric disturbances and dementia HD Huntington's chorea Huntington’s disease Huntington Chorea Huntington's disease HUNTINGTON DISEASE; HD Statements 1 reference Examples of autosomal dominant disorders[wikidata.org]
Irritability
  • In multivariate regression analyses, both suicidal ideation and suicidal behavior were associated with a depressed mood, and to a lesser extend to irritability.[ncbi.nlm.nih.gov]
  • Depression, irritability/aggression, and frontal lobe personality changes are common presentations of HDL2 and are comparable to classic HD.[ncbi.nlm.nih.gov]
  • Frequently reported neuropsychiatric symptoms are depressed mood, anxiety, irritability, and apathy, with prevalences of 33% to 76%.[ncbi.nlm.nih.gov]
  • During the early stages of HD, irritability, depression, anxiety and aggression are common behavior symptoms . In the later stages, individuals tend to be less irritable and aggressive, as apathy and a lack of concern become more pronounced.[web.stanford.edu]
  • During the early stages of HD, irritability, depression, anxiety and aggression are common behavior symptoms. In the later stages, individuals tend to be less irritable and aggressive, as apathy and a lack of concern become more pronounced.[web.archive.org]
Involuntary Movements
  • Abstract We herein report a case of late-onset Huntington's disease (HD) that presented without any involuntary movement.[ncbi.nlm.nih.gov]
  • Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by involuntary movements and psychiatric disturbances, found worldwide, with a variable prevalence.[ncbi.nlm.nih.gov]
  • Huntington's disease is an inherited, degenerative brain disease, characterized by involuntary movements, cognitive disorder and neuropsychiatric change. Men and women are affected equally.[ncbi.nlm.nih.gov]
  • Xenazine decreases the amount of dopamine available to interact with certain nerve cells, thereby decreasing the involuntary movements.[web.archive.org]
  • Abstract Huntington's disease (HD) is a neurodegenerative condition characterised by motor dysfunction with involuntary movements and loss of voluntary control, cognitive deterioration and psychiatric problems.[ncbi.nlm.nih.gov]
Ataxia
  • Abstract The autosomal dominant spinocerebellar ataxias, commonly referred to as SCAs, are clinically and genetically heterogeneous neurodegenerative disorders.[ncbi.nlm.nih.gov]
  • The authors highlight the importance of suspecting HD in the aetiology of spinocerebellar ataxias when dementia is a prominent feature in the proband or their family.[ncbi.nlm.nih.gov]
  • Lasek K et al . (2006) Morphological basis for the spectrum of clinical deficits in spinocerebellar ataxia 17 (SCA17) . Brain 129 : 2341–2352 39. Manganelli F et al . (2006) Electrophysiologic characterization in spinocerebellar ataxia 17 .[dx.doi.org]
  • Abstract Although Huntington's disease (HD) is primarily considered a rare neurodegenerative disorder, it has been linked to glucose metabolism alterations and diabetes, as has been described in other neuro syndromes such as Friedreich's ataxia or Alzheimer's[ncbi.nlm.nih.gov]
Apathy
  • Apathy severity increases in the motormanifest stages of Huntington's disease. HDGECs can adequately assess their level of apathy on a self-report questionnaire.[ncbi.nlm.nih.gov]
  • Future work should explore whether clinical interventions targeting different functional domains may have the potential to reduce apathy in this patient population. KEYWORDS: Apathy; Health-Related Quality of Life; Huntington-s Disease[ncbi.nlm.nih.gov]
  • HD mutation carriers with lower cognitive performances and higher apathy scores were more likely to be unemployed than were HD mutation carriers with higher cognitive scores and no signs of apathy.[ncbi.nlm.nih.gov]
  • Although aspects of apathy resemble depression, there are important distinctions. (see depression below) Many patients suffering from apathy deny being sad.[web.stanford.edu]

Workup

Diagnosis of Huntington’s disease can usually be made on clinical grounds; especially in the patients who present with the typical features of the disease, or those who have a genetically proven family history.
In other cases, certain investigations may be needed to establish the diagnosis with certainty.

  • Magnetic Resonance Imaging (MRI) or Computerized Tomography (CT) scan demonstrate atrophy of the head of the caudate nucleus. This is evaluated by measurement of the bicaudate diameter which is the distance between the heads of the two caudate nuclei.
  • DNA testing can also be used to confirm the diagnosis of Huntington’s disease.
Prolonged PR Interval
  • Cardiovascular evaluation showed mild aortic insufficiency, moderate mitral insufficiency and a prolonged PR interval.[ncbi.nlm.nih.gov]

Treatment

There is no definitive treatment of Huntington’s disease. Palliative and symptomatic management is provided to the patient.

  • Chorea is managed by administration of benzodiazepines (such as diazepam), valproic acid, dopamine depleting agents (such as reserpine) and neuroleptics.
  • A novel drug tetrabenazine has also been shown to have a beneficial effect in the treatment of chorea in Huntington’s disease [9].
  • Parkinson’s like symptoms of bradykinesia and rigidity are treated by levodopa or dopamine agonists [10].
  • Antidepressants are given to the patients who suffer from depression and suicidal tendencies.
  • Surgical treatments for Huntington’s disease are still under experimentation.

Prognosis

Once the disease develops, it is slowly progressive. The severity of the clinical features depends on the trinucleotide repeat length. Patients with 60 or more repeats often present early by the age of 20 years. In contrast, those with fewer than 40 repeats do not develop clinically apparent features [3]. 

On average, the patient lives for around 20 years after the onset of symptoms. Complications develop due to motor and cognitive abnormalities. Death most commonly results from pneumonia. Up to one third of the patients of Huntington’s disease die of this complication. Heart disease and suicide are the second and third most common causes of death in these patients [4].

Etiology

Huntington’s disease almost always has positive family history since it is an autosomal dominant disease. It is caused by a mutation in the Huntingtin gene (HTT) on the short arm of chromosome 4 that codes the protein Huntingtin (Htt). A trinucleotide repeat sequence that is normally present in this gene is expanded in case of this disease. The abnormal protein thus produced is called mutated Huntingtin protein (mHtt) and is responsible for the underlying pathological mechanism of the disease.

Epidemiology

The prevalence of Huntington’s disease varies greatly in different populations around the world. The prevalence is maximum in Western Europe (7 cases per 100,000 people) and much lower in Asia and Africa (one case per million people). A recent epidemiological study has calculated the average prevalence of Huntington’s disease in the UK during the past 20 years (1990 to 2010) to be 12.3 cases per 100,000 people [1]. Worldwide, the prevalence of this disease is around 5 to 10 cases per 100,000 people.

Huntington’s disease is equally prevalent in both sexes. The age of onset is variable; however, onset in the first decade and after the seventh decade is extremely rare. The average age of onset ranges from 35 to 44 years.

Sex distribution
Age distribution

Pathophysiology

Huntingtin protein (Htt) is present in high concentrations in the brain. The exact function of this protein is not clear but it is believed to have an anti-apoptotic and neuroprotective role. Mutated Huntingtin protein (mHtt) is not able to perform these neuroprotective functions and accumulates in the neurons in the form of aggregates to form inclusion bodies within them [2]. Mutated Huntingtin protein causes cell death by effect on chaperone proteins, interaction with caspases, impairment of energy production within the cells and effects on gene expression.

Cell death resulting in atrophy is most prominent in the portion of basal ganglia referred to as the neostriatum (which consists of the caudate nucleus and putamen). Cell death also occurs to a lesser extent in substantia nigra, certain layers of the cerebral cortex (2, 5 & 6) and portions of the cerebellum, thalamus and hypothalamus. Basal ganglia play a role in the inhibition of a many neuronal circuits that are responsible for initiation of movements. If basal ganglia are damaged, this inhibitory effect is lost and as a result, involuntary movements such as those seen in Huntington’s disease result.

Prevention

Since Huntington’s disease results from genetic abnormalities, there are no effective preventive measures against it.

Summary

Huntington’s disease is an autosomal dominant disorder caused by a mutation in the Huntingtin gene (HTT) on the short arm of chromosome 4. It is characterized by chorea, altered behavior, dementia and motor abnormalities. The disease is progressive and the patients survive for an average of 20 years after the onset of symptoms. There is no definite cure and the disease is treated symptomatically.

Patient Information

Huntington’s disease is a genetic disorder which is characterized by involuntary movements of the body, altered behavior, loss of memory and abnormalities of gait. There is no definite cure and the disease is treated symptomatically. The life expectancy after the onset of symptoms is around 20 years.

References

Article

  1. Evans SJ, Douglas I, Rawlins MD, Wexler NS, Tabrizi SJ, Smeeth L. Prevalence of adult Huntington's disease in the UK based on diagnoses recorded in general practice records. Journal of neurology, neurosurgery, and psychiatry. Oct 2013;84(10):1156-1160.
  2. Rubinsztein DC, Carmichael J. Huntington's disease: molecular basis of neurodegeneration. Expert reviews in molecular medicine. Aug 2003;5(20):1-21.
  3. Andrew S, Goldberg, YP, Kremer, B, Telenius, H, Theilmann, J, Adam, S, Starr, E, Squitieri, F, Lin, B, Kalchman, MA. The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease. Nat. Genet. 1993;4(4):398-403.
  4. Di Maio L, Squitieri F, Napolitano G, Campanella G, Trofatter JA, Conneally PM. Suicide risk in Huntington's disease. Journal of medical genetics. Apr 1993;30(4):293-295.
  5. Cleret de Langavant L, Fenelon G, Benisty S, Boisse MF, Jacquemot C, Bachoud-Levi AC. Awareness of memory deficits in early stage Huntington's disease. PloS one. 2013;8(4):e61676.
  6. Ho AK, Hocaoglu MB, European Huntington's Disease Network Quality of Life Working G. Impact of Huntington's across the entire disease spectrum: the phases and stages of disease from the patient perspective. Clinical genetics. Sep 2011;80(3):235-239.
  7. Montoya A, Price BH, Menear M, Lepage M. Brain imaging and cognitive dysfunctions in Huntington's disease. Journal of psychiatry & neuroscience : JPN. Jan 2006;31(1):21-29.
  8. van Duijn E, Kingma EM, van der Mast RC. Psychopathology in verified Huntington's disease gene carriers. The Journal of neuropsychiatry and clinical neurosciences. Fall 2007;19(4):441-448.
  9. Ondo WG, Tintner R, Thomas M, Jankovic J. Tetrabenazine treatment for Huntington's disease-associated chorea. Clinical neuropharmacology. Nov-Dec 2002;25(6):300-302.
  10. Racette BA, Perlmutter JS. Levodopa responsive parkinsonism in an adult with Huntington's disease. Journal of neurology, neurosurgery, and psychiatry. Oct 1998;65(4):577-579.

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Last updated: 2018-06-22 04:12