Chorea huntington

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Classification according to ICD-10
G10 Huntington's
disease Chorea chronica progressiva hereditaria
F02.2 * Dementia in Huntington's Disease
ICD-10 online (WHO version 2019)
The autosomal dominant inheritance

The Huntington's disease , also known as Huntington's chorea or Huntington's disease referred (older name: chorea , large chorea , chorea major ), is still incurable hereditary disease of the brain , which "is typically characterized by involuntary, uncoordinated movements at the same time flabby muscle tone ". Often it is with HD abbreviated what English Huntington's disease is.

Sufferers suffer from the progressive destruction of an area of ​​the brain that is important for muscle control and basic mental function, the striatum . There, brain cells are destroyed by a faulty protein that is formed as a result of a defect in the so-called Huntington's gene . The external symptoms of the disease include disorders of the emotional life, muscle control including facial expressions (which can give the affected person the impression that the disease has progressed much more than is actually the case) and finally the brain function as a whole (in the end stage dementia ).

Huntington's disease is an autosomal - dominantly inherited, neurodegenerative disease that usually leads to the first symptoms of disease - movement disorders and psychological symptoms - around the age of 40. The disease is always severe and leads to death on average 15 years after the first symptoms. With a few exceptions, all carriers of traits fall ill sooner or later (complete penetrance ). Since 1993, the allele causing the disease has been found on the short arm of the fourth chromosome ( gene locus p16.3), even in the unborn by amniocentesis or chorionic villus sampling .

origin of the name

The first page of George Huntington's publication

Huntington's chorea ( chorea , Greek χορεία 'dance') was described in detail by the New York doctor George Huntington in 1872 . He described a clinical triad that was valid for a long time:

  • hereditary (hereditary nature)
  • psychiatric abnormalities and suicidal tendencies (insanity and suicide)
  • severe symptoms only in adult life

The last criterion later turned out to be wrong. Huntington assumed initially that the spread of Huntington on Long Iceland ( United States ) was limited. In fact, the disease was already to be found worldwide at that time. The German name is hereditary Veitstanz . The name St. Vitus Dance (especially Great St. Vitus Dance ), which has been attested since the 16th century, has its origin in the fact that St. Vitus (Vitus) was invoked as a helper . It is not known why this saint was invoked. Perhaps the name was St. Vitus 'dance in the 15th or 16th century, when the St. Vitus' Day (June 15th) in Strasbourg and elsewhere people in large numbers from the " Tanzwut " have been taken.

The term Huntington's disease is now common in all medical and other specialist circles .

Epidemiology

Huntington's disease is one of the most common hereditary brain disorders. A meta-analysis published in 2012 indicates an average prevalence of 2.71: 100,000. The evaluated studies showed a prevalence of 5.7: 100,000 for Europe, North America and Australia, while it is only 0.40: 100,000 in Asia. However, the prevalence varies considerably from country to country. In Finland it is 2.12: 100,000 lower than in the rest of Europe. In Germany there are officially around 10,000 people affected (as of 2014). In individual populations, for example in Tasmania and in the Zulia region in Venezuela, the prevalence is much higher, which can be attributed in part to individual people who have immigrated from Europe and who have inherited the gene ( founder effect ). In contrast, very low prevalences are found in sub-Saharan Africa and also among African-Americans and, for example, in Japan, where the prevalence is lower than 1: 100,000. The mean new disease rate ( incidence ) is 4: 1,000,000. Men and women are equally affected.

Pathophysiology

genetics

Huntington's disease is an autosomal dominant inherited disease. This means that the offspring of an affected person are also affected with a probability of at least 50% - depending on whether the phenotypically diseased parent has one or two mutated alleles (two mutated alleles (homozygosity) = 100% probability of an illness in the offspring ). If both parents are sick and heterozygous, the probability of the offspring being sick is 75%. Generational leaps do not occur, men and women are equally affected. Deviating from this, around 5 to 10 percent of patients have a new mutation. The protein that causes the disease is called huntingtin , and the gene coding for it is located on the short arm of chromosome 4 (gene locus p16.3). Huntington's disease is a trinucleotide disease : in the representative normal population, the base triplet CAG is repeated around 16 to 20 times, in sick people 36 up to 250 times. If you repeat from 27 to 35, there is a small increase without the disease developing. In people with a number of 36 to 39 CAG repeats (triplet repeats) there is an exception to the complete penetrance of the disease, that is, not all people of this genotype develop the disease, and no definitive predictions are possible even after a genetic test. The more frequently this repetition occurs, the earlier the disease occurs (on average) ( anticipation effect ). Juvenile Huntington's disease manifests itself in over 60 CAG triplets. An outbreak in the fourth year of life has been described.

In a very small percentage of those affected, a pedigree analysis can not find a blood relative with Huntington's disease from whom they could have inherited it. In these rare cases, it is a new mutation, an increase in the number of CAG repeats, in which the limit of around 36 is exceeded. Usually, one of the parents of an affected person with a new mutation already has a number of 30 to 35 repetitions (premutation). When inherited from the father, the number of CAG triplets increases more frequently than when inherited from the mother ( imprinting phenomenon ). This is mainly caused by so-called " slippage " (a slippage of the DNA polymerase during replication ) or (less likely, but at least possible) by a non-reciprocal (asymmetrical) crossing-over .

Molecular biology

The mRNA resulting from the triplet CAG codes for the amino acid glutamine . The mutated huntingtin therefore has more than the usual number of glutamine residues in a row. It is possible that this is a "gain-of-function mutation", which means that the normal function of the HD protein could be preserved, but it also has other - toxic - properties. A high expression of huntingtin leads to amyloid-like intracellular deposits ( inclusions ) of mutated huntingtin, which are promoted by the ARF GTPase-activating protein1, probably also because the breakdown of the mutated protein by the proteasome no longer works properly. On the other hand, some working groups have also shown toxicity of the free mutated Huntingtin, so that the Huntington's aggregates can be regarded as protection. The affected cells have an impaired glucose metabolism. This leads to an increased sensitivity to oxidative stress and the exciting neurotransmitter glutamate . These cells are particularly rich in glutamate receptors and have many in-depth glutamatergic connections. Nevertheless, it can only be explained in an unsatisfactory manner why the toxicity can only be detected in the areas described, although huntingtin is formed in all nucleated cells.

The physiological function of huntingtin is not fully understood. There is a body of evidence that it plays an important role in the intracellular transport of vesicles and organelles .

Neuroanatomy and Physiology

In Huntington's disease, v. a. the neurons of the indirect path from the striatum to the globus pallidus.

The putamen , which is part of the corpus striatum in the basal ganglia and can influence the globus pallidus medialis (interna) via a direct and indirect path, is particularly affected .

The indirect one counteracts the direct path. The overall inhibiting effect of the indirect path is achieved in healthy individuals via the following stations: The movement-inhibiting parts of the striatum in turn inhibit the globus pallidus lateralis (externa). This now reduces its inhibitory effect on the subthalamic nucleus , which increases its activity. Since the subthalamic nucleus has glutamatergic efferents to the globus pallidus medialis, it promotes its inhibitory effect on the thalamus.

In people with Huntington's disease, GABA / enkephalin -ergic neurons primarily degenerate ; H. the beginning of the indirect path is destroyed. As a result, the globus pallidus medialis is more weakly inhibited via the direct route than in healthy people. Since the globus pallidus medialis itself normally inhibits the thalamus , it is now less inhibited, i.e. activated (= disinhibition). The consequence is overexcitation of the thalamus and cortex .

Since the indirect connections are usually destroyed first in the course of the disease, overactivation with excessive movements is in the foreground at the beginning of the disease. In the further course, the direct connections are also lost, and a lack of movement ( akinesia ) and rigidity ( rigidity ) dominate.

Clinical picture

course

The first symptoms of the disease usually appear between the ages of 30 and 40. Symptoms have been described between the ages of three and 75. Patients with an early onset of the disease often have more severe disease. Mental health problems often precede movement disorders by several years. The movement disorders usually begin with hyperkinesia (unwanted movements) with reduced muscle tone . Later on, hypokinesia ( sedentary lifestyle ) and an increase in muscle tone are more likely to appear . A form in which the sedentary lifestyle is in the foreground from the beginning is called Westphal variant after Carl Westphal and occurs more frequently with early onset of the disease. Huntington's disease usually progresses up to 30 years with increasing need for care. It comes through difficult food intake (dysphagia) and constantly increased power consumption often results in cachexia . Most patients die within 15 years of the onset of the disease. The progression of the disease can be accelerated by stress, conversely, favorable living conditions with an activation appropriate to the suffering have a positive influence on the course of the disease.

Psychological complaints and psychiatric symptoms

The first symptoms of psychological change usually include disorders of affect and drive. These can also precede the movement disorders. Later on, careless and impulsive behavior and disinhibition in interpersonal relationships can occur. Due to the inadequate control of the muscles (e.g. of the face with grimacing), the false impression of an already advanced loss of personality can arise, which can cause resignation and depression in the patient . This can lead to suicidal behavior, especially in the early stages of the disease. Disturbances in visual information processing also occur early on. B. leads to the fact that the sick especially critical facial expressions of their fellow human beings - such. B. Annoyance - not being able to perceive properly and thus not being able to react appropriately. In the early stages, mild impairments of intellectual abilities and memory disorders are often overlooked. In the late stages of the disease, patients develop subcortical dementia , i.e. H. there is a loss of their cognitive abilities . There are disturbances in the ability to remember, associated with disorientation and language impoverishment . Some patients develop delusions that lead to their being treated in psychiatric clinics (mentally stressed course).

Movement disorders

Chorea usually begins with an initially barely noticeable restlessness of movement of the arms and legs, the face, and later the head and the trunk. This restlessness can develop into violent choreic hyperkinesia. These are sudden, involuntary movements of various muscles that interrupt voluntary movements . Those affected first try to hide the choir movements by incorporating them into arbitrary sequences of movements, e.g. B. stroke your hair after a shooting movement of your arm. Increasingly, however, the muscle movements get out of control. When the disease is full, there is sudden grimacing and flinging movements ( chorea ) of the arms and legs. Speaking and swallowing become increasingly difficult ( dysarthria and dysphagia ). Typically, these hyperkinesias begin in the parts of the extremities distant from the trunk (in the hands) and in the face, the mouth is opened wide, the tongue is stretched out and immediately withdrawn ("chameleon tongue"). In the further course the extremities near the trunk are also affected. When the hamstring reflex is triggered, the knee remains extended (Gordon phenomenon). The restlessness of movement increases under emotional and physical stress. Although the uncontrolled movements stop during sleep , they tend to increase when you are tired . The initially choreic hyperkinesias change into choreoathetosis or dystonia as the disease progresses , whereby the limbs remain in a sometimes painful misalignment for minutes to hours as the muscle tension (muscle tone) increases. Instead of grimacing, an anarthria may occur, i. H. there may be a complete inability to perform speech movements and the patient is no longer able to react through facial expressions , gestures and speech . Swallowing is becoming increasingly difficult for the patient and can lead to life-threatening complications, especially since the patients have increased energy expenditure due to the hyperkinesia. In the final stages of the disease, this can increase to more than five times the normal basal metabolic rate, so that adequate supply is only possible with supplementary parenteral nutrition.

Regardless of the chorea, people with Huntington's disease show a lack of motor persistence, that is, unsteady muscle tone. This is also aptly described in English as milkmaid's grip . This discontinuity in muscle tone is better suited to diagnosing the progression of the disease than chorea, because in contrast to chorea it increases steadily as the disease progresses.

Diagnosis

The diagnosis can usually be made clinically based on the symptoms. Other options are magnetic resonance imaging or computed tomography . They show atrophy of the corpus striatum and especially of the caudate nucleus . This atrophy leads to enlargement of the lateral ventricles . The 18 FDG - PET shows a disturbance of the glucose metabolism in the corpus striatum . A possible differential diagnosis is CJD (Creutzfeldt-Jakob disease) and vCJD (variant CJD). There is also the option of confirming the diagnosis by means of genetic analysis. Even before the first symptoms appear, a DNA analysis can be carried out in an institute for human genetics, in the case of unborn children as part of an amniotic fluid test .

Ethical problems in human genetic diagnostics

It is now possible, long before any symptoms appear in people from affected families, to clearly determine whether or not they have the genetic defect leading to Huntington's disease and how many repeats of the CAG sequence are present. For children of an affected parent whose DNA analysis is not available, the probability of the disease occurring is 50%. You will either get the disease for sure or never.

The decision as to whether such a diagnosis is desired is a very personal one and can be made after comprehensive information. A DNA analysis is especially useful before deciding whether to have children. Such diagnostics also provide information about other blood relatives. With a positive diagnosis in a grandson of an affected person, it would also become clear that the corresponding parent is affected, even if they have not yet had any symptoms.

Differential diagnostics

Must be distinguished are Huntington's disease-like syndrome and Huntington's acanthocytosis .

therapy

There is no known therapy that cures the disease itself or stops it permanently. Different vitamins and dietary supplements are used with varying degrees of success to protect cells from oxidative stress and thus to slow down the course of the disease. The drug riluzole reduces the release of glutamate and is said to slow down the process. Studies indicate that pallidal deep brain stimulation (DBS) also appears to have positive effects, particularly on motor symptoms. The course of the disease cannot be stopped by the stimulation, but those affected report an increase in quality of life, as they are less dependent on outside help and can continue to actively participate in social life. Preclinical studies also suggest improvements in other non-motor symptoms, such as cognition and mood. Further studies have been and are being carried out to further investigate the positive results seen so far in individual patients. All therapies are flanked by physiotherapy, occupational therapy and speech therapy to improve the ability to move or speak and swallow. At the same time, the patient and his relatives should be treated psychologically or, in the case of psychiatric disorders, psychiatric treatment. The diet should take into account the patient's increased energy requirements, difficulty swallowing and increased sugar requirements. Individual symptoms can also be treated as needed.

Treatment of movement disorders

Against hyperkinesia next be tetrabenazine also dopamine - antagonists used mostly tiapride or sulpiride . However, clinical studies show that taking tetrabenazine could exacerbate depression and suicidal tendencies. In addition, tetrabenazine aggravated the extrapyramidal syndromes in some people .

When rigor sets in , dopamine agonists or L-Dopa are used, but they can exacerbate the hyperkinesias. Therefore, drug therapy is only initiated when the movement disorders severely impair the patient's everyday life. Deep brain stimulation (DBS) has a positive effect on choreic symptoms, which are difficult to treat with medication, with good tolerability. The influence on dystonia and other movement disorders is being tested in an international clinical study.

Treatment of mental symptoms

In the case of psychotic symptoms, atypical neuroleptics are used, and antidepressants from the group of SSRIs are primarily used for depressive symptoms . Benzodiazepines can be used for sleep disorders and anxiety .

Neuroprotective treatment

There are studies suggesting that gabapentin has a neuroprotective effect on patients with Huntington's disease. The aim of this drug is to reduce the excitotoxicity of the glutamate on the nerve cell.

further reading

Web links

Individual evidence

  1. ↑ Nikola Biller-Andorno: Veitstanz, Chorea major (modern times). In: Werner E. Gerabek , Bernhard D. Haage, Gundolf Keil , Wolfgang Wegner (eds.): Enzyklopädie Medizingeschichte. De Gruyter, Berlin / New York 2005, ISBN 3-11-015714-4 , pp. 1438 f .; here: p. 1438.
  2. ↑ Representation of the gene in the NCBI Map Viewer
  3. ^ EC Wicke: attempt of a monograph of the great St. Vitus dance and the involuntary muscle movement, nbest remarks on the tarantula dance and the Berberi. Leipzig 1844.
  4. ↑ Nikola Biller-Andorno: Veitstanz, Chorea major (modern times). In: Werner E. Gerabek , Bernhard D. Haage, Gundolf Keil , Wolfgang Wegner (eds.): Enzyklopädie Medizingeschichte. De Gruyter, Berlin / New York 2005, ISBN 3-11-015714-4 , pp. 1438 f .; here: p. 1438.
  5. ↑ T. Pringheim, K. Wiltshire, L. Day, J. Dykeman, T. Steeves, N. Jette: The incidence and prevalence of Huntington's disease: a systematic review and meta-analysis. In: Mov. Disord. Volume 27, No. 9, 2012, pp. 1083-1091. PMID 22692795
  6. ↑ JOSipilä, M. Hietala, A. Siitonen, M. Päivärinta, K. Majamaa: Epidemiology of Huntington's disease in Finland. In: Parkinsonism Relat. Disord. Volume 21, No. 1, 2015, pp. 6-49. PMID 25466405
  7. ↑ Veitstanz should make the public aware of it. In: Münchner Merkur . May 20, 2014.
  8. ↑ Entry on Huntington's disease in Flexikon , a wiki from DocCheck , accessed on July 7, 2019.
  9. ↑ EB Clabough: Huntington's disease: the past, present, and future in search for disease modifiers. In: Yale J. Biol. Med. Volume 86, No. 2, 2013, pp. 217-233. PMID 23766742
  10. ^ A b F. O. Walker: Huntington's disease. In: The Lancet . Volume 369, Number 9557, January 2007, pp. 218-228. doi: 10.1016 / S0140-6736 (07) 60111-1 . PMID 17240289 . (Review).
  11. ↑ NetDoctor: Huntington's disease .
  12. ↑ A protein promotes pathological deposits in chorea Huntington's disease protein interaction network led on the trail . Press release of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association, September 24, 2004, accessed on October 8, 2015.
  13. ↑ JP Caviston, EL Holzbaur: Huntingtin as an essential integrator of intracellular vesicular trafficking. In: Trends in cell biology . Volume 19, Number 4, April 2009, pp. 147-155. doi: 10.1016 / j.tcb.2009.01.005 . PMID 19269181 . PMC 2930405 (free full text). (Review).
  14. ↑ Mahlon R. DeLong: The Basal Ganglia. In: Eric R. Kandel, James H. Schwartz, Thomas M. Jessell : Principles of Neural Science . 2000, ISBN 0-8385-7701-6 , p. 860.
  15. ^ Huntington's disease . DocCheck.
  16. ↑ KK Zakzanis: The subcortical dementia of Huntington's disease. In: Journal of clinical and experimental neuropsychology. Volume 20, Number 4, August 1998, pp. 565-578. doi: 10.1076 / jcen.20.4.565.1468 . PMID 9892059 .
  17. ^ E. Moro, AE Lang, AP Strafella et al. a .: Bilateral globus pallidus stimulation for Huntington's disease. In: Ann Neurol. 56 (2), Aug 2004, pp. 290-294. doi: 10.1002 / ana.20183 . PMID 15293283 .
  18. ↑ B. Biolsi, L. Cif, HE Fertit, SG Robles, P. Coubes: Long-term follow-up of Huntington disease treated by bilateral deep brain stimulation of the internal globus pallidus. In: J Neurosurg. 109 (1), Jul 2008, pp. 130-132. doi: 10.3171 / JNS / 2008/109/7/0130 . PMID 18590443 .
  19. ^ MO Hebb, R. Garcia, P. Gaudet, IM Mendez: Bilateral stimulation of the globus pallidus internus to treat choreathetosis in Huntington's disease: technical case report. In: Neurosurgery. 58 (2), Feb 2006, p. E383; discussion E383. doi: 10.1227 / 01.NEW.0000195068.19801.18 . PMID 16462466
  20. ↑ L. Wojtecki, S. Groiss, S. Ferrea, S. Elben, CJ Hartmann, S. Dunnett, A. Rosser, C. Saft, M. Südmeyer, C. Ohmann, A. Schnitzler, J. Vesper: A prospective pilot trial for pallidal deep brain stimulation in Huntington's disease. In: Front. Neurol. 6, p. 177. doi: 10.3389 / fneur.2015.00177
  21. ↑ L. Wojtecki, SJ Groiss, CJ Hartmann, S. Elben, S. Omlor, A. Schnitzler, J. Vesper: Deep Brain Stimulation in Huntington's Disease-Preliminary Evidence on Pathophysiology, Efficacy and Safety. In: Brain Sci. 6 (3) .pii, 30 Aug 2016, p. E38, doi: 10.3390 / brainsci6030038 .
  22. ↑ Y. Temel, C. Cao, R. Vlamings and a .: Motor and cognitive improvement by deep brain stimulation in a transgenic rat model of Huntington's disease. In: Neurosci Lett. 406 (1-2), Oct 2, 2006, pp. 138-141. doi: 10.1016 / j.neulet.2006.07.036 . PMID 16905252 .
  23. ↑ a b Clinical study (phase II): Deep Brain Stimulation (DBS) of the Globus Pallidus (GP) in Huntington's Disease (HD) (HD-DBS) at Clinicaltrials.gov of the NIH
  24. ↑ a b Kara J. Wyant, Andrew J. Ridder, Praveen Dayalu: Huntington's Disease Update on treatments. In: Current Neurology and Neuroscience Reports. 17, 2017, doi: 10.1007 / s11910-017-0739-9 .
  25. ↑ M. de Tommaso: Management of Huntington's disease: role of tetrabenazine. In: Therapeutics and Clinical Risk Management. 7, 2011. pp. 123-129, doi: 10.2147 / TCRM.S17152 .
  26. ↑ D. Bonekamp: 1H magnetic resonance spectroscopy in Huntington's disease under neuroprotective therapy with gabapentin. Dissertation, Medical Faculty Charité - Universitätsmedizin Berlin, 2004.
  27. ^ C Cosentino, L. Torres, JM Cuba: Gabapentin for Huntington's disease. In: J Neurology. Volume 243, 1996, S: S75-S76.