DEFINITION
"A familial disorder inherited as an autosomal dominant trait and characterized by the onset of progressive CHOREA and DEMENTIA in the fourth or fifth decade of life. Common initial manifestations include paranoia; poor impulse control; DEPRESSION; HALLUCINATIONS; and DELUSIONS. Eventually intellectual impairment; loss of fine motor control; ATHETOSIS; and diffuse chorea involving axial and limb musculature develops, leading to a vegetative state within 10-15 years of disease onset. The juvenile variant has a more fulminant course including SEIZURES; ATHAXIA; dementia; and chorea.
(From Adams et al., Principles of Neurology, 6th ed, pp1060-4)
EPIDEMIOLOGY
The worldwide prevalence of HD is 5-10 cases per 100,000 persons,but varies geographically as a result of ethnicity, local migration and past immigration patterns. Prevalence is similar for men and women. The rate of occurrence is highest in peoples of Western European descent, averaging around seventy per million people, and is lower in the rest of the world,
There are some localized areas with a much higher prevalence than their regional average. One of the highest prevalences is in the isolated populations of the Lake Maracaibo region of Venezuela, where HD affects up to seven thousand per million people. Other areas of high localization have been found in Tasmania and specific regions of Scotland, Wales and Sweden..
SYMPTOMS
Mean age at onset of symptoms is 30-50 years. In some cases symptoms start before the age of 20 years with behavior disturbances and learning difficulties at school (Juvenile Huntington disease). The classic sign is chorea that gradually spreads to all muscles. Other movements include tics. Cerebellar signs can appear sporadically, similar to the presence of hypo- and hypermetria. Dystonia (e.g. torticollis) can be the first motor sign in Huntington disease. Other symptoms include weight loss, sleep- and circadian rhythm disturbances and autonomic nervous system dysfunction. Dysarthria and dysphagia become very prominent during the course of the disease. All patients develop hypokinesia and rigidity leading to bradykinesia and severe akinesia. All psychomotor processes become severely impaired. Patients also experience cognitive decline. Psychiatric symptoms are very common in the early stage of the disease, often prior to onset of motor symptoms. The percentage of patients with psychiatric signs, such as low self-esteem, feelings of guilt, anxiety and apathy, varies between 33% and 76%.
DIAGNOSIS
The clinical diagnosis of Huntington's Disease is possible in the presence of a compatible clinical picture and a familiarity for Huntington's Disease. The following are supportive but not essential for diagnosis: radiological examinations (CT or MRI brain), neuropsychological tests and neurophysiological tests ( EEG, etc.). The final confirmation of the clinical diagnosis is possible by genetic analysis of the gene IT-15.
PATHOGENESIS
Huntingtin is encoded by the gene "IT15" ("Interesting Transcript 15") located on chromosome 4. In the first stretch of this gene a series of repeating "CAG" nucleotides is localized.
In healthy people, the number of repetitions always remains between the 9 and 35; patients with Huntington, however, always have more than the 36 repetitions ("mutated huntingtin"). Additionally, the number of CAG repetitions in the IT15 gene appears to be inversely related to the age of onset of the disease. The mutated gene is inherited as an autosomal dominant trait.
Huntingtin is a protein that functions as anti-apoptotic molecule and several studies have shown that the loss of huntingtin normal function produces severe brain damage.
Normal huntingtin also stimulates the production of BDNF, a required factor for the survival and differentiation of striatal neurons. This factor is produced at the level of cortical neurons and transported in a retrograde fashion from the cell body along the cortical fibers that connect to the striatum, where it is then released for the benefit of striatal neurons.
This effect is due to the stimulation of transcription of the BDNF gene, acting at the level of its promoter, in particular at the level of promoter II. Conversely, the mutated huntingtin loses this effect of activation of promoter II.
In particular, the action takes place because huntingtin is capable, in the cytoplasm, to bind to the REST cofactor. REST is an essential cofactor for the activation of the element NRSE (silencer of gene expression, present at the level of promoter sequences) .
REST, when tied to normal huntingtin, can't enter the nucleus and can't go to activate the NRSE.
Consequently, the silencer is inactive and gene transcription is not inhibited.
In presence of mutant huntingtin, REST remains free to enter the nucleus, it activates the silencer and turns off the transcription of the NRSE-controlled genes.
The chorea describes the phenomenon of anticipation, i.e. an expansion of CAG from one individual to the offspring, especially if the mutation is of paternal origin.
The amplification of the CAG is a dynamic mutation and through small changes in the number of repetitions the maximum threshold beyond which it has pathology can be reached. Additionally, with the increase in the number of repetitions increases their instability and therefore the probability of exceeding the maximum threshold.
This phenomenon, which affects the trinucleotides but also longer repeated sequences, is explained by the fact that the CAG repeat can assume an anomalous conformation called "hairpin" with alteration of the secondary structure that appears to be resistant to endonucleases.
This means that during the replication a DNA fragment consisting of a repeated series of CAG can detach from the template strand and folds on itself forming the hairpin. The terminal portion of the hairpin is then reassociated in a more rearward position of the mold than expected, resulting in a excess number of CAG.
This event explains precisely why, especially in the paternal transmission and probably because of the large number of divisions in spermatogenesis, an increase in the number of triplets in the progeny can be frequently witnessed.
It is therefore possible that sons of affected fathers may have an onset of the disease at an earlier age than the father.
When the message is to be decoded for the production of huntingtin, for each CAF triplet a specific amino acid called glutamine (indicated with the letter "Q") is incorporated into the protein.
In healthy subjects, the huntingtin will therefore have a number of Q within the normal range, i.e. below the 35 units. In affected subjects, on the other hand, the mutant huntingtin will have a much greater number of glutamines, corresponding to the higher number of CAG repeats in the gene. For this reason, Huntington's chorea disease is also called polyglutamine disease.
PATHOGENETIC HYPOTHESES
1) the hypothesis of the toxic gain-of-function of the mutated protein that leads to the degeneration of striatal neurons.
This hypothesis postulates that the presence of a polyglutaminic stretch will alter the protein conformation, localization and therefore its function, causing abnormal interactions with other cellular proteins, making it susceptible to proteolytic cleavage and causing, ultimately, cellular toxicity.
2) the polyglutaminic stretch presents in fact an intrinsically toxic function. It has been widely described that the polyglutaminic stretch is able to evoke toxicity when expressed in animal or cellular models and even in small organisms such as Drosophila melanogaster (fruit flies).
3) huntingtin undergoes a proteolytic cleavage by enzymes protease belonging to the family of caspases and, in particular, that the enzyme kinetics increases significantly in the presence of the mutation. The action of caspases thus leads to the obtaining of different mutant huntingtin fragments, which are thus able to cross the nuclear membrane and give rise to inclusions.
The polyglutamine within this protein fragment are disposed so as to form a beta-sheet structure that acts as the glue, promoting the formation of bonds with other fragments of mutant huntingtin and with other proteins.
As a consequence, these fragments would give rise to aggregates nuclear and cytoplasmic able to alter the normal cellular architecture.
4) also streaked specific molecules that interact with mutant huntingtin, are trapped in the aggregates so as to determine cellular toxicity.
These molecules can be divided into three groups: (i) proteins involved in vesicular traffic, (ii) proteins involved in transcriptional events, (iii) proteins involved in signal transduction.
Additionally, also the glyceraldehyde phosphate dehydrogenase (GAPDH) and the cystathionine beta synthase, whose aberrant interactions with mutant huntingtin would cause metabolic and energetic abnormalities.
In conclusion, it seems that Huntington's chorea is caused by two dysfunctions.
On one hand, the mutant huntingtin has toxic effects to the cell. On the other the loss of the protective function of huntingtin normal.
NEUROPATHOLOGY
gradual atrophy of the striatum
caudate nucleus
putamen
Medium spiny neurons
95% of striatal neurons utilize GABA as a neurotransmitter.
The loss of inhibitory input is the cause the characteristic uncontrolled movements
THERAPY
There is no cure for Huntington's disease, but there are treatments available to reduce the severity of some of its symptoms.
Tetrabenazine for the control of the choreic disorder.
Other drugs that help to reduce chorea include the families of neuroleptics and benzodiazepines.
The hypokinesia and rigidity, especially in juvenile cases, can be treated with antiparkinsonian drugs, while ipercinesiaemiocloniche can be treated with valproic acid.
Antidepressant and anxiolytic.
Psychotic treatment with atypical neuroleptics such as clozapine.
