HuntingtonDisease – A Comprehensive ReviewABSTRACT : A gradualprogressive loss of function and number of neurons is called asneurodegeneration. Huntington disease is an autosomal dominant neurodegenerative disease which is a veryrare disease with prevalence of about 2-5 cases per 50,000 found worldwide.. Maingenetic cause is high number of repeats of CAG codon (poly glutamine) present on the 4thchromosome.
Due to autosomal dominantnature, an individual has 50 % chances of inheriting the mutant gene frominfected parent. Severity of the disease is directly related to the number ofrepeats. Higher the number of repeats, earlier and severe the onset ofsymptoms. Symptoms starts showing at an age of 30-40 years (15 years in case ofjuvenile Huntington disease (JHD) and develops progressively over a course of15-20 years. Up to date, no cure or treatment is available for the disease.
Howeverwith the aid of transgenic animal models of disease, scientists have been ableto have an insight look into mechanical causes and potential treatment of thedisease. HISTORYAND INTRODUCTION :Historical records of Huntington disease dates back to 1374 when an outbreak ofHD was seen. However until the late 1600s, it was misunderstood as “dancingdisorder” due to lack of medical knowledge. Parcelus was first to use term”chorea” for this due to its characteristic feature of involuntary muscletwitches suggesting CNS origin. It was not until 1872 when George Huntington, aprofessional doctor in USA, first timedescribed about Huntington disease in his paper called :On Chorea” published inthe Medical and Surgical Reporter of Philadelphia (volume 26, no.
15, April 13,1872) Bruyn . Since then disease was named as Huntington’s chorea. In 1993,scientists found that HD is associated with CAG repeats present on the 4thchr named it as Huntington’s disease. Hunington. A wild-type htt gene carries6-26 CAG repeats at N-terinal region. While a mutant gene having more thanthirty six repeats is associated with absolute occurrence of disease.
Fig 1.Shows relationship between CAG repeats with onset and severity of disease. Fig2. shows relationship between genotype with onset and severity of disease Fig1. Relationship between CAG repeats and Huntington disease NO OF CAG REPEATS SEVERITY OF HUNTINGTON’S DISEASE 6-26 Wild type gene. No mutation.
No disease. 29-35 Intermediate alleles. Unstability due to high no of CAG repeats. Are prone to mutation during reproduction. Children have a higher risk. 36-39 Incomplete penetrance of disease. Very late onset of disease. Symptoms appear at very late age.
40-50 Complete penetrance of disease. Symtoms start appearing at age of 30-40 years. 50-60 Complete penetrance of disease. Symptoms start appearing at an early age of about 15-20 years. Fig2.
Relationship between genotype and Huntington disease GENOTYPE FUNCTIONALITY SEVERITY OF DISEASE Hd+/W+ One mutant gene One wild type gene Less severe phenotype symptoms. Wild type gene counter balances toxic effects of mutant gene Hd+/ Hd+ Two mutant allele More severe phenotype symptoms. Both mutant allele contributes to toxic effects Hd+/W- one mutant allele wild type knockout Lethal Huntingtondisease is an autosomal dominant disease associated with progressive loss ofneuron functions and number with progressively behavioral, physical and mentalabnormalities occurrence in due course of time until death. In countries ofEurope, Africa, Central and South Asia, a relatively high prevalence (2-5 per50,000) of disease i.
e. is found .In Japan and Finland, disease is very rarelypresent.
Onsetof disease can be in any age between 2-80 years. Brain damage starts at anearly age at onset of puberty. About 40% of neurons are lost and 20% ofbrain weight loss also called as atropia is seen till severe stage of disease.first symptom appear at age of 30-40 years and develop slowly through a period of15-20 years with chronic condition till death of the patient. MOLECULARUNDERSTANDING OF HD:Genetic cause of HD is codon sequensce (CAG)n where n is any numberfrom 36-60 present on first coding region i.e exon of “IT15 (interestingtranscript) ” present on chr number 4th as a result of mutation. Ontranslation, results in poly glutamine residues on N-terminal region of a large 350 kDa protein named ashuntingtin(htt)” Hunington.
A wild-type htt gene carries 6-26 CAG repeats atN-terinal region. As a result, protein is unable to fold properly whichinterferes with normal functioning of protein. Protein forms aggregates inbrain which are proportional to no of repeats4. Caspases 2-, 3-, and 6- playa major role in this aggregation process. Ubiquitin degradation system is overloaded with aggregates and hencecannot get rid of unfolded protein.
Furthermore, htt also aggregates with otherproteins such as CERB and impairs functioning of a lot of other proteins aswell.4-8. STRUCTUREAND FUNCTION OF HUNTINGTIN (HTT) GENE : there are threemain feature of huntingtin gene as following :v PolyQ sequence : startsfrom the 18th position and consists of thirty-five poly glutamineresidues in normal individual. Presence in number greater than 35 results inonset of disease. In higher vertebrates (sp. Mammals), Poly Q sequence isfollowed by a stretch of proline amino acids which seems to function asprotein-protein interaction domain as well as maintaining stability of Poly Qsequence6,7.
v HEATrepeats : Theseare present downstream of poly Q sequence, are approximate forty a.a. long andpresent in multiple numbers. These repeats are suggested to be involved inphysiological function of htt gene8-10.
v Consensussequences : httcontains § consensuscleavage sites for caspases 2-, 3-, 6-, calpain and aspartyl proteases11-14.§ Presenceof nuclear localization signal (NLS) at N-terminal and nuclear export signal atC-terminal suggest its role in transport mechanism15-17.§ Posttranslational modification – Presence of phosphorylation sites for enzyme PKB and cdK-5 helps in reduction ofcaspase-mediated cleavage and hence reduced toxic activity of protein19-20. Huntingtiongene plays an important part in gastrulation, neural tube formation andmaturation of adult brain and also acts as an anti-apoptopic protein.Huntington protein helps in production of BDNF which is a neurotrophinnecessary for striated neurons survival. Huntington also plays an importantrole in vesicle transport. SYMPTOMS ANDSIGNS OF HD : Patientssuffers with cognitive and motor disability. Start of Involuntary muscle movements is early sign of disease.
With due time ofcourse, continuous choreatic movements are seen like difficulty in walking,swallowing, talking (Dysarthria and dysphagia) , movementsdispairments like bradykinesia, akinesia and dystonia, continued tongueprotruding from mouth, increased muscle tones, bending of limbs etc. at thelater stages of disease, patients may become mute, completely bed-ridden due tohigh rigidity levels, severe weight loss due to inability to eat, impairedsleeping and circadian rhythm25 and 24hour presence of care taker is a must21,22. Table 3. symptoms and signs of HD Behavioral impairment Hallucinations Impulsiveness Irritability moodiness Paranoia Cognitive impairment Confusion about time and place Loss of reasoning memory loss Personality changes Motor impairment Restlessness, fidgeting Facial movements Head turning to shift eye position Jerking movements Slow, uncontrolled movements Speech problems Swallowing problems Unsteady gait (walking pattern) Signs ofdepression, weight loss, apathy, low self esteem, irratibility and aggressionare common among patients of HD. Risk of suicide is highest when patient is inearly stages of loss of dependency.Suicide is the second most common cause of death among HD patients23-24.Patients lose ability to reason, unableto differentiate between what is relevant or what is not, unable to carry ondaily activities like reading, taking a bath, cleaning, cooking etc. ADULT AND JUVENILE HUNTINGTON DISEASE(JHD) : Ifsymptoms of disease starts appearing IN 20s or 30s we call it as adultHuntington disease.
First symtoms to appear at the involuntary musclemovements. Choreatic, Bradykinetic and hypokinetic movements occur withappearance of dystonia. Length of CAG repeats in JHD is between 36-54.
If symptoms of disease starts appearingbefore age of 20 years, we call it as juvenile Huntington disease. Firstsymtoms to appear at the school level is difficuty in learning. Bradykineticand hypokinetic movements occur with appearance of dystonia. No choreaticmovements. Fraternal type of inheritance is seen in 75% of cases i.e.
individual has inherited dominant mutantgene from affected father. Length of CAG repeats in JHD is between 55-60.DIAGNOSIS : diagnosis of huntingtondisease is related to visible motor movemevents impairment and individual musthave at least one affected parent. A detailed family clinical history of thepatient is observed to know the penetrance of the disease in family. Howeverthis information may not be always available in cases if parents are alreadydead or a person with mutant HD gene died early before the onset of disease dueto some other cause such as an accident, fatal injury or any other disease. Currentcriteria of diagnosis includes GAG number repeats greater than 36 withvisible clinical symptons in any one ofthe parents or grandparents. Clinical symptoms may refer toany abnormal involuntary movements along with behavioral and mental impairment.In some cases all three are present.
However a combination of any two is alsoapplicable. A consent from patient’s parents is mandatory in all kinds ofdiagnostic tests since if the person isfound HD+, it can have a major affect family members and other family memberscan be at a greater risk of being affected with HD26.Brain scan :We know thatbrain cells start deteriorating many years before the onset of first symptom.Scientists are now focusing on imaging procedures like computerisedtomography (CT scan) or a magnetic resonance imaging (MRI) scan. An MRI scan ismore detailed and is more sensitive at picking up changes in the brain that cangive us proper brain imaging detailing about brain volume and interconnections27.Genetic testing gives 98%accuracy and can be done at your nearby genetic clinic.
However age of individualopting for test must be greater than eighteen years. First, doctor provide youmedical counseling and then one week later, blood is collected for testingpurposes.Prenataldiagnosis: If both parent are well aware of their genotype and have an possibility oftransferring the disease, they can check the genotype of their unkown childeither through Chorionic Villus Sampling or through amniocentesis after tenthand twelveth week of pregnancy and between the fifteeenth and seventeenth weeks. Table.3 anoverview of various diagnostic tests for huntington’s disease DIAGNOSIS TESTS FOR HUNTINGTON’S DISEASE Adult Diagnosis Prenatal Diagnosis Computerised Tomography (CT) Chorionic Villus Sampling Magnetic Resonance Imaging (MRI) Amniocentesis Genetic Testing Preimplantation Diagnosis Through Invitro Fetilization TREATMENT : Present treatment of Huntingtondisease does not cure the patient but deals with the symptoms implicated inprogressive onset of disease. Mainly drugs are used for this and surgicaltreatment do not have anyimpact on disease.
Slow movement difficulties and choreais treated with drugs as shown in table no.4 and drugs for treatment ofpsychotic behavious is shown in table no. 5.Table.4 drugsused for HD chorea DRUG TYPE FUNCTION NAME OF DRUG SIDE EFFECTS Dopamine – modifying Communication between nerve cells tetrabenazine (TBZ) Restlessness falls Neuroleptics Psychotic treatments Haloperidol fluphenazine Clozapine Olanzapine Quetiapine Risperidone Glutamatergic-modifying Communication between nerve cells amantadine riluzole Blood problems Accumulation of fluid in the lungs Heart problems Hypersensitivity Other drugs supplement coenzyme Q10 moderate side effects Alleviating pain nabilone moderate side effects antibiotic minocycline moderate side effects multiuse Ethyl-EPA Muscle building Creatine Table.
3 Drug Treatment for HD Psychotic behavior Type of drug Name of drug Any side effects Antidepressant Citalopram Escitalopram Fluoxetine Sertraline Nausea, Diarrhea, Drowsiness and Low blood pressure Mood-stabilizing Valproate Carbamazepine Epitol Lamotrigine Antipsychotic drugs Quetiapine Risperidone Olanzapine Violent outbursts Agitation Alongwith drugs, other care measures should also be taken. Like patient must beprovided with talk therapy by psychiatrist to help overcome behavioralproblems. Proper physiotherapy must be given to patient so that by appropriateexercising, patient could learn better coordination of movement and canmaintain motility ability as long as possible.
Speaking ability also can beimproved with the help of a speech therapist.CONCLUSION AND DISCUSSION : Even after two centuries, sincediscovery of HD, no cure or treatment is available up to date. Treatmentcurrently in use only concerns with symptoms of the disease but plays no rolein elimination of disease.
We can imagine complications related to this diseaseby the fact that over 2000 research papers have been published since discoveryof this disease and yet scientists have not been able to fully understandbiochemical mechanism completely and have not succeed in finding a cure. It isnot a very rare disease so a significant portion of worldwide populationsuffers from HD. And we cannot even imagine what kind of mental torture andpressure patient including their family members have to go through, consideringthe multilevel dysfunctioning of body systems. Also it is very costly anddifficult to keep patients for 24 hr watch under a medical practitioner.Although through study of animal models of HD, we can better understandcellular processes of diseases and use different potential treatment approachesto treat it. FUTURE PERSPECTIVE : Finding a cure for HD is still inits baby steps.
We are still trying to understand cellular processes of poly Qsequence and its role in a cell which leads to mass cellular destruction atneural level. Poly Q sequence is also associated with many otherneurodegenerative disorder are Dentatorubropallidoluysianatrophy, Spinal and bulbarmuscular atrophyand Spinocerebellarataxia Type1,2, 3, , 7 and 17 etc. If we can find a cure or completely understandmolecular mechanism of disease, it willalso come handy in treating of finding cure of other diseases as well associated with this CAG repeats. Techniques likeCT and MRI still in initial stages.
If we can diagnose disease at an earlystage by brain scan with help of these imaging techniques then treating themwould possibly be pretty easy. There is also a scope in studyingmicrosatellites and and their functioning in the cell. Overall CAG expansionseems to have greater scope in reference to research prospects.
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