Huntington's chorea

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huntington's chorea


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Definition: :

Definition: It is neurodegenerative genetic disorder characterized by progressive movement disorder and histologically by degeneration of striatal neurons, caudate nucleus and putamen with loss of neurons that normally release GABA and Ach. Neurodegenerative: progressive loss of structure or function of neurons including death of neurons. Genetic disorder: illness caused by abnormalities in gene or chromosomes. It is generally known as Huntington’s chorea . JUVENILE HUNTINGTON’S DISEASE: The first sign and symptoms starts before the age of 20 years


CHOREA : Rapid, jerky and abnormal involuntary movements occur without any purpose. It is due to excess of DOPAMINE . Its initially more prominent in face and arms than in legs . HISTORY: First definite mention of HD is by Charles Oscar waters. He published 1 st edition of Robley Dunglison’s practice of medicine in 1842. 1 st complete description of disease was done by George Huntington in 1872. Discovery of location of a causal gene in 1983. About 30,000 people have it in U.S., CANADA, MEXICO and other areas of NORTH AMERICA .

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WHO GETS HUNTINGTON’S DISEASE??? Can affect anyone but research shows that EUROPEAN have it THE MOST. Equally occurs in male and female. Usually strikes people between age 25-55. Average age is 35. 2% case in children and 5% occurs at late as age 60. CAUSE: It is transmitted as an autosomal dominant trait and is inherit. Each child of an affected parent has 50% chance of inheriting it. Generally it is caused by mutation of gene called HUNTINGTIN .

SIGN AND SYMPTOMES: don’t occur until the age of 30/40 :

SIGN AND SYMPTOMES: don’t occur until the age of 30/40 Impaired intellectual functioning Interfere with normal activities Less ability to solve the problems Agitation and sleeping disturbance. Progressive mental deterioration Patient eventually become totally dependent Emotionally : its related ATHETOID [slow, twisting and snake like movement (specially of hand)] from injury to basal ganglion and torticollis due to shortening of neck muscles 2. Physically

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loss of musculoskeletal control. Tongue smacking Dysarthia: indistinct speech Bradykinesia: slow movement Dysphagia: mostly occur in advanced stage. It is difficulty in swallowing or feeling that food is sticking in your throat or chest. This lead to weight loss following malnutrition.


COGNITIVE SIGN AND SYMPTOMS: Dementia: collection of symptoms caused by the no. of disorders that affect the brain. Loss of brain function. It affects memory, language, judgment and behavior. Impaired impulse control PSYCHIATRIC SYMPTOMS: Depression Mania: earliest symptom related to altered level of dopamine and GABA. Seizure: abnormal excessive neuronal activity  dramatic thrashing movements  loss of awareness. Short term and long term memory loss is the most common symptom.

PATHOPHYSIOLOGY: how it differentiated from Parkinson's disease??? :

PATHOPHYSIOLOGY: how it differentiated from Parkinson's disease??? PARKINSON’S DISEASE HUNTINGTON’S CHOREA Loss of dopaminergic cells in substania nigra Loss of neurons of caudate nucleus and putamen Characterized by gradual loss of ability to initiate movement Inability to prevent the parts of body from moving unintentionally. It involves a disturbance in neurotransmitter substances, primarily gamma amino butyric acid (GABA) and DOPAMINE. In basal ganglia, frontal cortex and cerebellum, GABA neurons are destroyed and replaced by GLIAL CELLS.

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BASAL GANLIA: Group of nuclei in brain. It controls eye movements. Role in controlling behavior and movements and emotions, in learning. FRONTAL CORTEX: Part of human brain associated with aggressiveness and impulse control. Abnormalities in this part increases risk of suicide. CEREBELLUM: Major role in motor control, attention and language.

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GLIAL CELLS: To surround neurons and hold them in place and known as supporting cells of nervous system. To supply nutrition and oxygen to neurons To destroy pathogens and remove dead neurons Deficiency of GABA (inhibitory neurotransmitter)  results in excess of dopamine.

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GENETICS: All human have 2 copies of huntingtin gene (HTT) which codes for protein called huntingtin ( htt ).  Also called HD gene and IT15 (interesting transcript 15) HUNTINGTIN GENE: Located on short arm of chromosome 4 It contains a sequence of 3 DNA base: C: cytosine A: adenine Repeated multiple times G: guanine (CAGCAGCAGCAG)  Known as TRINUCLEOTIDE REPEAT This repeated part of gene is known as POLY Q region.

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CAG: It provides genetic code for amino acid GLUTAMINE.  So repetition of this gene cause production of chain of glutamine  Known as POLYGLUTAMIC TRACT Generally people have fewer than 36 repeated glutamine in poly Q region.


HUNTINGTIN PROTEIN: It regulates gene expression Functional role in cytoskeleton anchoring and transport of mitochondria Interacts with protein HIP1 (A clathrin binding protein to mediate endocytosis ) This protein plays a major role in shaping rounded vesicles. Protect neurons High conc.  brain Moderate conc.  liver, heart and lung In animals htt protein involved in embryonic development so its absence is related to embryonic death. If its expression is increased and more htt produced the brain cells survival is improved and the effect of mhtt is decreased and vice versa. It is thought that disease isn’t caused by inadequate production of mhtt but by a gain of toxic effect of mhtt .

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CELLULAR CHANGES DUE TO mhtt : During biological process of post-translation modification of mhtt , cleavage of protein occurs and left glutamine. This glutamine causes interaction with other proteins  cause aggregation  called inclusion body into cells  affect caudate nucleus and putamen  interfere with other neuronal function  stops transmission of neurotransmitter because vesicles no longer move through cytoskeleton  and over time less and less neurotransmitter available TRANSCRIPTION: It is the 1 st step of gene expression in which particular segment of DNA is copied into RNA by enzyme RNA polymerase. Stretch of DNA transcribed into RNA molecule called transcription unit which encode at least one gene. If gene transcribed encodes protein, the result of transcription is mRNA which is used to create protein.

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GENE EXPRESSION: Information from a gene used in synthesis of protein. Thus huntingtin gene provides genetic information for a protein called huntingtin . CAG triplet ( trinucleotide ) repeated on gene which varies in length between individuals and between generation. This repeat produce  altered form of protein  called mutant huntingtin protein ( mhtt ) Thus differing function of this protein cause pathological changes which in turn causes disease symptoms.


INHERITANCE: Huntington’s disease has autosomal dominant inheritance means affected individuals typically inherits one copy of gene with an expanded trinucleotide repeat. In the rare situation where both parents have an expanded HD gene, the risk increase to 75% and when either parent has 2 expanded copies, the risk is 100%.


MECHANISM: In short expansion of CAG triplet repeat stretch within HUNTINGTON GENE results in mutant form of protein which gradually damage cells in the brain.


COMPLICATION: Choking, aspiration pneumonia, heart failure and infection Pneumonia is the most common cause of death followed by cardiovascular disease Cause of pneumonia in HD is choking 86.8% patient’s death is because of aspiration pneumonia ASPIRATION PNEUMONIA : entrance of foreign material into bronchial tree CAUSE OF HEART FAILURE : In HD protein disturb cholesterol delivery system and cause accumulation of cholesterol in neurons and also in heart CARDIAC DYSFUNCTION IN R6/2 MOUSE MODEL OF HUNTINGTON’S DISEASE: R6/2 mice developed cardiac dysfunction by 8 weeks, progressing to sever failure at 12 weeks assessed by echocardiography Increase cardiac lysine acylation and protein nitration were observed and significantly associated impairment of cardiac function.


DIAGNOSIS: 1. MEDICAL DIAGNOSIS: Examination of appearance of physical symptoms. 2. GENETIC COUNCELLING: Provide advice and guidance throughout testing procedure. 3. CLINICAL COUNCELLING: A. PHYSICAL EXAMINATION: Combined with psychological examination determine whether onset of disease has begun. Check body of patient for sign and symptoms of disease like past medical history.

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B. GENETIC TESTING: BLOOD TEST: This counts no. of CAG repeat in each of HTT genes. It also confirm if an individual or embryo carries an expanded copy of trinucleotide repeat in HTT gene that causes this disease. Genetic testing of blood, hair, skin and amniotic fluid (fluid that surrounds a fetus during pregnancy) PROCEDURE Small brush collect sample of cells from inside surface of cheek. Small amount of saline mouthwash is used in mouth to collect cells. Check in laboratory for changes in chromosomes, DNA, protein. Routine new born screening test done on small blood sample obtained by pricking baby’s heel with LENCET.

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4. PNEUMOENCEPHALOGRAPHY: Cerebrospinal fluid drained from around brain  Replaced with air, oxygen or helium ( holes drilled in skull)  To allow structure of brain to show more clearly on X-ray image Lost fluid recovery by slow natural production It is extremely painful Not tolerated by patients Headache and sever vomiting are common side effects


POSITRON EMISSION TOMOGRAPHY: Produce 3 dimensional image Gamma rays emitted by positron emitting radionuclide introduced into body then computer analyzed. MAGNETIC RASONANCE TOMOGRAPHY (MRI) OR NUCLEUR MAGNETIC RESONANCE (NMR) Visualize internal structure of body X-ray computed tomography also called CT-scan utilize X-ray which produce image of specific area of body.


TREATMENT: No cure for HD Treatments are available to reduce severity of some of its symptoms Tetrabenazine was approved in 2008 for treatment in US. Other drugs help to reduce chorea include Neuroleptics Benzodiazepins Amantadine or remacemide Hypokinesia is treated with antiparkinson drugs Myoclonous hyperkinesias treated with valproic acid

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DRUG BRAND NAME DOSE Tiapride Tiaprid 600mg Olanzepine Zyprexa 20mg Tetrabenazine Xenazine 200mg Pimozide Orap 6mg Resperidone Risperdal 16mg Fluphenazine Fludecate 10mg

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DEPRESSION AGGRESSION DRUG DOSE BRAND NAME DRUG DOSE BRAND NAME Citalopram 60mg Celexa Citalopram 60mg Celexa Floxetine 60mg Prozac, Sertraline 200mg Lustral Mirtazapine 45mg Remeron, Olanzepine 20mg Zyprexa Valproinezuur 2000mg Depakine Dipiperon 360mg carbamazepine 1600mg Tegretol Haloperidol 10mg Haldol


MECHANISM: TETRABENAZINE: CATEGORY: VMAT INHIBITOR VMTA is vesicular monoamine transporter  transport dopamine, histamine, serotonin in synaptic cleft VMTA inhibitor promotes early metabolic degradation of monoamines in particular neurotransmitter dopamine. When its function is inhibited then dopamine can’t released via normal transport into synapse PSYCHIATRIC SYMPTOMS TREATED WITH… Selective serotonin reuptake inhibitors for depression Atypical antipsychotic for behavioral problems Weight loss and eating difficulties due to dysphagia is treated by nutritional management


MANAGEMENT: Thickening agents can be added to liquid as thickening fluids are easier and safer to swallow Reminding patient to eat slowly and to take smaller piece of food to prevent choking If eating become to hazardous and uncomfortable, the option is of using a percutaneous endoscopic gastrostomy It is a feeding tube which is permanently attached through abdomen into stomach which reduces risk of aspirating food and provides better nutritional management Cardiovascular exercise Walking


REFERENCE:'s_disease Orphanet journal of rare disease Handbook of pathophysiology ( january 15, 2001): by springhouse corporation. Page no: 205-206

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