HGD lecture 5 - Huntingtons disease PDF

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Huntington’s Disease (Trinucleotide repeat expansion)

1. Clinical features - Movement/cognitive/ psychiatric disorder - Avg. age usually by 40 yrs - Symptoms usually start 30 - 50 yrs - 10-25 yrs progression - >1 in 10,000 10 times more prevalent in western europeans compared to african/asian populations Physical features - Involuntary movements - Weight loss - Balance problems - Speech and swallowing impediments - Rigidity and dystonia (uncontrollable contraction of muscles) Cognitive dysfunction - Problem solving - Cognitive flexibility - Short term memory - Visuospatial functioning HD caused by NERVE CELL DEGENERATION in the BASAL GANGLIA

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Most damage is in the CORPUS STRIATUM Some lose 25% of total brain weight

Psychiatric Manifestations - Changes in personality: Aggression, Depression (30%), apathy and irritability, impulsive behaviour - Early onset dementia - Affective disorders - Increased suicide rates (5-10 times higher than gen pop) + alcohol use in early stages (impulsivity)

2. Prognosis

Beginning of symptoms - Cognitive, motor and psychiatric impairment - Death at an avg of 18 years after onset of symptoms - Causes of death: Pneumonia, infection, heart failure (2nd most common) or choking Pneumonia - Most common cause of death - Inability to clear lungs effectively, swallowing problems

3. Diagnosis Requirements - Medical history - Family history - Neurological exam - Brain imaging test (MRI, CT, PET) - Lab tests - Genetic tests

4. Genetics - Mutated gene is Inherited 80% - No evidence of sex linkage - Autosomal dominant - 80% cases with onset before 20 yrs are due to paternal transmission Nancy Wexler - developed a chromosomal test to identify carriers of HD

Repeat Expansions - mutation - TRINUCLEOTIDE REPEAT - Size of repeat region varies btwn individuals + is normally polymorphic - For some trinucleotide repeats, if the number of repeats exceeds a threshold, a neurological disease occurs

HTT gene is located on the short arm of chromosome 4 at 4p16.3 - CAG codes (codon) glutamine A produces a chain of glutamine called polyglutamine tract (PolyQ) - PolyQ region - repeated part of the gene - CAG REPEAT EXPANSION IS CAUSE OF HD Usually fewer than 36 repeated glutamines in the polyQ region Why are CAG repeats unstable? - Cause conformational changes in HD gene and protein

Trinucleotide repeat classification, disease status, and risk to offspring >36 glutamines results in an altered protein, mutant HTT (mHTT) that increases degeneration rate of certain types of neurons mostly in corpus striatum.

HD gene discovered in 1993 Examples of trinucleotide repeat disorders Friedreich Ataxia (loss of full control of body movements) - Autosomal recessive Spinocerebellar Ataxia - Autosomal dominant progressive neurological disorder Myotonic dystrophy - Autosomal dominant progressive neurological disorder Fragile X syndrome - X-linked dominant syndrome (cognitive and behavioural impairment) Features of trinucleotide repeat disorders - Cognitive symptoms - Autosomal dominant - Late onset - Meiotic and mitotic instability with some anticipation Anticipation: Increasing severity/ decreasing age of onset in successive generations

5. Pathogenesis & clinical management Genetic testing for HD Advantages - If negative: worries about offspring and self are removed - If positive: - making plans for the future - arrange future treatment - inform children/ decide not to pass the gene onto offspring - could become involved in genetic research Disadvantages - If negative: survivor guilt - If positive: - Removes hope, introduces uncertainty - known risk to offspring - impact on self/family - potential problems with insurance - destroying expectations Presymptomatic genetic testing - Individuals at risk of HD Diagnosis of HD requires: - Medical history - Family history - Neurological examination - Brain imaging test (MRI, CT or PET) - Lab tests (genetic testing) Genetic testing: Blood samples taken from patients and DNA obtained, as well as from relatives to confirm results

DNA testing: tests for CAG repeat expansions or DNA markers surrounding the HTT gene Definitive direct DNA test: prenatal diagnosis or pre-implantation genetic diagnosis (PGD) when one parent has inherited HD Pre-implantation genetic diagnosis (PGD) 1. DNA amplified from a single cell 2. Look for CAG repeat expansions and back up with DNA marker tests 3. Reveals patterns of markers passed down the family 4. DNA samples from 2 generations Exclusion test 1. Prenatal of PGD tests 2. Uses DNA marker tests 3. Grandparent is affected but parent doesn’t want to be tested 4. Test can determine the chance of inheritance is low - 50% or under ALL TESTS REQUIRE GENETIC COUNSELLING TO FOLLOW Genetic counselling and clinical management For diagnostic tests: there must be an awareness of the implications for family members (consequences) For predictive tests: fully informed and considered decision, financial, personal and career implications must be taken into account (ASYMPTOMATIC) Prenatal and PGD testing: need counselling, esp if one parent is showing no symptoms and hasn’t undergone any genetic testing. Services offered may include: - Direct HD1/HD3 PCR: measuring CAG expansion repeats up to 70 repeats - Triplet primed PCR: absence or presence of expansion, doesn’t measure the size.

Risk on asymptomatic individuals decreases with age. Present treatments Nothing slows or reverses the disease - Suppressing chorea (involuntary movement) - Managing mood altering aspects of HD - Help with communication and day to day living: 1. Speech therapy 2. Occupational therapy - Regular exercise Medication - Liquid form due to swallowing issues - Side effects difficult to distinguish from symptoms - Medicines to suppress chorea 1. antipsychotic - e.g. olanzapine and sulpiride - Side effects: stiffness, rigidity, sedation, slow movement - Antidepressants 1. SSRIs e.g. fluoxetine, citalopram and paroxetine 2. Tricyclic - Side effects: diarrhea, constipation, sweating, shaking, insomnia, loss of appetite, nausea

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Stabilisers for mood and irritability

Mouse models No current mouse model that provides a comprehensive example of HD pathogenesis Most popular is the R6/2 model - Expresses the Nterminal fragment of HTT’s first exon with different lengths of CAG repeats

Developing therapies

Suppress mHTT toxicity using NMDAR antagonists - Problem is with finding the exact dose High dose = inhibition of both synaptic and extrasynaptic NMDAR activity and exacerbates disease progression.

Low dose = selective inhibition of extrasynaptic NMDAR activity and suppress mHTT toxicity Targeting mutant Huntington fragments - Rectify mHTT - Target earlier events - Enhanced refolding of the protein and reduce expression or increased degradation Enhanced refolding: 1. Activation of heat shock transcription factor 1 (HSF1) 2. Increases protein folding through upregulation of multiple molecular chaperones - Inhibit HSP90 (-ve regulator), suppresses mHtt aggregation - Mouse models support this but long term inhibition could be dangerous 3. New classes of HSF1-activating molecules have been tested of cell and fly models HTT- targeted approaches Antisense oligonucleotides (ASOs) ASO mediated HTT silencing: 1. ASOs bind to complementary sequences in HTT pre-mRNA and mature mRNA 2. Promotes RNase H-mediated degradation of that sequence 3. Suppresses production of mutant protein (mHTT) Small interfering RNAs (siRNAs) Interfere with the endogenous cellular machinery and silence the gene. 1. Target sequences in HTT mRNA 2. Processed by endogenous cellular machinery 3. Promotes silencing of the gene POSSIBLE ISSUES - May reduce wild type HTT - Need for repeat administration - SNP-targeting limits choice of RNA binding sequences - Delivery to target Delivery of the drugs targetting mHTT mRNA Delivery to CNA in mice reduces mHTT protein with no effect on wild type HTT - Use of pump

Measuring efficacy in clinical trials - Testing at regular intervals - Placebo - Use the Unified Huntigton’s disease rating scale (UHDRS) to asess neurological and physical fitness - MRI imagine along with UHDRS - Biofluid markers to allow direct quantification...