Huntington's Disease PDF

AN L12 21/10/24 Huntington's Disease * - HD – familial neurodegenerative disorder - Autosomal dominant inheritance - Avg onset – 40yrs (no cure) Autosomal Dominant Inheritance: - Way a genetic trait or condition can be passed down from parent to child -...

AN L12 21/10/24 Huntington's Disease * - HD – familial neurodegenerative disorder - Autosomal dominant inheritance - Avg onset – 40yrs (no cure) Autosomal Dominant Inheritance: - Way a genetic trait or condition can be passed down from parent to child - One copy of a mutated (changed) gene from one parent can cause the genetic condition - A child who has a parent with the mutated gene has a 50% chance of inheriting that mutated gene - Men and women are equally likely to have these mutations and sons and daughters are equally likely to inherit them Symptoms: - Motor: o Involuntary twitching o Excessive restlessness o Rigidity o Spasticity o Decreased coordination o Voluntary movement abnormalities - Psychiatric: o Depression o Aggression o Irritability o Apathy o Impulsivity o Antisocial behaviour - Cognitive: o Planning/organising problems o Memory loss o Inattention o Dementia Chorea: - Brief, involuntary, unpredictable irregular movements - Appear to flow from one muscle to the next – ‘dance like’ - Can interfere with speech, swallowing, posture, gait – disappears in sleep AN L12 21/10/24 Stages of HD: - Early Stage: o Functional o Continue to work, drive, handle money, live independently o Symptoms: ▪ Minor involuntary movements ▪ Subtle loss of coordination ▪ Difficulty thinking through complex problems ▪ Depression ▪ Irritability - Middle Stage: o Lose ability to work/drive o Can perform ADLs, not IADLs o Prominent Chorea o Increasing difficulty with voluntary motor tasks o Swallowing, balance problems, weight loss, falls o Difficulty problem solving – cannot sequence, organise, prioritise info - Late Stage: o Require assist. In all ADLs o Often nonverbal and bedridden o Seem to retain some comprehension o Severe chorea – rigidity, dystonia, bradykinesia o Psychiatric symptoms are harder to recognise/treat in late stage (communication difficulties) Speech Impairments: - Slower with progression - Voice – hypophonic/explosive - Articulation impaired – decline of voluntary control of lips, tongue, mouth - Coordination of speaking/breathing declines, intelligibility of speech deteriorates What Causes HD? - Belongs to a family of inherited trinucleotide repeat disorders (most common repeat mutant genes expressed throughout body): o Friedreich’s ataxia o T1 Spinocerebellar Ataxia (8 types known) AN L12 21/10/24 o Spinal and Bulbar Muscular Dystrophies Huntington Gene/Protein: - Huntington gene of chromosome 4, where DNA sequence CAG (glutamine residue) is repeated up to 30x - Codes for protein Huntington (htt) - Htt is involved in cellular transport, protein processing, synaptic vesicle function, transcription, mitochondrial function - High expression in brain, predominant in neurons - HD is caused by mutation in huntingtin gene: o Mutation in huntingtin gene causes an expanded stretch of CAG’s (polyglutamine) o Expansions beyond 36 CAGs cause the disease How Does Huntington Gene Cause Neuronal Cell Death? - Unknown – proposed mechanisms: o Impaired protein trafficking which interferes with synaptic transmission o Polygutamine aggregation o Excitotoxicity o Oxidative stress o Programmed cell death (apoptosis) - → results in abnormal levels of GABA and dopamine Symptom Onset: - The higher the number of CAG repeats, the earlier the onset of symptoms Brain Regions Affected: - Basal Ganglia: o Caudate nucleus and putamen o Widespread neuronal loss initially in striatum and eventually all of BG and later, cerebral cortex o Accumulation of huntingtin protein aggregation in neurons of striatum and cerebral cortex o GABA neurons lost in striatum AN L12 21/10/24 Neurotransmitter Pathways Affected: 1. Dopamine: o Functions: ▪ Reward (motivation) ▪ Pleasure, euphoria ▪ Motor function ▪ Compulsion ▪ Perseveration 2. Serotonin: o Functions: ▪ Mood ▪ Memory processing ▪ Sleep ▪ Cognition - Degeneration of striatal GABAergic neurons can cause hyperactivity of dopaminergic systems - Reducing dopaminergic activity might help restore balance of neurotransmitter functions Risk Factors for HD: - A parent with a mutation in HD gene has 50% chance of passing on disease to their children Diagnosis: - Physical, neurological exam: o Medical, family history o Clinical rating scales to assess severity and frequency of symptoms - Genetic testing - Prenatal testing: o Amniocentesis o Chorionic villus sampling Treatment: - Symptomatic drug treatment: o Motor: AN L12 21/10/24 ▪ Tetrabenazine – reduces dopamine activity ▪ Baclofen – GABA receptor agonist o Psychiatric: ▪ Neuroleptics ▪ Antidepressants o Cognitive: ▪ Untreatable - Non Drug treatments: o SLT o PT o OT o Psychology Future Therapies: - Gene therapy - Htt aggregation blockers - Anti-apoptotic drugs - Antioxidants - Neurotrophic factors - Transplantation