Trinucleotide repeat expansion disease Notes

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Fragile X syndrome

Huntington disease

NOTES NOTES TRINUCLEOTIDE REPEAT EXPANSION DISEASES GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Group of genetic diseases; mutations characterized by increased number of 3 base pair repeats ▫ C, G nucleotides: loci at which repeats expanded ▪ Mechanism of disease ▫ Loss-of-function: transcriptional silencing ▫ Toxic, gain-of-function: may occur at mRNA, translational level/protein structure level RISK FACTORS SIGNS & SYMPTOMS ▪ See individual diseases DIAGNOSIS LAB RESULTS ▪ Genetic testing for number of repeats OTHER DIAGNOSTICS ▪ Family history, physical examination (disease-specific, pathognomonic findings) TREATMENT ▪ Family history OTHER INTERVENTIONS COMPLICATIONS ▪ Anticipation ▫ More severe, earlier-onset of disease as mutation passed down ▪ No curative treatment currently available ▪ Symptom management (hallmark of therapy) FRAGILE X SYNDROME osms.it/fragile-x-syndrome PATHOLOGY & CAUSES ▪ Autosomal recessive, X-linked disease; intellectual disability, typical facies, macroorchidism 176 OSMOSIS.ORG ▪ Inherited defect in 5’ untranslated region (UTR) of familial mental retardation-1 (FMR1) gene → trinucleotide expansion → abnormal length → ↑ methylation → promoter region methylation → ↓ transcription of FMR1 gene → ↓ familial mental retardation protein (FMRP) synthesis → clinical phenotype
Chapter 28 Trinucleotide Repeat Expansion Diseases FMRP ▪ High concentration in testes, brain ▪ mRNA transport protein ▫ ↓ FMRP → ↓ transport of neuronal proteins from perinuclear space → dendritic spines → dysregulated synaptic function ▪ Translation regulator ▫ ↓ FMRP → via ↑ metabotropic glutamate receptor activity → ↑ translation of bound mRNA at synaptic junction → dysregulated synaptic activity → intellectual disability CAUSES Trinucleotide (CGG) repeat expansion ▪ Trinucleotide (CGG) repeat expansion on 5’ UTR FMR1 gene at Xq27.3 locus ▫ 45–54: intermediate expansion repeat number ▫ 55–200: carrier/premutation individual repeat number ▫ 200–4,000: affected individual repeat number Inheritance ▪ Autosomal recessive (some caveats) ▪ Mutations occur/worsen during oogenesis, not spermatogenesis → abnormal autosomal recessive expression ▫ 20% of disease-genotype individuals who are biologically male: asymptomatic, carriers ▫ 30–50% of genotypically carrier individuals who are biologically female: symptomatic (preferential X-chromosome inactivation → inconsistent mutation expression → variable symptom presentation) ▪ Anticipation ▫ Genetic mutations continue through pedigree → ↑ length of expansion → ↑ severity of disease RISK FACTORS ▪ Genotype-phenotype correlation ▫ Repeat size, methylation mosaicism: ↑ % cells with same expression/methylation amount → ↑ phenotype penetrance COMPLICATIONS Behavioral features ▪ Autism, attention-deficit hyperactivity disorder (ADHD), anxiety disorders Seizures ▪ Simple/complex; occurs commonly in childhood, resolves in adulthood Fragile X tremor/ataxia ▪ Observed in carrier/premutation individuals ▪ Tremor/ataxia → parkinsonism ▫ Short-term memory loss, executive dysfunction (common) ▫ Individuals who are biologically female: ovarian insufficiency; early menopause (age ≤ 40) ▪ Pathogenesis ▫ Mild CGG repeat expansion → mild ↑ methylation (not including promoter region) → adequate transcription → RNA product → poor translation → abnormal protein → nuclear accumulation → aggregation of mRNAbinding protein → toxic effects to cell function → neurodegeneration SIGNS & SYMPTOMS Impaired cognitive function ▪ Developmental delay: delayed attainment of language, motor milestones ▫ Delayed milestones: sit alone (10 months), walk (18 months), clear spoken words (20 months) ▪ Intellectual disability: IQ range of 20–60 Physical features ▪ Prominent in adulthood; more common in individuals who are biologically male ▪ Facies ▫ Prominent forehead, jaw; long, narrow face; large ears ▪ Macroorchidism ▪ Connective tissue ▫ Joint hyperlaxity, arched palate, flat feet, mitral valve prolapse (benign) ▪ Behavioral features ▫ Hyperactivity, inattention, gaze aversion, stereotypic movements (e.g. handflapping, unusual speech patterns) OSMOSIS.ORG 177
TREATMENT MEDICATIONS ▪ Symptom-directed management Behavioral features ▪ ADHD presentation ▫ < 5 years old: non-stimulant therapy (e.g. guanfacine, clonidine) ▫ > 5 year old: stimulant prescription (e.g. methylphenidate) Anxiety/mood disorders ▪ Selective serotonin reuptake inhibitors (SSRIs) Figure 28.1 A child with fragile X syndrome. DIAGNOSIS LAB RESULTS DNA testing (obtained prenatally) ▪ Chorionic villus sampling (11–13 weeks of gestation) ▫ Degree of methylation variable in later development ▪ Amniocentesis (> 15 weeks of gestation) Complete prenatal screening ▪ DNA testing ▪ Fluorescent polymerase chain reaction (PCR) ▫ Identify degree of methylation ▪ AGG trinucleotide genotyping ▫ Determine risk in premutation/ carrier expansion individuals who are biologically female OTHER DIAGNOSTICS History Physical examination ▪ Phenotypic characteristics on musculoskeletal, genitourinary examination ▪ Neurological ▫ Mental status (intellectual, behavioral deficits) 178 OSMOSIS.ORG Seizures ▪ Anticonvulsants Premature ovarian insufficiency ▪ Estrogen replacement therapy PSYCHOTHERAPY ▪ Symptom-directed management Behavioral features ▪ Counseling, psychotherapy OTHER INTERVENTIONS ▪ No curative therapy Symptom-directed management ▪ Intellectual disability ▫ Speech/language therapy, early intervention, special education Prevention ▪ Genetic preconception counseling ▫ Preconception reproductive options (e.g. use of donor gametes from unaffected donor)
Chapter 28 Trinucleotide Repeat Expansion Diseases HUNTINGTON'S DISEASE osms.it/huntingtons-disease PATHOLOGY & CAUSES ▪ Autosomal dominant, neurodegenerative disease; chorea, dementia ▫ Average age of onset is 40 ▪ Medium spiny striatal (GABAergic) neuronal cell death → dysregulation of basal ganglia circuitry → unchecked dopamine, glutamate-mediated basal ganglia activity → ↑ motor output → hyperkinetic movement ▪ Cortical cell death → cognitive impairment CAUSES Trinucleotide repeat (CAG) expansion ▪ Trinucleotide repeat (CAG) expansion of first exon in huntingtin (HTT) gene on chromosome 4p16.3 ▫ Intermediate repeat number: 27–35 (rarely causes disease) ▫ Disease repeat number: 36–39 (incomplete penetrance) ▫ Disease repeat numbers: > 40 (complete penetrance ↑ repeat number → ↓ age of onset) ▪ Repeat CAG expansion in first exon of HTT → expansion of polyglutamine region at N terminus of HTT protein → gain-of-function ▪ Physiologic role of HTT protein unknown (high levels found in brain tissue) Possible pathophysiologic roles of HTT protein ▪ Aggregation of protein → cellular dysfunction ▫ Aggregation → uptake by neurons → neuronal death; akin to prionlike pathogenesis; most prominent aggregation (neuronal death) in caudate, putamen (AKA neostriatum) ▫ Aggregation → ↑ proteasomal, autophagic degradation pathways → dysregulated cell injury, death ▪ Transcriptional dysregulation ▫ Abnormal HTT protein → binding of various transcriptional regulators → ↓ mitochondrial oxidative stress protective genes → susceptibility of oxidative damage → neuronal death ▪ Altered levels of brain-derived neurotrophic factors Role of ras homolog enriched in striatum (Rhes) ▪ Avidly bind with mutant huntingtin ▪ Protein selectively expressed in striatum ▪ Rhes → mediates covalent attachment of small ubiquitin-like modifier (SUMO) to HTT → ↑ HTT aggregation → neurotoxicity Inheritance ▪ Autosomal dominant ▪ Anticipation ▫ Repeat expansion occurs during spermatogenesis → paternal transmission associated with early age of onset COMPLICATIONS ▪ Depression → suicide ▪ Dysphagia → aspiration pneumonia (common cause of death) SIGNS & SYMPTOMS ▪ Motor symptoms (movement inhibition; excessive, involuntary movements) ▫ Hypotonia with hyperreflexia (early symptom), chorea (e.g. face, head, neck, tongue, trunk, extremities), athetosis, dystonia, eye movement slows, gait abnormalities (unsteady, irregular → bradykinesia, rigidity in late disease) ▪ Psychiatric ▫ Apathy, irritability, depression, delusions, aggression, disinhibition, paranoia OSMOSIS.ORG 179
▪ Cognitive ▫ Progressive dementia, inflexibility of thought; ↓ insight, concentration; memory loss ▪ Weight loss, cachexia DIAGNOSIS DIAGNOSTIC IMAGING MRI ▪ Atrophy of head of caudate nuclei LAB RESULTS ▪ Genetic testing for CAG repeat in HTT (> 36 repeats) OTHER DIAGNOSTICS ▪ History ▪ Physical examination ▪ Neurological ▫ Motor, mental status examination TREATMENT MEDICATIONS Chorea (symptomatic therapy) ▪ Presynaptic VMAT2 (vesicular monoamine transporter Type II) inhibitors: tetrabenazine/deutetrabenazine ▫ ↑ synaptic metabolism of dopamine → ↓ dopamine → ↓ basal ganglia output → ↓ hyperkinetic output ▫ May exacerbate parkinsonism symptoms ▫ As late symptom (e.g. chorea abates), periodic review of dosing recommended ▪ Neuroleptics: haloperidol/chlorpromazine ▫ Dopamine receptor antagonists → ↓ dopaminergic input → ↓ basal ganglia output → ↓ hyperkinetic output ▫ Similar parkinsonism side effects/ exacerbation of symptoms ▪ Psychosis: quetiapine (dopamine, serotonin antagonist properties) PSYCHOTHERAPY ▪ Chorea (symptomatic therapy) ▫ Counseling, techniques to ↓ anxiety, stress OTHER INTERVENTIONS ▪ No curative therapy ▫ Palliative, advance care planning ▪ Symptomatic therapy ▫ Chorea (severe cases): assistive equipment (e.g. helmets, padded reclining chairs, low beds) ▫ Dysphagia: thickened liquids ▫ Speech, language problems: physical therapy ▫ Gait impairment: hip protectors → ↓ hip fractures → ↓ morbidity Figure 28.2 An MRI scan in the coronal plane of the head of an individual with Huntington’s disease. There is atrophy of both caudate nuclei which has led to hydrocephalus ex vacuo. There is also generalized cortical atrophy. 180 OSMOSIS.ORG

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