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Diagnosis of Huntington's Disease


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Dr. Mark Guttman's presentation for the Local Practitioner's Program at HSG 2015 in Tampa covers the clinical features of HD, diagnostic evaluation and differential diagnosis

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Diagnosis of Huntington's Disease

  1. 1. Diagnosis of Huntington’s Disease Mark Guttman MD, FRCPCMark Guttman MD, FRCPC
  2. 2. Disclosures • Received honorarium for presentations andReceived honorarium for presentations and participated in Advisory Panels forparticipated in Advisory Panels for Novartis, UCB, Medtronic, Roche, IsisNovartis, UCB, Medtronic, Roche, Isis Pharma and TevaPharma and Teva • Received research support from Teva,Received research support from Teva, Chelsea, Merck, CHDI, NIH, NPFChelsea, Merck, CHDI, NIH, NPF
  3. 3. Objectives • To reviewTo review • Clinical features of HDClinical features of HD • Diagnostic evaluationDiagnostic evaluation • Differential DiagnosisDifferential Diagnosis
  4. 4. Clinical Scenarios • Individual with a proven family history ofIndividual with a proven family history of HD without obvious clinical symptomsHD without obvious clinical symptoms • Individual with a proven family historyIndividual with a proven family history with obvious clinical symptomswith obvious clinical symptoms • Individual without a family history withIndividual without a family history with clinical symptoms compatible with HDclinical symptoms compatible with HD
  5. 5. Huntington’s Disease Clinical Features - 1 • motor dysfunctionmotor dysfunction • chorea is usually the earliest signchorea is usually the earliest sign • initially fingers, toes, faceinitially fingers, toes, face • progressiveprogressive • eye movement abnormalitieseye movement abnormalities • impaired initiation of saccadesimpaired initiation of saccades • slow saccadesslow saccades • motor impersistencemotor impersistence
  6. 6. Huntington’s Disease Clinical Features - 2 • motor dysfunctionmotor dysfunction • dystonia and parkinsonismdystonia and parkinsonism • progressive incoordination, unsteadiness,progressive incoordination, unsteadiness, immobilityimmobility • dysarthria, dysphagiadysarthria, dysphagia • motor signs eventually appear in allmotor signs eventually appear in all
  7. 7. Huntington’s Disease Clinical Features - 3 • juvenile onsetjuvenile onset • rigidity, dystonia, bradykinesia, myoclonusrigidity, dystonia, bradykinesia, myoclonus • seizuresseizures • rapidly progressive dementiarapidly progressive dementia
  8. 8. Huntington’s Disease Clinical Features - 4 • Cognitive impairmentCognitive impairment • executive dysfunctionexecutive dysfunction • Psychiatric featuresPsychiatric features • DepressionDepression • Obsessive compulsive trait with perseverationObsessive compulsive trait with perseveration • Psychosis uncommonPsychosis uncommon • Behavioral changesBehavioral changes • Apathy, frontal lobe featuresApathy, frontal lobe features • Aggressive outbursts, impulsive behaviorAggressive outbursts, impulsive behavior • Hypersexual behaviorHypersexual behavior
  9. 9. Different Clinical Presentations Motor Cognitive Psychiatric
  10. 10. Diagnostic Evaluation For a Patient with Early Symptoms • If there is a family history of HD:If there is a family history of HD: • Evaluate if the individual has signs andEvaluate if the individual has signs and symptoms that are compatible with thesymptoms that are compatible with the diagnosis of HDdiagnosis of HD • Are there diagnostic criteria?Are there diagnostic criteria?
  11. 11. Unified Huntington’s Disease Rating Scale • Developed by the Huntington Study Group andDeveloped by the Huntington Study Group and modified 1999modified 1999 • Used as an outcome measure in clinical trialsUsed as an outcome measure in clinical trials • Motor, Behavioural, Cognitive, FunctionalMotor, Behavioural, Cognitive, Functional SubscalesSubscales • Motor rating includes eye movements, chorea,Motor rating includes eye movements, chorea, dystonia, speech, finger tapping, Luria, rapiddystonia, speech, finger tapping, Luria, rapid alternating movements, gait, pull test,alternating movements, gait, pull test, bradykinesiabradykinesia
  12. 12. UHDRS Diagnostic Confidence To what degree are you confident that this person meets the operational definition of the unequivocal presence of an otherwise unexplained extrapyramidal movement disorder (e.g., chorea, dystonia, bradykinesia, rigidity) in a subject at risk for HD? 0 = normal (no abnormalities) 1 = non-specific motor abnormalities (< 50% confidence) 2 = motor abnormalities that may be signs of HD (50-89%) 3 = motor abnormalities that are likely signs of HD (90-98%) 4 = motor abnormalities that are unequivocal signs (≥ 99%)
  13. 13. Are there other presentations? • Patients and family members often reportPatients and family members often report other symptoms before physical featuresother symptoms before physical features • Evidence from observational studies haveEvidence from observational studies have identified changes before motor signsidentified changes before motor signs
  14. 14. N=105 cases Years Prior to Motor Diagnosis (number of subjects) (34) (40) (53) (69) (82) (105)
  15. 15. Mean Stroop Reading Scores Prior to Motor Diagnosis
  16. 16. Mean Behavioral Assessment Scores (Frequency x Severity) Prior to Motor Diagnosis
  17. 17. MRI in HD
  18. 18. Evaluation of the patient with chorea • Family historyFamily history • Time courseTime course • Exacerbating/relieving factorsExacerbating/relieving factors • Other neurological featuresOther neurological features • Other medical conditionsOther medical conditions • MedicationsMedications • Neuroimaging and laboratory work-upNeuroimaging and laboratory work-up
  19. 19. Huntington’s Disease-like 2 • Autosomal dominant inheritanceAutosomal dominant inheritance • African ancestryAfrican ancestry • Expanded trinucleotide (CTG) repeatsExpanded trinucleotide (CTG) repeats within junctophilin-3 genewithin junctophilin-3 gene • Chorea/dementia onset in 3Chorea/dementia onset in 3rdrd -4-4thth decade (agedecade (age inversely related to size of expansion)inversely related to size of expansion) • Pathology very similar to HDPathology very similar to HD • Acanthocytosis seen in 10% casesAcanthocytosis seen in 10% cases Margolis et al 2004
  20. 20. Benign hereditary chorea • Autosomal dominantAutosomal dominant • 14q (DeVries et al ’00), thyroid14q (DeVries et al ’00), thyroid transcription factor 1transcription factor 1 • Other genes/linkage sites alsoOther genes/linkage sites also • No dementia; little disease progressionNo dementia; little disease progression • Decreased striatal interneurons (Kleiner-Decreased striatal interneurons (Kleiner- Fisman et al. 2005)Fisman et al. 2005)
  21. 21. X-linked • Filipino males - Lubag (DYT3) dystonia-Filipino males - Lubag (DYT3) dystonia- parkinsonism, Capiz province, island ofparkinsonism, Capiz province, island of PanayPanay - Tremors, chorea, myoclonus also seen- Tremors, chorea, myoclonus also seen - Female carriers may be symptomatic- Female carriers may be symptomatic • Lesch-Nyhan (childhood, self-mutilation)Lesch-Nyhan (childhood, self-mutilation) • McLeod syndromeMcLeod syndrome
  22. 22. Chorea: autosomal recessive • Neurodegeneration with brain iron accumulationNeurodegeneration with brain iron accumulation (NBIA); PKAN, aceruloplasminemia(NBIA); PKAN, aceruloplasminemia • Wilson’s diseaseWilson’s disease • Chorea-acanthocytosisChorea-acanthocytosis • AR ataxias – chorea may rarely be presentingAR ataxias – chorea may rarely be presenting symptom; Friedreich’s ataxia; ataxia-telangiectasia;symptom; Friedreich’s ataxia; ataxia-telangiectasia; ataxia with oculomotor apraxia I, IIataxia with oculomotor apraxia I, II • Infantile bilateral striatal necrosis; may be AR orInfantile bilateral striatal necrosis; may be AR or mitochondrial, lesions on MRImitochondrial, lesions on MRI • HDL3 (one family)HDL3 (one family) • Other pediatric metabolic disorders (glutaricOther pediatric metabolic disorders (glutaric aciduria)aciduria)
  23. 23. Chorea: structural causes • Cerebral palsyCerebral palsy • StrokeStroke • Other vascular; AVM, vasculitides, moya-Other vascular; AVM, vasculitides, moya- moya, cavernous angiomamoya, cavernous angioma • TumourTumour • Multiple sclerosisMultiple sclerosis
  24. 24. Paroxysmal dyskinesias (autosomal dominant) • Paroxysmal kinesogenic dyskinesia; someParoxysmal kinesogenic dyskinesia; some associated with sz;associated with sz; • Paroxysmal non-kinesogenic dyskinesiaParoxysmal non-kinesogenic dyskinesia (caffeine, alcohol, stress, fatigue)(caffeine, alcohol, stress, fatigue) • Paroxysmal exertional dyskinesiaParoxysmal exertional dyskinesia (prolonged exertion)(prolonged exertion)
  25. 25. Chorea-acanthocytosis (autosomal recessive) • 9q21 –9q21 – VPS13AVPS13A (formerly(formerly CHACCHAC)) • Chorein – many point mutationsChorein – many point mutations • Onset 20-40 yrsOnset 20-40 yrs • Behavioural changes, psychiatric symptoms,Behavioural changes, psychiatric symptoms, dementiadementia • Chorea, dystonia, oro-buccal lingual dyskinesiasChorea, dystonia, oro-buccal lingual dyskinesias (self-mutilation), parkinsonism, tics(self-mutilation), parkinsonism, tics • SeizuresSeizures • Peripheral neuropathy and myopathyPeripheral neuropathy and myopathy • Elevated creatine kinase, liver enzymesElevated creatine kinase, liver enzymes
  26. 26. Orofacial dyskinesia, mutilations Courtesy Dr Jane Zheng, UNC-CH
  27. 27. chorein patient mother Performed by Dr Benedikt Bader, Munich Western blot showed absence of chorein: chorea-acanthocytosis (autosomal recessive)
  28. 28. Autoimmune causes • Sydenham’s chorea (ASO, anti-DNAse B)Sydenham’s chorea (ASO, anti-DNAse B) • Lupus (lupus anti-coagulant)Lupus (lupus anti-coagulant) • Anti-phospholipid ab (anti-cardiolipin)Anti-phospholipid ab (anti-cardiolipin) syndrome?syndrome? • Paraneoplastic; renal, small-cell lung,Paraneoplastic; renal, small-cell lung, breast, Hodgkin’s, non-Hodgkin’sbreast, Hodgkin’s, non-Hodgkin’s lymphoma, ovarian (anti-Hu, anti-CRMP5,lymphoma, ovarian (anti-Hu, anti-CRMP5, anti-Yo, anti-NMDA receptor)anti-Yo, anti-NMDA receptor) • Celiac diseaseCeliac disease
  29. 29. Metabolic Causes • DiabetesDiabetes (non-ketotic hyperglycemia,(non-ketotic hyperglycemia, hypoglycemia)hypoglycemia) • Electrolyte disturbancesElectrolyte disturbances • HyperthyroidismHyperthyroidism • Hyper-/hypo-parathyroidism (likelyHyper-/hypo-parathyroidism (likely secondary to calcium disturbances);secondary to calcium disturbances); “Fahr’s disease”“Fahr’s disease” • Chorea gravidarumChorea gravidarum?? (sensitization of(sensitization of dopamine receptors by estrogens, anti-basaldopamine receptors by estrogens, anti-basal ganglia antibodies)ganglia antibodies)
  30. 30. Chorea: drug-induced • Levo-dopa-induced dyskinesias in Parkinson’sLevo-dopa-induced dyskinesias in Parkinson’s disease (peak dose; on-off)disease (peak dose; on-off) • Direct drug effect; cocaine, amphetamine, Dilantin,Direct drug effect; cocaine, amphetamine, Dilantin, Lithium, and other stimulantsLithium, and other stimulants • Estrogens (oral contraceptives, hormoneEstrogens (oral contraceptives, hormone replacement therapy)?replacement therapy)? • Tardive (typical neuroleptics, AEDs, Li, SSRIs)Tardive (typical neuroleptics, AEDs, Li, SSRIs) • Use of neuroleptics for psychiatric symptomsUse of neuroleptics for psychiatric symptoms may mask appreciation of movement disordermay mask appreciation of movement disorder due to neurodegenerative etiology (HD, HDL2,due to neurodegenerative etiology (HD, HDL2, chorea-acanthocytosis, McLeod)chorea-acanthocytosis, McLeod)
  31. 31. Workup of the patient with chorea (1) • Glucose, electrolytes, calciumGlucose, electrolytes, calcium • CBC + peripheral blood smearCBC + peripheral blood smear • TFTsTFTs • LFTsLFTs • CKCK • ESRESR • ANA, RhF, ANCAANA, RhF, ANCA • Anticardiolipin absAnticardiolipin abs • Lupus anticoagulantLupus anticoagulant • ASO, anti-DNAse B titresASO, anti-DNAse B titres • RPRRPR • B12/folateB12/folate • Anti-gliadin absAnti-gliadin abs • FerritinFerritin • CeruloplasminCeruloplasmin • Pregnancy testPregnancy test • HIVHIV • Anti-CRMP5, anti-Hu,Anti-CRMP5, anti-Hu, anti-Yo, anti-NMDAanti-Yo, anti-NMDA receptor absreceptor abs • Lactate/pyruvateLactate/pyruvate • Serum/urinary organic/aminoSerum/urinary organic/amino acidsacids • Cholesterol, triglycerides,Cholesterol, triglycerides, very long chain fatty acidsvery long chain fatty acids
  32. 32. Workup of the patient with chorea (2) • MRI brain + gadoliniumMRI brain + gadolinium • CSF protein, glucose (lactate/pyruvate), 14-3-3, cells,CSF protein, glucose (lactate/pyruvate), 14-3-3, cells, infectious markers, paraneoplastic absinfectious markers, paraneoplastic abs • McLeod phenotype (Kx and Kell antigen expression –McLeod phenotype (Kx and Kell antigen expression – regional blood center)regional blood center) • Genetic testing - HD, HDL2, SCA 1, 2, 3, 17, DRPLAGenetic testing - HD, HDL2, SCA 1, 2, 3, 17, DRPLA …………………… • TITF-1TITF-1 • chorein assay ( assay ( • VPS13AVPS13A mutationmutation • EMG/NCVEMG/NCV • Muscle biopsyMuscle biopsy • EEGEEG • Echocardiogram, abdominal ultrasoundEchocardiogram, abdominal ultrasound