Wilson’s disease

Wilson disease overview for CME on Movement Disorder at GNRC Guwahati 2011 Feb 19th

1. Wilson’s Disease Dr PS Deb MD, DM GNRC Gawhati India

2. SAK Wilson MD Thesis: 1911 10 cases of ”Progressive lenticular degeneration, a familial nervous disase associated with cirrhosis of the liver” 6cases from past publication 4 cases of his own, 3 diagnosed at post mortom one antemortom

3. Gower’s 1888 - Tetanoid Chorea 10 years old boy, suffering with progressive extrapyramidal syndrome (dystonic) died in 7 months, but autopsy of brain was normal. brother and three other relations also died of similar illness

4. Gower’s case: 1888

5. Ormerod - 1890 A case of cirrhosis of liver with obscure fatal nervous symptom Mild bilateral atrophy of putamen

6. Homen - 1892 A peculiar disease in two brother and sister in the form of progressive dementia probably Lues Heriditaria Tarda Fixed smile, open mouth, contracture and emaciation Symmetrical softening of putamen

7. Wilson’s Cases 1 S.T.

8. Wilson’s case 3 E.P.

9. Wilson’s Case 1- Pathology Hepatic cirrhosis Bilateral symmetrical degeneration of leniticular nucleus

10. Wilson on - Etiology Diseases is not congenital, most likely acquired Familial, not hereditary The morbid agent is probably of the nature of a toxin but not syphilitic Acute or sudden onset Variability of symptom Toxin may be elaborated in the liver like Kernicterus Toxin has a specific action on the lenticular nucleus Nature of toxin is unknown but not microbial

11. Wilson’s Summary of cases

12. Clinical conclusion - Wilson In pure cases the affection constitutes an extrapyramidal motor disease occurring in young people and very often familial. It is progressive and fatal within a varying period months to years. It is characterized by : generalized tremor, dysarthria and dysphagia , muscular rigidity and hypertonicity , emaciation, spasmodic contractions, contractures, emotionalism. In some ways the disease bears a resemblance to paralysis agitans , and throws light on the problem of that affection. Although cirrhosis of the liver is constantly found in this affection, and-is an essential feature of it, there are no signs of liver disease during life.

13. Wilson on – Pathophysiology (IM) Jackson : “ Positive symptom cannot be caused by negative lesion” IM - not caused by pyramidal system irritation IM needs intact pyramidal system hence IM Extrapyramidal system must be injured Chroea Athetosis caused by lesion of Affrent Tremor rigidity by efferent Dysarthria dysphagia is due to hypertonia

14. Wilson on Treatment “What can be said of the treatment of disease? Its nature must be discovered before treatment can be lifted from empirical to the rational level”

15. Further development 1948 : Cumings – Cu increased in liver and brain, BAL (1951) 1952: Scheinberg – Ceruloplasmin 1956: J Walsh – Penicillamine, Trientine (82) 1980: Genetic basis Inida : 1963 first Case report Dr NH Wadia and Dasture 1970 WD Clinic at NIMHANS

16. Epidemiology Prevalence Europe: 30/100,000 Asia : 33-68/100,000 Incidence 1/30000 El Salvador 1 in 186. Carrier: 1/100 (El Salvador 1/4) India Neurological ? Hepatic 19.7% Metabolic liver disease in children commonest WD NIMHANS : 15-20 New cases per year Age of onset: 10-20 (<5 never, >50 rare) Hepatic :10-15 (40 %) Neurologic 15-20 (40 %) Sex: M>F .

17. WD – Genetic Link Autosomal recessive disorder The WD gene, ATP7B is located on the long arm of chrom . 13q14.1 The WD gene encodes a copper-transporting P-Type ATPase ) which is expressed predominantly in the liver

18. Mutations in WD gene (ATP7B) ATP7B gene Deletions 60 Insertions 21 Nonsense 19 Missense 166 Splice 23 total 289 India Chandigarh: T3305C, C2975A, 29977ins A Kolkata : C813A 19% Vellore : G3182A 16%, C813A 12% 51 Mutation of ATP7B, 34 novel C813A mutation commonest World European PH1069Q 60% Chinese pR778L 45%

19. Wilson Disease Pathophysiology

20. Pathology: Brain bilaterally symmetrical putaminal (P) softening (arrows) extending laterally up to the external capsule Whole mount preparation stained with Luxol Fast Blue shows relative preservation of internal capsule and pale and softened neuropil in the putamen (P, arrow). Softened area in the putamen has bizarre astrocytes with vesicular lobulated nuclei (arrow) with inset showing Alzheimer type 2 astrocytes in the neuropil (arrow). H and E Large opalski cell characteristic of Wilson’s disease has irregular eosinophilic cytoplasm and small peripherally placed pyknotic nucleus. H and E

21. Liver histology Histological abnormalities precede clinical appearance Helpful diagnostic clues: steatosis ballooned hepatocytes glycogenated nuclei moderate to marked copper deposition lymphocytic portal and interface hepatitis Untreated, progresses to cirrhosis

22. Liver Pathology Slice of enlarged liver shows microand macronodular cirrhosis. Inset demonstrates copper deposits within hepatocytes on rubeanic acid stain. Inset: Rubeanic acid

23. Pathological Stages Stage I - The initial period of accumulation of copper by hepatic binding sites Stage II - The acute redistribution of copper within the liver and its release into the circulation Stage III - The chronic accumulation of copper in the brain and other extrahepatic tissue, with progressive and eventually fatal disease Stage IV - The achievement of copper balance with chronic chelation therapy

24. Clinical Manifestation

25. WD: Clinical Features - Indian

26. NEUROLOGIC PRESENTATION : NIMHANS (307 cases) Symptoms Percentage Tremor 31.6 Dysarthria 15.6 Abnormal Gait 8.8 Musculoskeletal 5.2 Seizure 4.2 Behavioural 4.6 Dystonia 3.6 Clumsiness 2.6 Drooling 2.6 Altered sensorium 1.3 Dysphagia 0.9 Chorea 0.3

27. North west study (21 cases) Wilson's disease: A study of 21 cases from north-west India. Annals of Indian Academy of Neurology, December 2007 Symptoms Percentage Tremor 85.7 Dysarthria 76.2 Dystonia 57.1 Cognitive abnormality 57.5 Seizure 38 Cerebellar sign 31.7

28. North East India (49 cases) J Assoc Physicians India .  2001 Sep;49:881-4. Wilson's disease in Eastern India. Symptoms Percentage Dystonia 96 Silly smile 92 Dysarthria 80 Cognitive abnormality 71 Tremor 47 Bradykinesia 45

29. KF Ring Neuropsychiatric: 95% . Hepatic : 30 to 50 % KF rings are not specific for WD. They may be found in other chronic liver disease, PBC, PSC, AIH, and familial cholestatic syndromes.

30. PSYCHIATRIC PRESENTATION 15-20 % of patients may present with purely psychiatric symptoms . Phobias , compulsive behaviors, aggressive and antisocial behaviors Schizophrenia Psychosis Cognitive decline

31. HEPATIC PRESENTATION Acute hepatitis, C hronic liver disease— portal HTN . Autoimmune hepatitis . Fulminant hepatic failure , with sev . coagulopathy and encephalopathy . Recurrent bouts of hemolysis may predispose to the development of gallstones . Wilson disease is rarely complicated by hepatocellular carcinoma.

32. Extrahepatic disorders Hemolytic anemia Fanconi's syndrome Nephrolithiasis Hypoparathyroidism Amenorrhea and Testicular problems Infertility . Arthritis, Rhabdomyolysis . Cardiomyopathy Pancreatitis

33. Clinical Pointers Classical Unexplained jaundice Hepatic + Extrapyramidal syndrome Family History Most likely Extrapyramidal syndrome in young Progressive behavioral syndrome Multi axial neurological Psychiatric Poor school performance Seizure Recurrent pathological # Unexpalined hematological abnormality

34. Investigation Biochemical Serum ceruloplasmin <20mg/ dL 24hr Urinary Copper >100micg/d Serum free copper >10micg/ dL Liver Copper >250micg/g Ophthalmological Slit lamp KF ring Imaging X-ray Osteoporosis Ultrasound Cirrhosis CT Scan MRI Genetics

35. Pathway for Investigation

36. Electrophysiology EEG 41.1% VEP 35% BAER 42.1% Dyautomaumia ECG

37. Imaging Ultrasound Abdomen Cirrhosis Portal hypertension X-ray: Osteoarthritis, arthirtis CT brain : Low sensitivity, MRI brain High sensitivity Bilateral basal ganglionic changes Brain stem changes White matter changes

38. CT brain Cortical atrophy 44.8% Ventricular dilatation 44% Caudate atrophy 25% Brain stem atrophy 31.9% Cerebellar atrophy 19% Hemispheric hypodensities 29.3% B asal ganglionic hypodensities . 19.8% T halamic hypodensities . 10.3 %

39. MRI brain Atrophy of the cerebrum, 70% Brainstem, 66% Cerebellum 52% Signal abnormality in putamen , 72% Caudate, 61% Thalami, 58% Midbrain, 49% Pons , 20% Cerebral white matter 25% Cortex 9% Medulla 12% Cerebellum 10% Face of giant panda' sign 12% CPM like feature 7% Bright claustral sign 4%

40. MRI in WD ‘Face of giant panda’ sign; MRSS: decreased NAA and therefore a decreased ratio with other products Bright lateral putamen or claustral sign; P allidal hyperintensity

41. Brain Stem changes: CPM like Classical: Hyperintensity of whole of the central pons sparing a peripheral rim; Bisected pontine signal change by a horizontal line and; Trisected: Pontine hyperintensity trisected by a hypointense line like ‘Mercedes Benz’ sign

42. MRI other changes Bilateral basal ganglionic and thalamic hyperintensity in addition to mild-to-moderate degree diffuse atrophy Extensive diffuse white matter changes Bilateral lentiform , thalamic, midbrain and white matter hyperintensity Midbrain hyperintensity in the tectal region

43. Family Screening Biochemical Testing Children of patient: Begin at age 2 if asymptomatic, repeat once in 5 years unless reason to pursue further.   Siblings of patient: Physical examination and brief history of any liver or neurological symptoms. Liver Function Tests:  ALT, AST, Albumin, Bilirubin . Ceruloplasmin and Serum Copper. 24 hour urine copper Slit-lamp exam of the eyes for Kayser -Fleischer ring If no K-F rings, abnormal liver functions tests, and low ceruloplasmin :  liver bio

44. Molecular Genetic Testing Linkage analysis ( Haplotype analysis ) Identify a set of closely linked segments of DNA, patient with family members Gene sequencing (mutation screening of the entire ATP7B gene) Analysis of a specific location in the ATP7B gene for a known particular mutation

45. Treatment Options

46. Diet Avoid Copper rich diet liver, shellfish (especially lobster), nuts, chocolate, soya products, gelatin, and mushrooms. Water with copper >1ppm (well water)

47. Chelating agents : Penicillamine and Trientine intestine Copper Ceruloplasmin Penicillamine / Trientine urine

48. D- Penicillamine Dose Initial : 1-1.5 g/day adults or 20 mg/kg/day children Maintenance : 0.75-1 g/day Side effect Fever, rash Proteinuria Lupus like reaction Aplastic anemia Leukopenia Thrombocytopenia Nephrotic syndrome Degenerative changes in skin Hepatotoxicity Neurological Deterioration occurs in 10%-20% during initial phase

49. Trientine (triethylene tetramine dihydrochloride) Dose : 1-1.2 g/day Side effects : Gastritis Aplastic anemia rare Neurological Deterioration 10%-15% during initial phase .

50. Tetrathiomolybdate Mode : Chelator and also blocks copper absorption Side effects : BM suppresion Hepatotoxicity Rare reports of ND during initial phase of treatment

51. intestine Copper Albumin Ceruloplasmin Zinc metallothionein Zinc Acetate/Sulfate

52. Zinc Indication: Following penicillamine Penicillamine intolerance Prophylactic to aymptomatic sibs New cases (cannot afford Penicillamine) Dose : Initial : 50 mg T.I.D (adults) Side effects Gastritis Zinc accumulation Possible changes in immune ND can occur during initial phase

53. Indications (AALD) Penicillamine Hepatic disease Neurological disease Zinc Neurological disease Peinicillamine intolerance Maintenance treatment Pregnancy Trientine Hepatic disease (or first choice?) Neurological disease Penicillamine side effects Tetrathiomolybdate? Neurological patients?

54. Follow up Depends on the severity of the neurological or hepatic features Assess any sign of hepatic decompensation 24-h urinary Cu excretion (denotes adequate treatment) Monitor penicillamine side effects