Wilson Disease Mohit Bhatt Director Neurosciences Wilson Disease - - PowerPoint PPT Presentation

Wilson Disease

Mohit Bhatt

Director Neurosciences Wilson Disease Clinic Kokilaben Dhirubhai Ambani Hospital & Medical Research Institute Mumbai, INDIA

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Wilson facies, facetious smile, dysarthria, dystonia-parkinsonism

Samuel A K Wilson Brain, 1912 John N Cumming Brain, 1948 John Walshe Am J Med, 1956

Copper: Role and transport

• Active redox (cuprous - cupric): enzymatic activity; toxicity
• No free copper
• Tightly controlled copper homeostasis

Transport of dietary copper

1. Non-specific metal transporters 2. ATP7A / Menke’s protein (Cu -transporting ATPase) 3. CTR1 transporter 4. ATP7B / Wilson ATPase (Cu-transporting ATPase)

85% of dietary copper excreted in bile

Portal vein Liver Dietary copper 2-5 mg / day

15% of dietary copper retained in the body

2 1 3 4 4

Enterocyte

Robert EA and Cox DW. Wilson Disease. In: Zakim and Boyer's Hepatology: A Textbook of Liver Disease, 2011; Huster D. Best Pract Res Clin Gastroenterol, 2010

Prevalence and symptoms

• Rare (prevalence 1:30,000)
• Affecting children and young adults
• Autosomal recessive, ATP7B gene
• Chronic copper toxicity
• Fatal if untreated

6

Fleeting Jaundice Hemolytic Anemia Liver Cirrhosis Fulminant Liver Failure Extrapyramidal Neuropsychiatric Brain

Osseomuscular

Liver

3 years on Penicillamine

Wilson Disease

• Diagnosis
• Genetics
• Treatment

Challenge: Early diagnosis

7 year old 6 year old 3 year old

75% of patients with Wilson disease may go undiagnosed and die of the disease

Scheinberg IH. Penicillamine in Wilson’s disease. Lancet 1982 Coffey AJ, Durkie M, Hague S, et al. A genetic study of Wilson’s disease in the UK. Brain 2013

Normal

Wilson disease

Diagnosis of Neurological Wilson Disease

Diagnosis of Neurological Wilson disease

Step 1 Identify the typical Neurological Disorder Step 2 Establish as a multi-systemic disorder Step 3 Establish it as a familial disorder

Aggarwal and Bhatt. Neurological Wilson disease. In: Clinical and Translational Perspectives in Wilson

• Disease. Editors: Kerkar N, Roberts E, Elsevier, pp, 195-214, 2018

Movement Disorder Phenocopy

Tremor, ataxia, dystonia Patient 1

Dystonia, OMD, poor axial control

Step 1 Identify the typical Neurological Disorder Step 2 Establish as a multi- systemic disorder Step 3 Establish it as a familial disorder

Patient 2

Mixed movement disorder -Stereotype, Chora, Dystonia, OMD, poor axial control Patient 3 Patient 5 Patient 4

Cognitive and Behavioural Phenocopy

Patient 1 Patient 2

Step 1 Identify the typical Neurological Disorder Step 2 Establish as a multi- systemic disorder Step 3 Establish it as a familial disorder

Utilisation behaviour

Patient 3

Stereotype

Patient 4

Aggarwal A, Bhatt M, BMJ 2009

Step 1 Identify the typical Neurological Disorder Step 2 Establish as a multi- systemic disorder Step 3 Establish it as a familial disorder

Kayser - Fleischer rings

Step 1

Step 1 Identify the typical Neurological Disorder

Step 2 Establish as a multi systemic disorder Step 3 Establish it as a familial disorder

Movement disorder phenocopy

• Mixed movement disorder
• Early and prominent axial
• WD facies
• KF rings
• Cognitive and Behavioural problems

Cognitive and behavioural phenocopy

• WD facies
• KF rings
• Associated Movement disorders

Aggarwal and Bhatt. Neurological Wilson disease. In: Clinical and Translational Perspectives in Wilson

• Disease. Editors: Kerkar N, Roberts E, Elsevier, pp, 195-214, 2018

Step 1 Identify the typical Neurological Disorder Step 2 Establish as a multi systemic disorder Step 3 Establish it as a familial disorder

Aggarwal and Bhatt. Neurological Wilson disease. In: Clinical and Translational Perspectives in Wilson Disease. Editors: Kerkar N, Roberts E, Elsevier, pp, 195-214, 2018

Liver Bones

Fleeting Jaundice Hemolytic Anemia Liver Cirrhosis Fulminant Liver

Step 3

Step 1 Identify the typical Neurological Disorder Step 2 Establish as a multi systemic disorder Step 3 Establish it as a familial disorder

Mutational analysis conforming WD

• Family history of WD
• Family history of unexplained

neurological, liver or osseomuscular symptoms

• Family history of unexplained deaths

Aggarwal and Bhatt. Neurological Wilson disease. In: Clinical and Translational Perspectives in Wilson Disease. Editors: Kerkar N, Roberts E, Elsevier, pp, 195-214, 2018

Diagnosis of Neurological Wilson disease

Step 1 Identify the typical Neurological Disorder Step 2 Establish as a multi systemic disorder Step 3 Establish it as a familial disorder

Aggarwal and Bhatt. Neurological Wilson disease. In: Clinical and Translational Perspectives in Wilson

• Disease. Editors: Kerkar N, Roberts E, Elsevier, pp, 195-214, 2018

MRI brain

Normal Caudate, putamen Thalamus Caudate, putamen, GP, thalamus Cerebellum (rare) Midbrain: Giant Panda

T2W

Pons Pons Cortical Changes

Gupta S, et al. 19th Intl Congress of Parkinson Disease & Movement Disorders, San Diego, USA, 2015.

Laboratory tests

• Laboratory tests
• Low serum ceruloplasmin
• High 24-urinary copper excretion
• High liver copper (dry weight)

⎬

• 5% patients have normal ceruloplasmin
• Ceruloplasmin falsely increased in:
• Hepatitis and acute inflammation
• Ceruloplasmin falsely reduced in:
• Carriers of WD gene (70X > patients)
• Hypo-proteinemic states
• Newborns
• 24-hour urine Cu excretion falsely elevated
• Hepatitis
• Cholestatic syndromes
• Biliary cirrhosis

Wilson Disease

• Diagnosis
• Genetics
• Treatment

Genotypic variability

ATP7B gene (ATP7Wilson)

• On chromosome 13q14.3
• Large gene: 80 kilobases, 21 exons

Wilson disease

• Mutations of ATP7B gene
• Missense (57%); small deletions / insertions (28%); nonsense (7%);

splice site mutations (8%)

• > 600 mutations spread over entire gene + promoter region
• Autosomal recessive
• Most patients are compound heterozygotes

Schmidt HH. Role of genotyping in Wilson’s disease. J Hepatol, 2009.

ATB7B protein with functional domains

Mutational pattern of various regions in India and p.C271*: The common Indian mutation

Aggarwal et al, 2013, Gupta et al., 2005; Kumar et al., 2005; Santhosh et al., 2006; Gupta et al., 2007b; Kumar et al., 2007

Hatched areas = regions in India where mutation p.C271* has been identified.

Regional mutational pattern

• Whole gene sequencing - 98% mutation detection
• Regional variation in dominant mutations

Aggarwal A, et al. Ann Hum Genet 2013; Bem RS , et al.Arq Neuropsiquiatr 2013; Coffey AJ, et al. Brain 2013; Ferenci P. Hum Genet 2006; Deguti MM et al. Human Mutat 2004

Region Dominant mutation Exon Allelic Frequency Europe, North America, S Brazil p.H1069Q 14 30-70% Central Brazil c.3402delC p.L708P 8 15 47.5% China p.R778L 8 30-49% India p.C271* 2 9-20% Table: High frequency regional mutations

Phenotypic variability

• Age of onset
• Disease severity
• Disease presentation
• Early-onset hepatic disease
• Late-onset neurological disease + subclinical or overt liver involvement
• Intra-familial variability

Causes

• Type and location of the ATP7B mutation
• Phenotype in nonsense and frameshift mutations is severe
• Other proposed mechanisms
• Genetic polymorphisms in ATP7B
• Modifier genes: Genes involved in fat and cholesterol metabolism
• Role of COMMD1 unclear
• Yet undefined factors

Why studying genotype - phenotype correlation challenging?

• Genotypic variability
• Phenotypic variability
• Most mutations are rare

Establishment of first stable human ATP7B knockout hepatoma cell line

29

• HepG2 (human hepatoma cell line) used to create the ATP7B KO cell line
• Exon 8 of ATP7B gene spliced by zinc finger nucleases (ZFN)

ATP7B gene (exons boxed) Splicing exon 8 (ZFN binding sites boxed) Nucleotide sequence & codons of wtATP7B Nucleotide sequence of KO cell (both chromosomes) Exon 8 blown up

Chandhok G, et al. PloS ONE, 2014

Functional analysis of the human ATP7B knockout cell line Different ATP7B mutants showed different copper sensitivity

Chandhok G, et al. Functional analysis and drug response to zinc and D-penicillamine in stable ATP7B mutant hepatic cell lines. World J Gastroenterol, 2016

Wilson Disease

• Diagnosis
• Genetics
• Treatment

Neurological Wilson disease is reversible

Challenge: Adequate treatment

15 year old 13 year old 11 year old

Treatment options

• Low copper diet: Neither necessary nor sufficient
• Prevent GI copper absorption
• Zinc
• Copper chelators
• Penicillamine
• Trientine
• Ammonium tetrathiomolybdate
• British antilewisite (BAL)
• Liver transplant: Curative
• Fulminant liver failure
• Decompensated cirrhosis
• Intolerance to copper chelators (rare)
• Symptomatic treatment

Aggarwal A, Bhatt M. The pragmatic treatment of Wilson’s disease.Movement Disorders Clinical Practice 2014; Aggarwal and Bhatt. Advances in treatment of Wilson disease. Tremor Other Hyperkinet Mov 2018

3 hours fasting before Penicillamine / Trientine

5 am Medications 8 am Breakfast 7 pm Dinner 10 pm Medications

Monitoring treatment

Global Assessment Scale for Wilson Disease (GAS for WD)

• Wilson disease specific scale
• Reliable and valid
• Sensitive to clinical change
• http://www.movementdisorders.org/MDS/Education/Rating-Scales.htm

Aggarwal A, et al. A novel Global Assessment Scale for Wilson’s disease (GAS for WD). Mov Disord 2009

Global Assessment Scale for Wilson Disease (GAS for WD)

Tier 1 Global Disability 4 domains each scored 0-5

L= Liver C = Cognition O = Osseomuscular M = Motor

Tier 2 Neurological impairment 14 items each scored 0-4

• 3. Scholastic
• 4. Depression
• 5. Psychosis
• 6. Dystonia
• 7. Tremor
• 8. Chorea
• 9. Parkinsonism
• 10. Speech
• 11. Swallowing
• 12. Salivation
• 13. Gait
• 14. Seizure etc
• 1. Wilsons facies
• 2. Kayser - Fleischer Rings

Aggarwal A, et al. A novel Global Assessment Scale for Wilson’s disease (GAS for WD). Mov Disord 2009

Treatment scenarios

Clinical worsening due to:

• 1. Non-compliance
• 2. Disease progression
• 3. Copper chelation

38

GAS for WD Neurological score

2009 Baseline

33

2012

Normal delivery Normal Pregnancy Complete remission Lost to followup Normal child

Feb 2019 April 2019 May 2019

22 20 25 P=500mg P=750mg P=1000mg

July 2019 December 2019

14 10 P=1000mg P=1000mg

Treatment scenarios

Clinical worsening due to:

• 1. Non-compliance
• 2. Disease progression
• 3. Copper chelation

42

43

At 1 month

Neurological disability

24 0g

Pencillamine Neurological disability

32 750mg

Pencillamine

44

At 6 months

Neurological disability

19 250mg

Pencillamine Neurological disability

13 1.5g

Pencillamine

At 4 months

59% 7% 34%

Monitoring treatment

• Track disease progression
• Track treatment response
• Low compliance
• Under-treatment

45

• On inadequate decoppering
• Suboptimal /low dose decoppering: 63 %
• Stopped decoppering (accepted disability): 38%
• Non-compliant: 38%
• On adequate decoppering
• Drug Naive

Treatment status at time of referral to our centre (n=100)

Aggarwal A, Bhatt M. Complete neurological recovery in Wilson disease: experience with 100 consecutive patients seen from 2005-2013. 66th Annual Meeting of the AAN, Philadelphia, USA, 2014

GAS for WD Tier 2: KF rings grade 2 (at upper limbus, 11 to 1 o’clock position) Baseline After 1.5 years of copper chelation GAS for WD Tier 2: KF rings grade 0 KF rings have resolved

FLAIR Baseline 2 years later

Take home messages

The challenge

• Diagnosis of Wilson disease is often delayed
• Patients are often under-treated
• Treatment is not adequately monitored

The solution

• Maintaining a high degree of clinical suspicion is key to early

diagnosis.

• Copper chelation is effective and can reverse neurological

disability

• Close clinical monitoring is crucial for effective treatment

Wilson disease treatment strategy and algorithms

7 years 6 years 3 years 14 years of age

Acknowledgements

Clinical Collaborators, Dr Barnali Das, KDAH, Mumbai Dr Niren Dongre, KDAH, Mumbai Dr Neel Shah, KDAH, Mumbai Dr Sharad Maheshwari Dr Abhijeet Raut, KDAH, Mumbai Dr Subhash Agal, KDAH Mumbai Dr Gaurav Mehta, KDAH, Mumbai Dr Harsh D, St Johns, Banglore Dr Samir Shah, Global Hospital, Mumbai Partners National Liver Foundation, Mumbai , India WWU, Munster, Germany Patients and their families Research Collaborators Dr Annu Aggarwal, KDAH, Mumbai Dr Andree Zibert, WWU, Germany Dr HH Schmidt, WWU, Germany Dr Darshana Sanghvi, KDAH, Mumbai Dr Mihir Munshi, KDAH, Mumbai Dr Abha Nagral, JHRH,Mumbai Dr Govind Jhankaria, JHRH, Mumbai Research Fellows Dr Gursimran Chandhock Dr Sweta Gupta Dr Sharada Tilve Dr Amruta Ravan Ms Aksaya Kavasiya Ms Saloni Parikh Ms Pooja Rane Dr Vijay Gawali