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Wilson disease > Wilson disease > Flashcards

Wilson disease Flashcards

1
Q

Prevalence of wilson

A

1 in 30,000

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2
Q

Percentage of pts with kayser fleischer rings

A

95%, all neuro patients,
-50% of liver patients
-presymptomatic 20-30%

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3
Q

Most common neuro symptoms

A

-dysarthria 46-97%
-dystonia 38-69%
-Tremor 55%
-Parkinsonism
-Dysphagia (50%)
-gait abnormality 28-75%

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4
Q

24 hr urine copper measurement

A

> 100 mcg in 75% of pts

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5
Q

Copper intake goal in wilson

A

< 1.0 mg/day

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6
Q

Name of ultragenyx trial

A

UX701
Cyprus

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7
Q

UX701 Stage 1 breakdown

A

OPEN LABEL (dose selection)

Cohort 1: gene therapy + prednisone (n=5)
Cohort 2: gene therapy dose 2 + prednisone (n=5)
Cohort 3: gene therapy dose 3 + prednisone (n=5)

Follow up to 52 weeks

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8
Q

UX701 Stage 2 Breakdown

A

DOUBLE BLIND, PLACEBO CONTROLLED
Cohort 1: Gene therapy (dose determined in stage1 ) + prednisone (n=42)
Cohort 2: Placebo (n=21)

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9
Q

UX701 Stage 3 breakdown

A

Cohort 1: pts that originally received placebo will receive gene therapy + prednisone at stage 2 dose
Cohort 2: pts originally that got gene therapy will get placebo

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10
Q

Age cutoff of UX701

A

18+

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11
Q

Inclusion criteria of UX701

A

-confirmed diagnosis of wilson
-ongoing copper chelator and or zinc therapy for at least 12 months (no dose or med change for at least 6 months)
-ongoing copper restricted diet for at least 12 months–stable lab values

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12
Q

Normal copper movement in cell

A

-CTR (copper transporter) brings copper into hepatocyte
-ATP7b transports copper to golgi apparatus
-ceruloplasmin binds to copper
-ceruloplasmin + copper vesicles released into bile and excreted, some released into blood

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13
Q

Percentage of patients with low ceruloplasmin

A

> 90%, usually less than 20
<5 is fairly diagnostic

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14
Q

Name of diagnostic scoring system

A

Leipzig score = >4

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15
Q

How does zinc work?

A

Increases metallothionine (protein in gut) that binds copper and decreases absorption in Gi tract

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16
Q

Estimated worldwide prevalance

A

12.7 in 100,000

17
Q

Carrier frequency

A

1:90

18
Q

Most common symptom in pts with neuro wilson disease

A

Dysarthria (97%)

19
Q

Classic fixed dystonic smile

A

risus sardonicus

20
Q

Percentage of patients that present with psych symptoms

A

10%

21
Q

Wilson disease misdiagnosis: Alagille syndrome

A

-genetic condition, build builds up due to lack of bile ducts

22
Q

Leipzig score that = a diagnosis of wilsons

A

4

23
Q

American association for study of liver diseases (AASLD) diagnosis algorithm

A

-Pathways for liver and neuro symptoms
-Based on KF rings, ceruloplasmin, 24h urine copper measurements
-if still inconclusive, move on to liver biopsy and genetic testing

24
Q

Diagnostic guidelines that use Leipzig score

A

-European association for the study of the liver (EASL)
-European association for pediatric gastroenterology , hepatology and nutrition (ESPGHAN)

25
Q

normal dose of penicillamine

A

-titration to 1-1.5 g/day
-maintenance can be 750-1000 mg /day

-pediatrics: 20 mg/kg/day

Taken 2-4x per day on empty stomach

26
Q

Trientine dosing

A

-Adults: 750-1500 mg/day
-Peds: 20 mg/kg/day
-Taken 2-3x per day on empty stomach
-Has to be refridgerated

27
Q

Zinc dosing

A

Adults: 150 mg/d divided TID
Peds (6-16 y.o.): 75 mg/d divided TID
Peds (<6 y.o.): 50 mg/d divided BID

Must be taken 1 hour before or after meals

28
Q

What is the King score

A

Scale used to judge how severe liver disease is, requiring a transplant
-score more than or equal to 11 = death without transplant
-calculated by looking at INR, bili, albumin, AST, wbc

29
Q

Target urinary copper level in maintenance chelation therapy

A

-Chelators: 200-500 ug/day
-Zinc: < 75-100 ug/day

30
Q

What tests would show evidence of non compliance with therapies?

A

-increase in serum free copper > 15 ug/dl
-increase in urine copper in pts on chronic chelation
-appearance/reappearance of KF rings with persistent abnormal liver tests

31
Q

Average annual cost of trientine

A

~ $300,000

32
Q

AAV used in UX701

A

AAV9

33
Q

Difference in ATP7B and transgene used in UX701

A

contains last 3 of the 6 total metal binding domains

34
Q

In UX701, when will chelation/zinc withdrawal challenge occur?

A

week 12 for gene therapy pts

35
Q

UX701 Stage 1 endpoints

A

-safety (incidence of AE)
-biomarkers of copper metabolism
-percent reduction of standard of care
-response of chelation/zinc withdrawal

36
Q

UX701 stage 2 primary endpoints

A

-change in 24h urine copper in treatment vs placebo at week 52
-percent reduction of SOC by week 52 compared to placebo

37
Q

UX701 stage 2 secondary endpoints

A

CHANGE AT 52 WKS COMPARED TO PLACEBO
-change in ceruloplasmin activity
-change in WDFRS patient scores
-change in WDFRS clinician scores
-chelation/zinc withdrawal challenge (how many pts can discontinue this)
-liver biopsy copper concentration
-safety, AEs
-development of anti ATP7B antibodies

38
Q

UX701 sites

A

-Vanderbilt
-UCLA
-Stanford
-U of Miami
-Northwestern
-Indiana University
-U of Michigan
-Duke
-MGH
-Seattle Childrens

Wilson disease (3 decks)

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