Children with difficulty in speech and writing associated with pallor and abnormal liver

function tests and seizures

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13yr old boy history

• Difficulty in speech and writing for 4 years and also on walking for 1 year.• Difficulty to perform any work by

hands for 6 months• His speech was low volume slurred

and monotonous

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Examination

• Splenomegaly and bilateral gynaecomastia.• Muscle tone was mildly increased, and gait

was limping.• Slit lamp examination of eye revealed

bilateral Kayser-Fleischer ring with normal visual acuity.

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MRI T2 & T1-Weighted Image

Hyperintensity & Hypointensity in Bilateral Basal Ganglia & Putamen Region

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Normal MRI of the brain

Axial MRI image through the basal ganglia. Included in the basal ganglia are the caudate and putamen, globus pallidus externus (GPe), and globus pallidus internus (GPi). 

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11yr old boy history

• Progress pallor , lassitude ,mildly jaundice for the last 2 months

• Dysarthria• Salivation

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Examination

• Pallor , Jaundiced ,palmer erythema• Hepatomegaly• Postural tremor, dysdiadochokinesia• Dysarthria, Gait disturbances• The Kayser-Fleischer ring is found on

slit lamp examination of the eye

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Kayser-Fleischer ring

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Laboratory investigations

• Low serum albumin(26 gram/L)• Increased alanine transaminase

( A.L.T=57 U/L)

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Ultrasonogram

Hepatobiliary system revealed coarse hepatic tissue echotexture with splenomegaly.

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Liver scan

Slightly :• Nonuniform radiotracer distribution in

the liver • Increased bony uptake.

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Additional laboratory investigations

• Serum caeruloplasmin level was 11.51 mg/dl.

• 24 hours urinary copper excretion was 150 microgram per day

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17 years old boy history

• History of seizures for last 7 days• Generalized tonic clonic in nature.• For last 2 days he was having multiple

seizure episodes without regaining of consciousness in between.

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Prior history

• Behavioral disturbances in the form of :

- Disinterest in the surroundings

- Decreased interaction with friends

and relatives

- Occasional outburst of temper for last

4 months was present

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• Speech and gait difficulties for last 2 months.

• There was no history of headache, vomiting, visual disturbances or focal deficits.

• None of his siblings had similar illness.

Cont.

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• Vitals were stable • No jaundice or flaps• Abdominal examination did not reveal

organomegaly or free fluid.• On general examination Kayser-Fleischer

rings were present in cornea

General examination

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Neurological examination

• Mute, having mask like faces, drooling of saliva and dystonic tongue

• Generalized cogwheel rigidity in all 4 limbs including axial musculature

• Postural tremors of both upper limbs

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Cont.

• Hyperreflexia, extensor planters and

normal muscle strength. • Sensory and cerebellar system

examination was unremarkable• Ophthalmological exam showed Kayser-

Fleischer ring on slit lamp

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Diagnosis?

Wilson disease(Hepatolenticular Degeneration)

Prof. Dr. Saad S Al Ani

Senior Pediatric Consultant

Head of Pediatric Department

Khorfakkan hospital

Sharjah ,UAEsaadsalani@yahoo.com

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Wilson disease (Hepatolenticular degeneration)

Is an autosomal recessive disorder characterized by:

1.Degenerative changes in the brain

2. Liver disease

3.Kayser-Fleischer rings in the cornea

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Autosomal recessive inborn error of copper transport

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1/50,000-100,000 births

The incidence

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Introduction

• The abnormal gene for Wilson disease is on chromosome 13; linkage studies have assigned the Wilson disease locus to chromosome 13 at q14-q21.

• The gene encodes amino acid structural motifs consistent with a role in copper-binding, cation-transporting P-type ATPase .

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Basic mechanism

• Relates to decreased excretion of biliary copper, owing partly to a lysosomal defect of the liver cells

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Healthy subjects: intake and excretion is well balanced

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Normal absorption and distribution of copper

Cu = copper, CP = ceruloplasmin, green = ATP7B carrying copper.

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Pathogenesis

Defective mobilization of copper

from lysosomes in liver cells

Relentless accumulation of copper in the liver

Copper then escapes the liver to damage other organs

Oxidant injury to hepatocyte mitochondria

Lipid peroxidation of the mitochondria

→

↓↓

↓

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Clinical Manifestations Forms of hepatic disease:

• Include :

1.Asymptomatic hepatomegaly

(with or without splenomegaly)

2.Subacute or chronic hepatitis

3.Fulminant hepatic failure.

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Cont.

Other manifestations of Wilson disease include:

* Cryptogenic cirrhosis

* Portal hypertension,

* Ascites

* Edema,

* Variceal bleeding

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Cont.

*Other effects of hepatic dysfunction :

- Delayed puberty

- Amenorrhea,

- Coagulation defect

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Clinical Manifestations Neurologic and psychiatric disorders

• Intention tremor• Dysarthria• Dystonia• Deterioration in school performance, or

behavioral changes.

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• Hemolysis may be an initial manifestation• Manifestations of Fanconi syndrome and

progressive renal failure• Unusual manifestations include:

- Arthritis

- Endocrinopathies, such as hypoparathyroidism

Clinical Manifestations other features

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Diagnosis

Wilson disease should be considered in children and teenagers with :

1.Unexplained acute or chronic liver disease,

2. Neurologic symptoms of unknown cause,

3. Acute hemolysis

4.Psychiatric illnesses,

5. Behavioral changes,

6.Fanconi syndrome

7.Unexplained bone disease.

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Tests performed for the diagnosis of Wilson disease

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Cont.

• The best screening test is to measure the serum ceruloplasmin level.

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• Serum copper level :

>100 μg /day and often up to 1,000 μg or more per day.

Cont.

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• Is of value for :

1.Examination of the histology

2.Measurement of the hepatic copper

content (normally <10 μg/g dry weight).

Liver biopsy

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Should include determination of :

1.Serum ceruloplasmin level

2. Urinary copper excretion.

Screening family members of patients

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The first signs due to :

• Hepatic : (40% ) • Neurological : (35% ) • Psychiatric , Renal, Hematological ,

Endocrine ( In the remainder)

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Wilson's disease patients before treatment: reduced excretion and retention

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Treatment

Copper-chelating agents:• Oral administration of penicillamine (β, β-

dimethylcysteine) in a dose of :

* 0.5-0.75 g/day for patients younger than 10 yr.

*1 g/day in two doses before meals for adults

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Wilson's disease patients on chelator therapy: enhanced urinary excretion of copper

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Toxic effects of penicillamine

• Uncommon and consist of 1.Hypersensitivity reactions (Goodpasture

syndrome, systemic lupus erythematosus, polymyositis),

2. Interaction with collagen and elastin 3.Deficiency of other elements such as zinc 4.Aplastic anemia 5. Nephrosis

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• For those patients who are unable to tolerate penicillamine, triethylene tetramine dihydrochloride (Trien, TETA, trientine) at a dose of 0.5-2 g/24 hr is an acceptable alternative.

Treatment (cont.)

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• Zinc has also been used as adjuvant therapy or as maintenance therapy owing to its unique ability to impair the gastrointestinal absorption of copper.

• Zinc acetate is given in adults at a dose of 25 to 50 mg three times a day .

Treatment (cont.)

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Wilson's disease patients on zinc therapy: enhanced fecal excretion of copper

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Remember

• Foods such as:

liver, shellfish, nuts, and chocolate should be avoided

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Prognosis

• Untreated patients with Wilson disease die of the hepatic, neurologic, renal, or hematologic complications.

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Cont.

• The prognosis for patients receiving prompt and continuous d- penicillamine is variable and depends on :

* Time of initiation

* Individual responsiveness .

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Liver transplantation

• Should be considered for patients with:

1. fulminant liver disease

2. decompensated cirrhosis

3. progressive neurologic disease

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In asymptomatic siblings of affected patients

Early institution of chelation therapy can prevent expression of the disease.

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Remember Wilson disease

1.If "routine liver function tests" are inexplicably abnormal in a child

2.In a child with haemolysis and negative Coombs test

3. Changes in mood or school performance in a teenager, especially with speech slurring

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.

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References

• http://www.eurowilson.com/en/living/guide/pathway/index.phtml

• http://www.wilsonsdisease.org/• http://www.ars.usda.gov/Services/docs.htm?do

cid=17477 

• http://emedicine.medscape.com/article/183456-clinical

• http://www.eurowilson.org/data/pdf/For-medical-professionals.pdf

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