5. GENETICS
Monogenic, autosomal recessive
ATP7B mutations mostly missense mutation
CLINICAL MANIFESTATION
2nd or 3rd decade
2 /3 had neurological symptoms
Classical presentation: “wing-beating tremor” or “flapping
tremor” + dysarthrias
Dystonia (in 1/3 WD patients) / parkinsonism Irregular, and
somewhat jerky, dystonic tremor.
Psychiatric features are abnormal behaviour (typically increased
irritability or disinhibition), personality changes, anxiety and
depression.
Cognitive impairmentSeizure
Vertical smooth pursuit abnormality
6. • Wilson Disease Kayser-Fleischer Ring Copper
deposited in Decemet’s membrane
• Slit lamp required in most patients with
suspected Wilson Disease
• 50-62% of patients with liver disease 95%
of patients with neurologic disease
• Chronic cholestatic diseases associated with
K-F rings WD= K-F rings + low ceruloplasmin
8. DIAGNOSTIC INVESTIGATIONS
Low CP level: hepatic insufficiency due to advanced liver
disease
False normal CP: contraceptive pills, inflammatory
conditions
Laboratory findings that further support the diagnosis of
WD include low serum copper levels, elevated hepatic
transaminase levels, aminoaciduria, and hemolytic
anemia
Transaminase level may be normal in WD with
neurological symptoms only
24 hr urine copper excretion in urine; > 40 μg/24 hr
(0.64 μmol/24 hr) are suggestive of WD in
asymptomatic children
9. DIAGNOSIS
• Wilson’s Disease Diagnosis (neuro./ psych.
WD) (strongly suggested ) based on at least
two of the following;
• Low serum Cerulplasmin
• High 24 HR urine copper
• K.F Ring
• In the neuro. WD MRI shows lesions in the
basal ganglia, cerebral white matter, midbrain,
pons and cerebellum
10. IMAGING
“Face of the giant panda” sign (14,3%)
Tectal plate hyperintensity (75%)Central
pontinemyelinolysis-like abnormalities (62.5%)
Concurrent signal changes in basal ganglia, thalamus
and brain stem (55.3%)
11. ,
TREATMENT
Long life
Acute de-coppering therapy & maintainance therapy
copper chelators (D-penicillamine, trientine and tetrathiomolybdate)
and/or zinc salts which interfering copper absorption.
Liver transplantation
Symptomatic treatment
MONITORING OF WD PATIENTS
Serum parameters of copper metabolism, urinary copper as well as liver
function tests
Very low urinary copper levels and pancytopenia may indicate an
overtreatment.
Ultrasound screening for HCC
Newly developed hepatic or neurological symptoms, or reoccurance of
clinical findings like KFRs are “red flags” and indicate a noncontrolled
copper state.
12. • SUMMARY
• Rare
• Liver chirrhosis and neurological deficits
(extrapyramidal symptoms)
• ATP7B gene
• Wing-beating tremor” or “flapping tremor” +
dysarthria
• Dystonia, ataxia, parkinsonism
• MRI: Face of the giant panda, tectal plate
hyperintensity, CPM-like
• Treatment: chelating agents and Zinc salts
13. • HAEMOCHROMATOSIS.
• Most commonly due to mutations in the HFE gene. ( C282Y
Mutation)
• Autosomal Recessive
• mutations cause increased intestinal iron absorption
• Clinical features
• Liver function abnormalities – 75 percent
• Weakness and lethargy – 74 percent
• Skin hyperpigmentation – 70 percent
• Diabetes mellitus – 48 percent
• Arthralgia – 44 percentImpotence in males – 45 percent
• Electrocardiographic abnormalities – 31 percent
• The classic triad of cirrhosis, diabetes mellitus, and skin pigmentation
("bronze diabetes") occurs late in the disease, at a time when the
total body iron content has reached as much as 20 g (greater than
five times normal).
14. Diabetes Mellitus— progressive iron accumulation in the pancreas.
insulin and C-peptide secretion are reduced.
DM present in in up to 50 % HH patients who present with Symptoms.
Cardiomyopathy— Dilated cardiomyopathy, conduction disturbances,
such as the sick sinus syndrome.
Ix: Cardiac MRI.
Hypopituitarism.
Hypogonadism
Hypothyroidism— Low TSH, Positive Antithyroid antibodies.
15. • Classical HH is confirmed when genetic testing reveals
homozygosity for the C282Y genotype. Clinical
manifestations of iron overload appear to be
uncommon in patients who are heterozygous or
compound heterozygous for the C282Y or H63D
mutations
• In the past, liver biopsy was used to fully establish a
diagnosis of HH. However, we now rely on genetic
testing for making the diagnosis of a hereditary form of
hemochromatosis, and magnetic resonance imaging
(MRI), when such expertise is available, for a non-
invasive estimation of hepatic and cardiac iron
overload
16. We proceed directly to phlebotomy in patients
who have all of the following characteristics :
Age <40
Homozygous C282Y mutation
Presence of indirect markers of iron overload (ie,
elevated transferrin saturation and elevated
serum or plasma ferritin)
Normal liver enzymes (ALT, AST)
Asymptomatic + Ferritin <500 mcg/L, and
Transferrin Sats <60%.Transfusable
Aim: Ferritin < 50, and transferrin sats < 50%.
Annual physical exam and IS.
asymptomatics with Ferritin < 1000 are unlikely to
develop signs and symptoms in future.
17. • PATIENTS WITH IRON OVERLOAD:
• Regardless of genotype. If:
• Symptomatic patients with HH With end-organ
damage,
• and or with Progressively increasing levels of serum
ferritin and/or transferrin saturation
• Start with Weekly / second weekly Phlebotomy.
• Each 500 mL of whole blood removed contains 200 to
250 mg of iron.
• Men tolerate 1.5-2 units of phlebotomy a week.
• Women, elderely, Low BMI :0.5 Unit/week