E-supplement: Clinical information on WD patients with unusual genetic aspects:
A) Patients with uniparental isodisomy (UPD, see also Figure 2):
1. Female patient (Figure 2A): This patient presented when she was 15 years old with
jaundice, vomiting and lethargy. On admission, she was found to have haemolytic anaemia
and subacute liver failure. Kayser-Fleischer rings were present bilaterally. Her ceruloplasmin
levels were very low (0.03 mg/dl; normal range: 0.2- 0.6 mg/dl). She was started on
penicillamine treatment and has responded very well to this medication.
2. Male patient (Figure 2B): This patient presented when he was 12 years old with nonspecific abdominal pain and abnormal liver function tests. His liver biopsy revealed a copper
concentration of 563 mg/g dry liver (normal levels: < 50 mg/g dry liver). He responded
extremely well to chelation therapy and has recently graduated from University.
B) “Pseudodominant” families (see also Figure 3):
Pedigree 1: The deceased female index case presented in 1985 when she was 15 years old and
died of acute liver and renal failure. She had previously been well. Her clinically
asymptomatic sister was diagnosed at the age of 10 as part of the subsequent screening of the
entire family. Her liver function tests were normal but her ceruloplasmin levels and 24h
copper excretion in urine were clearly abnormal. The liver biopsy was pathological and
confirmed the diagnosis of WD. She has been treated with Penicillamine ever since and
continues to remain asymptomatic. The brother of these two sisters was an unaffected carrier,
but his clinically asymptomatic son was also diagnosed with WD at the age of 7 years as part
of the screening process. His serum ceruloplasmin level was abnormal (0.035 mg/dl) and the
copper concentration in his liver was also clearly in the pathological range (348mg/g dry
liver). He was started on penicillamine and has remained well ever since.
Pedigree 2: The affected father presented at the age of 11 years with jaundice. He was
initially admitted to an isolation unit for presumed infectious cause. He was subsequently
readmitted to the same isolation unit with a further recurrence of jaundice, significant edema
and general malaise. A diagnosis of WD was made and he was started on penicillamine. He
improved considerably on the chelation therapy but was then admitted with acute liver failure
at the age of 45 years. This was preceded by a prolonged period of time when he had been
working 18h days and not eating well which might have influenced his compliance with
medication. He had a liver transplant and has remained stable since. His daughter has never
been symptomatic but her liver function tests were abnormal and her ceruloplasmin was <
0.04 mg/dl. Her liver biopsy showed marked micro- and macro-steatosis, mild to moderate
portal inflammation and focal lobular hepatitis. There was also excess of copper in the
periportal hepatocytes. She was initially started on penicillamine but the treatment was then
switched to Zinc acetate due to persistent mild proteinuria.
Pedigree 3: The affected father presented at the age of 21 years with a 1 ½ history of
“stammering” and action tremor. His ceruloplasmin levels were very low (< 0.04 mg/dl),
Kayser-Fleischer rings were present on slit lamp examination. He was started on
pencillamine and made a complete recovery from all his neurological symptoms. His son has
always been clinically asymptomatic but his ceruloplasmin levels were “undetectable” and
the copper concentration in his liver was markedly elevated (988 mg/g dry liver). He was
started on Trientine and has remained asymptomatic since.
C) Patients with three mutations:
Patient 1: This patient presented with ascites when she was 22 years old. Kayser-Fleischer
rings were initially not seen on bedside examination but subsequently confirmed on slit lamp
examination. Her ceruloplasmin levels remained normal but her liver biopsy revealed a
markedly abnormal copper concentration (1490 mg/g dry liver). She was started on
penicillamine treatment but subsequently switched to trientine and has remained extremely
well on this.
Patient 2: This patient first presented with torticollis when she was 41 years old. She
subsequently developed progressive speech disturbance, tremor in both hands and an
unsteady gait. A diagnosis of WD was finally made 10 years after symptom onset, based on a
low ceruloplasmin (< 0.04 mg/dl) and an abnormal MRI signal in the midbrain and pons. She
was started on trientine which has resulted in a modest improvement of her gait and
torticollis.
Patient 3: This patient presented with acute liver failure, haemolytic anaemia and renal failure
at the age of 15. She received a liver transplant and continues to do extremely well 18 years
later.