European3ourr~ of
Europ. J. Pediat. 126, 147--154 (1977)
Pediatrics 9 by Springer-Verlag 1977
Prognosis of Wilson's Disease in Childhood* M. Arima, K. Takeshita, K. Yoshino, T. Kitahara, and Y. Suzuki Division of Child Neurology, Institute of Neurological Sciences, Tottori University School of Medicine, Yonago, Japan Abstract. Wilson's disease in childhood has several characters distinct from those in adults. The progression of the disease tends to be rapid, hepatic manifestations are common, cerebral symptoms related to dystonia are predominant, and tremor is rare. Forty-nine children with Wilson's disease under the age of 15 were treated with D-penicillamine for 2 to 15 years. None of the presymptomatic patients subsequently developed any symptoms of the disease. The results of treatment in patients who had exhibited only hepatic symptoms were also excellent, However, neurological manifestations associated with a history of jaundice or ascites responded less well to chelation, These observations clearly indicate that early diagnosis and treatment are extremely important to ensure normal lives for children with Wilson's disease. Key words: Wilson's disease - D-penicillamine.
The clinical manifestations of Wilson's disease are related to the deposition of copper in the liver, brain, cornea, and other tissues. The disease is progressive and the patients inevitably die unless properly treated. Since the introduction of penicillamine, the efficacy of therapy designed to increase the excretion of the copper has been well documented. However, even now some patients die of hepatic insufficiency or suffer from irreversible brain damage. The age at onset, the clinical symptoms and the mode of progression may vary from one patient to another. It is generally accepted that children with Wilson's disease show predominantly hepatic symptoms or rapidly progressive manifestations of dystonia (Silverberg, Denny-Brown, Walshe, 1967; Arima, 1963, 1968b). In order to provide some insight into the prognosis of the disease in children, we studied forty-nine children with Wilson's disease who were given continuous penicillamine therapy for periods of 2 to 15 years. * Supported by the Grant for the Research of Nanbyo, Ministry of Education, Science & Culture
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Subjects and M e t h o d s The 49 patients in this study were under the age of 15 years when d-penicillamine (PC) therapy was started. Patients were included only if: (1) Kayser-Fleischer rings were present in association with hepatic or progressive neurological disease, a n d / o r (2) at least two of the following criteria were present; (a) persistent low sert}m caeruloplasmin, (b) increased 24-hour urinary copper excretion, (c) abnormal copper deposition in the liver. On the basis of clinical symptoms of the disease, the patients were classified as follows; (a) hepatic (Group H), (b) cerebral (Group C), (c) hepato-cerebral (Group HC), (d) asymptomatic (Group A). G r o u p H: 13 patients had a history of jaundice, marked splenomegaly a n d / o r ascites without any neurological abnormality at the time of starting PC therapy. Occasionally, oedema was observed prior to development of the hepatic manifestations. In 10 of the 13 patients, the diagnosis of the disease was based on the presence of Kayser-Fleischer rings. The remaining 3 showed a persitent deficiency of serum caeruloplasmin, associated with increased urinary copper excretion, ranging from 150 to 500 ~tg per day (normal: less than 80 ~tg per day). The age at which hepatic symptoms developed was from 4 years 6 months to 12 years 4 months (Table 1). Groups C and HC: Twenty-six patients showed progressive cerebral symptoms such as dysarthria, drooling, gait disturbance, difficulty in writing, involuntary movement, stiffness, etc. at the time the diagnosis was made (Table 2). Kayser-Fleischer rings and increased urinary copper excretion were detected in all cases. G r o u p C: Twelve patients had no history of jaundice or ascites though hepatomegaly was noted in some cases. In this group, the age of onset of clinical symptoms ranged from 9 years to 13 years 11 months. In spite of inevitable association of cirrhosis of the liver, results of hepatic function tests were mostly normal.
Table 1. Patients with a history of hepatic symptoms but without any neurological manifestation (Group H) Case No.
Presenting Age at symptoms development hepatic symptoms yrs : mos
4
j
6
j,a
Age at start of treatment
Diagnostic criteria KF caerulorings plasmin deficiency
yrs : mos
8:4
8:9
+
+
10:6
11:3
+
+
urinary copper > 150 p g /
Age at last examination
day
yrs : mos
+
13:1 19:3
8
j
4:6
4:9
-
+
9
j,a
8:2
8" 4
+
+
+
12:9
19 21
a,h j,s
10 : 6 12 : 4
10 : 9 12 : 4
+ +
+ -
+ +
14 : 5 14 : 7
35 48
a,h j
6:11 7:0
7 : 5 7:7
+ -
+
+ +
9:10 20:2
49 52 53 54 79
j,a a j j,a j
8:4 8 : 9 10:2 9:0 10 : 8
9:9 8:11 10:4 9:6 11:10
+ + + +
+ + + + +
+ + + +
14:0 12 : 8 22:6 15:7 26 : 2
12:7
Symptoms: j (jaundice), a (ascites), s (marked splenomegaly), h (marked hepatomegaly) Except in cases 19 and 35 hepatic function tests gave normal results at the last examination
Prognosis of Wilson's Disease in Childhood
149
Table 2. Patients with manifest cerebral s y m p t o m s ( G r o u p C and G r o u p H) Case No.
H i s t o r y of hepatic symptoms
Onset o f cerebral symptoms
Start of treatment
yrs : m o s
yrs : m o s
Predominant disability
Age at last observation
Residual symptoms
yrs : m o s
22
-
9:5
9:8
g,w
17:9
-
25
-
9:0
10:1
g,w,s
16:2
+
w
26
-
10:3
12:2
g,w,s,p
15:2
+
g,p,c
33
-
10 : 3
13 : 0
g,w,s
16:10
+
g,w,s
37
-
11 : 0
14 : 6
bed, s
22 : 7
+
p,g,w
39
-
10 : 0
10 : 7
w,s,g
18 : 3
_+
s,g
40
-
11 : 3
13 : 2
w,s
22 : 4
+
p
45
-
10 : 4
10 : 4
w,s
17:10
-
70
-
12 : 3
12:10
bed, s
20:10
-
73
-
13 : 2
14 : 2
w , s , sp
19 : 2
-
75
-
13:11
14 : 4
s
16 : 8
-
76
-
10 : 5
10 : 9
g , s , sp
13:10
+
i
+
13
+
1i : 0
9:6
30
+
7:0
36
+
6 : 9
s, sp
11:1
g
15:2
-
13 : 0
s
17 : 2
-
10:0
g,w,s
16:2
+
g,w,s
g,w,s
10:10
_+
p p,g,w,s
8 : 8
42
+
10:6
15:2
g,w,s
24:8
+
44
+
8:1
8:1
g
11:10
-
w,s
19:2
+
w,s
g,a,w
22:4
+
s,w
w,s
19:6
_+
s,w
50
+
8:7
8:9
55
+
10:2
10:6
56
+
8:2
8:3
59
+
12 : 7
13 : 0
w
t6 : 2
died
e, bed
60
+
8 : 7
8:10
w
23 : 5
+
g,s,w,c
63
+
9:4
11 : 2
bed
16:4
died
e, bed
74
+
11 : 0
11 : 2
g
21 : 3
+
g,s,w,e,c
77
+
12 : 9
13 : 0
g,s,w
15 : 7
+
s
g: gait, w: writing, s: speech, p: psychiatric or mental, e: epileptic seizures, c: contracture of joints, bed: bed-ridden, sp: splenomegaly - a p p a r e n t l y n o r m a l , + mild disability, + m o d e r a t e or severe disability
G r o u p HC: F o u r t e e n patients h a d b o t h the progressive cerebral s y m p t o m s mentioned above and a history of hepatic s y m p t o m s . Usually, cerebral manifestations were noticed one m o n t h to two years after the o c c u r r e n c e of hepatic symptoms. In 2 patients in this group, jaundice was attributed to a c o m b i n a t i o n o f hepatic damage and haemolytic crisis (cases 44, 77). G r o u p A: The remaining 10 patients were a s y m p t o m a t i c at the time of examination. Their abnormalities were detected during routine examinations as the siblings o f patients with overt Wilson's disease. As previously reported (Arima, 1963, 1970) the screening was m a d e by c o m b i n i n g slit-lamp examination for Kayser-Fleischer rings with determinations of s e r u m caeruloplasmin, S G O T , S G P T , and 24-hour urinary copper excretion. T w o patients exhibited Kayser-Fleischer rings on the initial examination a n d a n o t h e r 2 subsequently exhibited the
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M. A r i m a et al.
Table 3. Diagnostic criteria for a s y m p t o m a t i c patients Case No.
Age at start o f therapy
Age at last observation
yrs : m o s
yrs : m o s
Disease Caeruloin sibs plasmin less than 5 mg/dl
Increased urinary copper
KF rings
Elevated Liver biopsy S-GPT cirrhosis increased S-GOT copper
> 200 I.tg 3
4:6
6:10
+
+
-
-
+
-
+
5
5:0
7:2
+
+
-
-
+
-
+
10
4:2
6:6
+
+
-
-
+
-
+
64
7:11
23 : 5
+
+
+
_4+
+ +
+
+
+
+
+
65
4:2
18:9
+
+
-
-
+
66
11:10
26 : 9
+
+
+
+
-
68
5:10
21 : 0
+
+
-
-
+
69
8 : 4
20 : 7
+
+
+
+
-
72
11 : 8
16:8
+
-
+
--+
-
78
5:0
10:8
+
+
-
-
+
Case 65 developed mild splenomegaly soon after biopsy. It disappeared later. Case 66 showed m o d e r a t e hepatomegaly. Case 78 h a d been irregularly treated in a n o t h e r hospital. O n examination he showed hepatomegaly and mild cupruria ranging f r o m 80--150 gg per day. In cases 65 a n d 68, liver copper was determined by Drs. I. H. Scheinberg and I. Sternlieb (Sternlieb et al., 1963). A t the last examination hepatic fuction tests gave n o r m a l results in all cases.
rings. A m a r k e d decrease in serum caeruloplasmin (less than 5 m g / d l ) was considered to almost certainly indicate a h o m o z y g o t e . A deficiency o f caeruloplasmin ranging f r o m 6 to 15 m g / d l was regarded as an indication o f either a h o m o z y g o t e or heterozygote. In these cases an increased 24-hour urinary c o p p e r excretion o f more than 200 ~tg was considered as a p r o o f o f homozygote. Increased urinary copper was detected in 4 patients over the age o f 7 years. Seven patients s h o w e d a high serum transaminase level, all o f them being under the age o f 7 years at the time o f examination. The levels became normal with advancing age. A biopsy o f the liver was p e r f o r m e d in 6 cases a n d all s h o w e d a marked increase in copper content o f more than 500~tg/g dry tissue. (Normal: less than 100 ~tg/g.) M o d e r a t e fibrosis and lymphocytic infiltration in the portal areas were observed in 3, and m i n o r histological changes in 3 (Table 3). O f 49 patients, 24 were males a n d the sex ratio was the same in each group o f patients. The patients were treated with P C soon after confirmation o f the diagnosis o f Wilson's disease. After observing the initial effects o f P C o n clinical s y m p t o m s , side effects, a n d laboratory findings for weeks to m o n t h s , the patients were discharged from hospital and regularly checked by us or by their local physicians. Treatment was withheld or was irregular in some cases, either because insufficient P C was available at the time diagnosis was confirmed or because o f neglect by the family. The m a i n t e n a n c e dose o f P C was 800 to 1400 mg daily, according to age or severity o f the disease. Thirty patients had continuous administration o f PC. In 11 patients it was given intermittently i.e. for 4 or 5 days a week, on alternate days or for 10 days with none on the following 10 days. In 4 patients, administration was continuous for several years; in 2 o f them it was given intermittently thereafter (cases 70, 72), and in 2 it was restarted m o n t h s to years after interruption (cases 50, 60). In the remaining 4 cases the therapy was irregular (cases 33, 59, 63, 79). The period o f observation ranged from 4 to 16 years in two thirds o f the patients. Prognosis o f the disease in each case was evaluated at the last observation from the following standpoints:
Prognosis of Wilson's Disease in Childhood
151
(1) Occurrence or recurrence of the hepatic symptoms such as jaundice, ascites, haematemesis, or oedema, (2) cerebral symptoms such as motor skills, dysarthria, involuntary movement, epileptic seizures and mental state, (3) shool performance or state of employment.
Results
Of 49 patients, 30 were apparently normal at the last observation. Ten patients continued to have mild disability, including slight dysarthria, clumsiness, emotional instability a n d / o r mild splenomegaly. Most patients of this group lived a normal life without much difficulty. Seven patients were moderately disabled. Their residual symptoms included dysarthria, rigidity, joint contractures, disturbances in gait and writing, involuntary movements, mental retardation, and epileptic seizures. The prognosis appeared to depend on the condition of the patients before starting PC therapy. All 10 asymptomatic patients continued to be asymptomatic. Four of them are now aged 20 to 26 and lead normal lives 10 to 19 years beyond the age at which their affected siblings died. Of the 13 Group H patients, 12 were apparently normal. Relapse of hepatic symptoms during the therapy was never observed. Neurological symptoms developed in only one case (48), and clumsiness persisted thereafter. In this case the daily dose of PC was 400 mg. Therapy started after development of cerebral symptoms (Group C arid HC) gave various results. Complete remission was induced in 8 patients whose handicap before the therapy had been mild in 3, moderate in 4 and bed-ridden in 1 (case 70). However, complete recovery was not always obtained, even in the patients with mild disability. The prognosis of the patients belonging to Group HC especially tended to be poor. Only 3 of 14 patients in this Group showed complete recovery from the cerebral symptoms. When the grades of motor or mental handicap between, before and after the therapy were compared, improvement was noted in 21 cases with no change in 1 case (33), and deterioration in 4 cases (59, 60, 63, 74). The deterioration of cerebral symptoms in 3 of the 4 cases was associated with the occurrence of seizures. The correlation between the prognosis and the time at which treatment was started was evaluated. The most beneficial effect was obtained in Group H where therapy had been initiated before the development of neurological symptoms or hepatic insufficiency. The prognosis in patients exhibiting only cerebral symptoms (Group C) appeared to depend on the time of the beginning PC therapy. Complete recovery from the cerebral symptoms occurred in 5 patients who started therapy within one year of the onset of symptoms. More delayed therapy resulted in moderate disability. On the other hand, the poorer prognosis observed in Group H C was not always related to delayed therapy (Table 4). In this group of patients, the cerebral symptoms responded less well to PC and improvement was slower. The maximum recovery was seen 1 to 3 years after the start of therapy. Continuous administration of PC has been regarded as a routine method for the treatment of Wilson's disease. Of 49 patients, 30--mostly symptomatic
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M. Arima et al.
Table 4. Interval between the onset of clinical symptoms and the start of treatment in relation to prognosis. In Group HC, the time of development of neurological symptoms was regarded as the onset Interval between onset of symptoms and start of PC therapy
Within 6 months 7--12 months 13--24 months More than 25 months Total
Condition after PC therapy apparently normal
slightly disabled
moderately disabled
dead
H C HC
H C HC
H C HC
H C HC
9 1 2 0
0 1 0 0
4 0 1 0
0 0 2 0 0 0 0 1 0 0 2 2
0 0 0 0
0 1 0 0 0 1 0 0
21 6 8 4
1 4 5
0 3 4
0 0 2
39
3 1 2 0 0 2 0 0
12 5 3
1 2 1 0
total
Table 5. Programmes of maintenance PC therapy and prognosis Method of administration
Continuous Intermittent Continuous and intermittent Continuous and interrupted Irregular
Condition after PC therapy apparently normal
slightly disabled moderately disabled
dead total
H
C
HC A
H
C
HC
C
HC
HC
9 2
3 1 1
1 2
1
3
4
2
3
4 5 1
1 1
1
1 1
2
30 11 2 2 4
patients--were treated continuously, and i 1--including 5 asymptomatic patients - - w e r e t r e a t e d with i n t e r m i t t e n t a d m i n i s t r a t i o n o f PC. C o m p a r i s o n o f the effectiveness o f each p r o g r a m m e dose n o t a l l o w a n y conclusions. F o u r a s y m p t o m a t i c p a t i e n t s (cases 65, 66, 68, 69) were given P C i n t e r m i t t e n t l y , 800 to 1000 m g d a i l y f o r 4 o r 5 d a y s a week, for the p a s t 12 to 15 years. T h e y neither d e v e l o p e d clinical s y m p t o m s n o r K a y s e r - F l e i s c h e r rings. One p r e s y m p t o m a t i c p a t i e n t (case 72) d e v e l o p e d K a y s e r - F l e i s c h e r rings 4 years after starting a l t e r n a t e - d a y t h e r a p y . It was t h e n c h a n g e d to c o n t i n u o u s t h e r a p y . T w o p a t i e n t s b e l o n g i n g to G r o u p H C (cases 59, 63) h a d u n c o n t r o l l e d epileptic seizures a n d d i e d 3 a n d 5 years after s t a r t i n g t h e r a p y . R e g u l a r t r e a m e n t was n o t given in these cases ( T a b l e 5). T w o p a t i e n t s , w h o are still alive (cases 60, 74), s h o w e d d e t e r i o r a t i o n o f cerebral s y m p t o m s f o r the first 3 y e a r s despite intensive P C t h e r a p y o f 1200 to 1600 m g daily. M a r k e d r e s i d u a l s y m p t o m s persist, a n d one o f t h e m h a d r e c u r r e n t epileptic seizures. S o m e u n t o w a r d r e a c t i o n s p r o b a b l y due to P C have been e n c o u n t e r e d in the course o f l o n g - t e r m t h e r a p y . H y p e r s e n s i t i v e skin rashes o c c u r r e d 7 to 10 d a y s after b e g i n n i n g P C t h e r a p y in 11 patients. This was c o n t r o l l e d b y desensitization
Prognosis of Wilson's Disease in Childhood
153
without difficulty. Leukopaenia and thrombocytopaenia appeared in 4 cases (9, 54, 73, 76). Haematuria and proteinuria developed in 3 cases (21, 73, 77). These haematological or renal manifestations were not progressive, and whether they were caused by PC or by Wilson's disease itself was not determined. A characteristic skin lesion with pigmentation, fragility and laxity was observed over the elbow and knee joints of 3 patients (cases 60, 74, 77). It appeared 2 to 7 years after continuous administration of PC 1200 to 1400mg daily. Serum and urinary zinc levels were normal. An 18-year-old girl developed an episode of dyspnoea and anoxic convulsions after 4 years of therapy (case 70). Haemoptysis or renal involvement was not encountered, and fatal Goodpasture syndrome has not been observed. Except for the hypersensitivity rash, these reactions have not been observed in the patients receiving the intermittent therapy. In this study, only children under the age of 15 years who received PC therapy for more than 2 years were selected. In the same period, 4 additional children aged 6 to 9 years died without starting therapy. One of them died of acute hepatic insufficiency with marked haemolytic crisis, and the remaining 3 died of fulminating hepatic insufficiency with coma. In addition, 4 children with severe cerebral manifestations and 1 with chronic hepatic insufficiency and accompanying haematamesis died within 2 years of starting therapy. All 5 patients had been irregularly treated with PC. Discussion
Before the introduction of PC therapy, one third of the patients with Wilson's disease died of hepatic disease with or without haemolytic crisis (Arima, 1968 b). Even at the present time, the prognosis of fulminating hepatic insufficiency in Wilson's disease is grave. The acute form is usually observed in children under the age of 10. The best way to avoid the fatal hepatic disease appears to be prophylaxis. The beneficial effect of preventive administration of PC has been reported (Walshe, 1968; Sternlieb et al., 1968; 1975; Arima et al., 1968 a; 1970). The age of onset of the disease tends to be similar within any one sibship (Beam, 1960; Arima, 1968). Therefore treatment in asymptomatic children is recommended before they reach the age at which the disease began in their affected siblings. In addition to caeruloplasmin deficiency, detection of high serum transaminase levels has been useful for early diagnosis in children under the age of 9 years (Arima, 1963; Lange, 1968; Tu, 1968; Walshe, 1968). Urinary copper determinations before and during oral PC administration have also been proved to be of diagnostic value (Tu, 1968; Schmid-Rtiter, 1973). With advancing age, the transaminase level tends to normalize, and detection of Kayser-Fleischer rings by slit-lamp examination or demonstration of increased urinary copper excretion may be useful. The criteria proposed by Sternlieb et al. (1963, 1968) are valuable in making a definitive diagnosis. If patients can survive the acute hepatic manifestations, the disease becomes latent (Stage 3, Deiss et al., 1971). In some cases, ascites or portal hypertension with splenomegaly may persist. In this study, therapy was started in 13 children at this stage (Group H). The results were excellent. All the children except one lead
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n o r m a l lives. A c c o r d i n g to p e r s o n a l experiences b e f o r e the i n t r o d u c t i o n o f PC, a b o u t h a l f the p a t i e n t s w o u l d have d e v e l o p e d c e r e b r a l s y m p t o m s within 2 years o f the o c c u r r e n c e o f h e p a t i c m a n i f e s t a t i o n s . These results indicate t h a t P C is v a l u a b l e in the t r e a t m e n t o f h e p a t i c d a m a g e a n d also effective in p r e v e n t i n g the d e v e l o p m e n t o f c e r e b r a l disease. T h e beneficial effect o f P C o n the c e r e b r a l s y m p t o m s has b e e n well established. I n this series, p r o g r e s s i v e a n d fatal n e u r o l o g i c a l disease was limited to those p a t i e n t s w h o received i r r e g u l a r P C t h e r a p y . H o w e v e r , c o m p l e t e remission was n o t always o b t a i n e d , even in the cases receiving c o n t i n u o u s t r e a t m e n t . I m p r o v e m e n t o f c e r e b r a l s y m p t o m s in p a t i e n t s with a h i s t o r y o f h e p a t i c disease t e n d e d to be p o o r e r . These results indicate t h a t m a k i n g the correct diagnosis o f W i l s o n ' s disease in c h i l d r e n with u n e x p l a i n e d h e p a t i c diseases is very i m p o r t a n t . Acknowledgement. The authors thank all those physicians, too numerous to mention, who have referred their patients to us, making this work possible.
References Arima, M., Komiya, K., Kamoshita, S., Mukai, N.: Clinical and pathological characteristics in Wilson's disease in cases under ten years of age. Paediat. Univ. Tokyo 9, 17--22 (1963) Arima, M.,Komiya, K., Fujisawa, A., Matsuoka, K.: Prevention of Wilson's disease in asymptomatic patients. Proc. Austral. Ass. Neurol. 5 (I), 197--201 (1968 a) Arima, M , Sano, I.: Genetic studies of Wilson's disease in Japan. In: Wilson's disease (D. Bergsma, I. H. Scheinberg, I. Sternlieb, eds.), pp. 54--59. New York: National Foundation 1968 b Arima, M., Komiya, K.: Prevention of Wilson's disease. A long-term follow-up. Pediat. Univ. Tokyo 18, 22--24 (1970) Bearn, A. G.: A genetical analysis of thirty families with Wilson's disease (hepatolenticular degeneration). Ann. Hum. Genet. 24, 33--43 (1960) Deiss, A., Lynch, R. E., Lee, G. R., Cartwright, G. E.: Long-term therapy of Wilson's disease. Ann. Int. Med. 75, 57--65 (1971) Denny-Brown, D.: Hepatolenticular degeneration (Wilson's disease). Two different components. New Engl. J. Med. 270, 1149--1156 (1964) Lange, J.: Long-term treatment of Wilson's disease with D-penicillamine. In: Wilson's disease (D. Bergsma, I. H. Scheinberg, I. Sternlieb, eds.), pp. 130--133. New York: National Foundation 1968 Silverberg, M., Gellis, S. S.: The liver in juvenile Wilson's disease. Pediatrics 30, 402--413 (1962) Schmid-Rtiter, E., Feist, D., Wesch, H., Rol~ner, J. A., Sch/irer, K.: Pr/isymptomatischer Morbus Wilson. Dtsch. Med. Wschr. 98, 1698--1703 (1973) Sternlieb, I., Scheinberg, I. H.: The diagnosis of Wilson's disease in asymptomatic patients. J.A.M.A. 183, 747--750 (1963) Sternlieb, I., Scheinberg, I. H.: Prevention of Wilson's disease in asymptomatic patients. New Engl. J. Med. 278, 352--359 (1968) Sternlieb, I.: Present status of diagnosis and prophylaxis of asymptomatic patients with Wilson's disease. In: Disease of the liver and biliary tract (C. M. Leevy, N. J. Newark, eds.), pp. 137--142. Bern: Karger 1976 Tu, J.-B., BlackweU, R. Q., Fresh, J. W., Watten, R. H.: Diagnosis and treatment studies of patients in asymptomatic stage. In: Wilson's disease (D. Bergsma, I. H. Scheinberg, I. Sternlieb, eds.), pp. 114--121. New York: National Foundation 1968 Walshe, J. M.: The physiology of copper in man and its relation to Wilson's disease. Brain 90, 149--176 (1967) Walshe, J. M.: Some observations on the treatment of Wilson's disease with penicillamine (D. Bergsma, I. H. Scheinberg, I. Sternlieb, eds.), pp. 126--129. New York: National Foundation 1968 Received October 10, 1976
