
U r i n a r y c y c l i c AMP : A s e n s i t i v e i n d e x f o r H. PRZYREMBEL*, K. BECKER*, H. J. BREMER, t h e h e a l i n n o f r i c k e t s . University Children's Hospital, DUsseldorf, West-Germanv.
The p r e s e n t work i s c o n c e r n e d w i t h s t u d i e s o f t h e r e n a l t u b u l a r d e f e c t i n a d v a n c e d s t a g e s o f r i c k e t s o f i n f a n c y . T h e i n c r e a s e d l o s s o f p h o s p h a t e i n t h e u r i n e i n t h i s d i s e a s e i s p r o b a b l y d u e t o h i g h p l a s m a l e v e l s o f p a r a t h y r o i d hormone (PTH).
We t h e r e f o r e i n v e s t i g a t e d u r i n a r y a d e n o s i n e 3 ' , 5 ' -m o n o p h o s p h a t e (CAMP) which i s p a r t l y formed i n t h e r e n a l t u b u l e s i n r e s p o n s e t o PTH. An 8 months o l d boy w i t h v i t a m i n D d e f i c i e n c y r i c k e t s showed a p r e -t r e a t m e n t u r i n a r y cAMP v a l u e o f 3 1 , 3 nmol p e r mg c r e a t i n i n e (Normal v a l u e s i n t h i s a g e g r o u p l e s s t h a n 1 1 , O w i t h o u r m e t h o d ) . On t r e a t m e n t w i t h v i t a m i n D2 (2700 I U d a i l y ) u r i n a r y cAMP was n o r m a l i z e d i n t h e c o u r s e o f 4 -5 m o n t h s , c o n c o m i t a n t l y w i t h a c o m p l e t e r a d i o l o g i c a l h e a l i n g . A 1 2 months o l d g i r l w i t h v i t a m i n D d e p e n d e n c y r i c k e t s was t r e a t e d w i t h v i t a m i n D 2 ( 4 0 . 0 0 0 I U d a i l y ) f o r o n e y e a r t o o b t a i n c o m p l e t e h e a l i n g . D u ri n g t h i s t i m e t h e r e was a s t e a d y d e c l i n e o f u r i n a r y cAMP f r o m a n i n i t i a l v a l u e o f 3 7 , 8 nmol p e r mg c r e a t i ni n e t o v a l u e s w i t h i n t h e n o r m a l r a n g e . T h e p a t t e r n s o f u r i n a r y cAMP i n t h e 2 t y p e s o f r i c k e t s c l e a r l y r e f l e c t s t h e t i m e f a c t o r i n t h e h e a l i n g p r o c e s s , a n d t h e r e s p o n s e t o v i t a m i n D.We c o n c l u d e t h a t u r i n a r y cAMP i s a s e n s it i v e i n d e x f o r t h e h e a l i n g o f i~i c k e t -s , r ; :~z t h In the 13 yrs since hepatic glycogen synthetase (GS) deficier~cy was f i r s t described i n identical twins no further cases seem t o have been observed. W e now report on K . S . who had suffered from morning convulsions since the age of 7 . Three 24-h metabolic prof i l e s showed f a s t i n g hypoglycaemia (mean 1.5 mM), hyperketonaemia (mean t o t a l ketones 8.5 mM) but normal l a c t a t e (mean 1.5 mM). One h a f t e r lunch the mean values were 1 1 . 7 mM glucose, 0.2 mM ketones and 6.0 mM l a c t a t e . The former levels reappeared a f t e r an 8 h f a s t . Glucagon (0.03 mg/kg i . m . ) caused a r i s e i n glucose (~: 2 mM) 3 h a f t e r a meal with a f a l l i n l a c t a t e and alanine. No e f f e c t was seen a f t e r a 1 2 h f a s t . Normal increments i n glucose followed o r a l galactose o r alanine. Liver and abdominal muscle biopsies were taken. Glycogen content was subnormal i n l i v e r : 0.65% (6 controls: 1-6%) but normal i n muscle: 0.76% (2 controls: 0.70,0.72%). Glycogen synthetase (EC 83.161.120.155) was v i r t u a l l y abs e n t from l i v e r : 0.04 U/g wet w t . E G-6-P, 0.01 U/g S G-6-P (6 controls 1.99-3.60, 0.03-0.16) but f u l l y active i n muscle: 1.71 U/g wet w t . 5 G-6-P, 0.11 ~/ g S G-6-P (2 controls 1.52,1.24; 0.11,0.06). GS i n K.S. l i v e r e x t r a c t was not activated by K.S. muscle e x t r a c t nor by control l i v e r o r muscle. Liver e x t r a c t of K . S . did not inh i b i t GS of K . S . muscle or of control l i v e r o r muscle. Hepatic GS deficiency causing fasting hypoglycaemia does indeed e x i s t . of Pediatrics and ophthalmology, University of Nijmegen, Nijmegen, The Netherlands. Gyrate atrofy of the choroid and r e t i n a and ornithine-ketoacid aminotransferase deficiency.
The p r e s e n t work i s c o n c e r n e d w i t h s t u d i e s o f t h e r e n a l t u b u l a r d e f e c t i n a d v a n c e d s t a g e s o f r i c k e t s o f i n f a n c y . T h e i n c r e a s e d l o s s o f p h o s p h a t e i n t h e u r i n e i n t h i s d i s e a s e i s p r o b a b l y d u e t o h i g h p l a s m a l e v e l s o f p a r a t h y r o i d hormone (PTH).
In a 10 years old g i r l with gyrate atrofy of the choroid and r e t i n a plasma ornithine concentration was consistently elevated ranging from 1000-1250 #mol/l. The ornithine concentration of the spina f l u i d was similary increased. The concentration of the other amino-acids was normal i n a l l samples. The urine showed a typical overflow aminoaciduria, with an increase i n ornithine only The prenatal and postnatal history was generally uneventful. Nc c l i n i c a l abnormality could be found; l i v e r was not enlarged. Intelligence was normal. The following laboratory t e s t s gave normal r e s u l t s : haematological examination, serum proteins and t h e i r electrophoretic pattern: SGOT, SGPT, LAP, YGT, b i l i r u b i n , ureum, creatinin, blood ammonia. A deficiency of ornithine ketoacid aminotransferase was found i n cultured f i b r o b l a s t s by radiochemical method. Pharmologic doses of V i t . B6 f o r 7 days and r e s t r i c t i o n of protein intake t o 0.8 g/kg f o r 2 months did not r e s u l t i n normal plasma ornithine concentration. Normal ornithine concentrations were found i n plasma of the parents and the healthy s i b s .
D-glyceric aciduria, an inborn e r r o r of serine metabolism?
An Afghanese boy i s described who presented with severe metabolic acidosis, failure to thrive and recurrent infections in the neonatal period. Symptomatic treatment with bicarbonate, combined with a low protein diet, resulted in clinical improvement. Gas chromatographic analysis of organic acids (trimethylsilyl derivatives) in the patient's urine revealed high concentrations of glyceric acid (10 to 100 mM), confirmed by mass spectrometry. Amino acid excretion was normal, especially no excess of glycine was present. The optical configuration of glyceric acid was determined a s follows: isolation of the acid by paper chromatography, esterification with L-menthol and acetylation of the OH-groups. Subsequent capillary gas chromatography, stationary phase SP-1000, yielded good separation of the enantiomers. Only D-glyceric acid was found in the urine. Glyceric acid may be derived from carbohydrate o r amino acids. To elucidate its origin we loaded the patient with fructose and L-serine. Fructose loading caused no increase of glycerate excretion. On the contrary, the loading test with 200 mg/kg L-serine resulted in a significant increase of glyceric acid excretion. 25% of the ingested serine was retrieved a s glyceric acid. L-serine loading in a control led to the excretion of only a trace of glyceric acid. It i s suggested that the enzyme defect 1s located somewhere in the serine degradation pathway. At 16 year the patient was moderately retarded and glyceric aciduria was bersistent (~1 2 mmoles/day). 
t a t h i o n e p e r o x i d a s e a c t i v i t y i n d i e t e t i c a l l y t r e a t e d p a t i e n t s w i t h m e t a b o l i c d i s e a s e s .
S e l e n i u m c o n c e n t r a t i o n s o f s e r u m , w h o l e b l o o d , h a i r a n d f o o d w e r e m e a s u r e d by i n s t r u m e n t a l n e u t r o n a c t i v at i o n a n a l y s i s i n d i e t e t i c a l l y t r e a t e d p a t i e n t s wi'th m a p l e -s y r u p -u r i n e d i s e a s e (M.S.U.D.) a n d p h e n y l k e t o nu r i a (P.K.U,) a n d i n c o n t r o l c h i l d r e n w i t h n o r m a l f o o d .
C o n c o m i t a n t l y g l u t a t h i o n e p e r o x i d a s e a c t i v i t y o f e r yt h r o c y t e s a s a m a r k e r enzyme o f s e l e n i u m d e f i c i e n c y was e s t i m a t e d . Follow-up s t u d i e s showed t h a t w i t h i n 2 months o f d i e t o t h e r a p y t h e serum s e l e n i u m c o n c e n t r at i o n f e l l f r o m n o r m a l v a l u e s a t b i r t h t o v e r y low v a l u e s . The a c t i v i t y o f t h e g l u t a t h i o n e p e r o x i d a s e o f
. t h e e r y t h r o c y t e s a l s o d e c r e a s e d t o 50 p e r c e n t o f t h e n o r m a l v a l u e s . A c c o r d i n g t o t h e i n t a k e t h e serum s e l enium c o n c e n t r a t i o n s a n d t h e a c t i v i t y o f t h e g l u t a t h io n e p e r o x i d a s e o f t h e e r y t h r o c y t e s i n 1 8 i n f a n t s a n d c h i l d r e n w i t h P.K.U. a n d M.S.U.D. r e m a i n e d s i g n i f i c a n tl y l o w e r d u r i n g d i e t o t h e r a p y t h a n t h o s e o f n o r m a l c h i l d r e n . The serum s e l e n i u m c o n c e n t r a t i o n o f t h e c o n t r o l p e r s o n s showed a n a g e d e p e n d e n c y .
C o n c o m i t a n t l y g l u t a t h i o n e p e r o x i d a s e a c t i v i t y o f e r yt h r o c y t e s a s a m a r k e r enzyme o f s e l e n i u m d e f i c i e n c y was e s t i m a t e d . Follow-up s t u d i e s showed t h a t w i t h i n 2 months o f d i e t o t h e r a p y t h e serum s e l e n i u m c o n c e n t r at i o n f e l l f r o m n o r m a l v a l u e s a t b i r t h t o v e r y low v a l u e s . The a c t i v i t y o f t h e g l u t a t h i o n e p e r o x i d a s e o f
S u l p h a t i d e , a n a c l d l c s p h i n~o l i p i d , i s a n i m p o r t a n t component o f m y e l i n , I t s r a t e o f s y n t h e s i s c h a n g e s s i g n i f i c a n t l y d u r i n g d e v e opment. I n mouse b r a i n , t h e s y n t h e s i s s t a r t s a t t h e Sth p o s t n a t a l d s y , r e a c h e s c maximum a t d a y 1 6 and d e c l~n e s u n t i l d a y 25, when a b a s e r a t e of synthesis i s a c h l e v e d , To i n v e s t i g a t e t h e mechanism of t h e r e g u l a t i o n of t h i s d e v e l o p r n e~~~a l p a t t e r n , microsontes o f mouse b r a i n w e r e d e l i p i d a t e d a n d a l i p i d r e q u i r e m e n t o f a k e y enzyme o f t h e s u lp h a t i d e -s y n t h e s i s , t h e Cerehroside-Sulphotransferase ( C S T ) , c o u l d b e shown, Ve c o u l d t h e n d e m o n s t r a t e , t h a t

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