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Cystathioninuria Not Associated with Vitamin B6 Dependency: a Probably New Type of Cystathioninuria

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Cystathioninuria Not Associated with Vitamin B6 Dependency: a Probably New Type of Cystathioninuria Tohoku .J. exp. Med., 1968. 95, 235-242 Cystathioninuria not Associated with Vitamin B6 Dependency: A Probably New Type of Cystathioninuria Keiya Tada, Toshio Yoshida, Yoshimasa Yokoyama, Tetsuo Sato, Hiroshi Nakagawa and Tsuneo Arakawa Department of Pediatrics (Prof. Ts. Arakaeva), Faculty of Medicine, Tohoku University, Sendai An infantile case of cvstathioninuria was described. The patient had retarded development and marked cvstathioninuria. Large doses of vitamin B6 were of no effect in diminishing cystathionine excretion, this finding being different from that in other patients with cvstathioninuria so far reported. Using liver specimens biopsied from the patient, a difinitely low activity of cystathionase was demonstrated in the presence of an excess of pyridoxal phosphate. Both in vim and in vitro studies indicate a defect in cystathionase itself. The present patient is thought to have a new type of cystathioninuria without vitamin B6 dependency. Cystathioninuria is an inborn error of metabolism described by Harris et al.1 in 1959. The first patient1 was a 64-year-old woman with mental defect and short stature. The second2 was a 44-year-old man with acromegaly and mental aberra tions. The third3 was a 12-year-old boy with retardation in mental and motor development and the fourth4 was a 2-year-old boy with normal intelligence, bilateral renal calculi and thrombocytopenic purpura. The fifth patient reported by Haraguchi et al.5 was a 13-year-old girl with no apparent symptoms except electroencephalographic abnormality. All four of these patients, except for the first patient of Harris et al., in whose paper there was no description of vitamin B6 treatment, were reported to show disappearance of cystathioninuria when they were given high doses of pyridoxine. These patients have, however, shown neither evidence of nutritional deficit nor that of vitamin B6 deficiency in any other biochemical system. Therefore, Scriver6 has included cystathioninuria in the disease category of vitamin B6 dependency. Frimpter et al.7 demonstrated, using liver homogenates from two cystathionin uric patients, that without addition of pyridoxal phosphate the activity of cystathionase was markedly reduced compared with that of controls' liver, but that the activity was restored to normal range by addition of an excess of pyridoxal phosphate. They suggested that the basic defect of cystathioninuria was an inability of the apoenzyme cystathionase to combine normally with the coenzyme pyridoxal phosphate. Received for publication, February 12, 1968. 235 236 K. Tada et al. This paper will describe an infant with cystathioninuria who showed no re sponse to large doses of vitamin B6 in both in vieo and in vitro studies . REPORT OF CASE N.S., a male, was born after an uncomplicated full term pregnancy and spontaneous delivery. His neonatal period was uneventful. The parents were healthy but consanguineaus (first causins). The patient had three siblings. One of them (sister) showed retarded development and died of pneumonia at the age of 3 years. The other two siblings were living and well. The patient was fed on mother's milk for the early two months and then was changed to artificial feeding (cow's milk). The mother noticed that the patient might be backward in motor and mental development at the age of 8months. There was a history of febrile convulsions but none of severe illness. Physical examination on admission at the age of nine months revealed a moderately nourished boy. His weight and height were within normal limits. He could not sit alone yet. The lungs and heart were clear to auscultation . Neither the liver nor the spleen was palpable. The extremities were somewhat flaccid and the deep tendon reflexes were weak . No pathological reflexes were elicited. Otherwise there were no abnormal findings on physical examinations . D.Q. was found to be 65. Fig. 1. Amino acid chromatogram of urine from the patient with cystathioninuria by automatic amino acid analyzer. Cystathioninuria not Associated with Vitamin B6 Dependency 237 TABLE 1. Urinary amino acids in a cystathioninuric patient (umoles/mg of cratinine) TABLE 2. Serum amino acid leeels in a cystathioninuric patient (pmoles/l) Laboratory finfings. Routine blood studies and determinations of chemical constituents of serum, including protein, electrolytes and lipids, were within the normal range. Liver function tests gave normal results. The urine was clear with acid reaction, negative for protein, sugar, acetone, or phenylpyruvie acid, and moderately positive for the cyaniden-itroprusside reaction. The sediment was unremarkable. Fundoscopic examination showed no abnormality. Chromo somal analysis showed no abnormality in both number and configuration. 238 K. Tada et al. Electroencelphalographicfindings. Sleeping record exhibited sporadic sharp waves in both central areas and irregular HVS in both occipital areas. Resting record showed a slight dysrrhythmia, but neither paroxysmal discharge nor asym metry was detected. Two-dimensional thin-layer chromatography of urinary amino acids showed a remarkable increase in cystathionine. Quantitative determination of amino acids in urine and serum was made by an automatic amino acid analyzer (cf. Fig. 1 and Tables 1 and 2). It was found that urinary excretion of cystathionine was 210 to 250mg per day and its serum level was 1.34mg per 100ml. METABOLICSTUDIES L-Tryptophan loading test (orally 100mg/kg) revealed no abnormal increase in xanthurenic acid excretion. The activity of erythrocyte GOT (glutamic oxalo acetic transaminase), which was thought to be parallel with the amount of pyridoxal phosphate in blood, was within normal limits (6.37 Karmen units per 1mg of Hb; normal range 5.15-9.15 units). The contents of vitamin B6 in serum were estimated by microbiological assay.9 The levels of vitamin B6 in serum from the patient were within the normal range (cf. Table 3). Urinary excretion of pyridoxic acid determined by Reddy et al.'s method10 was also within the normal range (0.315mg/day; normal range 0.280 0.672mg/day). TABLE3. The contents of vitamin B6 in serum from the patient with cystathioninuria (my/ml) Methionine loading test. A hundred mg of L-methionine per kg of bodyweight were orally administered to the patient. Twenty-four-hour urines were collected before and following the test dose and the amounts of cystathionine and of inorganic sulfate were determined by an automatic amino acid analyzer and Folin's method,11 respectively. The results were shown in Table 4. Methionine loading caused a marked elevation of cystathionine excretion but no significant increase in inorganic sulfate excretion. These results clearly indicate the presence of a block in the process catalyzed by cystathionase (cf. Fig. 2). Cystathioninuria not Associated with Vitamin B6 Dependency 239 TABLE4. Urinary excretion of cystathionine and inorganic sulfate following an oral dose of methionine (100mg/kg) Fig. 2. Degradation pathway of methionine. Response to vitamin B6 administration. Large doses of pyridoxine or pyridoxal phosphate (PALP) were given parenterally to the patient and urinary output of cystathionine was determined (cf. Table 5). The results showed no significant dif ference in cystathionine excretion by the treatment with vitamin B6, being differ ent from the report of other patients with cystathioninuria. Enzyme studies. The activity of cystathionase was determined by the liver specimens obtained by the Menghini needle from this particular patient and from three control children without hepatic involvement. The biopsied liver specimens were immediately homogenized at 0•‹C in 0.2M phosphate buffer (pH 8.0) and the liver homogenates were incubated with an excessive amount of PALP for 120minutes at 37•‹C in the following way: To each flask 2 ƒÊmoles of 14C 3-L-serine (2ƒÊC), 5 ,moles of DL-homocysteine and 200y of pyridoxal phosphate were added to make a final volume of 1.8ml by the 240 K. Tada et al. TABLE 5. Response of cystathioninuria to vitamin B6 administration in our patient phosphate buffer (pH 8.0). At the end of incubation, three volumes of 4% sulfosali cylic acid were added for deproteinization and the mixture was centrifuged. The sediment was used for determination of protein by the method of Folin-Ciocalteu.12 From the supernatant cystathionine and cystine were isolated by collecting fractions from ion-exchange column (18 x 1,500mm of amberite 325). Then each fraction of cystine or cystathionin was passed through the column of Dowex 50 and eluted with 2 N NH4OH to remove the citrate buffer. The effluent was dried up and radioactivity was determined by a gas-flow counter. Table 6 shows the results of these experiments. The conversion of serine to cystine was markedly reduced in the patient's liver than in controls' liver, while there was no significant difference in the conversion of serine to cystathionine between the patient's and controls' livers. These results indicated a defect of the cystathionase activity in the patient's liver. TABLE 6. The conversion of 14C.-3-serine to cystathionine and to cystine by the liver According to Frimpter et al,7 the activity of cystathionase was restored by addition of 100y of PALP to the incubation mixture. The present studies showed a definitely low activity of cystathionase in the patient's liver in spite of the presence of an excess of PALP (200y). The results of both the in, vivo and in vitro experiments in our patient deny vitamin B6, dependency and suggest that the basic biochemical lesion is a defect
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