A Review of the Clinical Presentation and Laboratory Findings in Two Uncommon Hereditary Disorders of Sulfur Amino Acid Metabolism, 13-Mercaptolactate Cysteine Disulfideuria and Sulfite Oxidase Deficiency J. C. CRAWHALL Division of Clinical Biochemistry, Royal Victoria Hospital, 687 Pine Avenue West, Montreal, P.Q. Canada whose significance will be discussed in the course of Two hereditary disorders of sulfur amino acid metabolism, 13-mer- captolactate-cysteine disulfideuria and sulfite oxidase deficiency, this paper. were described twenty years ago. Other examples of these disorders have been limited to about 5 of each in the world literature since then. Clinical presentation of ~-mercaptolactate- Reasons for the apparent rarity of these conditions are discussed and cysteine disulfideuria the analytical procedures to identify them are reviewed. The detection of the first depends on the positive result of a The first patient to be detected with this disorder was cyanide-nitroprusside test followed by positive identification of the an adult male found as the result of a metabolic screen- specific mixed disulfide. The enzyme mercaptopyruvate sulfur ing program established by Efron and Bixby at the transferase has been shown to be deficient. In the second dis- Wrentham State School for the Mentally Retarded in order of sulfite oxidase deficiency, the clinical presentation with pro- Massachusetts. The urines of five patients were found gressive dystonia and dislocated lenses in an infant should suggest further laboratory investigations for this disorder which would not be to be positive by the cyanide-nitroprusside test. Of the- detected by conventional laboratory screening procedures. Lab- se, four were shown to be due to cystinuria, and in the oratory diagnosis can be obtained by use of the Merckoquant sulfite fifth, the presence of a hitherto unknown sulfur- test on a fresh urine sample. Quantitative thiosulfate and taurine containing amino acid was observed (1). The unknown measurements can also be made. Positive identification of the specific amino acid S-sulfo-L-cysteine should also be made. The spot was identified by the method of two-way sepa- enzyme sulfite oxidase is missing from such organs as liver, kidney ration by high voltage electrophoresis followed by pa- and brain. This latter condition may also be associated with xanthi- per chromatography developed by Efron (2). This sub- nuria. For this combined disorder of sulfite oxidase and xanthine stance was eventually isolated and characterised as oxidase, a deficiency of a molybdenum-containing cofactor has been ~-mercaptolactate-cysteine disulfide with confirmation demonstrated. of the structure by mass spectrometry (3, 4). Synthesis of this compound was carried out by Hope and Walti (5) KEY WORDS: ~-mercaptolactate-cysteine disulfideuria, and the same authors synthesised the various isomers sulfite oxidase deficiency, xanthine oxidase deficiency, bio- and identified the appropriate isomer excreted in this chemical genetic screening, sulfur amino acid metabolism, patient's urine (6). The presence of traces of this un- cysteine. usual mixed disulfide can sometimes be found in su~l-Mercaptolactate-cysteine disulfideuria and sulfite normal human urine (7). It has also been shown that oxidase deficiency were two hereditary disorders of administration of cysteine to normal human subjects fur amino acid metabolism described in the United can give rise to the presence of ~-mercaptolactate- States in the mid 1960's. It is now twenty years later cysteine disulfide in the urine (8). and only about five other cases of each have been found The next subjects with this abnormal metabolite in in the Western world. In the disorder ~-mercapto- the urine were found as the result of a screening pro- lactate-cysteine disulfideuria, no other case has been gram of healthy school children in Zurich which identi- reported in North America out of a total population of fied two female siblings, age 11 and 13. They were about 250 million people. Only one other case of sulfite extensively investigated (9). The fourth subject to be 0xidase deficiency has been reported in North America. found was a 20-year-old male with mild mental re- These are apparently very rare disorders, and in this tardation and bilateral congenital dislocation of the report I will review the accumulated information on lenses who was found as the result of a screening these patients up to the present time, including their program of 3000 mentally handicapped patients in clinical presentation and the laboratory procedures Aberdeen, Scotland (10). Since then, only one other available for diagnosis. female patient has been reported. Her associated dis- The relevant structural formulae and metabolic re- eases were ulcerative colitis and autoimmune hemo- lationships are shown in Figure 1. It can be seen that lytic anemia but these were probably not related to her cysteine plays a central role in the production of many metabolic abnormality. She was mentally normal (11). interesting intermediates and important end products The first patient was studied to identify the specific enzyme defect which was shown to be a deficiency of Correspondence: Dr. J. C. Crawhall, Division of Clinical mercaptopyruvate sulfurtransferase (E.C.2.8.1.2) ac- Biochemistry, Royal Victoria Hospital, 687 Pine Avenue tivity in erythrocytes (12). This enzyme defect was also West, Montreal, Quebec H3A 1A1. confirmed in the fifth patient (11). This latter report Manuscript submitted June 12, 1984; revised manuscript included an extensive study of several metabolites in received September 19, 1984, accepted for publication October 9,1984. the urines of the propositus and many members of the CLINICAL BIOCHEMISTRY, VOLUME 18, JUNE 1985 139
CRAWHALL ~..~" H S- Hydrosulfide ~ SCN- Thiocyanate S2022-Thiosulfite Mercaptopyruvate Sulfur Transferase (M ST) (Y Mercaptopyruvate Cysteine m Cysteamine Figure 1 -- The metabolism of cysteine CH2--C--COOH CH2--CHCOOH ~H2QH2--NH2 showing the derivation of ~-mercapto- I II SH 0 SH ~NH 2 SH lactate, sulfite and S-sulfocysteine. Cysteine sulfinic acid Hypotaurine CH2--CHCOOH CH2--CH2--NH 2 I ~ I SO2H NH S02H ~, #Mercaptolaetate CH2--CHCOOH I I Sulfinylpyruvic acid ~ S03H SH OH CH 2- C--COOH ~ I II Cysteic acid + Cysteine CH2~ CHCOOH SO2H 0 1 ' ' SO3H NH 2 Mercaptolactate- cysteine disulfide + Cysteine Thiosulfate Sulfite ~ HO2SSCH2CHCOOH (8203) -2 (S03) 2- I~IH 2 S-Sulfocysteine Sulfite oxidase Sulfate (S04) 2- family. These studies allowed a tentative classification chromatographic steps are required before the mer- of the disorder as being hereditary autosomal recessive. captolactate is finally converted to its chromatographic Of the five patients, two have been reported to be derivative by extractive alkylation. Final confirmation mentally retarded and three have been found to be of the structure has been made in two of the patients by mentally normal (Table 1). It is not clear that the met- mass spectrometry (4, 9). The presence of the appropri- abolic defect is related to the mental retardation and it ate enzyme defect can be determined by measurement is just possible that these people were found because of of beta-mercaptopyruvate sulfurtransferase activity in specifically directed screening programs within mental erythrocytes as previously described (11, 12). institutions. At present no treatment for the condition Clinical presentation of sulfite oxidase deficiency is known and possibly would not be indicated. How- ever, the rarity of the condition at present precludes This disorder (Table 2) was first described in a any generalisations concerning the significance of the 30-month-old boy with extreme brain damage, mental phenotype. retardation and dislocated lenses. The first biochemical abnormality to be detected in the urine was the excre- Laboratory criteria for establisment of the tion of an unusual amino acid S-sulfo-L-cysteine (14). diagnosis of mercaptolactate-eysteine Up to that time S-sulfo-L-cysteine had only been found disulfideuria as a urinary excretion product in the mammalian The first finding is generally that the urine is posi- species called the blotched Kenya genet (15). Other tive by the cyanide-nitroprusside test. Other conditions findings in the patient's urine were a lack of inorganic giving this result would be cystinuria, some hetero- sulfate, an abnormally increased quantity of sulfite and zygotes for cystinuria and homocystinuria. These latter abnormal quantities of thiosulfate and taurine. A defi- possibilities can be eliminated on the basis of con- ciency of the enzyme sulfite oxidase (Sulfite:oxygen ventional chromatography. The abnormal substance oxidoreductase E.C. 1.8.3.1) was confirmed by these should then be identified by a separate technique. This authors in tissue obtained at autopsy in liver, kidney could be the high voltage electrophoresis followed by and brain of this patient (16). Since that time only one paper chromatography described by Efron (2). A other patient with this condition has been described method for analysis by gas chromatography has re- (17). However, in 1978, another patient was described cently been proposed (13). However, in this technique who had the same clinical findings but in addition had the mixed disulfide first has to be reduced on a hypouricaemia and xanthinuria (18). Investigation of thiopropyl-Sepharose column, and two further this patient showed that she not only had sulfite ox- 140 CLINICAL BIOCHEMISTRY, VOLUME 18, JUNE 1985
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