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Mental retardation in Down syndrome: a hydrogen sulfide hpothesis
Medical Hypotheses (2001) 57(3), 389–392 © 2001 Harcourt Publishers Ltd doi: 10.1054/mehy.2001.1377, available online at http://www.idealibrary.com on
Mental retardation in Down syndrome: a hydrogen sulfide hpothesis P. Kamoun Laboratoire de Biochimie médicale B, Hôpital Necker – Enfants Malades, Paris, France
Summary Mental retardation is progressive in Down syndrome: individuals are born with normal intelligence which starts to decline linearly within the first year. This phenomenon can be observed with phenylalanine in patients with phenylketonuria, therefore it is compatible with metabolic intoxication. The toxic compound could be hydrogen sulfide. The amount of the compound is probably increased in Down syndrome by increasing active cystathionine beta synthase. This heuristic hypothesis requires further investigation. © 2001 Harcourt Publishers Ltd
THE HYPOTHESIS Although newborns with Down syndrome may, with the exception of the profound hypotonia, appear reasonably normal behaviorally, developmental retardation generally becomes obvious during the first few months of life. The attainment of developmental landmarks generally becomes increasingly delayed as time goes on. Thus the average delay may be approximately two months for the very early landmarks (e.g. rolling over, transferring objects); this gradually lengthens, reaching one to two years for functions that normally appear at about two years of age. Table 1 shows the results obtained by Share and Veale (1). Many studies of development during the first decade of life indicate that even if Down syndrome children are raised at home, there is a progressive, virtually linear decline in intelligence quotient which starts within the first year (Table 2) (2). A similar age-related decrease in intellectual quotient has been described in untreated patients with phenylketonuria (3). The increased amount of phenylalanine in the
Received 27 November 2000 Accepted 5 February 2001 Correspondence to: Professor Pierre Kamoun, Laboratoire de Biochimie médicale B – UMR-CNRS 8602, Hôpital Necker – Enfants Malades, 75743 Paris Cedex 15, France. Phone: +33 1 44 49 51 31; Fax: +33 1 44 49 51 30; E-mail: [email protected]
brain is directly responsible for the mental retardation observed in these patients. Indeed if the phenylalanine intake in the diet is decreased immediately after birth, the brain develops normally (4). By analogy the mental retardation in Down syndrome patients may also be of metabolic origin. The metabolism of sulfur aminoacids is probably the source of the toxic compound. The cystathionine beta synthase enzyme or CBS (EC 4.2.1.22) is encoded by a gene found on chromosome 21 (21 q 23). Enzymatic activity of CBS increases by approximately 150% in the fibroblasts of Down syndrome patients compared to normal individuals (5). The main function of CBS is to catalyze the first step of the transsulfurating pathway. This involves the hydrolysis of cystathionine by cystathionase or CST (EC 4.4.1.1). The in vivo increase in CBS activity induces a decrease in the CBS substrate (homocysteine) in the plasma of Down syndrome patients (6). CBS also has another enzymatic activity, the production of H2S from cysteine (7). Two other enzymes can also produce H2S: CST and mercaptopyruvate sulfur transferase (MPST: EC 2.8.1.2) (7). Mercaptopyruvate, the substrate of MPST, is obtained by transaminating cysteine. Studies on rats or man (8,9) showed that after H2S poisoning the excretion of thiosulfate in urine is significantly increased. Thiosulfate is formed by the condensation of H2S and sulfite (SO32–) which is produced by the thiol catabolism of cysteine (10). In adult humans thiosulfate production is estimated to be 31 µmol/day (11). In rats concentrations of H2S in 389
390
Kamoun
Table 1 Median time in months of appearance of developmental landmarks in children with Down syndrome as compared with a normal population [data from Share and Veale (1)] Developmental landmarks
Normal children
Smiles Hold head erect Rolls over Transfer objects in hand Sits unsupported Feeds self in part Pulls to stand Says dada/mama Cruises at rail Stands alone Walks alone Obeys simple commands Drinks from cup alone 2–3 word combinations Draws / imitates circle Feed self fully 3 word sentences
1.9 2.9 4.7 6.8 7.8 8.9 9.8 9.8 11.8 13.9 15.0 17.7 20.9 21.9 23.8 23.8 28.0
Table 2 Intelligence quotient of children with Down syndrome as a function of age [Data from Morgan (2)] Age (years) <1 1–3 3–5 5–7 7–9 9–11 > 11
Intelligence quotient: mean (range) 73 (35–107) 59 (15–80) 46 (15–66) 41 (25–69) 39 (9–60) 34 (17–44) 28 (10–56)
the tissues have been determined after exposure to large amounts of gaseous H2S, or after intraperitoneal administration of an equal amount of NaHS. The normal concentration of H2S in the rat brainstem is 1.23 ± 0.06 µg/g tissue (n = 10): the lethal concentration is only 5.00 ± 0.89 µg/g of brainstem tissue. The 50% lethal dose of NaHS is 16 mg/kg even though this dose only doubles the normal H2S concentration in the brain (12). The lethal concentration is very close to the normal concentration, which explains its high toxicity. This toxicity in the central nervous system may be due, at least in part, to the action of H2S and HS– on cytochrome aa3 (12,14,15,16). Indeed, H2S is a more potent inhibitor of this cytochrome than cyanide (17). However, there may be other explanations for H2S toxicity such as the formation of persulfides. Sulfhydryl modification leading to altered enzymatic function has been demonstrated for over a dozen enzymes after persulfide generation (18). Similarly, sulfhydryl modification of receptor proteins by mercaptans which act as sulfide donors has been demonstrated (19). H2S has also been shown to strongly inhibit human carbonic anhydrase (20). Carbonic anhydrase resides mainly in glial cells, specifically in oligodendrocytes, and in hippocampal neurons (21). It has also been demonstrated Medical Hypotheses (2001) 57(3), 389–392
Down syndrome patients 4.1 4.8 5.4 9.8 10.8 15.8 16.8 11.8 17.9 22.9 23.8 23.8 28.0 35.7 48.2 33.0 48.2
that monoamine oxidase is readily inactivated by sulfhydryl reagents, and high doses of NaHS are known to inhibit monoamine oxidase activity in a dose-dependent manner (22). The half-life for the recovery of monoamine oxidase isolated from rat brain after irreversible inhibition is up to 30 days (23). Chronic exposure to low concentrations (20 and 50 ppm) of hydrogen sulfide causes alterations in the central nervous system. To determine the effect of exposure during perinatal development pregnant rats were exposed to H2S 7 hours per day from Day 5 postcoitus, until Day 21 postnatal. H2S treatment produced severe alterations in the architecture and growth characteristics of the Purkinje cell dendritic fields (24). Levels of serotonin and norepinephrine were determined in the rat cerebellum and frontal cortex during perinatal development. Concentrations of both amines were altered compared to the controls; serotonin levels were significantly increased at days 14 and 21 postnatal in both brain regions. Norepinephrine levels were significantly increased at days 7, 14 and 21 postnatal in the cerebellum, and at day 21 in the frontal cortex (25,26). It is well established that monoamines influence most aspects of neural development, including neural cell division, migration, morphogenesis and synapse formation. Serotonin is known to inhibit neurite outgrowth in the brains of developing rats probably via type a receptors (24). H2S exposure may also alter monoamine levels in other brain regions such as the hippocampus (27). Excessive increases in serotonin release in the hippocampus may cause learning deficits, by interacting with type II glucocorticoid receptors in the hippocampus (28). This may explain the memory loss and the impaired cognitive and perceptual functions reported following H2S intoxication (29). It is noteworthy that CBS is continuously and strongly expressed in the central nervous system of © 2001 Harcourt Publishers Ltd
Mental retardation in Down syndrome
391
Table 3 Corrected and uncorrected cerebellar volume for subjects with Down syndrome and matched controls [From E. H. Aylward (31)] Down syndrome n = 30 3
Cerebellar volume (cm ) Cerebellar volume (Intracranial volume) Cerebellar volume (Brain volume)
92.6 ± 15.1 0.74 ± 0.11 0.87 ± 0.15
human embryos from the earliest stage studied (22 days post conception) (30). CBS gene expression was weak in the deep cerebellar nuclei of 25-week-old fetuses, and the strongest labeling was observed in the cerebellar cortex. It was recently discovered that Down syndrome patients have significantly smaller cerebellar volumes than matched controls, even after adjusting for total brain volume or total intracranial volume (Table 3) (31). The specificity of the chronic toxic effect of H2S on the cerebellum (24) is consistent with this observation. The hyperproduction of H2S in Down syndrome patients could be related either to a direct effect of CBS on L-cysteine, or to an indirect effect of CBS hyperactivity by increasing cysteine production via an accelerated transsulfuration pathway. Thus the cysteine produced could be transaminated, and the mercaptopyruvate produced could become the substrate of MPST accompanying H2S production. Some studies indicate that endogenous H2S has a physiological function: acting as a smooth muscle relaxant in synergy with nitric oxide, or as an endogenous neuromodulator by inducing hippocampal long-term potentiation by enhancing NMDA receptor activity (32,33). Hyperproduction of H2S in Down syndrome could thus induce dysfunction in muscles (hypotonia) and brain (mental retardation). We have recently made important progress in this field by showing that thiosulfate urinary excretion is significantly increased (P < 0.01) in Down syndrome patients. Further studies are in progress to determine the concentration of H2S in the blood of these patients and to search for clinical signs of chronic H2S poisoning in Down syndrome patients.
ACKNOWLEDGMENTS This work was supported by the following: Fondation Jerome Lejeune, Association Française pour la recherche sur la Trisomie 21, Laboratoires Baxter.
REFERENCES 1. Share J-B., Veale A. M. Developmental Landmarks for Children with Down’s syndrome. Duneden: University of Otago Press, 1974. 2. Morgan S. B. Development and distribution of intellectual and adaptative skills in Down syndrome children: implications for early intervention. Ment Retard 1979; 17: 247–249.
© 2001 Harcourt Publishers Ltd
Controls n = 30 127.2 ± 10.8 0.88 ± 0.09 1.01 ± 0.10
P < 0.001 < 0.002 < 0.002
3. Scriver C. R., Rosenberg L. E. Amino Acid Metabolism and Its Disorders. Philadelphia: Saunders, 1973; 39. 4. Dobson J. C., Kushida E., Williamson M., Friedman G. Intellectual performance of 36 phenylketonuria patients and their non-affected siblings. Pediatrics 1978; 58: 53–58. 5. Chadefaux B., Rethore M. O., Raoul O., Ceballos I., Gilgenkrantz S., Allard D. Cystathionine beta synthase: gene dosage effect in trisomy 21. Biochem Biophys Res Commun 1985; 128: 40–44. 6. Chadefaux B., Ceballos I., Hamet M., Coude M., Poissonier M., Kamoun P., Allard D. Is absence of atheroma in Down syndrome due to decreased homocystéine levels? Lancet 1988; 2: 741. 7. Stipanuk M. H., Beck P. W. Characterization of the enzymic capacity for cysteine desulphydration in liver and kidney of the rat. Biochem J 1982; 206: 267–277. 8. Curtis C. G., Bartholmew T. C., Rose F. A., Dodgson K. S. Detoxication of sodium 35 S-sulphide in the rat. Biochem Pharmacol 1972; 21: 2313–2321. 9. Snyder J. W., Safir E. F., Summerville G. P., Middleberg R. A. Occupational fatality and persistent neurological sequelae after mass exposure to hydrogen sulfide. Am J Emerg Med 1995; 13: 199–203. 10. Ubuka T., Yuasa S., Ishimoto Y., Shimomura M. Desulfuration of L-cysteine through transamination and transsulfuration in rat liver. Physiol Chem Physics 1977; 9: 241–246. 11. Sorbo B., Ohman S. Determination of thiosulphate in urine. Scand J Clin Lab Invest 1978; 38: 521–527. 12. Warenycia M. W., Goodwin L. R., Benishin C. G., Reiffenstein R. J., Francom D. M., Taylor J. D., Dicken F. P. Acute hydrogen sulfide poisoning. Biochem Pharmacol 1989; 38: 973–981. 13. Nagata T., Kage S., Kimura K., Kudo K., Noda M. Sulfide concentrations in post-mortem mammalian tissues. J Forens Sci 1990; 35: 706–712. 14. Roth S. H., Skarajny B., Bennington R., Brookes J. Neurotoxicity of hydrogen sulfide may result from inhibition of respiratory enzymes. Proc West Pharmacol Soc 1997; 40: 41–43. 15. Reiffenstein R. J., Hulbert W. C., Roth S. H. Toxicology of hydrogen sulfide. Ann Rev Pharmacol Toxicol 1992; 109–134. 16. Nicholson R. A., Roth S. H., Zhang J., Zheng A., Brookes J., Skrajny B., Bennington R. Inhibition of respiratory and bioenergetic mechanisms by hydrogen sulfide in mammalian brain. J Toxicol Environ Health Part A 1998; 54: 491–507. 17. Nichols P. The effect of sulfide on cytochrome aa3 isoteric and allosteric shifts of the reduced 1 peak. Biochim Biophys Acta 1975; 396: 24–35. 18. Valentine W. N., Toohey J. I., Paglia D. E., Nakatani M., Brockway R. A. Modification of erythrocytes enzyme activities by persulfides and methanethiol: possible regulatory role. Proc Natl Acad Sci USA 1987; 84: 1394–1398. 19. Brandt R., Kawamoto R. M., Caswell A. H. Effects of mercaptans upon dihydropyridine binding sites on transverse tubules isolated from triad of rabbit striated muscle. Biochem Biophys Res Commun 1985; 127: 205–212. 20. Mangani S., Haakansson K. Crystallographic studies of the binding of protonated and unprotonated inhibitors to carbonic
Medical Hypotheses (2001) 57(3), 389–392
392
21.
22.
23.
24.
25.
26.
Kamoun
anhydrase using hydrogen sulphide and nitrate anions. Eur J Biochem 1992; 210: 867–871. Pasternack M., Voipio J., Kaila K. Intracellular carbonic anhydrase activity and its role in GABA-induced acidosis in isolated rat hippocampal pyramidal neurones. Acta Physiol Scand 1993; 148: 229–231. Warenycia M. W., Smith K. A., Blashko C. S., Kombian S. B., Reiffenstein R. S. Monoamine inhibition as a sequel of hydrogen sulfide intoxication: increases in brain catecholamine and 5-hydroxytryptamine. Arch Toxicol 1989; 63: 131–136. Arnett C. D., Fowler J. S., MacGregor R. R., Schlyer D. J., Wolf A. P., Langstrom B., Halldin C. Turnover of brain monoamine oxidase in vivo by positron emission tomography using L [11C] deprenyl. J Neurochem 1987; 49: 522–527. Hannah R. S., Roth S. H. Chronic exposure to low concentration of hydrogen sulfide produces abnormal growth in developing cerebellar Purkinje cells. Neurosci Letters 1991; 122: 225–228. Skrajny B., Hannah R. S., Roth S. N. Low concentrations of hydrogen sulfide alter monoamine levels in the developing rat central nervous system. Can J Physiol Pharmacol 1992; 70: 1515–1518. Roth S. H., Skrajny B., Reiffenstein R. J. Alteration of the morphology and neurochemistry of the developing mammalian nervous system by hydrogen sulfide. Clin Experim Pharmacol Physiol 1995; 22: 379–380.
Medical Hypotheses (2001) 57(3), 389–392
27. Skrajny B., Reiffenstein R. J., Sainsbury R. S., Roth S. H. Effects of repeated exposures of hydrogen sulphide on rat hippocampal EEG. Toxicol Letters 1996; 84: 43–53. 28. Mitchell J-B., Iny L. J., Meaney M. J. The role of serotonin in the development and environmental regulation of type II corticosteroid receptor binding in rat hippocampus. Dev Brain Res 1990; 55: 231–235. 29. Tvedt B., Skyberg K., Aaserud O., Hobbesland A., Mathiesen T. Brain damage caused by hydrogen sulfide: a follow-up study of six patients. Am J Ind Med 1991; 20: 91–101. 30. Quere I., Paul V., Rouillac C., Janbon C., London J., Demaille J., Kamoun P., Dufier J. L., Abitbol M., Chasse J. F. Spatial and temporal expression of the cystathionine beta synthase gene during early human development. Biochem Biophys Res Commun 1999; 254: 127–137. 31. Aylward E. H., Habbak R., Warren A. C., Pulsifer M. B., Barta P. O., Jerram M., Pearlson G. D. Cerebellar volume in adults with Down syndrome. Arch Neurol 1997; 54: 209–212. 32. Hosoki R., Matsuki N., Kimura H. The possible role of hydrogen sulfide as an endogenous smooth muscle relaxant in synergy with nitric oxide. Biochem Biophys Res Commun 1997; 237: 527–531. 33. Abe K., Kimura H. The possible role of hydrogen sulfide as an endogenous neuromodulator. J Neurosc 1996; 16: 1066–1071.
© 2001 Harcourt Publishers Ltd
Mental retardation in Down syndrome: a hydrogen sulfide hpothesis P. Kamoun Laboratoire de Biochimie médicale B, Hôpital Necker – Enfants Malades, Paris, France
Summary Mental retardation is progressive in Down syndrome: individuals are born with normal intelligence which starts to decline linearly within the first year. This phenomenon can be observed with phenylalanine in patients with phenylketonuria, therefore it is compatible with metabolic intoxication. The toxic compound could be hydrogen sulfide. The amount of the compound is probably increased in Down syndrome by increasing active cystathionine beta synthase. This heuristic hypothesis requires further investigation. © 2001 Harcourt Publishers Ltd
THE HYPOTHESIS Although newborns with Down syndrome may, with the exception of the profound hypotonia, appear reasonably normal behaviorally, developmental retardation generally becomes obvious during the first few months of life. The attainment of developmental landmarks generally becomes increasingly delayed as time goes on. Thus the average delay may be approximately two months for the very early landmarks (e.g. rolling over, transferring objects); this gradually lengthens, reaching one to two years for functions that normally appear at about two years of age. Table 1 shows the results obtained by Share and Veale (1). Many studies of development during the first decade of life indicate that even if Down syndrome children are raised at home, there is a progressive, virtually linear decline in intelligence quotient which starts within the first year (Table 2) (2). A similar age-related decrease in intellectual quotient has been described in untreated patients with phenylketonuria (3). The increased amount of phenylalanine in the
Received 27 November 2000 Accepted 5 February 2001 Correspondence to: Professor Pierre Kamoun, Laboratoire de Biochimie médicale B – UMR-CNRS 8602, Hôpital Necker – Enfants Malades, 75743 Paris Cedex 15, France. Phone: +33 1 44 49 51 31; Fax: +33 1 44 49 51 30; E-mail: [email protected]
brain is directly responsible for the mental retardation observed in these patients. Indeed if the phenylalanine intake in the diet is decreased immediately after birth, the brain develops normally (4). By analogy the mental retardation in Down syndrome patients may also be of metabolic origin. The metabolism of sulfur aminoacids is probably the source of the toxic compound. The cystathionine beta synthase enzyme or CBS (EC 4.2.1.22) is encoded by a gene found on chromosome 21 (21 q 23). Enzymatic activity of CBS increases by approximately 150% in the fibroblasts of Down syndrome patients compared to normal individuals (5). The main function of CBS is to catalyze the first step of the transsulfurating pathway. This involves the hydrolysis of cystathionine by cystathionase or CST (EC 4.4.1.1). The in vivo increase in CBS activity induces a decrease in the CBS substrate (homocysteine) in the plasma of Down syndrome patients (6). CBS also has another enzymatic activity, the production of H2S from cysteine (7). Two other enzymes can also produce H2S: CST and mercaptopyruvate sulfur transferase (MPST: EC 2.8.1.2) (7). Mercaptopyruvate, the substrate of MPST, is obtained by transaminating cysteine. Studies on rats or man (8,9) showed that after H2S poisoning the excretion of thiosulfate in urine is significantly increased. Thiosulfate is formed by the condensation of H2S and sulfite (SO32–) which is produced by the thiol catabolism of cysteine (10). In adult humans thiosulfate production is estimated to be 31 µmol/day (11). In rats concentrations of H2S in 389
390
Kamoun
Table 1 Median time in months of appearance of developmental landmarks in children with Down syndrome as compared with a normal population [data from Share and Veale (1)] Developmental landmarks
Normal children
Smiles Hold head erect Rolls over Transfer objects in hand Sits unsupported Feeds self in part Pulls to stand Says dada/mama Cruises at rail Stands alone Walks alone Obeys simple commands Drinks from cup alone 2–3 word combinations Draws / imitates circle Feed self fully 3 word sentences
1.9 2.9 4.7 6.8 7.8 8.9 9.8 9.8 11.8 13.9 15.0 17.7 20.9 21.9 23.8 23.8 28.0
Table 2 Intelligence quotient of children with Down syndrome as a function of age [Data from Morgan (2)] Age (years) <1 1–3 3–5 5–7 7–9 9–11 > 11
Intelligence quotient: mean (range) 73 (35–107) 59 (15–80) 46 (15–66) 41 (25–69) 39 (9–60) 34 (17–44) 28 (10–56)
the tissues have been determined after exposure to large amounts of gaseous H2S, or after intraperitoneal administration of an equal amount of NaHS. The normal concentration of H2S in the rat brainstem is 1.23 ± 0.06 µg/g tissue (n = 10): the lethal concentration is only 5.00 ± 0.89 µg/g of brainstem tissue. The 50% lethal dose of NaHS is 16 mg/kg even though this dose only doubles the normal H2S concentration in the brain (12). The lethal concentration is very close to the normal concentration, which explains its high toxicity. This toxicity in the central nervous system may be due, at least in part, to the action of H2S and HS– on cytochrome aa3 (12,14,15,16). Indeed, H2S is a more potent inhibitor of this cytochrome than cyanide (17). However, there may be other explanations for H2S toxicity such as the formation of persulfides. Sulfhydryl modification leading to altered enzymatic function has been demonstrated for over a dozen enzymes after persulfide generation (18). Similarly, sulfhydryl modification of receptor proteins by mercaptans which act as sulfide donors has been demonstrated (19). H2S has also been shown to strongly inhibit human carbonic anhydrase (20). Carbonic anhydrase resides mainly in glial cells, specifically in oligodendrocytes, and in hippocampal neurons (21). It has also been demonstrated Medical Hypotheses (2001) 57(3), 389–392
Down syndrome patients 4.1 4.8 5.4 9.8 10.8 15.8 16.8 11.8 17.9 22.9 23.8 23.8 28.0 35.7 48.2 33.0 48.2
that monoamine oxidase is readily inactivated by sulfhydryl reagents, and high doses of NaHS are known to inhibit monoamine oxidase activity in a dose-dependent manner (22). The half-life for the recovery of monoamine oxidase isolated from rat brain after irreversible inhibition is up to 30 days (23). Chronic exposure to low concentrations (20 and 50 ppm) of hydrogen sulfide causes alterations in the central nervous system. To determine the effect of exposure during perinatal development pregnant rats were exposed to H2S 7 hours per day from Day 5 postcoitus, until Day 21 postnatal. H2S treatment produced severe alterations in the architecture and growth characteristics of the Purkinje cell dendritic fields (24). Levels of serotonin and norepinephrine were determined in the rat cerebellum and frontal cortex during perinatal development. Concentrations of both amines were altered compared to the controls; serotonin levels were significantly increased at days 14 and 21 postnatal in both brain regions. Norepinephrine levels were significantly increased at days 7, 14 and 21 postnatal in the cerebellum, and at day 21 in the frontal cortex (25,26). It is well established that monoamines influence most aspects of neural development, including neural cell division, migration, morphogenesis and synapse formation. Serotonin is known to inhibit neurite outgrowth in the brains of developing rats probably via type a receptors (24). H2S exposure may also alter monoamine levels in other brain regions such as the hippocampus (27). Excessive increases in serotonin release in the hippocampus may cause learning deficits, by interacting with type II glucocorticoid receptors in the hippocampus (28). This may explain the memory loss and the impaired cognitive and perceptual functions reported following H2S intoxication (29). It is noteworthy that CBS is continuously and strongly expressed in the central nervous system of © 2001 Harcourt Publishers Ltd
Mental retardation in Down syndrome
391
Table 3 Corrected and uncorrected cerebellar volume for subjects with Down syndrome and matched controls [From E. H. Aylward (31)] Down syndrome n = 30 3
Cerebellar volume (cm ) Cerebellar volume (Intracranial volume) Cerebellar volume (Brain volume)
92.6 ± 15.1 0.74 ± 0.11 0.87 ± 0.15
human embryos from the earliest stage studied (22 days post conception) (30). CBS gene expression was weak in the deep cerebellar nuclei of 25-week-old fetuses, and the strongest labeling was observed in the cerebellar cortex. It was recently discovered that Down syndrome patients have significantly smaller cerebellar volumes than matched controls, even after adjusting for total brain volume or total intracranial volume (Table 3) (31). The specificity of the chronic toxic effect of H2S on the cerebellum (24) is consistent with this observation. The hyperproduction of H2S in Down syndrome patients could be related either to a direct effect of CBS on L-cysteine, or to an indirect effect of CBS hyperactivity by increasing cysteine production via an accelerated transsulfuration pathway. Thus the cysteine produced could be transaminated, and the mercaptopyruvate produced could become the substrate of MPST accompanying H2S production. Some studies indicate that endogenous H2S has a physiological function: acting as a smooth muscle relaxant in synergy with nitric oxide, or as an endogenous neuromodulator by inducing hippocampal long-term potentiation by enhancing NMDA receptor activity (32,33). Hyperproduction of H2S in Down syndrome could thus induce dysfunction in muscles (hypotonia) and brain (mental retardation). We have recently made important progress in this field by showing that thiosulfate urinary excretion is significantly increased (P < 0.01) in Down syndrome patients. Further studies are in progress to determine the concentration of H2S in the blood of these patients and to search for clinical signs of chronic H2S poisoning in Down syndrome patients.
ACKNOWLEDGMENTS This work was supported by the following: Fondation Jerome Lejeune, Association Française pour la recherche sur la Trisomie 21, Laboratoires Baxter.
REFERENCES 1. Share J-B., Veale A. M. Developmental Landmarks for Children with Down’s syndrome. Duneden: University of Otago Press, 1974. 2. Morgan S. B. Development and distribution of intellectual and adaptative skills in Down syndrome children: implications for early intervention. Ment Retard 1979; 17: 247–249.
© 2001 Harcourt Publishers Ltd
Controls n = 30 127.2 ± 10.8 0.88 ± 0.09 1.01 ± 0.10
P < 0.001 < 0.002 < 0.002
3. Scriver C. R., Rosenberg L. E. Amino Acid Metabolism and Its Disorders. Philadelphia: Saunders, 1973; 39. 4. Dobson J. C., Kushida E., Williamson M., Friedman G. Intellectual performance of 36 phenylketonuria patients and their non-affected siblings. Pediatrics 1978; 58: 53–58. 5. Chadefaux B., Rethore M. O., Raoul O., Ceballos I., Gilgenkrantz S., Allard D. Cystathionine beta synthase: gene dosage effect in trisomy 21. Biochem Biophys Res Commun 1985; 128: 40–44. 6. Chadefaux B., Ceballos I., Hamet M., Coude M., Poissonier M., Kamoun P., Allard D. Is absence of atheroma in Down syndrome due to decreased homocystéine levels? Lancet 1988; 2: 741. 7. Stipanuk M. H., Beck P. W. Characterization of the enzymic capacity for cysteine desulphydration in liver and kidney of the rat. Biochem J 1982; 206: 267–277. 8. Curtis C. G., Bartholmew T. C., Rose F. A., Dodgson K. S. Detoxication of sodium 35 S-sulphide in the rat. Biochem Pharmacol 1972; 21: 2313–2321. 9. Snyder J. W., Safir E. F., Summerville G. P., Middleberg R. A. Occupational fatality and persistent neurological sequelae after mass exposure to hydrogen sulfide. Am J Emerg Med 1995; 13: 199–203. 10. Ubuka T., Yuasa S., Ishimoto Y., Shimomura M. Desulfuration of L-cysteine through transamination and transsulfuration in rat liver. Physiol Chem Physics 1977; 9: 241–246. 11. Sorbo B., Ohman S. Determination of thiosulphate in urine. Scand J Clin Lab Invest 1978; 38: 521–527. 12. Warenycia M. W., Goodwin L. R., Benishin C. G., Reiffenstein R. J., Francom D. M., Taylor J. D., Dicken F. P. Acute hydrogen sulfide poisoning. Biochem Pharmacol 1989; 38: 973–981. 13. Nagata T., Kage S., Kimura K., Kudo K., Noda M. Sulfide concentrations in post-mortem mammalian tissues. J Forens Sci 1990; 35: 706–712. 14. Roth S. H., Skarajny B., Bennington R., Brookes J. Neurotoxicity of hydrogen sulfide may result from inhibition of respiratory enzymes. Proc West Pharmacol Soc 1997; 40: 41–43. 15. Reiffenstein R. J., Hulbert W. C., Roth S. H. Toxicology of hydrogen sulfide. Ann Rev Pharmacol Toxicol 1992; 109–134. 16. Nicholson R. A., Roth S. H., Zhang J., Zheng A., Brookes J., Skrajny B., Bennington R. Inhibition of respiratory and bioenergetic mechanisms by hydrogen sulfide in mammalian brain. J Toxicol Environ Health Part A 1998; 54: 491–507. 17. Nichols P. The effect of sulfide on cytochrome aa3 isoteric and allosteric shifts of the reduced 1 peak. Biochim Biophys Acta 1975; 396: 24–35. 18. Valentine W. N., Toohey J. I., Paglia D. E., Nakatani M., Brockway R. A. Modification of erythrocytes enzyme activities by persulfides and methanethiol: possible regulatory role. Proc Natl Acad Sci USA 1987; 84: 1394–1398. 19. Brandt R., Kawamoto R. M., Caswell A. H. Effects of mercaptans upon dihydropyridine binding sites on transverse tubules isolated from triad of rabbit striated muscle. Biochem Biophys Res Commun 1985; 127: 205–212. 20. Mangani S., Haakansson K. Crystallographic studies of the binding of protonated and unprotonated inhibitors to carbonic
Medical Hypotheses (2001) 57(3), 389–392
392
21.
22.
23.
24.
25.
26.
Kamoun
anhydrase using hydrogen sulphide and nitrate anions. Eur J Biochem 1992; 210: 867–871. Pasternack M., Voipio J., Kaila K. Intracellular carbonic anhydrase activity and its role in GABA-induced acidosis in isolated rat hippocampal pyramidal neurones. Acta Physiol Scand 1993; 148: 229–231. Warenycia M. W., Smith K. A., Blashko C. S., Kombian S. B., Reiffenstein R. S. Monoamine inhibition as a sequel of hydrogen sulfide intoxication: increases in brain catecholamine and 5-hydroxytryptamine. Arch Toxicol 1989; 63: 131–136. Arnett C. D., Fowler J. S., MacGregor R. R., Schlyer D. J., Wolf A. P., Langstrom B., Halldin C. Turnover of brain monoamine oxidase in vivo by positron emission tomography using L [11C] deprenyl. J Neurochem 1987; 49: 522–527. Hannah R. S., Roth S. H. Chronic exposure to low concentration of hydrogen sulfide produces abnormal growth in developing cerebellar Purkinje cells. Neurosci Letters 1991; 122: 225–228. Skrajny B., Hannah R. S., Roth S. N. Low concentrations of hydrogen sulfide alter monoamine levels in the developing rat central nervous system. Can J Physiol Pharmacol 1992; 70: 1515–1518. Roth S. H., Skrajny B., Reiffenstein R. J. Alteration of the morphology and neurochemistry of the developing mammalian nervous system by hydrogen sulfide. Clin Experim Pharmacol Physiol 1995; 22: 379–380.
Medical Hypotheses (2001) 57(3), 389–392
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