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Metabolic Aspects University of Nebraska - Lincoln DigitalCommons@University of Nebraska - Lincoln Public Health Resources Public Health Resources 1997 CYSTATHIONINE β-SYNTHASE DEFICIENCY: METABOLIC ASPECTS S. Harvey Mudd National Institute of Mental Health, Bethesda, MD, Follow this and additional works at: https://digitalcommons.unl.edu/publichealthresources Part of the Public Health Commons Mudd, S. Harvey, "CYSTATHIONINE β-SYNTHASE DEFICIENCY: METABOLIC ASPECTS" (1997). Public Health Resources. 206. https://digitalcommons.unl.edu/publichealthresources/206 This Article is brought to you for free and open access by the Public Health Resources at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in Public Health Resources by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. Published in: HOMOCYSTEINE METABOLISM: FROM BASIC SCIENCE TO CLINICAL MEDICINE Editors Ian Graham, MD THE ADELAIDE HOSPITAL TRINITY COLLEGE DUBLIN IRELAND Helga Refsum, MD UNIVERSITY OF BERGEN DEPARTMENT OF CLINICAL BIOLOGY BERGEN NORWAY Irwin H. Rosenberg, MD JEAN MAYER USDA HUMAN NUTRITION RESEARCH CENTER ON AGING AT TUFTS UNIVERSITY BOSTON, MA USA Per Magne Ueland, MD UNIVERSITY OF BERGEN DEPARTMENT OF CLINICAL BIOLOGY BERGEN NORWAY Scientific Editor: Jill M. Shuman, MS, RD, ELS TUFTS UNIVERSITY SCHOOL OF NUTRITION SCIENCE AND POLICY MEDFORD,MA USA Kluwer Academic Publishers BOSTON DORDRECHT LONDON 1997 S. Harvey Mudd National Institute of Mental Health Bethesda, MD, USA 11. CYSTATHIONINE P-SYNTHASE DEFICIENCY: METABOLIC ASPECTS s. Harvey Mudd Introduction nonresponders was 56; for responders, 78. Among untreated patients, optic lens dislocation had oc­ Cystathionine ~-synthase (CBS) deficiency was first curred in 50% of nonresponders by age six years, a demonstrated in 1964 in an eight-year-old mentally clinically apparent thromboembolic event had oc­ retarded girl with bilaterally dislocated optic lenses curred in 25% of patients by age 15 years, and spinal who excreted abnormally elevated amounts of homo­ osteoporosis was detected in 50% by age 12. By con­ cystine in her urine {l]. Patients with similar meta­ trast, the corresponding ages for untreated B - bolic abnormalities and clinical findings had first 6 responders were 10,20, and 20 years. been discovered 2 years earlier by Carson and her colleagues during a survey of mentally backward children in Northern Ireland [2}. CBS deficiency Metabolic Aspects has proven to be the most frequently encountered of The primary abnormality in CBS-deficient patients is the human genetic diseases causing homoeystinuria a failure to covert homocysteine to cystathionine, a and severe hyperhomocyst(e)inemia. Worldwide, it is process that normally must occur chiefly in the liver. detected with a frequency of about 1: 344,000 by Mansoor and colleagues [5} have shown that in nor­ screening programs of the newborn, but this is un­ mal plasma, only 2% of the homocysteine-derived doubtedly an underestimate because some indi­ moieties exist as homocysteine itself; 16% occur as viduals are being missed [3]. This chapter will briefly free disulfides (homocystine, homocysteine-cysteine focus on the major clinical manifestations and meta­ mixed disulfide, other mixed disulfides); and 82% are bolic aspects of CBS deficiency. bound to protein as mixed disulfides of homocysteine and protein cysteine [5}. Comparable measurements Major Clinical Features by modern methods have not been reported for in­ Clinically, the most prominent features of CBS defi­ tracellular homocysteine-derived moieties in CBS­ ciency are mental retardation, dislocation of the optic deficient patients. Clearly there is some export of lenses, a tendency toward early thromboembolic the abnormally accumulated homocysteine so that the events, and osteoporosis and other bony abnormali­ total plasma homocyst(e)ine (tHcy) rises dramatically. ties. An international survey published in 1985 [4} The greatest relative rise occurs in homocysteine, with presented data on 629 CBS-deficient patients. Among lesser rises in free disulfides and the protein-bound those so classified, some 44% were judged to be B6- mixed disulfide (up to 400-fold, 90-fold, and 20-fold responsive; that is, when given high doses of pyridox­ above normal, respectively) [6}. Plasma methionine ine they underwent prompt and marked decreases in also rises in most CBS-deficient patients, presumably plasma homocyst(e)ine and methionine concentra­ due to enhanced methylation of abnormally elevated tions. An equal proportion were judged nonrespon­ homocysteine. The source(s) of the methyl group for sive, with little or no decreases in the abnormally such methylation is (are) uncertain. The availability elevated concentrations of these amino acids follow­ of betaine must be limiting under normal dietary ing pyridoxine administration. Although this crude conditions because administration of betaine usually classification is undoubtedly an oversimplification, results in further decreases in tHey. N 5 -Methyltetra­ the results clearly showed that in the absence of spe­ hydrofolate would be expected to provide an cific treatment, as a group the B6-nonresponsive pa­ alternative supply of methyls (see below). tients were more severely affected clinically than were Additional compounds that would be expected to the B6-responsive patients. The median IQ for accumulate abnormally in cells of CBS-deficient pa- 78 I. BIOCHEMISTRY AND GENETIC STUDIES tients include S-adenosylhomocysteine (AdoHcy) (if The metabolic consequences of CBS deficiency adenosine is available) and S-adenosylmethionine might be expected to include abnormally low rates of (AdoMet). The former is expected to accumulate be­ synthesis of compounds distal to the enzyme block, cause the equilibrium of AdoHcy hydrolase favors including cystathionine and cysteine. Because a rela­ AdoHcy formation, and the latter because of the el­ tively small residual activity of CBS may support a evated methionine concentration in the presence of substantial flux of homocysteine into cystathionine intact methionine adenosyltransferase that (in the (see below), the extent of the abnormalities in liver) is normally operating far below saturation with cystathionine and cysteine in a given patient will respect to that substrate. Neither of these compounds probably depend upon how much residual CBS activ­ has been measured in liver or other tissue of CBS­ ity is present. Cystathionine is present in normal deficient patients by use of methods that are now human brain at high concentrations (12), but was known to be necessary to avoid rapid changes after present at most only in trace amounts in brains tissue is removed from the body. Indirect evidence obtained at postmortem examination of three homo­ for an abnormal elevation of AdoHcy is provided cystinuric individuals {l3,14). In the absence of data by the fact that Perry and coworkers {7,8) found on the B6-responsiveness of these patients, it is uncer­ unusual amounts of this compound and of 5-amino-4- tain whether or not they had any residual CBS activ­ imidazolecarboxamide-5'-S-homocysteinylriboside, a ity. Reliable assays of tissue cysteine concentrations compound structurally (and presumably metaboli­ have not been reported, but Mansoor et al. (6) found cally) closely related to AdoHcy, in the urines of their that in seven patients with homocystinuria and CBS-deficient patients. hypermethioninemia consistent with CBS deficiency The intracellular AdoMet/AdoHcy ratio, often (but not specified with respect to B6-responsiveness), termed the "methylation index," will determine plasma concentrations of total cyst(e)ine ranged from the relative activities of most AdoMet-dependent 52 to 167~, below the mean normal value of ap­ methyltransferases (9). It can be inferred that this proximately 250~ (6). ratio may be relatively undisturbed in CBS-deficient patients by the fact that they seem not to suffer from the neurologic abnormalities associated with The Mechanism of B6-responsiveness defective myelination that are common in patients As discussed above, a major determinant of the clini­ with methylenetetrahydrofolate reductase (MTHFR) cal prognosis for CBS-deficient patients is whether or deficiency {lO) who, because of their low, or low not they are B6-responsive. In considering possible normal, methionine and elevated tHcy concentra­ mechanisms of response it is important to realize that tions, may be expected have low AdoMet/AdoHcy although B6 administration may bring about marked ratios. Jencks and Matthews stated that the physi­ drops in plasma tHcy and methionine in responsive ologic activity of MTHFR "must ... be determined patients together with rises in abnormally low plasma by competition between AdoMet and AdoHcy for cyst(e)ine concentrations, these patients are not re­ a common ligand-binding site and would therefore stored to biochemical normalcy. They usually con­ be expected to be very sensitive to the AdoMet/ tinue to have some elevation of homocystine in AdoHcy ratio" (11). The inferred normality of this plasma and urine, and respond abnormally to a me­ ratio in CBS-deficient patients would mean that there thionine load as judged by the extent and/or duration is no interference with the biosynthetic pathway to of elevations of plasma methionine and of plasma and N l -methyltetrahydrofolate, and that there should be urinary homocystine (15,16). sufficient amounts of this compound to support me­ In principle, the B6-induced response could be due thylation
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