Gas-liquid chromatographic determination of galactitol in amniotic fluid for possible use in prenatal diagnosis of galactosaemia

Allen, John T.; Holton, John; Gillett, M G

doi:10.1016/0009-8981(81)90300-4

Cited by 14 publications

(6 citation statements)

References 8 publications

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“…Galactitol and inositol were not detectable in the second portion but 25% of the total mannitol and 5% of the total sorbitol were eluted with the second 3 ml. The recoveries of galactitol and Dzgalactitol were 80%, which is comparable to the 84% reported by Allen et al (2). Recovery of mannitol was nearly 75% and sorbitol 70%, while the recovery of inositol was close to 100%.…”

Section: Methodssupporting

confidence: 84%

“…The coeluting compound which has a retention time close to that of galactitol hexaacetate on the SIM trace of mfz 450 would not be distinguished in a simple GC analysis. This might be the explanation for the 2-fold higher normal value of 1.40~mol/Iiter for galactitol in amniotic fluid reported by Allen et al (2) compared to the value of O.70~mol/liter which has been found by stable isotope dilution . This compound has not been identified.…”

Section: Discussionmentioning

confidence: 68%

“…The procedure of Allen et al (2) was modified. To I ml of amniotic fluid, 5 nmol of'Dsgalactitol were added and proteins were precipitated by the addition of 200 ILl of 4% sulfosalicylic acid.…”

Section: Methodsmentioning

confidence: 99%

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Stable Isotope Dilution Analysis of Galactitol in Amniotic Fluid: an Accurate Approach to the Prenatal Diagnosis of Galactosemia

Jakobs¹,

Warner²,

Sweetman³

et al. 1984

Pediatr Res

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SummaryA stable isotope dilution assay for galactitol in amniotic fluid has been developed using selected ion monitoring chemical ionization gas chromatography-mass spectrometry of the hexaacetate derivative.ll,I- The amniotic fluid of a fetus with galactosemia had a concentration of 7.96 ILmol/liter. Mannitol, sorbitol, and inositol were also found to be normal constituents of amniotic fluid. This stable isotope dilution assay is a rapid accurate method for measurement of gaIactitol in amniotic fluid for prenatal diagnosis of galactosemia.Abbreviations GCMS, gas chromatography-mass spectroscopy SIM, selected ion monitoringGenetically determined disorders of galactose metabolism include classical galactosemia, galactose-I-phosphate uridylyltransferase (EC 2.7.7.12) deficiency, galactokinase (EC 2.7.1.6) deficiency, and uridine diphosphate galactose-4-epimerase (EC 5.1.3.2) deficienc y (6,7,12). Each of the enzymes is known to be present in cultured skin fibroblasts and in cultured amniotic fluid cells. The disorders of galactose metabolism have serious implications for the untreated affected child . Galactosemia may lead to death in early infancy, usually from sepsis, and this could occur even in infants detected in programs of routine neonatal screening . Further manifestations are failure to thrive, jaundice, and hepatic cirrhosis. Later, cataracts and mental retardation develop . Patients with galactokinase deficiency develop cataracts. If detection is early, postnatal dietary treatment is effective although there may be some irreversible damage, especially to the central nervous system . Prenatal diagnosis can assist in determining the need for restrict ive dietary management during gestation (11, 13). Prenatal diagnosis has been reported using enzymatic assays (5, 10).The accumulation of galactitol in body fluids of patients with disorders of galactose metabolism raises the possibility of the development of a rapid, precise chemical method of prenatal diagnosis by direct analysis of the aminiotic fluid for galactitol.Allen et al. (I) have reported the accumulation of galactitol in amniotic fluid and have published (2) a method for the prenatal diagnosis of galactosemia using GC for the determination of galactitol in amniotic fluid. There are two major disadvantages of this method. The first was the use of mannitol as an internal standard, because this compound is a normal constituent of amniotic fluid. Furthermore, the use of GC instrumentation alone has a limited resolving capacity and the detection system is relatively nonspecific, allowing the possible interference by a coeluting compound. ' We have developed a stable isotope dilution method for galactitol , utilizing an on-line GCMS system operated in the CI SIM mode . CI-SIM-GCMS circumvents the limitations of previous methodology and provides stable isotopically labeled 11,1-ZHz]galactitol as an internal standard not found in physiological fluids. MATERIALS AND METHODSNormal amniotic fluids were obtained between 16 and 18 weeks of pregnancy by amnioce...

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Section: Methodssupporting

confidence: 84%

Section: Discussionmentioning

confidence: 68%

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Stable Isotope Dilution Analysis of Galactitol in Amniotic Fluid: an Accurate Approach to the Prenatal Diagnosis of Galactosemia

Jakobs¹,

Warner²,

Sweetman³

et al. 1984

Pediatr Res

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“…In galactosemia, galactose-1-phosphate accumulates within cells and damages brain, liver, kidney and ovary. One can conclude from this compari- [2], At any rate, the findings seem to indicate that the fetus is exposed to potentially noxious compounds and is not completely protected by its mother. Unfortunately, animal experi ments can not answer the question whether damage to the galactosémie occurs in utero or after birth [14,36].…”

Section: Pathogenesis Of Galactosemiamentioning

confidence: 94%

Galactosemia: How Does Long-Term Treatment Change the Outcome?

Gitzelmann¹,

Steinmann²

1984

Enzyme

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In galactosémie subjects, treatment prevents liver and kidney failure, brain damage and cataracts, but total exclusion of galactose from the diet does not ensure the absence of all pathology. Early and well-treated children show satisfactory general health and growth, make reasonable though suboptimal intellectual progress, are prone to speech defects, and commonly experience visual perceptual difficulties and some social maladjustment. Two different metabolites are potentially toxic: galactitol is responsible for the cataracts while galactose- 1-phosphate causes the rest of the pathology. As both metabolites are present in the fetus and in postnatal life, pathological changes may develop at any time in life, even when treatment is strict. Owing to UDP-galactose 4'-epimerase, man can generate galactose from glucose from early embryonic life on. Therefore, transferase-deficient individuals can form galactose- 1-phosphate in the absence of exogenous galactose, a process for which UDP-glucose pyrophosphorylase is essential. Biosynthesis of galactose from glucose in well-treated galactosémies constitutes a mechanism of self-intoxication, not only in utero but also in adult life. The prognosis for some treated galactosémies may depend on their own ability to limit this process. Galactosémie girls, whether well-treated or not, run a considerable risk of developing ovarian dysfunction. Hypergonadotropinism has been diagnosed from 2 years of age to the third decade. Prenatal ovarian failure is not excluded but the observed facts suggest that ovarian failure is acquired after ovarian differentiation and initiation of folliculogenesis, at an individual rate and possibly through continuous self-intoxication with galactose-1-phosphate. Up to now, mild hypergonadotropinism has been documented in only 2 galactosémie males, but the male cohort of galactosémies studied for gonadal dysfunction is yet small.

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“…Allen and colleagues (1980) reported that galactitol, a reduction product of galactose, accumulated in the liver of a galactosaemic fetus, along with galactose and galactose-l-phosphate, and raised levels were detected in amniotic fluid. The observation led to a method of prenatal diagnosis for transferase deficiency, measuring galactitol in amniotic fluid supernatant using a gas chromatograph with a flame ionisation detector (Allen et al, 1981). Subsequently the method has been made more accurate and precise by the use of gas chromatography with mass spectrometric detection (unpublished observation).…”

Section: Transferase Deficiencymentioning

confidence: 98%

Prenatal diagnosis of disorders of galactose metabolism

Holton

Allen

Gillett

1989

J of Inher Metab Disea

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Of three clinically significant galactose disorders, there is only a real need and experience of prenatal diagnosis in classical galactosaemia. Prenatal diagnosis for this disorder may be carried out by galactose-1-phosphate uridyl transferase assay in cultured amniotic fluid cells or in chorionic villus biopsies and by galactitol estimation in amniotic fluid supernatant. Although the long-term outcome of patients treated on a galactose-restricted diet is recognized to be unsatisfactory, prenatal diagnosis is only rarely performed with a view to terminating the affected pregnancy.

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Gas-liquid chromatographic determination of galactitol in amniotic fluid for possible use in prenatal diagnosis of galactosaemia

Cited by 14 publications

References 8 publications

Stable Isotope Dilution Analysis of Galactitol in Amniotic Fluid: an Accurate Approach to the Prenatal Diagnosis of Galactosemia

Stable Isotope Dilution Analysis of Galactitol in Amniotic Fluid: an Accurate Approach to the Prenatal Diagnosis of Galactosemia

Galactosemia: How Does Long-Term Treatment Change the Outcome?

Prenatal diagnosis of disorders of galactose metabolism

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