Value of Amniotic Fluid Homocysteine Assay in Prenatal Diagnosis of Combined Methylmalonic Acidemia and Homocystinuria, Cobalamin C Type

Abstract Background: Combined methylmalonic acidemia and homocystinuria, cobalamin C type (cblC defect) is the most common inborn error of cobalamin metabolism. Even with rapid diagnosis and treatment, the long-term outcome remains poor. A reliable method for the prenatal diagnosis of cblC defect is needed for parental decisions regarding continuation of pregnancies of cblC defect fetuses.Results: The between-day and within-day imprecision of Hcy assay were 1.60%∼5.87% and 1.11%∼4.31%, respectively. For the 248 at-risk fetuses, there were 63 affected fetuses with cblC defect and 185 unaffected fetuses. The levels of Hcy in 63 affected fetuses were significantly higher than those in 185 unaffected fetuses, without overlap between the affected and unaffected groups. Sixteen fetuses displayed inconclusive genetic results of MMACHC variants, in which seven fetuses were determined to be affected with elevated amniotic fluid levels of Hcy, C3, C3/C2 and MMA. The remaining nine fetuses were considered unaffected based on a normal amniotic fluid metabolite profile. The diagnostic sensitivities of Hcy and other characteristic metabolites including propionylcarnitine (C3), ratio of C3 to acetylcarnitine (C2; C3/C2), methylmalonic acid (MMA), and methylcitrate acid (MCA) in amniotic fluid were 100%, 87.50%, 100%, 85.71%, and 28.57%, respectively. The respective specificities were 92.05%, 100%, 100%, 97.73%, and 99.43%. Conclusions: Hcy appears to be another sensitive characteristic metabolite biomarker for the prenatal diagnosis of cblC defect. The combination of Hcy assay with acylcarnitine and organic acid analysis is a fast, sensitive, and reliable prenatal diagnostic biochemical approach. This approach could overcome the challenge of the lack of genetic analysis for families with at-risk cblC defect fetuses.

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Value of amniotic fluid homocysteine assay in prenatal diagnosis of combined methylmalonic acidemia and homocystinuria, cobalamin C type

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-01762-z ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Ting Chen ◽

Lili Liang ◽

Huiwen Zhang ◽

Jun Ye ◽

Wenjuan Qiu ◽

...

Keyword(s):

Mass Spectrometry ◽

At Risk ◽

Prenatal Diagnosis ◽

Genetic Analysis ◽

Amniotic Fluid ◽

Organic Acid ◽

Methylmalonic Acidemia ◽

Predictive Values ◽

Organic Acid Analysis ◽

Prenatal Diagnostic

Abstract Background Combined methylmalonic acidemia and homocystinuria, cobalamin C type (cblC defect) is the most common inborn error of cobalamin metabolism, and different approaches have been applied to its prenatal diagnosis. To evaluate the reliability of biochemical method for the prenatal diagnosis of cblC defect, we conducted a retrospective study of our 10-year experience at a single center. Methods 248 pregnancies whose probands were diagnosed as cblC defect were referred to our center for prenatal diagnosis from January 2010 to December 2019. Prenatal data of Hcy levels determined by enzymatic cycling assay, acylcarnitine analysis using liquid chromatography tandem mass spectrometry, organic acid analysis using gas chromatography mass spectrometry, and genetic analysis by direct sequencing of 248 at-risk fetuses were retrospectively reviewed. Results For 2.0 and 16.0 μmol/L levels of Hcy AF samples, the relative errors were − 2.5% and 2.8%, respectively. The respective measurement uncertainties were 13.07% and 14.20%. For the 248 at-risk fetuses, 63 fetuses were affected and 185 fetuses were unaffected. Hcy level of 13.20 (6.62–43.30) μmol/L in 63 affected fetuses was significantly higher than that in 185 unaffected fetuses of 2.70 (0.00–5.80) μmol/L, and there was no overlap between the affected and unaffected groups. The diagnostic sensitivity and specificity of Hcy were 100% and 92.05%, respectively. The positive and negative predictive values of the combination of Hcy, propionylcarnitine (C3), ratio of C3 to acetylcarnitine (C2; C3/C2), methylmalonic acid (MMA), and methylcitric acid (MCA) were both 100%. Sixteen fetuses displayed inconclusive genetic results of MMACHC variants, in which seven fetuses were determined to be affected with elevated levels of Hcy, C3, C3/C2 and MMA, and their levels were 18.50 (6.70–43.30) μmol/L, 8.53(5.02–11.91) μmol/L, 0.77 (0.52–0.97), 8.96 (6.55–40.32) mmol/mol Cr, respectively. The remaining nine fetuses were considered unaffected based on a normal amniotic fluid metabolite profile. Conclusions Hcy appears to be another characteristic biomarker for the prenatal diagnosis of cblC defect. The combination of Hcy assay with acylcarnitine and organic acid analysis is a fast, sensitive, and reliable prenatal diagnostic biochemical approach. This approach could overcome the challenge of the lack of genetic analysis for families with at-risk cblC defect fetuses.

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Prenatal diagnosis of clubfoot in low-risk population: associated anomalies and long-term outcome

Prenatal Diagnosis ◽

10.1002/pd.1984 ◽

2008 ◽

Vol 28 (4) ◽

pp. 343-346 ◽

Cited By ~ 23

Author(s):

M. J. Canto ◽

S. Cano ◽

J. Palau ◽

F. Ojeda

Keyword(s):

Prenatal Diagnosis ◽

Low Risk ◽

Associated Anomalies ◽

Term Outcome ◽

Risk Population ◽

Long Term Outcome

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Prenatal Diagnosis of Methylmalonic Aciduria

PEDIATRICS ◽

10.1542/peds.54.4.511 ◽

1974 ◽

Vol 54 (4) ◽

pp. 511-513

Author(s):

D. Gompertz ◽

Patricia A. Goodey ◽

J. M. Saudubray ◽

Christiane Charpentier ◽

Agnes Chignolle ◽

...

Keyword(s):

At Risk ◽

Prenatal Diagnosis ◽

Amniotic Fluid ◽

Methylmalonic Acid ◽

Methylmalonic Aciduria ◽

Postnatal Period ◽

Small Molecular Weight ◽

Inborn Errors ◽

Abnormal Accumulation ◽

Amniotic Cell

The abnormal accumulation of small molecular weight metabolites in amniotic fluid in inborn errors of metabolism is unusual and prenatal diagnosis usually requires amniotic cell culture and specific enzyme assay. However, Morrow et al.1 reported raised concentrations of methylmalonic acid in the amniotic fluid of a pregnancy at risk from methylmalonic aciduria and confirmed the diagnosis in the postnatal period. More recently Mahoney et al.2 have reported an abnormal methylmalonic acid concentration in the amniotic fluid of one of two pregnancies at risk. They confirmed that the fetus in this case was affected by showing an impaired oxidation of methylmalonic acid in cultured amniotic cells.

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Long-term outcome after DNA-based prophylactic neck surgery in children at risk of hereditary medullary thyroid cancer

Best Practice & Research Clinical Endocrinology & Metabolism ◽

10.1016/j.beem.2019.04.008 ◽

2019 ◽

Vol 33 (4) ◽

pp. 101274 ◽

Cited By ~ 2

Author(s):

Andreas Machens ◽

Henning Dralle

Keyword(s):

At Risk ◽

Thyroid Cancer ◽

Medullary Thyroid Cancer ◽

Neck Surgery ◽

Children At Risk ◽

Term Outcome ◽

Long Term Outcome ◽

Medullary Thyroid ◽

Hereditary Medullary Thyroid Cancer

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Prenatal diagnosis of trisomy 20 by chorionic villus sampling (CVS): a case report with long-term outcome

Prenatal Diagnosis ◽

10.1002/pd.169 ◽

2001 ◽

Vol 21 (13) ◽

pp. 1111-1113 ◽

Cited By ~ 19

Author(s):

Nancy Steinberg Warren ◽

Shirley Soukup ◽

Jennifer L. King ◽

Peter St. J. Dignan

Keyword(s):

Case Report ◽

Prenatal Diagnosis ◽

Chorionic Villus ◽

Chorionic Villus Sampling ◽

Term Outcome ◽

Long Term Outcome

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The long-term outcome of subthreshold depression in later life

Psychological Medicine ◽

10.1017/s0033291716001549 ◽

2016 ◽

Vol 46 (13) ◽

pp. 2855-2865 ◽

Cited By ~ 13

Author(s):

H. W. Jeuring ◽

M. Huisman ◽

H. C. Comijs ◽

M. L. Stek ◽

A. T. F. Beekman

Keyword(s):

At Risk ◽

High Body Mass Index ◽

Later Life ◽

Subthreshold Depression ◽

Term Outcome ◽

Long Term Outcome ◽

Screening Design ◽

Longitudinal Aging Study Amsterdam ◽

Aging Study

BackgroundSubthreshold depression (SUBD) in later life is common and important as prodromal state and prominent risk factor in the development of major depressive disorder (MDD). Indicated prevention can reduce the incidence of MDD among people with SUBD substantially, but needs to be targeted to those that are truly at risk of developing MDD.MethodN = 341 eligible participants with SUBD were included from the first (1992/1993), second (1995/1996) and third (1998/1999) cycle from the Longitudinal Aging Study Amsterdam (LASA) by using a two-stage screening design. LASA is an ongoing prospective cohort study in The Netherlands among the older population (55–85 years). At baseline (1992/1993) N = 3107 participants were interviewed and follow-up cycles were conducted every 3 years until 2008/2009, resulting in maximal 17 years of observational period. The proportion of people that developed MDD, remained SUBD, or recovered from SUBD was measured and Cox proportional regression analyses were performed to investigate 29 putative predictors of MDD and recovery from SUBD.ResultsN = 153 (44.9%) recovered from SUBD, N = 138 (40.5%) remained chronically SUBD, and N = 50 (14.7%) developed MDD (incidence rate 15.1/1000 person-years). Women, high neuroticism, more chronic diseases, high body mass index, smoking and less social support predicted conversion to MDD. Men, low neuroticism and absence of pain predicted recovery from SUBD.ConclusionsAlthough older people with SUBD are clearly at risk of developing MDD, the majority did not, even after a long and thorough follow-up. Given the risk factors that were uncovered, targeting and prevention of MDD in those at very high risk is feasible.

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