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Case report: birth of healthy twins after preimplantation genetic diagnosis of propionic acidemia.

ABSTRACT: PURPOSE: Development of an ad hoc protocol for the preimplantion genetic diagnosis of propionic acidemia in a couple carrying the mutations c.737G>T (G246V) and c.1218del14ins12 (ins/del) in the PCCB gene. Propionic acidemia is an autosomal recessive metabolic disorder where the body is unable to process certain parts of proteins and lipids. Symptoms manifest few days after birth and sometimes progress to more serious medical problems, including heart abnormalities, coma and death. METHODS: Four short tandem repeat markers closely linked to the PCCB gene were tested, in order to support the direct mutation detection diagnosis. Multiplex fluorescent heminested polymerase chain reaction followed by fragment analysis and minisequencing was used. RESULTS: Fourteen single blastomeres from nine embryos were tested and two carrier embryos were transferred, resulting in the birth of two healthy boys. CONCLUSIONS: Preimplantation genetic diagnosis represents a valid reproductive option for couples affected of propionic acidemia, in order to avoid transmission to offspring.

SUBMITTER: Alberola TM

PROVIDER: S-EPMC3082661 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Case report: birth of healthy twins after preimplantation genetic diagnosis of propionic acidemia.

Alberola Trinitat M TM Bautista-Llácer Rosa R Vendrell Xavier X García-Mengual Elena E Pardo Merche M Vila Maria M Calatayud Carmen C

Journal of assisted reproduction and genetics 20101203 3

<h4>Purpose</h4>Development of an ad hoc protocol for the preimplantion genetic diagnosis of propionic acidemia in a couple carrying the mutations c.737G>T (G246V) and c.1218del14ins12 (ins/del) in the PCCB gene. Propionic acidemia is an autosomal recessive metabolic disorder where the body is unable to process certain parts of proteins and lipids. Symptoms manifest few days after birth and sometimes progress to more serious medical problems, including heart abnormalities, coma and death.<h4>Met ...[more]

PMID: 21125326

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Project description:BACKGROUND:Propionic acidemia (PA) is a serious metabolic disorder, and different approaches have been applied to its prenatal diagnosis. To evaluate the reliability and validity of a biochemical strategy in the prenatal diagnosis of PA, we conducted a retrospective study of our 11-year experiences at a single center. METHODS:We accumulated data from 78 pregnancies from 58 families referred to our center and provided prenatal diagnosis by directed genetic analysis and/or metabolite measurement using tandem mass spectrometry (MS/MS) and gas chromatography/mass spectrometry (GC/MS) of amniotic fluid (AF) samples. RESULTS:Sixty-five unaffected fetuses (83.33%) and 13 affected fetuses (16.67%) were confirmed in our study. The characteristic metabolites including propionylcarnitine (C3) level, C3/acetylcarnitine (C2) ratio and 2-methylcitric acid (2MCA) level in unaffected and affected groups showed significant differences (P <?0.0001), while the level of 3-hydroxypropionic acid (3HPA) showed no significant difference between the two groups (P >?0.05).Of the 78 pregnancies, 24 fetuses were found to have either one causative pathogenic variant or were without genetic information in the proband. Three of these fetuses had elevated AF levels of C3, C3/C2 ratio, and 2MCA and, thus, were determined to be affected, while the remaining fetuses were determined to be unaffected based on a normal AF metabolite profile. Our genetic and biochemical results were highly consistent with postnatal follow-up results on all unaffected fetuses. CONCLUSIONS:We conclude that a biochemical approach can serve as a fast and convenient prenatal diagnostic method for pregnancies at an increased risk for PA, which could be used in conjunction with genetic testing for precise prenatal diagnosis of this disorder. In our analysis, the characteristic metabolites C3 level, C3/C2 ratio, and 2MCA level in AF supernatant were dependable biochemical markers for diagnosis, of which the C3/C2 ratio appears to be the most reliable biochemical marker for the prenatal diagnosis of PA.

Project description:Propionic acidemia is a rare metabolic disorder caused by a deficiency of propionyl- CoA carboxylase, the enzyme converting propionyl-CoA to methylmalonyl-CoA that subsequently enters the citric acid cycle as succinyl-CoA. Patients with propionic acidemia cannot metabolize propionic acid, which combines with oxaloacetate to form methylcitric acid. This, with the defective supply of succinyl-CoA, may lead to a deficiency in citric acid cycle intermediates.The objective of this study was to determine whether supplements with glutamine (400mg/kg per day), citrate (7.5mEq/kg per day), or ornithine ?-ketoglutarate (400mg/kg per day) (anaplerotic agents that could fill up the citric acid cycle) would affect plasma levels of glutamine and ammonia, the urinary excretion of Krebs cycle intermediates, and the clinical outcome in 3 patients with propionic acidemia.Each supplement was administered daily for four weeks with a two week washout period between supplements. The supplement that produced the most favorable changes was supplemented for 30 weeks following the initial study period and then for a 2 year extension.The urinary excretion of the Krebs cycle intermediates, ?-ketoglutarate, succinate, and fumarate increased significantly compared to baseline during citrate supplementation, but not with the other two supplements. For this reason, citrate supplements were continued in the second part of the study. The urinary excretion of methylcitric acid and 3-hydroxypropionic acid did not change with any intervention. No significant changes in ammonia or glutamine levels were observed with any supplement. However, supplementation with any anaplerotic agents normalized the physiological buffering of ammonia by glutamate, with plasma glutamate and alanine levels significantly increasing, rather than decreasing with increasing ammonia levels. No significant side effects were observed with any therapy and safety labs (blood counts, chemistry and thyroid profile) remained unchanged. Motor and cognitive development was severely delayed before the trial and did not change significantly with therapy. Hospitalizations per year did not change during the trial period, but decreased significantly (p<0.05) in the 2years following the study (when citrate was continued) compared to the 2years before and during the study.These results indicate that citrate entered the Krebs cycle providing successful anaplerotic therapy by increasing levels of the downstream intermediates of the Krebs cycle: ?-ketoglutarate, succinate and fumarate. Citrate supplements were safe and might have contributed to reduce hospitalizations in patients with propionic acidemia.

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Case report: birth of healthy twins after preimplantation genetic diagnosis of propionic acidemia.

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Case report: birth of healthy twins after preimplantation genetic diagnosis of propionic acidemia.

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