Successful pregnancy and delivery in a woman with propionic acidemia from the Amish community.
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ABSTRACT:
SUBMITTER: Scott Schwoerer J
PROVIDER: S-EPMC5471548 | biostudies-literature | 2016 Sep
REPOSITORIES: biostudies-literature
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Successful pregnancy and delivery in a woman with propionic acidemia from the Amish community.
Scott Schwoerer Jessica J van Calcar Sandra S Rice Gregory M GM Deline James J
Molecular genetics and metabolism reports 20160602
Propionic acidemia (PA) is an inborn error of protein metabolism with a variable clinical presentation ranging from neonatal encephalopathy to seemingly asymptomatic individuals who present with cardiomyopathy or sudden death. PA is recognized in the Amish population, often with an early asymptomatic course and eventual cardiac complications. Thus, Amish women with PA may reach reproductive age without clinical sequelae, but are at increased risk for metabolic decompensation during pregnancy, de ...[more]
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Project description:Although individuals of Amish descent with propionic acidemia (PA) are generally thought to have a milder disease phenotype, we now have a better understanding of the natural history of PA in this population. Here we describe two Amish patients with emergent presentations of PA, one with metabolic decompensation and another with cardiogenic shock. PA can present with life-threatening metabolic decompensation or an adult-onset severe cardiomyopathy. We discuss critical clinical implications of this observation.
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Project description:BACKGROUND Identifying a potential single monogenetic disorder in healthy couples is costly due to the Assisted Reproduction facilities' current methodology for screening, which focuses on the detecting multiple genetic disorders at once. Here, we report the successful application of a low-cost and fast preimplantation genetic testing for monogenic/single gene defects (PGT-M) approach for detecting propionic acidemia (PA) in embryos obtained from a confirmed heterozygous propionyl-CoA carboxylase alpha subunit (PCCA) couple. CASE SUMMARY A fertile 32-years old Mexican couple with denied consanguinity sought antenatal genetic counseling. They were suspected obligate PA carriers due to a previous deceased PA male newborn with an unknown PCCA/propionyl-CoA carboxylase beta subunit (PCCB) genotype. Next-Generation Sequencing revealed a heterozygous genotype for a pathogenic PCCA variant (c.2041-1G>T, ClinVar:RCV000802701.1; dbSNP:rs1367867218) in both parents. The couple requested in vitro fertilization (IVF) and PGT-M for PA. From IVF, 12 oocytes were collected and fertilized, of which two resulted in high-quality embryos. Trophectoderm biopsies and Whole Genome Amplification by a fragmentation/amplification-based method were performed and revealed that the two embryos were euploid. End-point polymerase chain reaction and further Sanger sequencing of the exon-intron borders revealed a wild-type PCCA male embryo and a heterozygous c.2041-1G>T female embryo. Both embryos were transferred, resulting in a clinical pregnancy and the delivery of a healthy male newborn (38 wk, weight: 4080 g, length: 49 cm, APGAR 9/9). The absence of PA was confirmed by expanded newborn screening. CONCLUSION We show that using PGT-M with Whole Genome Amplification templates, coupled with IVF, can reduce the transmission of a pathogenic variant of the PCCA gene.
| S-EPMC8546821 | biostudies-literature
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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Project description:Propionic acidemia or aciduria is an intoxication-type disorder of organic metabolism. Patients deteriorate in times of increased metabolic demand and subsequent catabolism. Metabolic decompensation can manifest with lethargy, vomiting, coma and death if not appropriately treated. On January 28-30, 2011 in Washington, D.C., Children's National Medical Center hosted a group of clinicians, scientists and parental group representatives to design recommendations for acute management of individuals with propionic acidemia. Although many of the recommendations are geared toward the previously undiagnosed neonate, the recommendations for a severely metabolically decompensated individual are applicable to any known patient as well. Initial management is critical for prevention of morbidity and mortality. The following manuscript provides recommendations for initial treatment and evaluation, a discussion of issues concerning transport to a metabolic center (if patient presents to a non-metabolic center), acceleration of management and preparation for discharge.
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Project description:Purpose: Propionic acidemia (PA) is a severe metabolic disorder characterized by multiorgan pathology, including renal disease. The prevalence of chronic kidney disease (CKD) in PA patients and factors associated with CKD in PA are not known.Methods: Thirty-one subjects diagnosed with PA underwent laboratory and clinical evaluations through a dedicated natural history study at the National Institutes of Health (ClinicalTrials.gov identifier: NCT02890342).Results: Cross-sectional analysis of the creatinine-based estimated glomerular filtration rate (eGFR) in subjects with native kidneys revealed an age-dependent decline in renal function (P?<?0.002). Among adults with PA, 4/8 (50%) had eGFR <60?mL/min/1.73?m2. There was a significant discrepancy between eGFRs calculated using estimating equations based on serum creatinine compared with serum cystatin C (P?<?0.0001). The tubular injury marker, plasma lipocalin-2, and plasma uric acid were strongly associated with CKD (P?<?0.0001). The measured 24-hour creatinine excretion was below normal, even after adjusting for age, height, and sex.Conclusion: CKD is common in adults with PA and is associated with age. The poor predictive performance of standard eGFR estimating equations, likely due to reduced creatine synthesis in kidney and liver, could delay the recognition of CKD and management of ensuing complications in this population.
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Project description:Glycogen storage disease type VI is caused by biallelic variants in the PYGL gene that result in hepatic glycogen phosphorylase deficiency. The disorder is clinically characterized by hepatomegaly and recurrent ketotic hypoglycemia from infancy. Although most patients reach adulthood without major complications, no pregnancies in women with GSD VI have been reported so far. We report on a successful pregnancy in a GSD VI patient that resulted in a healthy offspring and describe the pre- and perinatal management.
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Project description:BACKGROUND:The definitive dietary management of propionic acidaemia (PA) is unknown although natural protein restriction with adequate energy provision is of key importance. AIM:To describe European dietary practices in the management of patients with PA prior to the publication of the European PA guidelines. METHODS:This was a cross-sectional survey consisting of 27 questions about the dietary practices in PA patients circulated to European IMD dietitians and health professionals in 2014. RESULTS:Information on protein restricted diets of 186 PA patients from 47 centres, representing 14 European countries was collected. Total protein intake [PA precursor-free L-amino acid supplements (PFAA) and natural protein] met WHO/FAO/UNU (2007) safe protein requirements for age in 36 centres (77%). PFAA were used to supplement natural protein intake in 81% (n = 38) of centres, providing a median of 44% (14-83%) of total protein requirement. Seventy-four per cent of patients were prescribed natural protein intakes below WHO/FAO/UNU (2007) safe levels in one or more of the following age groups: 0-6 m, 7-12 m, 1-10 y, 11-16 y and > 16 y. Sixty-three per cent (n = 117) of patients were tube fed (74% gastrostomy), but only 22% received nocturnal feeds. CONCLUSIONS:There was high use of PFAA with intakes of natural protein commonly below WHO/FAO/UNU (2007) safe levels. Optimal dietary management can only be determined by longitudinal, multi-centre, prospective case controlled studies. The metabolic instability of PA and small patient cohorts in each centre ensure that this is a challenging undertaking.
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Project description:BACKGROUND:Propionic acidemia (PA), an autosomal recessive metabolic disorder, has an estimated incidence of 1:105,000-130,000 in the United States.1,2 Nutrition management is a main intervention for PA. Research in inborn errors of metabolism such as phenylketonuria has identified association of parental perceptions and practices with dietary outcomes. Parental perceptions and practices in the nutrition management of PA have not been investigated. OBJECTIVE:To assess the dietary perceptions and practices of parental caregivers of children affected by PA. METHODS:PA parents were surveyed about perceptions and practices associated with feeding their affected child(ren). The single-page survey was anonymous, and responses to survey items were not identifiable. Parents provided information on how often they followed the prescribed diet and the rationale for any adjustments. RESULTS:Parents "always" or "most of the time" followed the prescribed diet for children 4-20 years of age; yet, open-ended responses indicated that 71.4% made situational adjustments to their child's diet for a variety of reasons, including illness, iatrogenic effects, and social events. CONCLUSIONS:PA parents make situational adjustments to their child's highly specialized diet. Uncertainty exists as to the situational adjustments being within the guidelines used by the metabolic healthcare team who rely on parents to inform them about dietary situational adjustments.
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Project description:INTRODUCTION:Propionic acidemia is a metabolic disease produced by a deficiency of the enzyme propionyl-CoA carboxylase. It can lead to coma, with severe neurologic encephalopathy or present later in life with vomiting, hypotonia, and seizures. An early diagnosis with adequate treatment helps to prevent the sequelae. Among the described complications is optic neuropathy, although not commonly reported, it is very disabling. OBJECTIVES:To describe two patients with propionic acidemia and optic neuropathy. PATIENTS AND METHODS:Patient 1: 16 years old, male, parents without consanguinity. He was diagnosed at 5 months of age because of hypotonia and seizures. Until the age of 9 years, he evolved satisfactorily; therefore, he stopped treatment. At 13 years, he presented bilateral optic neuropathy. Patient 2: 20 years, female, parents without consanguinity. She was diagnosed with PA at 11 months of age because of hypotonia and seizures. She evolved satisfactorily until the age of 9 years when she presented a metabolic decompensation followed by a bad metabolic control. At 18 years, she presented bilateral progressive optic neuropathy. RESULTS:Both patients have psychometric scores with borderline IQ 84-75 (WISC-R) beside optic neuropathy. They were evaluated by an ophthalmologist and also by neuroimaging (MRI of optic pathway). CONCLUSIONS:Pathophysiology of optic neuropathy is not completely understood. There is evidence that the damage is due to an accumulation of neurotoxic compounds secondary to the metabolic block increasing the oxidative stress. We suggest an annual ophthalmologic evaluation in the long-term follow-up of organic acidurias with visual loss, in order to detect this disabling sequela at an earlier stage.
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