Aciduria Research Articles

Mutational analysis of glutaryl CoA dehydrogenase gene in glutaric aciduria type-I patients: A study from India

Mutational analysis of glutaryl CoA dehydrogenase gene in glutaric aciduria type-I patients: A study from India

全羧化酶合成酶基因新发突变致以皮肤为首发症状的多种羧化酶缺乏症一例

A male patient, who was aged 3 months and 12 days, presented with well-circumscribed erythema and scales on the scrotum, perineum, buttocks and perianal region at 1 month after birth. The lesions gradually involved the perioral and axillary regions, flexor aspect of the elbow, popliteal fossa and neck. Shortness of breath, crying, dysphoria and vomiting occurred without fever and cough 3 days before hospitalization. Laboratory examinations at admission showed metabolic acidosis, hyperlactacidemia, hyperammonemia and organic aciduria. Second-generation sequencing and Sanger sequencing of the holocarboxylase synthetase gene revealed a known mutation c.1522C>T in exon 9 and a novel mutation c.1796_1814del in exon 11. According to a guideline from the American College of Medical Genetics and Genomics, this novel mutation was ranked as a pathogenic mutation. The patient was diagnosed as multiple carboxylase deficiency. His clinical symptoms were improved after oral biotin treatment, no neurological symptoms or signs were observed. Key words: Multiple carboxylase deficiency; Skin manifestations; Biotin; Holocarboxylase synthetase gene; Mutation

Analysis of inborn error metabolism in 277 children with autism spectrum disorders from Hainan

To assess the value of dry blood spot tandem mass spectrometry for the diagnosis of autism spectrum disorder (ASD). Peripheral blood samples of 277 autistic children were collected. Their amino acid and carnitine profiles were detected by liquid chromatography tandem mass spectrometry. Urine samples of suspected patients were collected for verification by gas chromatography mass spectrometry. Blood samples were also taken for genetic testing. Of the 277 children with ASD, 19 (6.9%) were suspected to be with inborn error of metabolism (IEM), which included 6 cases with amino acidemia, 9 with organic acidemia and 4 with fatty acidemia. Three cases of phenylketonuria, one case of homocysteinemia, one case of propionemia, one case of methylmalonic acidemia, one case of glutaric acidemia, one case of isovaleric acidemia, one case of argininemia, one case of citrullinemia I and four cases of primary carnitine deficiency were confirmed by genetic testing, which yielded an overall diagnostic rate of 5.1% (14/277). Our result has provided further evidence for the co-occurrence of ASD and IEM. Tandem mass spectrometry has a great value for the diagnosis and treatment of ASD in childhood.

Analysis of CGDH gene variants and clinical features in three patients with glutaric aciduria type Ⅰ

To screen for potential variants of GCDH gene in 3 patients clinically diagnosed as glutaric aciduria type Ⅰ. GCDH gene variants was detected by Sanger sequencing among the three children and their family members. Sanger sequencing showed that patient 1 carried compound heterozygosity variants of c.532G>A (p.Gly178Arg) and c.655G>A (p.Ala219Thr) of the GCDH gene, while his father and mother respectively carried heterozygous c.532G>A(p.Gly178Arg) and c.655G>A (p.Ala219Thr) variants. Patient 2 carried c.532G>A (p.Gly178Arg) and a novel c.1060G>T (p.Gly354Cys) compound heterozygous variant, while his father and mother respectively carried heterozygous c.532G>A (p.Gly178Arg) and c.1060G>T (p.Gly354Cys) variant. Patient 3 carried homozygous c.532G>A (p.Gly178Arg) variant of the GCDH gene, for which both of his parents were heterozygous carriers. The GCDH gene variant probably underlie the glutaric aciduria type Ⅰ among the 3 patients. Identifcation of the novel variant has enriched the spectrum of GCDH gene variants.

Potential complementation effects of two disease-associated mutations in tetrameric glutaryl-CoA dehydrogenase is due to inter subunit stability-activity counterbalance

Glutaric Aciduria Type I (GA-I), is an autosomal recessive neurometabolic disease caused by mutations in the GCDH gene that encodes for glutaryl-CoA dehydrogenase (GCDH), a flavoprotein involved in the metabolism of tryptophan, lysine and hydroxylysine. Although over 200 disease mutations have been reported a clear correlation between genotype and phenotype has been difficult to establish. To contribute to a better molecular understanding of GA-I we undertook a detailed molecular study on two GCDH disease-related variants, GCDH-p.Arg227Pro and GCDH-p.Val400Met. Heterozygous patients harbouring these two mutations have increased residual enzymatic activity in relation to homozygous patients with only one of the mutations, suggesting a complementation effect between the two.Combining biochemical, biophysical and structural methods we here establish the effects of these mutations on protein folding, stability and catalytic activity. We show that both variants retain the overall protein fold, but with compromised enzymatic activities. Detailed enzyme kinetic studies reveal that GCDH-p.Arg227Pro has impaired function due to deficient substrate affinity as evidenced by its higher Km, and that the lower activity in GCDH-p.Val400Met results from weaker interactions with its physiological redox partner (electron transfer flavoprotein). Moreover, the GCDH-p.Val400Met variant has a significantly lower thermal stability (ΔTm ≈ 9 °C), and impaired binding of the FAD cofactor in relation to wild-type protein. On these grounds, we provide a rational for the possible interallelic complementation observed in heterozygous patients based on the fact that in GCDH, the low active p.Arg227Pro variant contributes to stabilize the tetramer while the structurally unstable p.Val400Met variant compensates for enzyme activity.

Prenatal Diagnosis of Organic Acidemias at a Tertiary Center.

The aim of this study was to share our experience in the prenatal diagnosis (PND) of organic acidemias (OAs) in our clinic. This study consisted of 10 cases in whom an invasive prenatal diagnostic test (IPNDT) was performed by a single physician for the PND of OAs. Median maternal age, parity, gestational week of IPNDT, prenatal test indications, OA types, method of IPNDT, IPNDT results and gestational outcomes were evaluated. Targeted mutation analysis was performed in fetal DNA for the specific mutations by using polymerase chain reaction (PCR) and direct Sanger sequencing. The diagnosis was confirmed by genetic targeted mutation analysis after birth. Median maternal age, parity and gestational week of IPNDT values were 30 (range 21-35), one (range 0-4) and 11.5 (range 11-17), respectively. Indications for IPNDT were mother being a carrier of the disease for one case (10.0%) and at least one child with OA in the family for nine cases (90.0%). Organic acidemia types investigated were maple syrup urine disease (MSUD), methylmalonic acidemia (MMA) and isovaleric acidemia (IVA) in five (50.0%), three (30.0%) and two (20.0%) patients, respectively. Chorion villus sampling (CVS) was done in seven (70.0%) patients and amniocentesis was performed in three (30.0%) patients. Eight fetuses (80.0%) were found to be healthy and two fetuses (20.0%) were found to be affected (one case with IVA and one case with MMA). The two pregnancies (20.0%) with affected fetuses were terminated. Prenatal diagnosis of OAs is critical. Appropriate prenatal counseling should be given to families with known risk factors.

Acylcarnitine profiling by low-resolution LC-MS.

Acylcarnitines are fatty acyl esters of L-carnitine and facilitate the entry of long-chain fatty acids into mitochondria via the carnitine shuttle, where they are metabolized via ß-oxidation. Alterations of acylcarnitine species can be diagnostic for fatty acid oxidation disorders and organic aciduria and are thus frequently used to screen newborns. Only a subfraction of all known acylcarnitines is thereby monitored and quantified. Therefore, a method for the simultaneous fast and robust detection of all known acylcarnitines was developed using a single concise liquid chromatography mass spectrometry (LC-MS) approach. Derivatization by 3-nitrophenylhydrazine increased the signal intensity of the acylcarnitines and a linear elution from a reversed phase column was observed that was dependent on the length of the carbon chain. This allowed a precise prediction of the exact elution time for each acylcarnitine class, which depended solely on the chemical nature of the carbon chain. This method can be further used to screen for yet unknown acylcarnitine species and adds a layer of confidence for their correct identification. Altogether 123 acylcarnitines species were used to establish a targeted low-resolution LC-MS method. The method was applied to acylcarnitine profiling in several mouse tissues and fluids, in order to identify large differences in the quantity and composition of acylcarnitines.

Regulation of Glutarate Catabolism by GntR Family Regulator CsiR and LysR Family Regulator GcdR in Pseudomonas putida KT2440.

Glutarate, a metabolic intermediate in the catabolism of several amino acids and aromatic compounds, can be catabolized through both the glutarate hydroxylation pathway and the glutaryl-coenzyme A (glutaryl-CoA) dehydrogenation pathway in Pseudomonas putida KT2440. The elucidation of the regulatory mechanism could greatly aid in the design of biotechnological alternatives for glutarate production. In this study, it was found that a GntR family protein, CsiR, and a LysR family protein, GcdR, regulate the catabolism of glutarate by repressing the transcription of csiD and lhgO, two key genes in the glutarate hydroxylation pathway, and by activating the transcription of gcdH and gcoT, two key genes in the glutaryl-CoA dehydrogenation pathway, respectively. Our data suggest that CsiR and GcdR are independent and that there is no cross-regulation between the two pathways. l-2-Hydroxyglutarate (l-2-HG), a metabolic intermediate in the glutarate catabolism with various physiological functions, has never been elucidated in terms of its metabolic regulation. Here, we reveal that two molecules, glutarate and l-2-HG, act as effectors of CsiR and that P. putida KT2440 uses CsiR to sense glutarate and l-2-HG and to utilize them effectively. This report broadens our understanding of the bacterial regulatory mechanisms of glutarate and l-2-HG catabolism and may help to identify regulators of l-2-HG catabolism in other species.IMPORTANCE Glutarate is an attractive dicarboxylate with various applications. Clarification of the regulatory mechanism of glutarate catabolism could help to block the glutarate catabolic pathways, thereby improving glutarate production through biotechnological routes. Glutarate is a toxic metabolite in humans, and its accumulation leads to a hereditary metabolic disorder, glutaric aciduria type I. The elucidation of the functions of CsiR and GcdR as regulators that respond to glutarate could help in the design of glutarate biosensors for the rapid detection of glutarate in patients with glutaric aciduria type I. In addition, CsiR was identified as a regulator that also regulates l-2-HG metabolism. The identification of CsiR as a regulator that responds to l-2-HG could help in the discovery and investigation of other regulatory proteins involved in l-2-HG catabolism.

Plasma FGF‐21 and GDF‐15 are elevated in different inherited metabolic diseases and are not diagnostic for mitochondrial disorders

Recently, the plasma cytokines FGF-21 and GDF-15 were described as cellular metabolic regulators. They share an endocrine function and are highly expressed in the liver under stress and during starvation. Several studies found that these markers have high sensitivity and specificity for the diagnosis of mitochondrial diseases, especially those with prominent muscular involvement. In our study, we aimed to determine whether these markers could help distinguish mitochondrial diseases from other groups of inherited diseases. We measured plasma FGF-21 and GDF-15 concentrations in 122 patients with genetically confirmed primary mitochondrial disease and 127 patients with non-mitochondrial inherited diseases. Although GDF-15 showed better analytical characteristics (sensitivity = 0.66, specificity = 0.64, area under the curve [AUC] = 0.88) compared to FGF-21 (sensitivity = 0.51, specificity = 0.76, AUC = 0.78) in the pediatric group of mitochondrial diseases, both markers were also elevated in a variety of non-mitochondrial diseases, especially those with liver involvement (Gaucher disease, galactosemia, glycogenosis types 1a, 1b, 9), organic acidurias and some leukodystrophies. Thus, the overall positive and negative predictive values were not acceptable for these measurements to be used as diagnostic tests for mitochondrial diseases (FGF-21 positive predictive value [PPV] = 34%, negative predictive value [NPV] = 73%; GDF-15 PPV = 47%, NPV = 28%). We suggest that FGF-21 and GDF-15 increase in patients with metabolic diseases with metabolic or oxidative stress and inflammation.

Liver neoplasms in methylmalonic aciduria: An emerging complication.

Methylmalonic aciduria (MMA) is an inherited metabolic disease caused by methylmalonyl-CoA mutase deficiency. Early-onset disease usually presents with a neonatal acute metabolic acidosis, rapidly causing lethargy, coma, and death if untreated. Late-onset patients have a better prognosis but develop common long-term complications, including neurological deterioration, chronic kidney disease, pancreatitis, optic neuropathy, and chronic liver disease. Of note, oncogenesis has been reported anecdotally in organic acidurias. Here, we present three novel and two previously published cases of MMA patients who developed malignant liver neoplasms. All five patients were affected by a severe, early-onset form of isolated MMA (4 mut0 , 1 cblB subtype). Different types of liver neoplasms, that is, hepatoblastoma and hepatocellular carcinoma, were diagnosed at ages ranging from infancy to adulthood. We discuss pathophysiological hypotheses involved in MMA-related oncogenesis such as mitochondrial dysfunction, impairment of tricarboxylic acid cycle, oxidative stress, and effects of oncometabolites. Based on the intriguing occurrence of liver abnormalities, including neoplasms, we recommend close biochemical and imaging monitoring of liver disease in routine follow-up of MMA patients.

Is Expanded Newborn Screening Adequate to Detect Indian Biochemical Low Excretor Phenotype Patients of Glutaric Aciduria Type I?

To investigate if expanded newborn screening using tandem mass spectroscopy (TMS) is adequate to detect low excretor phenotype in Indian Glutaric aciduria type I (GA-I) patients. Ten GA-I patients were investigated for blood glutaryl carnitine (C5DC) levels on dried blood spot (DBS) by tandem mass spectroscopy and urine glutaric acid (GA) and 3-hydroxyglutaric acid (3-OH-GA) by gas chromatography-mass spectroscopy. The student's T test and Pearson's correlation were applied to draw a relationship between various biochemical parameters. Further confirmation of low excretors by DNA mutation analysis in the glutaryl CoA dehydrogenase (GCDH) gene was performed by polymerase chain reaction and Sangers sequencing. Among 10 GA-I patients, 7 patients were found to have high excretor, and 3 were found to have low excretor phenotype. The low excretors were found to have GCDH gene mutations. The mean C5DC levels in high and low excretors were 2.61 ± 2.02μmol/L and 2.31 ± 1.00μmol/L, respectively. In high excretors, C5DC levels correlated with GA (r = 0.95). In low excretors, C5DC levels correlated with 3-OH-GA (r = 0.99). No significant difference was found between C5DC levels of high and low excretors (p = 0.82). The MS/MS, C5DC screening is a sensitive technique and detected 10 GA-I patients. Irrespective of the urine organic acid levels, Indian GA-I patients including low excretors seem to have a significantly elevated C5DC level and well above the stipulated cut-off values and therefore, expanded newborn screening is probably adequate to diagnose them.

Metabolic Disorders and Anesthesia.

Metabolic disorders encompass a group of inherited inborn errors of metabolism that are uncommonly encountered but can pose challenges when encountered during the perioperative period. Hence, it is paramount that anesthesiologists are experienced and familiar with management of these conditions. Hundreds of inborn errors of metabolism have already been identified, yet new metabolic disorders continue to be discovered with advancements in genomic science. In our general review, we define the more common metabolic disorders encountered in perioperative medicine and discuss the perioperative anesthetic considerations and challenges associated with each disorder. The following disorders are covered in our review: disorders of carbohydrate metabolism, disorders of amino acid metabolism, disorders of branched-chain amino acid metabolism, organic acidemias, mitochondrial disorders, lysosomal storage disorders, metal metabolism disorders, and urea cycle disorders.

Urease-immobilized magnetic microparticles in urine sample preparation for metabolomic analysis by gas chromatography-mass spectrometry

Urea, as an end product of protein metabolism and an abundant polar compound, significantly complicates the metabolomic analysis of urine by GC–MS. We developed a sample preparation method removing urea from urine samples prior the GC–MS analysis. The method based on urease immobilized on magnetic microparticles was compared with the others that are conventionally used (liquid-liquid extraction, free urease protocol), and samples without any treatment. To study the impact of sample preparation approaches on the quality of analytical data, we employed comprehensive metabolomic analysis (using both GC–MS and LC–MS/MS platforms) of standard material based on human urine. Multivariate statistical analysis has shown that immobilized urease treatment provides similar results to a free urease approach. However, significant alterations in the profiles of metabolites were observed in the samples without any treatment and after the extraction. Compared to other approaches that were tested, the immobilization of urease on microparticles reduces both the number of artifacts and the variability of the metabolites (average CV of extraction 19.7%, no treatment 11.4%, free urease 5.0%, and immobilized urease 2.5%). The method that was developed was applied in a GC–MS metabolomic experiment of glutaric aciduria type I, where both known diagnostically important biomarkers and unknowns, as the most discriminating compounds, were found.

An unusual presentation of biotinidase deficiency in infant: High anion gap metabolic acidosis and Burkholderia cepacia sepsis

Biotinidase deficiency (BD) is an inborn metabolic disorder caused by low enzyme activity giving rise to impaired biotin release from dietary proteins. The first symptoms may be seen at first week following birth until 1 year of age. The goal of the therapy is to increase biotin bioavailability by daily 5-20 mg lifelong biotin replacement. Three-month-old girl born to nonconsanguineous parents, admitted to pediatric intensive care with multiple seizures, breathing difficulty and posturing. Blood investigations showed thrombocytopenia and high anion gap metabolic acidosis (HAGMA). Enzyme assay for biotinidase revealed low activities. Urinary organic acid analysis was normal. Enzyme activity is <10% in severe cases whereas between 10-30% in partial deficiency. BD can cause metabolic ketoacidosis, Hyperammonemia and organic Aciduria. BD behaves like immunodeficiency. Rarely bacterial infection can be seen. Treatment is lifelong biotin replacement.

Metabolic analysis reveals evidence for branched chain amino acid catabolism crosstalk and the potential for improved treatment of organic acidurias

Branched chain amino acid (BCAA) metabolism occurs within the mitochondrial matrix and is comprised of multiple enzymes, some shared, organized into three pathways for the catabolism of leucine, isoleucine, and valine (LEU, ILE, and VAL respectively). Three different acyl-CoA dehydrogenases (ACADs) are active in each catabolic pathway and genetic deficiencies in each have been identified. While characteristic metabolites related to the enzymatic block accumulate in each deficiency, for reasons that are not clear, clinical symptoms are only seen in the context of deficiency of isovaleryl-CoA dehydrogenase (IVDH) in the leucine pathway. Metabolism of fibroblasts derived from patients with mutations in each of the BCAA ACADs were characterized using metabolomics to better understand the flux of BCAA through their respective pathways. Stable isotope labeled LEU, ILE, and VAL in patient and control cell lines revealed that mutations in isobutyryl-CoA dehydrogenase (IBDH in the valine pathway) lead to a significant increase in isobutyrylcarnitine (a surrogate for the enzyme substrate isobutyryl-CoA) leading to metabolism by short-branched chain acyl-CoA dehydrogenase (SBCADH in the isoleucine pathway) and production of the pathway end product propionylcarnitine (a surrogate for propionyl-CoA). Similar cross activity was observed for SBCADH deficient patient cells, leading to a significant increase in propionylcarnitine, presumably by metabolism of 2 methylbutyryl-CoA via IBDH activity. Labeled BCAA studies identified that the majority of the intracellular propionyl-CoA pool in fibroblasts is generated from isoleucine, but heptanoic acid (a surrogate for odd-chain fatty acids) is also efficiently converted to propionate.

Carnitine-acylcarnitine translocase deficiency with homozygous mutation of c.199-10T>G: a case report and literature review

Objective To investigate the clinical features of carnitine-acylcarnitine translocase deficiency (CACTD) with c.199-10T>G homozygous mutation and the characteristics of SLC25A20 gene mutation. Methods This study retrospectively analyzed the clinical data, biochemical and genetic features, treatment and outcome of a boy with CACTD with c.199-10T>G homozygous mutation, who admitted to Guangzhou Women and Children's Medical Center in September 2017. Pertinent articles were retrieved from China National Knowledge Infrastructure (CNKI), Wanfang Database, National Center for Biotechnology Information and PubMed from the establishment of these databases to April 2018 using key words including CACT, SLC25A20 and carnitine-acylcarnitine translocase. Clinical information of all affected cases in the retrieved publications was analyzed. Results (1) The full-term boy born vaginally at a local hospital was transferred to neonatal intensive care unit (NICU) of Guangzhou Women and Children's Medical Center at 2 days and 5 hours due to groaning, cyanosis and severe hypoglycemia (0.8 mmol/L) at 15 h after birth. His elder brother with similar symptoms died of unknown reason at 50 days of age. In this case, ammonemia, liver enzyme and creatine kinase were significantly elevated, amino acid analysis suggested liver damage, and high amounts of dicarboxylic aciduria, low free carnitine, markedly increased long-chain acylcarnitine and hypoketotic hypoglycemia were also observed. His electrocardiogram showed atrioventricular block and ventricular tachycardia. After a series of treatments, including repeated electrical cardioversion, lidocaine and amiodarone for arrhythmia, arginine for blood ammonia level reduction, formula supplement containing L-carnitine and medium-chain fatty acid, the patient whose conditions had significantly improved and was discharged at the request of his parents at 29 days old. Two weeks later, he was re-admitted due to diarrhea, and discharged two days later when he was 45 days old. He was lost to follow up since then. (2) A homozygous mutation of c.199-10T>G was detected in this boy in SLC25A20 gene, which was also carried by his parents. (3) Thirty-two publications in English were retrieved, involving 50 cases of CACTD and 100 sequenced alleles. A total of 40 mutations in SLC25A20 gene were found so far, and c.199-10T>G was the most common mutation with a frequency of 22/100. It was identified in 13 patients, including nine homozygous mutations and four compound heterozygous mutations. Symptoms presented within 72 h after birth (25 min-52 h) in all the 13 infants, such as hypoketotic hypoglycemia, hyperammonemia, elevated liver enzyme and creatine kinase, significantly decreased free carnitine level, markedly increased level of long-chain acylcarnitine, dicarboxylic aciduria, arrhythmia and cardiomyopathy. The mortality rate of CACTD was 11/12 (the outcome of one case was not reported). Conclusions c.199-10T>G is the most common SLC25A20 gene mutation reported in Asia population with severe phenotypes and poor outcomes. Early diagnosis and timely treatment of CACTD are crucial. Inborn metabolic diseases such as CACTD should be considered if unexplainable exacerbation of clinical signs in neonatal period, or sudden infant death occurs. Key words: Carnitine acyltransferases; Lipid Metabolism, Inborn Errors; Membrane transport proteins; Mutation

Clinical, biochemical, neuroradiological and molecular characterization of Egyptian patients with glutaric acidemia type 1

Glutaric acidemia type 1 (GA1) is an inherited metabolic autosomal recessive disorder that is caused by a deficiency in glutaryl-CoA dehydrogenase (GCDH). Untreated patients suffer primarily from severe striatal damage. More than 250 variants in the GCDH gene have been reported with a variable frequency among different ethnic groups. In this study, we aimed to characterize 89 Egyptian patients with GA1 and identify the variants in the 41 patients who were available for genotyping. All of our patients demonstrated clinical, neuroradiological, and biochemical characteristics that are consistent with a diagnosis of GA1. All patients presented with variable degrees of developmental delay ranging from mild to severe. Most of the 89 patients presented with acute onset type (71.9%), followed by insidious (19%) and asymptomatic (9%). A delay in diagnosis was inversely associated with macrocephaly. The prevalence rate ratio (PR) for macrocephaly that was associated with each 6-month delay was 0.95 (95%CI 0.91–0.99). However, high body weight was associated with a higher likelihood of having macrocephaly (PR 1.16, 95%CI 1.06–1.26 per 1 SD increment of Z score weight). However, body weight was inversely associated with the morbidity score. Consanguinity level was 64% among our patient’s cohort and was positively associated with the C5DC level (β (95%CI) 1.06 (0.12–1.99)). Forty-one patients were available for genotyping and were sequenced for the GCDH gene. We identified a total of 25 variants, of which the following six novel variants were identified: three missense variants, c.320G > T (p.Gly107Val), c.481C > T (p.Arg161Trp) and c.572 T > G (p.Met191Arg); two deletions, c.78delG (p.Ala27Argfs34) and c.1035delG (p.Gly346Alafs*11); and one indel, c.272_331del (p.Val91_Lys111delinsGlu). All of the novel variants were absent in the 300 normal chromosomes. The most common variant, c.*165A > G, was detected in 42 alleles, and the most commonly detected missense variant, c.1204C > T (p.Arg402Trp), was identified in 29 mutated alleles in 15/41 (34.2%) of patients. Our findings suggest that GA1 is not uncommon organic acidemia disease in Egypt; therefore, there is a need for supporting neonatal screening programs in Egypt.

Diagnosis and treatment of a child with propionic acidemia - an issue both near and distant

Propionic acidemia (PA) is a genetic heterogeneous hereditary disease, that is due to deficiency of the mitochondrial enzyme propionyl-CoA carboxylase. As a result of the inherited genetic error of metabolism, propionic acid and propionyl-CoA-related metabolites accumulate in the body. The clinical manifestation of PA is caused by the toxic effect of the formed substances. PA presents with acute encephalopathy, progressive eating disorders, vomiting, dehydration and hypotension, running against the background of severe metabolic ketoacidosis, an increased anion gap (AnGap) ≥15 and hyperammonemia. The clinical condition is defined as an acute metabolic crisis of PA. The early diagnosis and the timely treatment are crucial for the outcome of the disease. We present a clinical case of PA in a two-month-old infant who was admitted to the Pediatric Intensive Care Unit in St. Marina University Hospital, Varna with seizures and disturbance of consciousness. The current clinical case is presented with the aim of focusing on the problems of hereditary diseases of the metabolism, in particular organic acidemias and the critical importance of the initial stabilization and adequate management of the lives of the affected patients.

Energy Metabolism in Branched-chain Organic Acidemias

Energy Metabolism in Branched-chain Organic Acidemias

Continuous Renal Replacement Therapy with High Flow Rate Can Effectively, Safely, and Quickly Reduce Plasma Ammonia and Leucine Levels in Children.

Introduction: Peritoneal dialysis and continuous renal replacement therapy (CRRT) are the most frequently used treatment modalities for acute kidney injury. CRRT is currently being used for the treatment of several non-renal indications, such as congenital metabolic diseases. CRRT can efficiently remove toxic metabolites and reverse the neurological symptoms quickly. However, there is not enough data for CRRT in children with metabolic diseases. Therefore, we aimed a retrospective study to describe the use of CRRT in metabolic diseases and its associated efficacy, complications, and outcomes. Materials and Methods: We performed a retrospective analysis of the records of all patients admitted in the pediatric intensive care unit (PICU) for CRRT treatment. Results: Between December 2014 and November 2018, 97 patients were eligible for the present study. The age distribution was between 2 days and 17 years, with a mean of 3.77 ± 4.71 years. There were 13 (36.1%) newborn with metabolic diseases. The patients were divided into two groups: CRRT for metabolic diseases and others. There was a significant relationship between the groups, including age (p ≤ 0.001), weight (p = 0.028), blood flow rate (p ≤ 0.001); dialysate rate (p ≤ 0.001), and replacement rate (p ≤ 0.001). The leucine reduction rate was 3.88 ± 3.65 (% per hour). The ammonia reduction rate was 4.94 ± 5.05 in the urea cycle disorder group and 5.02 ± 4.54 in the organic acidemia group. The overall survival rate was 88.9% in metabolic diseases with CRRT. Conclusion: In particularly hemodynamically unstable patients, CRRT can effectively and quickly reduce plasma ammonia and leucine.