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Propionic acidemia
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
Propionic acidemia is inherited as an autosomal recessive trait. The enzymatic site of the defect is propionyl CoA carboxylase [36, 37]. Activity in extracts of leukocytes and fibroblasts is very low, usually less than 5 percent of control (Table 2.1). Studies with somatic cell hybrids have provided evidence of two complementation groups, PccA and PccBC, which correspond to abnormalities in the α and β subunits, respectively [38–43]. The BC group contains two subgroups, B and C, in which intragroup complementation is thought to be interallelic. Patients in the A subgroup have mutations in the A gene for the α chain, and those in the BC groups have mutations in the B gene for the β chain. Residual activity of propionyl CoA carboxylase correlates poorly with severity of disease or outcome [14].
Neonatal Seizures
Published in Stanley R. Resor, Henn Kutt, The Medical Treatment of Epilepsy, 2020
Of the large number of inborn errors of metabolism, only a few cause very early seizures. Phenylketonuria has almost lost its significance by virtue of routine newborn screening and early treatment (27). Deficiencies of branched-chain ketoacids (maple-syrup disease being the most common) can trigger seizures within 1 to 3 weeks of birth, with feeding problems, hypotonia alternating with opisthotonic crisis, true convulsions, and coma. Hypoglycemia (often leucine-induced) may trigger the seizures, but ketoacids also directly affect nerve cells and myelination. Screening for urine dinitrophenylhydrazine (DNPH) allows early diagnosis. Repeated exchange transfusions and strict dietary measures are required. Propionic acidemia, isovaleric acidemia, methylmalonic acidemia, and other rare disorders of amino acids produce a variety of neurologic symptoms. Characteristic, frequent, abnormal movements can be taken for convulsive seizures, but these are in fact rare in the newborn period. Biotinidase deficiency may cause early seizures, which improve with biotin therapy. Disorders causing hyperglycinemia present with seizures after a short period of no apparent CNS problem. They are often myoclonic or focal tonic but also may present with clonic and autonomic components and are resistant to common AEDs. The course is usually downhill with severe hypotonia, lethargy, and coma. Ketonuria, thrombocytopenia, acidosis, and elevated ammonia are diagnostic clues. The nonketotic variety is the most common (we encountered 10 (0.9%) cases in our prospective studies). The deficit seems to be due to lack of a glycine cleavage enzyme. Therapies with sodium benzoate, strychnine, and other agents have failed to arrest this condition. Acute, severe hyperammonemia (secondary to urea cycle disorders or to primary hepatic disorders) may trigger early seizures. We have seen two cases of carbamylphosphate synthetase deficiency and one of arginosuccinase deficiency. Sporadic cases of neonatal seizures have been reported in babies with congenital lysine intolerance and in babies with citrillinemia. The role of elevated ammonia in causing seizures is debatable, since elevated serum ammonia is found in other conditions without seizures. Premature babies show transient but marked hyperammonemia; some exhibit CNS derangements, including seizures, while others escape without sequelae. Diseases with abnormalities of glycogen or lipid storage disorders almost never exhibit seizures in the newborn period. One exception in our earliest series was a baby with infantile Gm, gangliosidosis type 1 (who had clusters of tonic spasms) and another with glycogen synthetase deficiency (with erratic myoclonic seizures).
Inherited causes of exocrine pancreatic insufficiency in pediatric patients: clinical presentation and laboratory testing
Published in Critical Reviews in Clinical Laboratory Sciences, 2023
Tatiana N. Yuzyuk, Heather A. Nelson, Lisa M. Johnson
Pancreatic dysfunction is not commonly seen in inborn errors of metabolism. Nevertheless, in addition to Pearson syndrome, methylmalonic acidemia (MMA; isolated) and propionic acidemia (PA) are two other inborn errors of metabolism characterized by pancreatic complications. MMA and PA are autosomal recessive disorders of propionate catabolism caused by the impaired function of mitochondrial enzymes, methylmalonyl-CoA mutase or propionyl-CoA carboxylase, respectively [75,76]. The enzymatic defects lead to a metabolic block in the final steps of the catabolic pathways of valine, isoleucine, methionine, threonine, cholesterol, and odd-chain fatty acids, resulting in the accumulation of specific metabolites (propionylcarnitine, methylcitric and 3-hydroxypropionic acids; methylmalonic acid specific to MMA). Most patients are identified by NBS and present in the neonatal period with vomiting, dehydration, weight loss, temperature instability, neurological involvement, irritability, and lethargy progressing to coma and seizures if left untreated. Mild and late-onset cases are also well documented [77,78].
Genotoxicity mechanism of food preservative propionic acid in the in vivo Drosophila model: gut damage, oxidative stress, cellular immune response and DNA damage
Published in Toxicology Mechanisms and Methods, 2023
Fatma Turna Demir, Eşref Demir
The amount of propionic acid concentration in humans is highest in the ascending colon (30 mM/kg) and lowest in the ileum (1.5 mM/kg). A concentration of ∼88 µM/L of propionic acid is absorbed in the portal vein (Frye et al. 2016). Currently, food additives are aimed to protect against the pathological effects of ROS associated with cardiovascular disease, aging, and cancer (Maier et al. 2010). In this study, two highest concentrations (5 and 10 mM) of propionic acid did induce significant changes in the levels of hemocyte intracellular ROS. Studies showing increased amounts of ROS in propionic acidemia patient fibroblasts (Gallego-Villar et al. 2013) and Candida albicans (Yun and Lee 2016) are consistent with the fact that higher propionic acid concentrations increase ROS. In a study that detected ROS accumulation and metacaspase activation using 2,7-dichlorodihydrofluorescein diacetate and CaspACE FITC-VAD-FMK staining, increased fluorescence intensities were observed after exposure to propionic acid (Yun and Lee 2016).
Liver-directed gene-based therapies for inborn errors of metabolism
Published in Expert Opinion on Biological Therapy, 2021
Pasquale Piccolo, Alessandro Rossi, Nicola Brunetti-Pierri
Patients with IEM are often treated by orthotopic liver transplantation (OLT) that replaces thousands of liver enzymes from the donor to correct a single enzyme defect. IEM corrected by OLT are targets also for liver-directed gene therapy. Therefore, IEM that are currently treated with OLT, such as Progressive familial intrahepatic cholestasis type 3 (PFIC3) [141,142], or Wilson disease [8,143] are disease candidates for gene therapy. In these disorders, intravenous AAV injections have indeed shown phenotypic correction in mouse models. For disorders affecting biochemical pathways expressed in extra-hepatic tissues, OLT provides only partial benefit. In classic organic acidurias, such as methylmalonic and propionic acidemia, which are complicated by multiorgan involvement and risk of acute metabolic decompensation, OLT can improve metabolic stability and arrest the progression of some complications, but it does not appear to completely abolish some extra-hepatic findings, such as stroke [144,145]. Therefore, liver-directed gene therapy in these disorders is less likely to provide full phenotype correction.