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Frontiers in Genetics 2023Hereditary orotic aciduria is an extremely rare, autosomal recessive disease caused by deficiency of uridine monophosphate synthase. Untreated, affected individuals may...
Hereditary orotic aciduria is an extremely rare, autosomal recessive disease caused by deficiency of uridine monophosphate synthase. Untreated, affected individuals may develop refractory megaloblastic anemia, neurodevelopmental disabilities, and crystalluria. Newborn screening has the potential to identify and enable treatment of affected individuals before they become significantly ill. Measuring orotic acid as part of expanded newborn screening using flow injection analysis tandem mass spectrometry. Since the addition of orotic acid measurement to the Israeli routine newborn screening program, 1,492,439 neonates have been screened. The screen has identified ten Muslim Arab newborns that remain asymptomatic so far, with DBS orotic acid elevated up to 10 times the upper reference limit. Urine organic acid testing confirmed the presence of orotic aciduria along with homozygous variations in the gene. Newborn screening measuring of orotic acid, now integrated into the routine tandem mass spectrometry panel, is capable of identifying neonates with hereditary orotic aciduria.
PubMed: 36999056
DOI: 10.3389/fgene.2023.1135267 -
JIMD Reports Sep 2022N-acetylglutamate synthase (NAGS) deficiency is a rare autosomal recessive disorder, which results in the inability to activate the key urea cycle enzyme,...
N-acetylglutamate synthase (NAGS) deficiency is a rare autosomal recessive disorder, which results in the inability to activate the key urea cycle enzyme, carbamoylphosphate synthetase 1 (CPS1). Patients often suffer life-threatening episodes of hyperammonaemia, both in the neonatal period and also at subsequent times of catabolic stress. Because NAGS generates the cofactor for CPS1, these two disorders are difficult to distinguish biochemically. However, there have now been numerous case reports of 3-methylglutaconic aciduria (3-MGA), a marker seen in mitochondrial disorders, occurring in CPS1 deficiency. Previously, this had not been reported in NAGS deficiency. We report a four-day-old neonate who was noted to have 3-MGA at the time of significant hyperammonaemia and lactic acidosis. Low plasma citrulline and borderline orotic aciduria were additional findings that suggested a proximal urea cycle disorder. Subsequent molecular testing identified bi-allelic pathogenic variants in . The 3-MGA was present at the time of persistent lactic acidosis, but improved with normalization of serum lactate, suggesting that it may reflect secondary mitochondrial dysfunction. NAGS deficiency should therefore also be considered in patients with hyperammonaemia and 3-MGA. Studies in larger numbers of patients are required to determine whether it could be a biomarker for severe decompensations.
PubMed: 36101823
DOI: 10.1002/jmd2.12318 -
Frontiers in Immunology 2022The hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive inborn error of the urea cycle caused by mutations in the gene....
The hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is a rare autosomal recessive inborn error of the urea cycle caused by mutations in the gene. Besides the well-known metabolic complications, patients often present intercurrent infections associated with acute hyperammonemia and metabolic decompensation. However, it is currently unknown whether intercurrent infections are associated with immunological alterations besides the known metabolic imbalances. Herein, we describe the case of a 3-years-old girl affected by the HHH syndrome caused by two novel gene mutations associated with immune phenotypic and functional alterations. She was admitted to the hospital with an episode of recurrent otitis, somnolence, confusion, and lethargy. Laboratory tests revealed severe hyperammonemia, elevated serum levels of liver transaminases, hemostasis alterations, hyperglutaminemia and strikingly increased orotic aciduria. Noteworthy, serum protein electrophoresis showed a reduction in the gamma globulin fraction. Direct sequencing of the gene revealed two heterozygous non-conservative substitutions in the exon 5: c.649G>A (p.Gly217Arg) and c.706A>G (p.Arg236Gly). analysis indicated that both mutations significantly impair protein structure and function and are consistent with the patient clinical status confirming the diagnosis of HHH syndrome. In addition, the immune analysis revealed reduced levels of serum IgG and striking phenotypic and functional alterations in the T and B cell immune compartments. Our study has identified two non-previously described mutations in the gene underlying the HHH syndrome. Moreover, we are reporting for the first time functional and phenotypic immunologic alterations in this rare inborn error of metabolism that would render the patient immunocompromised and might be related to the high frequency of intercurrent infections observed in patients bearing urea cycle disorders. Our results point out the importance of a comprehensive analysis to gain further insights into the underlying pathophysiology of the disease that would allow better patient care and quality of life.
Topics: Amino Acid Transport Systems, Basic; Child, Preschool; Female; Humans; Hyperammonemia; Mitochondrial Membrane Transport Proteins; Ornithine; Quality of Life; Urea Cycle Disorders, Inborn
PubMed: 35711415
DOI: 10.3389/fimmu.2022.861516 -
Frontiers in Neurology 2022Hereditary orotic aciduria (HOA) is a rare genetic disorder of pyrimidine metabolism caused by variations in the uridine monophosphate synthetase () gene and inheritance...
BACKGROUND
Hereditary orotic aciduria (HOA) is a rare genetic disorder of pyrimidine metabolism caused by variations in the uridine monophosphate synthetase () gene and inheritance are autosomal recessive. Heterozygous mutations can also lead to orotic aciduria without clinical consequence.
METHODS
We conducted molecular genetic analyses on proband using whole-exome sequencing (WES) and on 12 family members using Sanger sequencing for mutation. We analyzed the urine metabolites of family members carrying heterozygous variants with standard gas chromatography-mass spectrometry (GC-MS).
RESULTS
We identified a novel mutation (c.517G>C) in a Chinese-origin of orotic aciduria pedigree. The proband presented with epilepsy and intellectual disability (ID). Other mutation carriers in our pedigree presented with mild orotic aciduria without relevant medical complaints except for the proband.
CONCLUSION
Our study further expanded the genotype of orotic aciduria and highlighted the probability of misdiagnosis in clinical practice.
PubMed: 35356460
DOI: 10.3389/fneur.2022.819116 -
Journal of Cellular and Molecular... Apr 2021Urea cycle disorders (UCDs) are a group of rare metabolic conditions characterized by hyperammonemia and a broad spectrum of phenotypic severity. They are caused by the...
Urea cycle disorders (UCDs) are a group of rare metabolic conditions characterized by hyperammonemia and a broad spectrum of phenotypic severity. They are caused by the congenital deficiency in the eight biomolecules involved in urea cycle. In the present study, five cases of UCD were recruited and submitted to a series of clinical, biochemical, and genetic analysis with a combination of high throughput techniques. Moreover, in silico analysis was conducted on the identified missense genetic variants. Various clinical and biochemical indications (including profiles of amino acids and urinary orotic acids) of UCD were manifested by the five probands. Sequence analysis revealed nine diagnostic variants, including three novel ones, which caused Argininosuccinic aciduria (ASA) in one case, Carbamoyl phosphate synthetase 1deficiency (CPS1D) in two cases, Ornithine transcarbamylase deficiency (OTCD) in one case, and Citrin deficiency in 1case. Results of in silico biophysical analysis strongly suggested the pathogenicity of each the five missense variants and provided insight into their intramolecular impacts. In conclusion, this study expanded the genetic variation spectrum of UCD, gave solid evidence for counselling to the affected families, and should facilitate the functional study on the proteins in urea cycle.
Topics: Computer Simulation; DNA Mutational Analysis; Female; Humans; Infant; Infant, Newborn; Male; Mutation, Missense; Ornithine Carbamoyltransferase; Pedigree; Prognosis; Urea Cycle Disorders, Inborn
PubMed: 33611823
DOI: 10.1111/jcmm.16379 -
Molecular Genetics and Metabolism... Mar 2021Hereditary orotic aciduria (HOA) is a very rare inborn error of pyrimidine metabolism. It results from a defect of the uridine-5-monophosphate synthase () gene. To date,...
Hereditary orotic aciduria (HOA) is a very rare inborn error of pyrimidine metabolism. It results from a defect of the uridine-5-monophosphate synthase () gene. To date, only about twenty patients have been described. We report a case of HOA with a novel variant in the gene. A 17-year-old Emirati girl was born to first-cousin parents. During the first year, she had recurrent, severe infections including disseminated varicella. After evaluation for immunodeficiency, an impression of immunodeficiency of unknown etiology was presumed. Frequent episodes of pancytopenia were also noted. Bone marrow biopsy showed trilineage megaloblastoid maturation with dysplastic changes that were refractory to hematinic therapy. Also, she was noted to have failure to thrive, developmental delay and epilepsy. She was referred to the Genetics clinic where whole-exome sequencing (WES) was done and showed a novel homozygous variant in the gene confirming a diagnosis of HOA. She was started on uridine triacetate after which she showed clinical, hematologic and biochemical improvement. Although extremely rare, hereditary orotic aciduria should be suspected in any child with megaloblastic bone marrow, immunodeficiency or when developmental delay and anemia coexist.
PubMed: 33489760
DOI: 10.1016/j.ymgmr.2020.100703 -
JIMD Reports Jan 2021The combination of neonatal hyperammonemia, lactic acidosis, ketonuria, and hypoglycemia is pathognomonic for carbonic anhydrase VA (CA-VA) deficiency. We present two...
Two cases of carbonic anhydrase VA deficiency-An ultrarare metabolic decompensation syndrome presenting with hyperammonemia, lactic acidosis, ketonuria, and good clinical outcome.
The combination of neonatal hyperammonemia, lactic acidosis, ketonuria, and hypoglycemia is pathognomonic for carbonic anhydrase VA (CA-VA) deficiency. We present two cases of this rare inborn error of metabolism. Both newborns with South Asian ancestry presented with a metabolic decompensation characterized by hyperammonemia, lactic acidosis and ketonuria; one also had hypoglycemia. Standard metabolic investigations (plasma amino acids, acylcarnitine profile, and urine organic acids) were not indicative of a specific organic aciduria or fatty acid oxidation defect but had some overlapping features with a urea cycle disorder (elevated glutamine, orotic acid, and low arginine). Hyperammonemia was treated initially with nitrogen scavenger therapy and carglumic acid. One patient required hemodialysis. Both have had a favorable long-term prognosis after their initial metabolic decompensation. Genetic testing confirmed the diagnosis of carbonic anhydrase VA (CA-VA) deficiency due to biallelic pathogenic variants in . These cases are in line with 15 cases previously described in the literature, making the phenotypic presentation pathognomonic for this ultrarare (potentially underdiagnosed) inborn error of metabolism with a good prognosis.
PubMed: 33473334
DOI: 10.1002/jmd2.12171 -
EMBO Molecular Medicine Feb 2021Urea cycle disorders (UCD) are inherited defects in clearance of waste nitrogen with high morbidity and mortality. Novel and more effective therapies for UCD are needed....
Urea cycle disorders (UCD) are inherited defects in clearance of waste nitrogen with high morbidity and mortality. Novel and more effective therapies for UCD are needed. Studies in mice with constitutive activation of autophagy unravelled Beclin-1 as druggable candidate for therapy of hyperammonemia. Next, we investigated efficacy of cell-penetrating autophagy-inducing Tat-Beclin-1 (TB-1) peptide for therapy of the two most common UCD, namely ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) deficiencies. TB-1 reduced urinary orotic acid and improved survival under protein-rich diet in spf-ash mice, a model of OTC deficiency (proximal UCD). In Asl mice, a model of ASL deficiency (distal UCD), TB-1 increased ureagenesis, reduced argininosuccinate, and improved survival. Moreover, it alleviated hepatocellular injury and decreased both cytoplasmic and nuclear glycogen accumulation in Asl mice. In conclusion, Beclin-1-dependent activation of autophagy improved biochemical and clinical phenotypes of proximal and distal defects of the urea cycle.
Topics: Animals; Argininosuccinic Aciduria; Autophagy; Beclin-1; Mice; Ornithine Carbamoyltransferase Deficiency Disease; Urea Cycle Disorders, Inborn
PubMed: 33369168
DOI: 10.15252/emmm.202013158 -
Annals of Clinical and Translational... Jan 2021Refractory epilepsy and encephalopathy are frequently encountered in patients with inborn errors of metabolism. We report a case of an 8-year-old girl with history of... (Review)
Review
Refractory epilepsy and encephalopathy are frequently encountered in patients with inborn errors of metabolism. We report a case of an 8-year-old girl with history of developmental delay, autism and intractable epilepsy that was found to have a pathogenic variant in CAD. We briefly review the biochemical pathway of CAD and the preclinical and clinical studies that suggest uridine supplementation can rescue the CAD deficiency phenotypes. Our case demonstrates a relatively late-onset case of refractory epilepsy with a rapid response to treatment using the uridine pro-drug triacetyluridine (TAU), the FDA-approved treatment for hereditary orotic aciduria.
Topics: Acetates; Aspartate Carbamoyltransferase; Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing); Child; Dihydroorotase; Epilepsy, Generalized; Female; Humans; Mutation, Missense; Uridine
PubMed: 33249780
DOI: 10.1002/acn3.51257 -
Molecular Genetics and Metabolism Aug 2018Carbamoyl phosphate synthetase 1 (CPS1) is a urea cycle enzyme that forms carbamoyl phosphate from bicarbonate, ammonia and ATP. Bi-allelic mutations of the CPS1 gene...
Conditional disruption of hepatic carbamoyl phosphate synthetase 1 in mice results in hyperammonemia without orotic aciduria and can be corrected by liver-directed gene therapy.
Carbamoyl phosphate synthetase 1 (CPS1) is a urea cycle enzyme that forms carbamoyl phosphate from bicarbonate, ammonia and ATP. Bi-allelic mutations of the CPS1 gene result in a urea cycle disorder presenting with hyperammonemia, often with reduced citrulline, and without orotic aciduria. CPS1 deficiency is particularly challenging to treat and lack of early recognition typically results in early neonatal death. Therapeutic interventions have limited efficacy and most patients develop long-term neurologic sequelae. Using transgenic techniques, we generated a conditional Cps1 knockout mouse. By loxP/Cre recombinase technology, deletion of the Cps1 locus was achieved in adult transgenic animals using a Cre recombinase-expressing adeno-associated viral vector. Within four weeks from vector injection, all animals developed hyperammonemia without orotic aciduria and died. Minimal CPS1 protein was detectable in livers. To investigate the efficacy of gene therapy for CPS deficiency following knock-down of hepatic endogenous CPS1 expression, we injected these mice with a helper-dependent adenoviral vector (HDAd) expressing the large murine CPS1 cDNA under control of the phosphoenolpyruvate carboxykinase promoter. Liver-directed HDAd-mediated gene therapy resulted in survival, normalization of plasma ammonia and glutamine, and 13% of normal Cps1 expression. A gender difference in survival suggests that female mice may require higher hepatic CPS1 expression. We conclude that this conditional murine model recapitulates the clinical and biochemical phenotype detected in human patients with CPS1 deficiency and will be useful to investigate ammonia-mediated neurotoxicity and for the development of cell- and gene-based therapeutic approaches.
Topics: Ammonia; Animals; Carbamoyl-Phosphate Synthase (Ammonia); Carbamoyl-Phosphate Synthase I Deficiency Disease; Carbamyl Phosphate; Female; Gene Expression Regulation, Enzymologic; Genetic Therapy; Glutamine; Humans; Hyperammonemia; Liver; Male; Mice; Mice, Knockout; Mutation; Orotate Phosphoribosyltransferase; Orotidine-5'-Phosphate Decarboxylase; Purine-Pyrimidine Metabolism, Inborn Errors
PubMed: 29801986
DOI: 10.1016/j.ymgme.2018.04.001