Novel Inborn Error Of Metabolism Research Articles

Fifty years of lyase and a moment of truth: sphingosine phosphate lyase from discovery to disease

Sphingosine phosphate lyase (SPL) is the final enzyme in the sphingolipid degradative pathway, catalyzing the irreversible cleavage of long-chain base phosphates (LCBPs) to yield a long-chain aldehyde and ethanolamine phosphate (EP). SPL guards the sole exit point of sphingolipid metabolism. Its inactivation causes product depletion and accumulation of upstream sphingolipid intermediates. The main substrate of the reaction, sphingosine-1-phosphate (S1P), is a bioactive lipid that controls immune-cell trafficking, angiogenesis, cell transformation, and other fundamental processes. The products of the SPL reaction contribute to phospholipid biosynthesis and programmed cell-death activation. The main features of SPL enzyme activity were first described in detail by Stoffel et al. in 1969. The first SPL-encoding gene was cloned from budding yeast in 1997. Reverse and forward genetic strategies led to the rapid identification of other genes in the pathway and their homologs in other species. Genetic manipulation of SPL-encoding genes in model organisms has revealed the contribution of sphingolipid metabolism to development, physiology, and host-pathogen interactions. In 2017, recessive mutations in the human SPL gene SGPL1 were identified as the cause of a novel inborn error of metabolism associated with nephrosis, endocrine defects, immunodeficiency, acanthosis, and neurological problems. We refer to this condition as SPL insufficiency syndrome (SPLIS). Here, we share our perspective on the 50-year history of SPL from discovery to disease, focusing on insights provided by model organisms regarding the pathophysiology of SPLIS and how SPLIS raises the possibility of a hidden role for sphingolipids in other disease conditions.

2FC3.3 Identification and characterization of a novel inborn error of metabolism caused by a defect in Dihydrofolate reductase

2FC3.3 Identification and characterization of a novel inborn error of metabolism caused by a defect in Dihydrofolate reductase

Neonatal intrahepatic cholestasis caused by citrin deficiency: Clinical and laboratory investigation of 13 subjects in mainland of China

Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is a novel inborn error of metabolism due to dysfunction of citrin protein, and much more information about this new disease is still needed for its clinical management. To investigate in detail the clinical and laboratory features of NICCD. 13 NICCD subjects in mainland of China diagnosed in our department since 2006. The anthropometric parameters of the patients at birth were compared with controls, representative biochemical changes and metabolome findings were investigated cross-sectionally, and mutations in the causative gene SLC25A13 were analyzed by protocols established previously. The patients showed reduced birth weight, length and ponderal index. Main clinical manifestations consisted of jaundice, hepato/hepatosplenomegaly and steatohepatosis on ultrasonography. Biochemical analysis revealed intrahepatic cholestasis, delayed switch of AFP to albumin, and elevated triglyceride, total cholesterol and LDL-cholesterol together with reduced HDL-cholesterol. Metabolome findings included co-existence of markers for galactosemia and tyrosinemia in urine, and elevated Cit, Met, Thr, Tyr, Lys, Arg and Orn in blood. Mutations of 851-854del, IVS6+5G>A, 1638-1660dup, A541D, IVS16ins3kb, R319X and G333D were detected in the gene SLC25A13. The diagnosis of NICCD cannot be established based just on the numerous but non-specific clinical manifestations and biochemical changes. The relatively specific metabolome features provide valuable tools for its screening and diagnosis, while SLC25A13 mutation analysis should be taken as one of the reliable tools for the definitive diagnosis. The body proportionality at birth, steatohepatosis on ultrasonography, delayed switch of AFP to albumin, dyslipidemia pattern, urinary metabolome features and the novel mutation G333D expanded the clinical spectrum of NICCD.

NMR spectroscopy of aminoacylase 1 deficiency, a novel inborn error of metabolism

Aminoacylase 1 deficiency is a novel inborn error of metabolism. The clinical significance of the deficiency is under discussion, as well as the possible consequences of the defect for brain metabolism and function. This study includes the five originally published cases as well as three novel ones. NMR spectroscopy of urine, serum and cerebrospinal fluid has been used to study these patients. A typical profile with 11 accumulating N-acetylated amino acids was observed in urine from the patients. The concentration of most of the accumulating metabolites is typically 100-500 micromol/mmol creatinine. Two additional minor N-acetylated metabolites remain unidentified. The concentrations of the accumulating metabolites are <20 micromol/L in serum from the patients. Interestingly we found no evidence of an increased concentration of N-acetylated amino acids in the cerebrospinal fluid from one patient. Our data define aminoacylase 1 deficiency at the metabolite level providing a specific urinary profile of accumulating N-acetylated amino acids.

NEUROLOGICAL FINDINGS IN AMINOACYLASE 1 DEFICIENCY

Recessive ACY1 mutations are responsible for a novel inborn error of metabolism.1 Consistent with ACY1 deficiency (MIM 609924), all affected individuals exhibited markedly increased urinary excretion of several N -acetylated amino acids. Aminoacylase 1 (ACY1) catalyzes the release of free amino acids from a variety of N -acylated precursors, but not from N -acetylaspartate.2 The latter is hydrolyzed by aminoacylase 2 (ACY2, aspartoacylase),2 a deficiency of which is the cause of the neurodegenerative Canavan disease (MIM 271900). ### Patients. Here, we report three additional unrelated children with ACY1 deficiency detected by routine urine screening for organic acidurias by gas chromatography–mass spectrometry.1,3 One individual (OS-138II-1) is the only child of Asian consanguineous parents. She presented with febrile seizures at 11 months of age followed by further seizure episodes 3 months later associated with a viral infection. At the age of 4 years, she displays delayed speech and language development. Another patient (OS-146II-1) is the second son of healthy Romani cousins. Two cousins and a niece of the …

Mutations in ACY1, the Gene Encoding Aminoacylase 1, Cause a Novel Inborn Error of Metabolism

N-terminal acetylation of proteins is a widespread and highly conserved process. Aminoacylase 1 (ACY1; EC 3.5.14) is the most abundant of the aminoacylases, a class of enzymes involved in hydrolysis of N-acetylated proteins. Here, we present four children with genetic deficiency of ACY1. They were identified through organic acid analyses using gas chromatography-mass spectrometry, revealing increased urinary excretion of several N-acetylated amino acids, including the derivatives of methionine, glutamic acid, alanine, leucine, glycine, valine, and isoleucine. Nuclear magnetic resonance spectroscopy analysis of urine samples detected a distinct pattern of N-acetylated metabolites, consistent with ACY1 dysfunction. Functional analyses of patients' lymphoblasts demonstrated ACY1 deficiency. Mutation analysis uncovered recessive loss-of-function or missense ACY1 mutations in all four individuals affected. We conclude that ACY1 mutations in these children led to functional ACY1 deficiency and excretion of N-acetylated amino acids. Questions remain, however, as to the clinical significance of ACY1 deficiency. The ACY1-deficient individuals were ascertained through urine metabolic screening because of unspecific psychomotor delay (one subject), psychomotor delay with atrophy of the vermis and syringomyelia (one subject), marked muscular hypotonia (one subject), and follow-up for early treated biotinidase deficiency and normal clinical findings (one subject). Because ACY1 is evolutionarily conserved in fish, frog, mouse, and human and is expressed in the central nervous system (CNS) in human, a role in CNS function or development is conceivable but has yet to be demonstrated. Thus, at this point, we cannot state whether ACY1 deficiency has pathogenic significance with pleiotropic clinical expression or is simply a biochemical variant. Awareness of this new genetic entity may help both in delineating its clinical significance and in avoiding erroneous diagnoses.

Aminoacylase I deficiency: A novel inborn error of metabolism

This is the first report of a patient with aminoacylase I deficiency. High amounts of N-acetylated amino acids were detected by gas chromatography–mass spectrometry in the urine, including the derivatives of serine, glutamic acid, alanine, methionine, glycine, and smaller amounts of threonine, leucine, valine, and isoleucine. NMR spectroscopy confirmed these findings and, in addition, showed the presence of N-acetylglutamine and N-acetylasparagine. In EBV transformed lymphoblasts, aminoacylase I activity was deficient. Loss of activity was due to decreased amounts of aminoacylase I protein. The amount of mRNA for the aminoacylase I was decreased. DNA sequencing of the encoding ACY1 gene showed a homozygous c.1057 C > T transition, predicting a p.Arg353Cys substitution. Both parents were heterozygous for the mutation. The mutation was also detected in 5/161 controls. To exclude the possibility of a genetic polymorphism, protein expression studies were performed showing that the mutant protein had lost catalytic activity.

ACY1 mutations cause aminoacylase 1 deficiency: A novel inborn error of metabolism

ACY1 mutations cause aminoacylase 1 deficiency: A novel inborn error of metabolism

Bile acids: from genomics to disease and therapyEdited by G. Paumgartner, D. Keppler, U. Leuschner, and A. Stiehl. 320 pp. $181.00. Kluwer Academic Publishers: the Netherlands, 2003. ISBN 0-79238-781-3. Web address for ordering: www.wkap.nl

Bile acids: from genomics to disease and therapyEdited by G. Paumgartner, D. Keppler, U. Leuschner, and A. Stiehl. 320 pp. $181.00. Kluwer Academic Publishers: the Netherlands, 2003. ISBN 0-79238-781-3. Web address for ordering: www.wkap.nl

A novel inborn error of metabolism detected by elevated methionine and/or galactose in newborn screening: neonatal intrahepatic cholestasis caused by citrin deficiency.

Adult-onset type II citrullinaemia, caused by deficiency of the citrin protein encoded by the SLC25A13 gene, is characterised by a liver-specific argininosuccinate synthetase deficiency. DNA analysis for citrin deficiency revealed that SLC25A13 mutations are the cause of a particular type of neonatal intrahepatic cholestasis. We retrospectively investigated nine infants with cholestatic jaundice of unknown origin, detected by newborn screening over a period of 17 years, to determine the role of SLC25A13 defects in children. The results of the newborn screening were varied; four neonates were positive for hypermethioninaemia, two for hyperphenylalaninaemia, one for hypergalactosaemia and two for both hypermethioninaemia and hypergalactosaemia. Clinical characteristics of the patients were severe intrahepatic cholestasis, hypercitrullinaemia, and fatty liver. The symptoms resolved in all patients by 12 months of age without special treatment other than nutritional management. Although five patients were lost to follow-up, we detected SLC25A13 mutations in the remaining four patients examined. the differential diagnosis of cholestatic jaundice of unknown origin in infants should therefore include citrin deficiency. In this paper, we stress the importance of newborn screening to detect infants with neonatal intrahepatic cholestasis caused by citrin deficiency.

β‐Ureidopropionase deficiency: A novel inborn error of metabolism discovered using NMR spectroscopy on urine

In this work, NMR investigations that led to the discovery of a new inborn error of metabolism, β-ureidopropionase (UP) deficiency, are reported. 1D 1H-NMR experiments were performed using a patient's urine. 3-Ureidopropionic acid was observed in elevated concentrations in the urine spectrum. A 1D 1H-1H total correlation spectroscopy (TOCSY) and two heteronuclear 2D NMR techniques (heteronuclear multiple bond correlation (HMBC) and heteronuclear single-quantum correlation (HSQC)) were used to identify the molecular structure of the compound that caused an unknown doublet resonance at 1.13 ppm. Combining the information from the various NMR spectra, this resonance could be assigned to 3-ureidoisobutyric acid. These observations suggested a deficiency of UP. With 1D 1H-NMR spectroscopy, UP deficiency can be easily diagnosed. The 1H-NMR spectrum can also be used to diagnose patients suffering from other inborn errors of metabolism in the pyrimidine degradation pathway. Magn Reson Med 46:1014–1017, 2001. © 2001 Wiley-Liss, Inc.

β‐Ureidopropionase deficiency: A novel inborn error of metabolism discovered using NMR spectroscopy on urine

In this work, NMR investigations that led to the discovery of a new inborn error of metabolism, beta-ureidopropionase (UP) deficiency, are reported. 1D (1)H-NMR experiments were performed using a patient's urine. 3-Ureidopropionic acid was observed in elevated concentrations in the urine spectrum. A 1D (1)H-(1)H total correlation spectroscopy (TOCSY) and two heteronuclear 2D NMR techniques (heteronuclear multiple bond correlation (HMBC) and heteronuclear single-quantum correlation (HSQC)) were used to identify the molecular structure of the compound that caused an unknown doublet resonance at 1.13 ppm. Combining the information from the various NMR spectra, this resonance could be assigned to 3-ureidoisobutyric acid. These observations suggested a deficiency of UP. With 1D (1)H-NMR spectroscopy, UP deficiency can be easily diagnosed. The (1)H-NMR spectrum can also be used to diagnose patients suffering from other inborn errors of metabolism in the pyrimidine degradation pathway.

Creatine replacement therapy in guanidineoacetate methyltransferase deficiency, a novel inborn error of metabolism

The creatine/creatine-phosphate system is essential for the storage and transmission of phosphate-bound energy in muscle and brain. In infants, inefficiency or failure of this metabolic pathway can impair the development of motor control and mentation. We studied and treated an infant with extrapyramidal signs who was shown--by assay for urinary creatinine and by analysis of brain metabolites with use of nuclear magnetic resonance spectra--to have depletion of body and brain creatine, due to inborn deficiency of guanidinoacetate methyltransferase (GAMT). Long-term oral administration of creatine-monohydrate (4-8 g per day) to this index patient resulted in substantial clinical improvement, disappearance of magnetic resonance (MRI) signal abnormalities in the globus pallidus, and normalisation of slow background activity on the electroencephalogram (EEG). During the 25-month treatment period, both brain and total body creatine concentrations became normal. Oral creatine replacement has proved to be effective in one child with an inborn error of GAMT. It may well be effective in the treatment of other disorders of creatine synthesis.