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Patients with urea cycle disorders intermittently develop episodes of decompensation with hyperammonemia. Although such an episode is often associated with starvation and catabolism, its molecular basis is not fully understood. First, we attempted to elucidate the mechanism of such starvation‐associated hyperammonemia. Using a mouse embryonic fibroblast (MEF) culture system, we found that glucose starvation increases ammonia production, and that this increase is associated with enhanced glutaminolysis. These results led us to focus on α‐ketoglutarate (AKG), a glutamate dehydrogenase inhibitor, and a major anaplerotic metabolite. Hence, we sought to determine the effect of dimethyl α‐ketoglutarate (DKG), a cell‐permeable AKG analog, on MEFs and found that DKG mitigates ammonia production primarily by reducing flux through glutamate dehydrogenase. We also verified that DKG reduces ammonia in an NH4Cl‐challenged hyperammonemia mouse model and observed that DKG administration reduces plasma ammonia concentration to 22.8% of the mean value for control mice that received only NH4Cl. In addition, we detected increases in ornithine concentration and in the ratio of ornithine to arginine following DKG treatment. We subsequently administered DKG intravenously to a newborn pig with hyperammonemia due to ornithine transcarbamylase deficiency and found that blood ammonia concentration declined significantly over time. We determined that this effect is associated with facilitated reductive amination and glutamine synthesis. Our present data indicate that energy starvation triggers hyperammonemia through enhanced glutaminolysis and that DKG reduces ammonia accumulation via pleiotropic mechanisms both in vitro and in vivo. Thus, cell‐permeable forms of AKG are feasible candidates for a novel hyperammonemia treatment. [ABSTRACT FROM AUTHOR]

Abstract Introduction Ornithine transcarbamylase deficiency is the most common hereditary urea cycle defect. It is inherited in an X-linked manner and classically presents in neonates with encephalopathy and hyperammonemia in males. Females and males with hypomorphic mutations present later, sometimes in adulthood, with episodes that are frequently fatal. Case presentation A 13-year-old Caucasian girl presented with progressive encephalopathy, hyperammonemic coma and lactic acidosis. She had a history of intermittent regular episodes of nausea and vomiting from seven years of age, previously diagnosed as abdominal migraines. At presentation she was hyperammonemic (ammonia 477 μmol/L) with no other biochemical indicators of hepatic dysfunction or damage and had grossly elevated urinary orotate (orotate/creatinine ratio 1.866 μmol/mmol creatinine, reference range A) mutation was identified in the ornithine transcarbamylase gene (OTC) in our patient confirming the first symptomatic female shown heterozygous for the R40H mutation. A review of the literature and correspondence with authors of patients with the R40H mutation identified one other symptomatic female patient who died of hyperammonemic coma in her late teens. Conclusions This report expands the clinical spectrum of presentation of ornithine transcarbamylase deficiency to female heterozygotes for the hypomorphic R40H OTC mutation. Although this mutation is usually associated with a mild phenotype, females with this mutation can present with acute decompensation, which can be fatal. Ornithine transcarbamylase deficiency should be considered in the differential diagnosis of unexplained acute confusion, even without a suggestive family history.

Importance: Sapropterin hydrochloride, a natural coenzyme (6R‐tetrahydrobiopterin) of phenylalanine hydroxylase, was first approved as a treatment for tetrahydrobiopterin deficiency in 1992 in Japan, and was then approved as a treatment for a tetrahydrobiopterin‐responsive hyperphenylalaninemia in 2007 and 2008, in the USA and Japan, respectively. Guidelines are required on the proper use of sapropterin hydrochloride for tetrahydrobiopterin‐responsive hyperphenylalaninemia. Observations: It is recommended that tetrahydrobiopterin‐responsive hyperphenylalaninemia should be diagnosed in all cases of hyperphenylalaninemia, including phenylketonuria, by tetrahydrobiopterin administration tests rather than by phenotype or blood phenylalanine levels. Conclusions and Relevance: If tetrahydrobiopterin‐responsive hyperphenylalaninemia is diagnosed, all ages can be treated with sapropterin hydrochloride. Although there are reports that sapropterin hydrochloride is effective and safe for the prevention of maternal phenylketonuria, further investigation is required. [ABSTRACT FROM AUTHOR]

Introduction: Ornithine transcarbamylase deficiency is the most common hereditary urea cycle defect. It is inherited in an X-linked manner and classically presents in neonates with encephalopathy and hyperammonemia in males. Females and males with hypomorphic mutations present later, sometimes in adulthood, with episodes that are frequently fatal.Case Presentation: A 13-year-old Caucasian girl presented with progressive encephalopathy, hyperammonemic coma and lactic acidosis. She had a history of intermittent regular episodes of nausea and vomiting from seven years of age, previously diagnosed as abdominal migraines. At presentation she was hyperammonemic (ammonia 477 μmol/L) with no other biochemical indicators of hepatic dysfunction or damage and had grossly elevated urinary orotate (orotate/creatinine ratio 1.866 μmol/mmol creatinine, reference range <500 μmol/mmol creatinine) highly suggestive of ornithine transcarbamylase deficiency. She was treated with intravenous sodium benzoate and arginine and made a rapid full recovery. She was discharged on a protein-restricted diet. She has not required ongoing treatment with arginine, and baseline ammonia and serum amino acid concentrations are within normal ranges. She has had one further episode of hyperammonemia associated with intercurrent infection after one year of follow up. An R40H (c.119G>A) mutation was identified in the ornithine transcarbamylase gene (OTC) in our patient confirming the first symptomatic female shown heterozygous for the R40H mutation. A review of the literature and correspondence with authors of patients with the R40H mutation identified one other symptomatic female patient who died of hyperammonemic coma in her late teens.Conclusions: This report expands the clinical spectrum of presentation of ornithine transcarbamylase deficiency to female heterozygotes for the hypomorphic R40H OTC mutation. Although this mutation is usually associated with a mild phenotype, females with this mutation can present with acute decompensation, which can be fatal. Ornithine transcarbamylase deficiency should be considered in the differential diagnosis of unexplained acute confusion, even without a suggestive family history. [ABSTRACT FROM AUTHOR]

We performed haplotype analysis using nine single nucleotide polymorphisms in the ornithine transcarbamylase gene to explore the ancestral origins of three mutations associated with late-onset phenotype in male patients: p.R40H, p.R277W and p.Y55D. Overall, 8 haplotypes were defined among 14 families carrying p.R40H, 5 families carrying p.R277W and 2 families with p.Y55D mutations. Of nine Japanese families carrying p.R40H, eight exhibited haplotype (HT)1, whereas the other family harbored HT2. Among three Caucasian families, one Spanish and one Australian family bore HT3; one Austrian family had HT4. Two US patients harbored HT2 and HT4. Among families carrying p.R277W, HT5 was found in one Japanese, one Korean and one US family. Two other US families had HT2 and HT6. Two families carrying p.Y55D, both Japanese, shared HT1. These results indicate that the p.R40H mutation has arisen recurrently in all populations studied, although there is evidence for a founder effect in Japan, with most cases probably sharing a common origin, and to a lesser extent in subjects of European ancestry (HT3). It is evident that p.R277W mutation has recurred in discrete populations. The p.Y55D mutation appears to have arisen from a common ancestor, because this transversion (c.163T>G) occurs rarely. [ABSTRACT FROM AUTHOR]

Mucolipidosis (ML) II alpha/beta and III alpha/beta are autosomal recessive diseases caused by a deficiency of α and/or β subunits of the enzyme N-acetylglucosamine-1-phosphotransferase, which is encoded by the GNPTAB gene. We analyzed the GNPTAB gene in 25 ML II and 15 ML III Japanese patients. In most ML II patients, the clinical conditions ‘stand alone’, ‘walk without support’ and ‘speak single words’ were impaired; however, the frequency of ‘heart murmur’, ‘inguinal hernia’ and ‘hepatomegaly and/or splenomegaly’ did not differ between ML II and III patients. We detected mutations in GNPTAB in 73 of 80 alleles. Fourteen new mutations were c.914_915insA, c.2089_2090insC, c.2427delC, c.2544delA, c.2693delA, c.3310delG, c.3388_3389insC+c.3392C>T, c.3428_3429insA, c.3741_3744delAGAA, p.R334L, p.F374L, p.H956Y, p.N1153S and duplication of exon 2. Previously reported mutations were p.Q104X, p.W894X, p.R1189X and c.2715+1G>A causing skipping of exon 13. Homozygotes or compound heterozygotes of nonsense and frameshift mutations contributed to the severe phenotype. p.F374L, p.N1153S and splicing mutations contributed to the attenuated phenotype, although coupled with nonsense mutation. These results show the effective molecular diagnosis of ML II and III and also provide phenotypic prediction. This is the first and comprehensive report of molecular analysis for ML patients of Japanese origin.Journal of Human Genetics (2009) 54, 145–151; doi:10.1038/jhg.2009.3; published online 6 February 2009 [ABSTRACT FROM AUTHOR]

A series of star-like poly(ethylene oxide)s were synthesized using anhydride-terminated hyperbranched polyimides as the central cores and poly(ethylene oxide)s (PEOs) as the linear arms. Their physical and gas permeation properties were investigated in comparison with those of PEO segmented block copolyimides (PEOPIs). The solubility of star-like PEOs was affected by the terminal groups. The amine- terminated star-like PEOs displayed better solubility property than the methoxy- and acetamido-terminated ones. The DSC and dynamic mechanical spectroscopy suggested the morphology of star-like PEOs was different from that of PEO-PIs. The thermo-mechanical property of amine-terminated star-like PEOs was significantly improved by cross- linking with ethylene glycol diglycidyl ether. The star-like PEO membranes were much more permeable to CO2 than to N2 and even to H2. However, their CO2 separation performance was slightly lower than that of PEO- PIs, probably due to the difference in the morphology. The AgBF4-doped star-like PEO membrane with a loading of 40 wt% (corresponding to 67 wt% in PEO matrix) showed a very high ideal selectivity of C2H4/C2H6 of more than 100 with a low ethylene permeability of 1.5 x 10-10 cm³ (STP) cm-1 s-1 cm Hg- 1 in single-component permeation at 2 atm and 308 K. However, the permselectivity decreased down to 14 in mixed gas permeation. The permeation behavior was discussed based on the solubility and diffusivity. [ABSTRACT FROM AUTHOR]

Effects of pyrolysis and preparation conditions on the gas permeation properties of pyrolytic membranes derived from sulfonated phenolic resin were investigated. Pyrolysis temperature, dip-coating conditions and coating/pyrolysis (C/P) cycle had significant influence on the gas permeation properties of pyrolytic membranes. Membrane obtained under optimum preparation conditions exhibited O2 permeance of 30 GPU and ideal O2/N2 separation factor of 12 at 35 °C, which are comparable to the O2/N2 separation performances of carbon molecular sieve (CMS) membranes on the upper-bound line in the plots of permeance versus selectivity. N2 adsorption and desorption at 77 K suggested that the pore structures of CMS membranes pyrolyzed around 500 °C seemed to be made up of interconnected pores with different size and shape. [Copyright &y& Elsevier]

Carbonized membranes were prepared by pyrolyzing an asymmetric hollow fiber membrane of a copolyimide from equimolar portion of 2,2-bis(3,4-dicarboxyphenyl)hexafluoro-propane dianhydride (6FDA) and 3,3′,4,4′-biphenyltetracarboxylic dianhydride (BPDA) with 3,7-diamino-2,8(6)-dimethyldibenzothiophene sulfone (DDBT) at temperatures of 773–973 K under a nitrogen stream. The carbonized membranes had an asymmetric structure with a skin layer of around 200 nm in thickness and a much denser support layer compared with the precursor hollow fiber. The increase in permeance to propylene RC3H6 by the pyrolysis was up to 10 times. An appropriate holding time during the pyrolysis in a nitrogen stream tended to increase the olefin/paraffin selectivity. The membranes pyrolyzed at 813 K for 1 h displayed the best performance of RC3H6=26 GPU and αC3H6/C3H8=22 for mixed-component (50/50%) at 373 K and 1 atm. The effect of silicone rubber coating was also investigated. [Copyright &y& Elsevier]

Gas permeation properties of asymmetric hollow fiber membrane of copolyimide prepared from equimolar portion of 2,2-bis(3,4-dicarboxyphenyl)hexafluoropropane dianhydride (6FDA) and 3,3′,4,4′-biphenyltetracarboxylic dianhydride (BPDA) with 3,7-diamino-2,8(6)-dimethyldibenzothiophene sulfone (DDBT) were investigated for single-component light gases, olefins and paraffins and for mixed components of C3H6/C3H8 and C4H6/C4H10. The gas permeability of the copolyimide film was close to that of 6FDA–DDBT polyimide and much larger than that of BPDA–DDBT. Gas permeance of the asymmetric copolyimide hollow fiber membrane decreased significantly in the first several months and leveled off after about 10 months of aging. The skin layer thickness calculated from the gas permeability and permeance was in the range of 0.6 (for H2) to 1.7 μm (for C3H6) and about 10 times larger than the thickness estimated from the SEM observation. These results indicated that the significant densification of the skin layer was caused by physical aging. The silicone rubber coating hardly changed the selectivity for light gas pairs such as H2/CH4 and O2/N2, but enhanced that for C3H6/C3H8 and C4H6/C4H10 significantly especially at low temperatures. The evaluation of membrane quality based on the resistance model suggested that the extremely small surface porosity of defect pores significantly reduced the selectivity for the larger gas pairs. The asymmetric copolyimide hollow fiber membrane displayed better performance for C3H6/C3H8 and C4H6/C4H10: for example, permeances of C3H6 and C4H6 of 3.6 and 7.4 GPU, respectively, and separation factors of 15 and 69 for C3H6/C3H8 and C4H6/C4H10 (50/50 mol% in feed) at 373 K and 1 atm. [Copyright &y& Elsevier]

Examines the management of acute metabolic decompensation in maple syrup urine disease (MSUD). Clinical phenotypes of MSUD; Therapeutic measures employed toward metabolic decompensation; Number of patients in the study who developed episodes of ketoacidosis during the neonatal period.

Primary systemic carnitine deficiency (SCD; OMIM 212140) is an autosomal recessive disorder characterized by progressive cardiomyopathy, skeletal myopathy, hypoglycaemia and hyperammonaemia. SCD has also been linked to sudden infant death syndrome. Membrane-physiological studies have suggested a defect of the carnitine transport system in the plasma membrane in SCD patients and in the mouse model, juvenile visceral steatosis (jvs; ref. 6). Although the responsible loci have been mapped in both human and mouse, the underlying gene has not yet been identified. Recently, we cloned and analysed the function of a novel transporter protein termed OCTN2 ( ref. 9). Our observation that OCTN2 has the ability to transport carnitine in a sodium-dependent manner prompted us to search for mutations in the gene encoding OCTN2, SLC22A5. Initially, we analysed the mouse gene and found a missense mutation in Slc22a5 in jvs mice. Biochemical analysis revealed that this mutation abrogates carnitine transport. Subsequent analysis of the human gene identified four mutations in three SCD pedigrees. Affected individuals in one family were homozygous for the deletion of a 113-bp region containing the start codon. In the second pedigree, the affected individual was shown to be a compound heterozygote for two mutations that cause a frameshift and a premature stop codon, respectively. In an affected individual belonging to a third family, we found a homozygous splice-site mutation also resulting in a premature stop codon. These mutations provide the first evidence that loss of OCTN2 function causes SCD. [ABSTRACT FROM AUTHOR]

Abstract: This is the first report for a Japanese case of arthrochalasia type of Ehlers–Danlos syndrome (EDS). A 46-year-old woman consulted us for joint hypermobility and skin hyperextensibility that had been present soon after birth. There was no family history of a similar disease. She was diagnosed as having bilateral congenital hip dislocation and bilateral habitual shoulder dislocation at her childhood. Her skin was velvety, doughy and hyperextensible. She showed hypermobility of the joints of the hands and feet and generalized joint laxity, with no evidence of scoliosis. Electrophoretic analysis of collagenous proteins revealed the presence of an additional band in the position of pNα2(I) in the sample from culture medium of the patient fibroblasts. Analysis of the α2 chains of type I collagen gene, COL1A2, showed a heterozygous G to T transition at the +1 position of the exon 6 donor splice site (c.279+1G>T). This mutation resulted in skipping of exon 6, which leads to deficient processing of the amino-terminal end of proα2(I) chains of type I collagen. Based on these findings, we made a diagnosis of the arthrochalasia type of EDS, which corresponds to EDS type VIIB in the former classification. [Copyright &y& Elsevier]