DNA damage and transcription stress cause ATP-mediated redesign of metabolism and potentiation of anti-oxidant buffering.

Accumulation of DNA lesions causing transcription stress is associated with natural and accelerated aging and culminates with profound metabolic alterations. Our understanding of the mechanisms governing metabolic redesign upon genomic instability, however, is highly rudimentary. Using Ercc1-defective mice and Xpg knock-out mice, we demonstrate that combined defects in transcription-coupled DNA repair (TCR) and in nucleotide excision repair (NER) directly affect bioenergetics due to declined transcription, leading to increased ATP levels.

Laboratory diagnosis of creatine deficiency syndromes: a technical standard and guideline of the American College of Medical Genetics and Genomics.

Disclaimer: These ACMG Standards and Guidelines are intended as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these standards and guidelines is voluntary and does not necessarily assure a successful medical outcome. These Standards and Guidelines should not be considered inclusive of all proper procedures and tests or exclusive of others that are reasonably directed to obtaining the same results.

A haploproficient interaction of the transaldolase paralogue NQM1 with the transcription factor VHR1 affects stationary phase survival and oxidative stress resistance.

Background: Studying the survival of yeast in stationary phase, known as chronological lifespan, led to the identification of molecular ageing factors conserved from yeast to higher organisms. To identify functional interactions among yeast chronological ageing genes, we conducted a haploproficiency screen on the basis of previously identified long-living mutants. For this, we created a library of heterozygous Saccharomyces cerevisiae double deletion strains and aged them in a competitive manner.

Continuous age- and sex-adjusted reference intervals of urinary markers for cerebral creatine deficiency syndromes: a novel approach to the definition of reference intervals.

Background: Urinary concentrations of creatine and guanidinoacetic acid divided by creatinine are informative markers for cerebral creatine deficiency syndromes (CDSs). The renal excretion of these substances varies substantially with age and sex, challenging the sensitivity and specificity of postanalytical interpretation.

Methods: Results from 155 patients with CDS and 12 507 reference individuals were contributed by 5 diagnostic laboratories.

First two unrelated cases of isolated sedoheptulokinase deficiency: A benign disorder?

We present the first two reported unrelated patients with an isolated sedoheptulokinase (SHPK) deficiency. The first patient presented with neonatal cholestasis, hypoglycemia, and anemia, while the second patient presented with congenital arthrogryposis multiplex, multiple contractures, and dysmorphisms. Both patients had elevated excretion of erythritol and sedoheptulose, and each had a homozygous nonsense mutation in SHPK.

The return of metabolism: biochemistry and physiology of the pentose phosphate pathway.

The pentose phosphate pathway (PPP) is a fundamental component of cellular metabolism. The PPP is important to maintain carbon homoeostasis, to provide precursors for nucleotide and amino acid biosynthesis, to provide reducing molecules for anabolism, and to defeat oxidative stress. The PPP shares reactions with the Entner-Doudoroff pathway and Calvin cycle and divides into an oxidative and non-oxidative branch.

Clinical characterization, genetic mapping and whole-genome sequence analysis of a novel autosomal recessive intellectual disability syndrome.

We identified six patients presenting with a strikingly similar clinical phenotype of profound syndromic intellectual disability of unknown etiology. All patients lived in the same village. Extensive genealogical work revealed that the healthy parents of the patients were all distantly related to a common ancestor from the 17th century, suggesting autosomal recessive inheritance.

Clinical and molecular characteristics of two transaldolase-deficient patients.

Unlabelled: Transaldolase (TALDO) deficiency is a rare metabolic disease in the pentose phosphate pathway, which manifests as a severe, early-onset multisystem disease. The body fluids of affected patients contain increased polyol concentrations and seven-carbon chain carbohydrates. We report the molecular and clinical findings in two recently diagnosed transaldolase-deficient children, both presented at birth.

Novel association of early onset hepatocellular carcinoma with transaldolase deficiency.

We evaluated a family with a 16-month-old boy with cirrhosis and hepatocellular carcinoma and his 30-month-old brother with cirrhosis. After failing to identify a diagnosis after routine metabolic evaluation, we utilized a combination of RNA-Seq and whole exome sequencing to identify a novel homozygous p.Ser171Phe Transaldolase (TALDO1) variant in the proband, his brother with cirrhosis, as well as a clinically asymptomatic older 8-year-old brother.

Pulmonary manifestations in a patient with transaldolase deficiency.

Transaldolase deficiency is a newly recognized metabolic disorder. It is an autosomal recessive genetic disease (OMIM #606003). The effects of the defect in the TALDO gene are pleiotropic with a clinical presentation of growth retardation, dysmorphic features, cutis laxa, congenital heart disease, hepatosplenomegaly, pancytopenia, and bleeding tendencies.

Transaldolase deficiency: report of 12 new cases and further delineation of the phenotype.

Purpose: Transaldolase deficiency is a recently described inborn error of pentose phosphate pathway. We conducted this study to further delineate the associated phenotype.

Methods And Results: We report on 12 new cases representing six families with this metabolic defect that were observed over an 8 year span.

Nephrological abnormalities in patients with transaldolase deficiency.

Background: Transaldolase deficiency (OMIM 606003) is a multisystem disorder first described in 2001. Transaldolase is an enzyme of the reversible part of the pentose phosphate pathway. Affected patients have abnormal polyol concentrations in body fluids, mostly in urine.

Pyruvate kinase triggers a metabolic feedback loop that controls redox metabolism in respiring cells.

In proliferating cells, a transition from aerobic to anaerobic metabolism is known as the Warburg effect, whose reversal inhibits cancer cell proliferation. Studying its regulator pyruvate kinase (PYK) in yeast, we discovered that central metabolism is self-adapting to synchronize redox metabolism when respiration is activated. Low PYK activity activated yeast respiration.

The pentose phosphate pathway is a metabolic redox sensor and regulates transcription during the antioxidant response.

Aims: A shift in primary carbon metabolism is the fastest response to oxidative stress. Induced within seconds, it precedes transcriptional regulation, and produces reducing equivalents in form of NADPH within the pentose phosphate pathway (PPP).

Results: Here, we provide evidence for a regulatory signaling function of this metabolic transition in yeast.

Mitochondrial involvement and erythronic acid as a novel biomarker in transaldolase deficiency.

Background: Sedoheptulose, arabitol, ribitol, and erythritol have been identified as key diagnostic metabolites in TALDO deficiency.

Method: Urine from 6 TALDO-deficient patients and TALDO-deficient knock-out mice were analyzed using ¹H-NMR spectroscopy and GC-mass spectrometry.

Results: Our data confirm the known metabolic characteristics in TALDO-deficient patients.

The difference between rare and exceptionally rare: molecular characterization of ribose 5-phosphate isomerase deficiency.

Ribose 5-phosphate isomerase (RPI) deficiency is an enzymopathy of the pentose phosphate pathway. It manifests with progressive leukoencephalopathy and peripheral neuropathy and belongs, with one sole diagnosed case, to the rarest human disorders. The single patient was found compound heterozygous for a RPI frameshift and a missense (RPI(Ala61Val)) allele.

Transaldolase deficiency in two new patients with a relative mild phenotype.

Transaldolase (TALDO) deficiency is a recently described inborn error of metabolism of the pentose phosphate pathway that so far has been diagnosed in only eight patients. In this article, we report the clinical course and biochemical findings of two newly identified patients with TALDO deficiency-two sons of consanguineous parents from Polish origin, presenting with neonatal onset of bleeding diathesis, haemolytic anemia, thrombocytopenia and hepatosplenomegaly. Subsequently the patients had persistent thrombocytopenia, a bleeding tendency, impaired liver function and fibrosis.

A catabolic block does not sufficiently explain how 2-deoxy-D-glucose inhibits cell growth.

The glucose analogue 2-deoxy-D-glucose (2-DG) restrains growth of normal and malignant cells, prolongs the lifespan of C. elegans, and is widely used as a glycolytic inhibitor to study metabolic activity with regard to cancer, neurodegeneration, calorie restriction, and aging. Here, we report that separating glycolysis and the pentose phosphate pathway highly increases cellular tolerance to 2-DG.

Transaldolase deficiency in a two-year-old boy with cirrhosis.

Transaldolase (TALDO) deficiency is a rare inborn error of the pentose phosphate pathway. We report the clinical presentation and laboratory findings of a new patient with TALDO deficiency. The two-year-old Arabic boy presented with neonatal onset of anemia and thrombocytopenia, tubulopathy, and rickets and was subsequently found to have cirrhosis and deafness.

Sedoheptulokinase deficiency due to a 57-kb deletion in cystinosis patients causes urinary accumulation of sedoheptulose: elucidation of the CARKL gene.

The most common mutation in the nephropathic cystinosis (CTNS) gene is a homozygous 57-kb deletion that also includes an adjacent gene carbohydrate kinase-like (CARKL). The latter gene encodes a protein that is predicted to function as a carbohydrate kinase. Cystinosis patients with the common 57-kb deletion had strongly elevated urinary concentrations of sedoheptulose (28-451 mmol/mol creatinine; controls and other cystinosis patients <9) and erythritol (234-1110 mmol/mol creatinine; controls and other cystinosis patients <148).

Dynamic rerouting of the carbohydrate flux is key to counteracting oxidative stress.

Background: Eukaryotic cells have evolved various response mechanisms to counteract the deleterious consequences of oxidative stress. Among these processes, metabolic alterations seem to play an important role.

Results: We recently discovered that yeast cells with reduced activity of the key glycolytic enzyme triosephosphate isomerase exhibit an increased resistance to the thiol-oxidizing reagent diamide.

Quantification of sugar phosphate intermediates of the pentose phosphate pathway by LC-MS/MS: application to two new inherited defects of metabolism.

We describe a liquid chromatography tandem mass spectrometry (LC-MS/MS) method to quantify pentose phosphate pathway intermediates (triose-3-phosphates, tetrose-4-phosphate, pentose-5-phosphate, pentulose-5-phosphates, hexose-6-phosphates and sedoheptulose-7-phosphate (sed-7P)) in bloodspots, fibroblasts and lymphoblasts. Liquid chromatography was performed using an ion pair loaded C(18) HPLC column and detection of the sugar phosphates was carried out by tandem mass spectrometry using an electron ion spray source operating in the negative mode and multiple reaction monitoring. Reference values for the pentose phosphate pathway intermediates in blood spots, fibroblasts and lymphoblasts were established.