TY - JOUR AB - Dihydrolipoamide dehydrogenase deficiency (MIM 246900/DLDD) is an autosomal recessive mitochondrial disease with three clinical subgroups. The hepatic form leads to recurrent metabolic decompensations often accompanied by elevated levels of liver transaminases (ELT) in blood, sometimes progressing to acute liver failure (ALF). Genetically, it is linked to the p.G229C variant in the DLD gene, which has been reported in the Ashkenazi Jewish and Arabic population. In this study, we analyzed phenotypic diversity, therapeutic management, and outcome in novel symptomatic individuals with hepatic DLDD identified by whole exome sequencing (n = 7) in Central Europe as well as in previously reported cases (n = 45). Fifty-one of 52 DLDD patients carried the p.G229C variant (39 in a homozygous state). During decompensations, precipitated by febrile infectious disease or fasting, affected individuals presented with nausea, vomiting, abdominal pain, hepatomegaly, hypoglycemia, and lactic acidosis. In individuals homozygous for the p.G229C variant, neurologic manifestations were rare, whereas mild neurologic symptoms were found in individuals (n = 8) carrying a different DLD variant in trans. During decompensation, levels of specific plasma amino acids like citrulline or branched-chain amino acids, and urinary organic acids, like 2-oxoglutaric acid, were frequently elevated. However, known biomarkers-with the exception of lactate-were not consistently elevated during these episodes and typically normal in the interval, highlighting the usefulness of early genetic testing in all children with unexplained ELT or ALF to reduce the time to diagnosis. While there exists consensus for rescue therapy with intravenous glucose during decompensations and maintenance therapy with riboflavin, therapies with thiamine and antioxidants (e.g., N-acetylcysteine) were reported to be useful in single individuals with recurrent decompensations. AU - Hammann, N.* AU - Staufner, C.* AU - Schlieben, L.D. AU - Dezsőfi-Gottl, A.* AU - Feichtinger, R.G.* AU - Häberle, J.* AU - Junge, N.* AU - Konstantopoulou, V.* AU - Kopajtich, R. AU - McLin, V.* AU - Rymen, D.* AU - Slavetinsky, C.* AU - Sturm, E.* AU - Mayr, J.A.* AU - Wagner, M. AU - Kölker, S.* AU - Prokisch, H. AU - Hoffmann, G.F.* AU - Lenz, D.* C1 - 74671 C2 - 57554 CY - 111 River St, Hoboken 07030-5774, Nj Usa TI - Hepatic form of dihydrolipoamide dehydrogenase deficiency (DLDD): Phenotypic spectrum, laboratory findings, and therapeutic approaches in 52 patients. JO - J. Inherit. Metab. Dis. VL - 48 IS - 3 PB - Wiley PY - 2025 SN - 0141-8955 ER - TY - JOUR AB - Among genetic disorders of vesicular trafficking, there are three causing recurrent acute liver failure (RALF): NBAS, RINT1, and SCYL1-associated disease. These three disorders are characterized by liver crises triggered by febrile infections and account for a relevant proportion of RALF causes. While the frequency and severity of liver crises in NBAS and RINT1-associated disease decrease with age, patients with SCYL1 variants present with a progressive, cholestatic course. In all three diseases, there is a multisystemic, partially overlapping phenotype with variable expression, including liver, skeletal, and nervous systems, all organ systems with high secretory activity. There are no specific biomarkers for these diseases, and whole exome sequencing should be performed in patients with RALF of unknown etiology. NBAS, SCYL1, and RINT1 are involved in antegrade and retrograde vesicular trafficking. Pathomechanisms remain unclarified, but there is evidence of a decrease in concentration and stability of the protein primarily affected by the respective gene defect and its interaction partners, potentially causing impairment of vesicular transport. The impairment of protein secretion by compromised antegrade transport provides a possible explanation for different organ manifestations such as bone alteration due to lack of collagens or diabetes mellitus when insulin secretion is affected. Dysfunction of retrograde transport impairs membrane recycling and autophagy. The impairment of vesicular trafficking results in increased endoplasmic reticulum stress, which, in hepatocytes, can progress to hepatocytolysis. While there is no curative therapy, an early and consequent implementation of an emergency protocol seems crucial for optimal therapeutic management. AU - Peters, B.* AU - Dattner, T.* AU - Schlieben, L.D. AU - Sun, T.* AU - Staufner, C.* AU - Lenz, D.* C1 - 69852 C2 - 55283 CY - 111 River St, Hoboken 07030-5774, Nj Usa TI - Disorders of vesicular trafficking presenting with recurrent acute liver failure: NBAS, RINT1, and SCYL1 deficiency. JO - J. Inherit. Metab. Dis. PB - Wiley PY - 2024 SN - 0141-8955 ER - TY - JOUR AB - Coenzyme A (CoA) is an essential cofactor required for over a hundred metabolic reactions in the human body. This cofactor is synthesized de novo in our cells from vitamin B5, also known as pantothenic acid, a water-soluble vitamin abundantly present in vegetables and animal-based foods. Neurodegenerative disorders, cancer, and infectious diseases have been linked to defects in de novo CoA biosynthesis or reduced levels of this coenzyme. There is now accumulating evidence that CoA limitation is a critical pathomechanism in cardiac dysfunction too. In the current review, we will summarize our current knowledge on CoA and heart failure, with emphasis on two primary cardiomyopathies, phosphopantothenoylcysteine synthetase and phosphopantothenoylcysteine decarboxylase deficiency disorders biochemically characterized by a decreased level of CoA in patients' samples. Hence, we will discuss the potential benefits of CoA restoration in these diseases and, more generally, in heart failure, by vitamin B5 and its derivatives pantethine and 4'-phosphopantetheine. AU - Wedman, J.J.* AU - Sibon, O.C.M.* AU - Mastantuono, E.* AU - Iuso, A. C1 - 70416 C2 - 55608 CY - 111 River St, Hoboken 07030-5774, Nj Usa TI - Impaired coenzyme A homeostasis in cardiac dysfunction and benefits of boosting coenzyme A production with vitamin B5 and its derivatives in the management of heart failure. JO - J. Inherit. Metab. Dis. PB - Wiley PY - 2024 SN - 0141-8955 ER - TY - JOUR AB - Over the past decade high-throughput DNA sequencing approaches, namely whole exome and whole genome sequencing became a standard procedure in Mendelian disease diagnostics. Implementation of these technologies greatly facilitated diagnostics and shifted the analysis paradigm from variant identification to prioritisation and evaluation. The diagnostic rates vary widely depending on the cohort size, heterogeneity and disease and range from around 30% to 50% leaving the majority of patients undiagnosed. Advances in omics technologies and computational analysis provide an opportunity to increase these unfavourable rates by providing evidence for disease-causing variant validation and prioritisation. This review aims to provide an overview of the current application of several omics technologies including RNA-sequencing, proteomics, metabolomics and DNA-methylation profiling for diagnostics of rare genetic diseases in general and inborn errors of metabolism in particular. AU - Smirnov, D. AU - Konstantinovskiy, N.* AU - Prokisch, H. C1 - 68016 C2 - 54494 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 824-838 TI - Integrative omics approaches to advance rare disease diagnostics. JO - J. Inherit. Metab. Dis. VL - 46 IS - 5 PB - Wiley PY - 2023 SN - 0141-8955 ER - TY - JOUR AB - Pyruvate, the end product of glycolysis, is a key metabolic molecule enabling mitochondrial adenosine triphosphate synthesis and takes part in multiple biosynthetic pathways within mitochondria. The mitochondrial pyruvate carrier (MPC) plays a vital role in transporting pyruvate from the cytosol into the organelle. In humans, MPC is a hetero-oligomeric complex formed by the MPC1 and MPC2 paralogs that are both necessary to stabilize each other and form a functional MPC. MPC deficiency (OMIM#614741) due to pathogenic MPC1 variants is a rare autosomal recessive disease involving developmental delay, microcephaly, growth failure, and increased serum lactate and pyruvate. To date, two MPC1 variants in four cases have been reported, though only one with a detailed clinical description. Herein, we report three novel pathogenic MPC1 variants in six patients from three unrelated families, identified within European, Kuwaiti, and Chinese mitochondrial disease patient cohorts, one of whom presented as a Leigh-like syndrome. Functional analysis in primary fibroblasts from the patients revealed decreased expression of MPC1 and MPC2. We rescued pyruvate-driven oxygen consumption rate in patient's fibroblasts by reconstituting with wild-type MPC1. Complementing homozygous MPC1 mutant cDNA with CRISPR-deleted MPC1 C2C12 cells verified the mechanism of variants: unstable MPC complex or ablated pyruvate uptake activity. Furthermore, we showed that glutamine and beta-hydroxybutyrate were alternative substrates to maintain mitochondrial respiration when cells lack pyruvate. In conclusion, we expand the clinical phenotypes and genotypes associated with MPC deficiency, with our studies revealing glutamine as a potential therapy for MPC deficiency. AU - Jiang, H.* AU - Alahmad, A.* AU - Fu, S.* AU - Fu, X.* AU - Liu, Z.* AU - Han, X.* AU - Li, L.* AU - Song, T.* AU - Xu, M.* AU - Liu, S.* AU - Wang, J.* AU - Albash, B.* AU - Alaqeel, A.* AU - Catalina, V. AU - Prokisch, H. AU - Taylor, R.W.* AU - McFarland, R.* AU - Fang, F.* C1 - 63804 C2 - 51717 CY - 111 River St, Hoboken 07030-5774, Nj Usa TI - Identification and characterisation of novel MPC1 gene variants causing mitochondrial pyruvate carrier deficiency. JO - J. Inherit. Metab. Dis. PB - Wiley PY - 2022 SN - 0141-8955 ER - TY - JOUR AB - Given the rapidly decreasing cost and increasing speed and accessibility of massively parallel technologies, the integration of comprehensive genomic, transcriptomic, and proteomic data into a "multi-omics" diagnostic pipeline is within reach. Even though genomic analysis has the capability to reveal all possible perturbations in our genetic code, analysis typically reaches a diagnosis in just 35% of cases, with a diagnostic gap arising due to limitations in prioritization and interpretation of detected variants. Here we review the utility of complementing genetic data with transcriptomic data and give a perspective for the introduction of proteomics into the diagnostic pipeline. Together these methodologies enable comprehensive capture of the functional consequence of variants, unobtainable by the analysis of each methodology in isolation. This facilitates functional annotation and reprioritization of candidate genes and variants-a promising approach to shed light on the underlying molecular cause of a patient's disease, increasing diagnostic rate, and allowing actionability in clinical practice. AU - Stenton, S. AU - Kremer, L.S. AU - Kopajtich, R. AU - Ludwig, C.* AU - Prokisch, H. C1 - 56132 C2 - 46850 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 25-35 TI - The diagnosis of inborn errors of metabolism by an integrative "multi-omics" approach: A perspective encompassing genomics, transcriptomics, and proteomics. JO - J. Inherit. Metab. Dis. VL - 43 IS - 1 PB - Wiley PY - 2020 SN - 0141-8955 ER - TY - JOUR AB - Triosephosphate isomerase (TPI) deficiency is a fatal genetic disorder characterized by hemolytic anemia and neurological dysfunction. Although the enzyme defect in TPI was discovered in the 1960s, the exact etiology of the disease is still debated. Some aspects indicate the disease could be caused by insufficient enzyme activity, whereas other observations indicate it could be a protein misfolding disease with tissue-specific differences in TPI activity. We generated a mouse model in which exchange of a conserved catalytic amino acid residue (isoleucine to valine, Ile170Val) reduces TPI specific activity without affecting the stability of the protein dimer. TPIIle170Val/Ile170Val mice exhibit an approximately 85% reduction in TPI activity consistently across all examined tissues, which is a stronger average, but more consistent, activity decline than observed in patients or symptomatic mouse models that carry structural defect mutant alleles. While monitoring protein expression levels revealed no evidence for protein instability, metabolite quantification indicated that glycolysis is affected by the active site mutation. TPIIle170Val/Ile170Val mice develop normally and show none of the disease symptoms associated with TPI deficiency. Therefore, without the stability defect that affects TPI activity in a tissue-specific manner, a strong decline in TPI catalytic activity is not sufficient to explain the pathological onset of TPI deficiency. AU - Segal, J.* AU - Mülleder, M.* AU - Krüger, A.* AU - Adler, T. AU - Scholze-Wittler, M.* AU - Becker, L. AU - Calzada-Wack, J. AU - Garrett, L. AU - Hölter, S.M. AU - Rathkolb, B. AU - Rozman, J. AU - Rácz, I. AU - Fischer, R. AU - Busch, D.H.* AU - Neff, F. AU - Klingenspor, M.* AU - Klopstock, T.* AU - Grüning, N.M.* AU - Michel, S.* AU - Lukaszewska-McGreal, B.* AU - Voigt, I.* AU - Hartmann, L.* AU - Timmermann, B.* AU - Lehrach, H.* AU - Wolf, E.* AU - Wurst, W. AU - Gailus-Durner, V. AU - Fuchs, H. AU - Hrabě de Angelis, M. AU - Schrewe, H.* AU - Yuneva, M.* AU - Ralser, M.* C1 - 56096 C2 - 46818 SP - 839-849 TI - Low catalytic activity is insufficient to induce disease pathology in triosephosphate isomerase deficiency. JO - J. Inherit. Metab. Dis. VL - 42 IS - 5 PY - 2019 SN - 0141-8955 ER - TY - JOUR AB - Diagnostics for suspected mitochondrial disease (MD) can be challenging and necessitate invasive procedures like muscle biopsy. This is due to the extremely broad genetic and phenotypic spectrum, disease genes on both nuclear and mitochondrial DNA (mtDNA), and the tissue specificity of mtDNA variants. Exome sequencing (ES) has revolutionized the diagnostics for MD. However, the nuclear and mtDNA are investigated with separate tests, increasing costs and duration of diagnostics. The full potential of ES is often not exploited as the additional analysis of “off-target reads” deriving from the mtDNA can be used to analyze both genomes. We performed mtDNA analysis by ES of 2111 cases in a clinical setting. We further assessed the recall rate and precision as well as the estimation of heteroplasmy by ES data by comparison with targeted mtDNA next generation sequencing in 49 cases. ES identified known pathogenic mtDNA point mutations in 38 individuals, increasing the diagnostic yield by nearly 2%. Analysis of mtDNA variants by ES had a high recall rate (96.2 ± 5.6%) and an excellent precision (99.5 ± 2.2%) when compared to the gold standard of targeted mtDNA next generation sequencing. ES estimated heteroplasmy levels with an average difference of 6.6 ± 3.8%, sufficient for clinical decision making. Taken together, the mtDNA analysis from ES is of sufficient quality for clinical diagnostics. We therefore propose ES, investigating both nuclear and mtDNA, as first line test in individuals with suspected MD. One should be aware, that a negative result does not exclude MD and necessitates further test (in additional tissues). AU - Wagner, M. AU - Berutti, R. AU - Lorenz-Depiereux, B. AU - Graf, E. AU - Eckstein, G. AU - Mayr, J.A.* AU - Meitinger, T. AU - Ahting, U.* AU - Prokisch, H. AU - Strom, T.M. AU - Wortmann, S.B. C1 - 55992 C2 - 46745 SP - 909-917 TI - Mitochondrial DNA mutation analysis from exome sequencing—A more holistic approach in diagnostics of suspected mitochondrial disease. JO - J. Inherit. Metab. Dis. VL - 42 IS - 5 PY - 2019 SN - 0141-8955 ER - TY - JOUR AB - In humans, the important water soluble, vitamin-like nutrient choline, is taken up with the diet or recycled in the liver. Deficiencies of choline have only been reported in experimental situations or total parenteral nutrition. Currently, no recommended dietary allowances are published; only an adequate daily intake is defined. Choline is involved in three main physiological processes: structural integrity and lipid-derived signaling for cell membranes, cholinergic neurotransmission, and methylation. Choline is gaining increasing public attention due to studies reporting a relation of low choline levels to subclinical organ dysfunction (nonalcoholic fatty liver or muscle damage), stunting, and neural tube defects. Furthermore, positive effects on memory and a lowering of cardiovascular risks and inflammatory markers have been proposed. On the other hand, dietary choline has been associated with increased atherosclerosis in mice. This mini review will provide a summary of the biochemical pathways, in which choline is involved and their respective inborn errors of metabolism (caused by mutations in SLC5A7, CHAT, SLC44A1, CHKB, PCYT1A, CEPT1, CAD; DHODH, UMPS, FMO3, DMGDH, and GNMT). The broad phenotypic spectrum ranging from malodor, intellectual disability, to epilepsy, anemia, or congenital myasthenic syndrome is presented, highlighting the central role of choline within human metabolism. AU - Wortmann, S.B. AU - Mayr, J.A.* C1 - 55703 C2 - 46447 CY - 111 River St, Hoboken 07030-5774, Nj Usa SP - 237-242 TI - Choline-related-inherited metabolic diseases - A mini review. JO - J. Inherit. Metab. Dis. VL - 42 IS - 2 PB - Wiley PY - 2019 SN - 0141-8955 ER - TY - JOUR AB - Flatworms of the species Schmidtea mediterranea are immortal-adult animals contain a large pool of pluripotent stem cells that continuously differentiate into all adult cell types. Therefore, single-cell transcriptome profiling of adult animals should reveal mature and progenitor cells. By combining perturbation experiments, gene expression analysis, a computational method that predicts future cell states from transcriptional changes, and a lineage reconstruction method, we placed all major cell types onto a single lineage tree that connects all cells to a single stem cell compartment. We characterized gene expression changes during differentiation and discovered cell types important for regeneration. Our results demonstrate the importance of single-cell transcriptome analysis for mapping and reconstructing fundamental processes of developmental and regenerative biology at high resolution. AU - Kremer, L.S. AU - Wortmann, S.B. AU - Prokisch, H. C1 - 52840 C2 - 44500 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa SP - 525-532 TI - "Transcriptomics": Molecular diagnosis of inborn errors of metabolism via RNA-sequencing. JO - J. Inherit. Metab. Dis. VL - 41 IS - 3 PB - Amer Assoc Advancement Science PY - 2018 SN - 0141-8955 ER - TY - JOUR AB - Congenital disorders of glycosylation (CDG) have a broad spectrum of clinical manifestations. They can affect multiple organ systems, including skin and subcutaneous tissue. We report on an infant with severe ichthyosis caused by MPDU1 mutations. The case illustrates that skin manifestations are an important feature of CDG syndromes. Therefore, metabolic investigations should be included in the workup of infantile ichthyosis disorders. AU - Thiel, C.* AU - Wortmann, S.B. AU - Riedhammer, K.* AU - Alhaddad, B. AU - Mayatepek, E.* AU - Prokisch, H. AU - Distelmaier, F.* C1 - 55162 C2 - 46093 CY - Van Godewijckstraat 30, 3311 Gz Dordrecht, Netherlands SP - 1293-1294 TI - Severe ichthyosis in MPDU1-CDG. JO - J. Inherit. Metab. Dis. VL - 41 IS - 6 PB - Springer PY - 2018 SN - 0141-8955 ER - TY - JOUR AB - Flatworms of the species Schmidtea mediterranea are immortal-adult animals contain a large pool of pluripotent stem cells that continuously differentiate into all adult cell types. Therefore, single-cell transcriptome profiling of adult animals should reveal mature and progenitor cells. By combining perturbation experiments, gene expression analysis, a computational method that predicts future cell states from transcriptional changes, and a lineage reconstruction method, we placed all major cell types onto a single lineage tree that connects all cells to a single stem cell compartment. We characterized gene expression changes during differentiation and discovered cell types important for regeneration. Our results demonstrate the importance of single-cell transcriptome analysis for mapping and reconstructing fundamental processes of developmental and regenerative biology at high resolution. AU - van Karnebeek, C.D.M.* AU - Wortmann, S.B. AU - Tarailo-Graovac, M.* AU - Langeveld, M.* AU - Ferreira, C.R.* AU - van de Kamp, J.M.* AU - Hollak, C.E.* AU - Wasserman, W.W.* AU - Waterham, H.R.* AU - Wevers, R.A.* AU - Haack, T.B.* AU - Wanders, R.J.A.* AU - Boycott, K.M.* C1 - 52831 C2 - 44501 CY - 1200 New York Ave, Nw, Washington, Dc 20005 Usa SP - 571-582 TI - The role of the clinician in the multi-omics era: Are you ready? JO - J. Inherit. Metab. Dis. VL - 41 IS - 3 PB - Amer Assoc Advancement Science PY - 2018 SN - 0141-8955 ER - TY - JOUR AB - Recently, CLPB deficiency has been shown to cause a genetic syndrome with cataracts, neutropenia, and 3-methylglutaconic aciduria. Surprisingly, the neurological presentation ranges from completely unaffected to patients with virtual absence of development. Muscular hypo- and hypertonia, movement disorder and progressive brain atrophy are frequently reported. We present the foetal, peri- and neonatal features of 31 patients, of which five are previously unreported, using a newly developed clinical severity scoring system rating the clinical, metabolic, imaging and other findings weighted by the age of onset. Our data are illustrated by foetal and neonatal videos. The patients were classified as having a mild (n = 4), moderate (n = 13) or severe (n = 14) disease phenotype. The most striking feature of the severe subtype was the neonatal absence of voluntary movements in combination with ventilator dependency and hyperexcitability. The foetal and neonatal presentation mirrored the course of disease with respect to survival (current median age 17.5 years in the mild group, median age of death 35 days in the severe group), severity and age of onset of all findings evaluated. CLPB deficiency should be considered in neonates with absence of voluntary movements, respiratory insufficiency and swallowing problems, especially if associated with 3-methylglutaconic aciduria, neutropenia and cataracts. Being an important differential diagnosis of hyperekplexia (exaggerated startle responses), we advise performing urinary organic acid analysis, blood cell counts and ophthalmological examination in these patients. The neonatal presentation of CLPB deficiency predicts the course of disease in later life, which is extremely important for counselling. AU - Pronicka, E.* AU - Ropacka-Lesiak, M.* AU - Trubicka, J.* AU - Pajdowska, M.* AU - Linke, M.* AU - Ostergaard, E.* AU - Saunders, C.* AU - Horsch, S.* AU - van Karnebeek, C.* AU - Yaplito-Lee, J.* AU - Distelmaier, F.* AU - Õunap, K.* AU - Rahman, S.* AU - Castelle, M.* AU - Kelleher, J.* AU - Baris, S.* AU - Iwanicka-Pronicka, K.* AU - Steward, C.G.* AU - Ciara, E.* AU - Wortmann, S.B. C1 - 51558 C2 - 43215 CY - Dordrecht SP - 853-860 TI - A scoring system predicting the clinical course of CLPB defect based on the foetal and neonatal presentation of 31 patients. JO - J. Inherit. Metab. Dis. VL - 40 IS - 6 PB - Springer PY - 2017 SN - 0141-8955 ER - TY - JOUR AB - Background: Elevated urinary excretion of orotic acid is associated with treatable disorders of the urea cycle and pyrimidine metabolism. Establishing the correct and timely diagnosis in a patient with orotic aciduria is key to effective treatment. Uridine monophosphate synthase is involved in de novo pyrimidine synthesis. Uridine monophosphate synthase deficiency (or hereditary orotic aciduria), due to biallelic mutations in UMPS, is a rare condition presenting with megaloblastic anemia in the first months of life. If not treated with the pyrimidine precursor uridine, neutropenia, failure to thrive, growth retardation, developmental delay, and intellectual disability may ensue. Methods and results: We identified mild and isolated orotic aciduria in 11 unrelated individuals with diverse clinical signs and symptoms, the most common denominator being intellectual disability/developmental delay. Of note, none had blood count abnormalities, relevant hyperammonemia or altered plasma amino acid profile. All individuals were found to have heterozygous alterations in UMPS. Four of these variants were predicted to be null alleles with complete loss of function. The remaining variants were missense changes and predicted to be damaging to the normal encoded protein. Interestingly, family screening revealed heterozygous UMPS variants in combination with mild orotic aciduria in 19 clinically asymptomatic family members. Conclusions: We therefore conclude that heterozygous UMPS-mutations can lead to mild and isolated orotic aciduria without clinical consequence. Partial UMPS-deficiency should be included in the differential diagnosis of mild orotic aciduria. The discovery of heterozygotes manifesting clinical symptoms such as hypotonia and developmental delay are likely due to ascertainment bias. AU - Wortmann, S.B. AU - Chen, M.A.* AU - Colombo, R.* AU - Pontoglio, A.* AU - Alhaddad, B.* AU - Botto, L.D.* AU - Yuzyuk, T.* AU - Coughlin, C.R.* AU - Descartes, M.* AU - Grűnewald, S.* AU - Maranda, B.* AU - Mills, P.B.* AU - Pitt, J.* AU - Potente, C.* AU - Rodenburg, R.* AU - Kluijtmans, L.A.J.* AU - Sampath, S.* AU - Pai, E.F.* AU - Wevers, R.A.* AU - Tiller, G.E.* C1 - 50555 C2 - 42521 CY - Dordrecht SP - 423-431 TI - Mild orotic aciduria in UMPS heterozygotes: A metabolic finding without clinical consequences. JO - J. Inherit. Metab. Dis. VL - 40 IS - 3 PB - Springer PY - 2017 SN - 0141-8955 ER - TY - JOUR AB - Tetrahydrobiopterin (BH4) is an essential cofactor for the aromatic amino acid hydroxylases, alkylglycerol monooxygenase, and nitric oxide synthases (NOS). Inborn errors of BH4 metabolism lead to severe insufficiency of brain monoamine neurotransmitters while augmentation of BH4 by supplementation or stimulation of its biosynthesis is thought to ameliorate endothelial NOS (eNOS) dysfunction, to protect from (cardio-) vascular disease and/or prevent obesity and development of the metabolic syndrome. We have previously reported that homozygous knock-out mice for the 6-pyruvolytetrahydropterin synthase (PTPS; Pts-ko/ko) mice with no BH4 biosynthesis die after birth. Here we generated a Pts-knock-in (Pts-ki) allele expressing the murine PTPS-p.Arg15Cys with low residual activity (15 % of wild-type in vitro) and investigated homozygous (Pts-ki/ki) and compound heterozygous (Pts-ki/ko) mutants. All mice showed normal viability and depending on the severity of the Pts alleles exhibited up to 90 % reduction of PTPS activity concomitant with neopterin elevation and mild reduction of total biopterin while blood L-phenylalanine and brain monoamine neurotransmitters were unaffected. Yet, adult mutant mice with compromised PTPS activity (i.e., Pts-ki/ko, Pts-ki/ki or Pts-ko/wt) had increased body weight and elevated intra-abdominal fat. Comprehensive phenotyping of Pts-ki/ki mice revealed alterations in energy metabolism with proportionally higher fat content but lower lean mass, and increased blood glucose and cholesterol. Transcriptome analysis indicated changes in glucose and lipid metabolism. Furthermore, differentially expressed genes associated with obesity, weight loss, hepatic steatosis, and insulin sensitivity were consistent with the observed phenotypic alterations. We conclude that reduced PTPS activity concomitant with mildly compromised BH4-biosynthesis leads to abnormal body fat distribution and abdominal obesity at least in mice. This study associates a novel single gene mutation with monogenic forms of obesity. AU - Korner, G.* AU - Scherer, T.* AU - Adamsen, D.* AU - Rebuffat, A.* AU - Crabtree, M.* AU - Rassi, A.* AU - Scavelli, R.* AU - Homma, D.* AU - Ledermann, B.* AU - Konrad, D.* AU - Ichinose, H.* AU - Wolfrum, C.* AU - Horsch, M. AU - Rathkolb, B. AU - Klingenspor, M.* AU - Beckers, J. AU - Wolf, E.* AU - Gailus-Durner, V. AU - Fuchs, H. AU - Hrabě de Angelis, M. AU - Blau, N.* AU - Rozman, J. AU - Thöny, B.* C1 - 47811 C2 - 39496 CY - Dordrecht SP - 309-319 TI - Mildly compromised tetrahydrobiopterin cofactor biosynthesis due to Pts variants leads to unusual body fat distribution and abdominal obesity in mice. JO - J. Inherit. Metab. Dis. VL - 39 IS - 2 PB - Springer PY - 2016 SN - 0141-8955 ER - TY - JOUR AB - BACKGROUND: Acute liver failure (ALF) in infancy and childhood is a life-threatening emergency and in about 50 % the etiology remains unknown. Recently biallelic mutations in NBAS were identified as a new molecular cause of ALF with onset in infancy, leading to recurrent acute liver failure (RALF). METHODS: The phenotype and medical history of 14 individuals with NBAS deficiency was studied in detail and functional studies were performed on patients' fibroblasts. RESULTS: The phenotypic spectrum of NBAS deficiency ranges from isolated RALF to a multisystemic disease with short stature, skeletal dysplasia, immunological abnormalities, optic atrophy, and normal motor and cognitive development resembling SOPH syndrome. Liver crises are triggered by febrile infections; they become less frequent with age but are not restricted to childhood. Complete recovery is typical, but ALF crises can be fatal. Antipyretic therapy and induction of anabolism including glucose and parenteral lipids effectively ameliorates the course of liver crises. Patients' fibroblasts showed an increased sensitivity to high temperature at protein and functional level and a disturbed tethering of vesicles, pointing at a defect of intracellular transport between the endoplasmic reticulum and Golgi. CONCLUSIONS: Mutations in NBAS cause a complex disease with a wide clinical spectrum ranging from isolated RALF to a multisystemic phenotype. Thermal susceptibility of the syntaxin 18 complex is the basis of fever dependency of ALF episodes. NBAS deficiency is the first disease related to a primary defect of retrograde transport. Identification of NBAS deficiency allows optimized therapy of liver crises and even prevention of further episodes. AU - Staufner, C.* AU - Haack, T.B. AU - Köpke, M. AU - Straub, B.K.* AU - Kolker, S.* AU - Thiel, C.* AU - Freisinger, P.* AU - Baric, I.* AU - McKiernan, P.J.* AU - Dikow, N.* AU - Harting, I.* AU - Beisse, F.* AU - Burgard, P.* AU - Kotzaeridou, U.* AU - Lenz, D.R.* AU - Kühr, J.* AU - Himbert, U.* AU - Taylor, R.W.* AU - Distelmaier, F.* AU - Vockley, J.* AU - Ghaloul-Gonzalez, L.* AU - Ozolek, J.A.* AU - Zschocke, J.* AU - Kuster, A.* AU - Dick, A.* AU - Das, A.M.* AU - Wieland, T. AU - Terrile, C. AU - Strom, T.M. AU - Meitinger, T. AU - Prokisch, H. AU - Hoffmann, G.F.* C1 - 47221 C2 - 39183 CY - Dordrecht SP - 3-16 TI - Recurrent acute liver failure due to NBAS deficiency: Phenotypic spectrum, disease mechanisms, and therapeutic concepts. JO - J. Inherit. Metab. Dis. VL - 39 IS - 1 PB - Springer PY - 2016 SN - 0141-8955 ER - TY - JOUR AB - BACKGROUND: Hydroxyprolinemia is an inborn error of amino acid degradation that is considered a non-disease. Known for more than 50 years, its genetic cause and prevalence have remained unclear. In MS/MS newborn screening, the mass spectrum of hydroxyproline cannot be differentiated from isoleucine and leucine causing false positive newborn screening test results for maple syrup urine disease (MSUD). METHODS: We studied two siblings with hydroxyprolinemia via exome sequencing and confirmed the candidate gene in five further individuals with hydroxyprolinemia, who were all characterized biochemically and clinically. The prevalence was calculated based on the number of individuals with hydroxyprolinemia detected via MS/MS newborn screening at our centre from 2003 to 2014. RESULTS: In six cases, we identified homozygous or compound heterozygous mutations in PRODH2 as the underlying genetic cause of hydroxyprolinemia. One individual was heterozygous for a deletion in PRODH2 and had an intermittent biochemical phenotype with partial normalization of hydroxyproline concentrations. In one further individual with persistent hydroxyprolinemia no mutation in PRODH2 was found, raising the possibility of another defect of hydroxyproline degradation yet to be identified as the underlying cause of hydroxyprolinemia. Plasma hydroxyproline concentrations were clearly elevated in all individuals with biallelic mutations in PRODH2. All studied individuals remained asymptomatic, giving further evidence that hydroxyprolinemia is a benign condition. The estimated prevalence of hydroxyprolinemia in Germany is about one in 47,300 newborns. CONCLUSION: Our results establish mutations in PRODH2 as a cause of human hydroxyprolinemia via impaired dehydrogenation of hydroxyproline to delta1-pyroline-3-hydroxy-5-carboxylic acid, and we suggest PRODH2 be renamed HYPDH. Hydroxyprolinemia is an autosomal-recessively inherited benign condition. It is a frequent cause of false positive screening results for MSUD, the prevalence being about 2.5 times higher than that of MSUD. AU - Staufner, C.* AU - Haack, T.B. AU - Feyh, P.* AU - Gramer, G.* AU - Raga, D.E.* AU - Terrile, C. AU - Sauer, S.* AU - Okun, J.G.* AU - Fang-Hoffmann, J.* AU - Mayatepek, E.* AU - Prokisch, H. AU - Hoffmann, G.F.* AU - Kolker, S.* C1 - 48524 C2 - 41127 CY - Dordrecht SP - 625-632 TI - Genetic cause and prevalence of hydroxyprolinemia. JO - J. Inherit. Metab. Dis. VL - 39 IS - 5 PB - Springer PY - 2016 SN - 0141-8955 ER - TY - JOUR AB - FBXL4 deficiency is a recently described disorder of mitochondrial maintenance associated with a loss of mitochondrial DNA in cells. To date, the genetic diagnosis of FBXL4 deficiency has been established in 28 individuals. This paper retrospectively reviews proxy-reported clinical and biochemical findings and evaluates brain imaging, morphological and genetic data in 21 of those patients. Neonatal/early-onset severe lactic acidosis, muscular hypotonia, feeding problems and failure to thrive is the characteristic pattern at first presentation. Facial dysmorphic features are present in 67 % of cases. Seven children died (mean age 37 months); 11 children were alive (mean age at follow-up 46 months), three children were lost to follow-up. All survivors developed severe psychomotor retardation. Brain imaging was non-specific in neonates but a later-onset, rapidly progressive brain atrophy was noted. Elevated blood lactate and metabolic acidosis were observed in all individuals; creatine kinase was elevated in 45 % of measurements. Diagnostic workup in patient tissues and cells revealed a severe combined respiratory chain defect with a general decrease of enzymes associated with mitochondrial energy metabolism and a relative depletion of mitochondrial DNA content. Mutations were detected throughout the FBXL4 gene albeit with no clear delineation of a genotype-phenotype correlation. Treatment with "mitochondrial medications" did not prove effective. In conclusion, a clinical pattern of early-onset encephalopathy, persistent lactic acidosis, profound muscular hypotonia and typical facial dysmorphism should prompt initiation of molecular genetic analysis of FBXL4. Establishment of the diagnosis permits genetic counselling, prevents patients undergoing unhelpful diagnostic procedures and allows for accurate prognosis. AU - Huemer, M.-T.* AU - Karall, D.* AU - Schossig, A.* AU - Abdenur, J.E.* AU - Al Jasmi, F.* AU - Biagosch, C.* AU - Distelmaier, F.* AU - Freisinger, P.* AU - Graham, B.H.* AU - Haack, T.B. AU - Hauser, N.* AU - Hertecant, J.* AU - Ebrahimi-Fakhari, D.* AU - Konstantopoulou, V.* AU - Leydiker, K.* AU - Lourenco, C.M.* AU - Scholl-Bürgi, S.* AU - Wilichowski, E.* AU - Wolf, N.I.* AU - Wortmann, S.B.* AU - Taylor, R.W.* AU - Mayr, J.A.* AU - Bonnen, P.E.* AU - Sperl, W.* AU - Prokisch, H. AU - McFarland, R.* C1 - 44738 C2 - 36984 CY - Dordrecht SP - 905-914 TI - Clinical, morphological, biochemical, imaging and outcome parameters in 21 individuals with mitochondrial maintenance defect related to FBXL4 mutations. JO - J. Inherit. Metab. Dis. VL - 38 IS - 5 PB - Springer PY - 2015 SN - 0141-8955 ER - TY - JOUR AB - Inherited disorders of mitochondrial energy metabolism form a large and heterogeneous group of metabolic diseases. More than 250 gene defects have been reported to date and this number continues to grow. Mitochondrial diseases can be grouped into (1) disorders of oxidative phosphorylation (OXPHOS) subunits and their assembly factors, (2) defects of mitochondrial DNA, RNA and protein synthesis, (3) defects in the substrate-generating upstream reactions of OXPHOS, (4) defects in relevant cofactors and (5) defects in mitochondrial homeostasis. Deficiency of more than one respiratory chain enzyme is a common finding. Combined defects are found in 49 % of the known disease-causing genes of mitochondrial energy metabolism and in 57 % of patients with OXPHOS defects identified in our diagnostic centre. Combined defects of complexes I, III, IV and V are typically due to deficiency of mitochondrial DNA replication, RNA metabolism or translation. Defects in cofactors can result in combined defects of various combinations, and defects of mitochondrial homeostasis can result in a generalised decrease of all OXPHOS enzymes. Noteworthy, identification of combined defects can be complicated by different degrees of severity of each affected enzyme. Furthermore, even defects of single respiratory chain enzymes can result in combined defects due to aberrant formation of respiratory chain supercomplexes. Combined OXPHOS defects have a great variety of clinical manifestations in terms of onset, course severity and tissue involvement. They can present as classical encephalomyopathy but also with hepatopathy, nephropathy, haematologic findings and Perrault syndrome in a subset of disorders. AU - Mayr, J.A.* AU - Haack, T.B. AU - Freisinger, P.* AU - Karall, D.* AU - Makowski, C.C.* AU - Koch, J.* AU - Feichtinger, R.G.* AU - Zimmermann, F.A.* AU - Rolinski, B.* AU - Ahting, U.* AU - Meitinger, T. AU - Prokisch, H. AU - Sperl, W.J.K.* C1 - 43973 C2 - 36713 CY - Dordrecht SP - 629-640 TI - Spectrum of combined respiratory chain defects. JO - J. Inherit. Metab. Dis. VL - 38 IS - 4 PB - Springer PY - 2015 SN - 0141-8955 ER - TY - JOUR AB - Pyruvate oxidation defects (PODs) are among the most frequent causes of deficiencies in the mitochondrial energy metabolism and represent a substantial subset of classical mitochondrial diseases. PODs are not only caused by deficiency of subunits of the pyruvate dehydrogenase complex (PDHC) but also by various disorders recently described in the whole pyruvate oxidation route including cofactors, regulation of PDHC and the mitochondrial pyruvate carrier. Our own patients from 2000 to July 2014 and patients identified by a systematic survey of the literature from 1970 to July 2014 with a pyruvate oxidation disorder and a genetically proven defect were included in the study (n=628). Of these defects 74.2% (n=466) belong to PDHC subunits, 24.5% (n=154) to cofactors, 0.5% (n=3) to PDHC regulation and 0.8% (n=5) to mitochondrial pyruvate import. PODs are underestimated in the field of mitochondrial diseases because not all diagnostic centres include biochemical investigations of PDHC in their routine analysis. Cofactor and transport defects can be missed, if pyruvate oxidation is not measured in intact mitochondria routinely. Furthermore deficiency of the X-chromosomal PDHA1 can be biochemically missed depending on the X-inactivation pattern. This is reflected by an increasing number of patients diagnosed recently by genetic high throughput screening approaches. PDHC deficiency including regulation and import affect mainly the glucose dependent central and peripheral nervous system and skeletal muscle. PODs with combined enzyme defects affect also other organs like heart, lung and liver. The spectrum of clinical presentation of PODs is still expanding. PODs are a therapeutically interesting group of mitochondrial diseases since some can be bypassed by ketogenic diet or treated by cofactor supplementation. PDHC kinase inhibition, chaperone therapy and PGC1α stimulation is still a matter of further investigations. AU - Sperl, W.J.K.* AU - Fleuren, L.* AU - Freisinger, P.* AU - Haack, T.B. AU - Ribes, A.A.* AU - Feichtinger, R.G.* AU - Rodenburg, R.J.T.* AU - Zimmermann, F.A.* AU - Koch, J.* AU - Rivera, I.A.* AU - Prokisch, H. AU - Smeitink, J.A.M.* AU - Mayr, J.A.* C1 - 43011 C2 - 35972 CY - Dordrecht SP - 391-403 TI - The spectrum of pyruvate oxidation defects in the diagnosis of mitochondrial disorders. JO - J. Inherit. Metab. Dis. VL - 38 IS - 3 PB - Springer PY - 2015 SN - 0141-8955 ER - TY - JOUR AB - Defects of mitochondrial oxidative phosphorylation constitute a clinical and genetic heterogeneous group of disorders affecting multiple organ systems at varying age. Biochemical analysis of biopsy material demonstrates isolated or combined deficiency of mitochondrial respiratory chain enzyme complexes. Co-occurrence of impaired activity of the pyruvate dehydrogenase complex has been rarely reported so far and is not yet fully understood. We investigated two siblings presenting with severe neonatal lactic acidosis, hypotonia, and intractable cardiomyopathy; both died within the first months of life. Muscle biopsy revealed a peculiar biochemical defect consisting of a combined deficiency of respiratory chain complexes I, II, and II+III accompanied by a defect of the pyruvate dehydrogenase complex. Joint exome analysis of both affected siblings uncovered a homozygous missense mutation in BOLA3. The causal role of the mutation was validated by lentiviral-mediated expression of the mitochondrial isoform of wildtype BOLA3 in patient fibroblasts, which lead to an increase of both residual enzyme activities and lipoic acid levels. Our results suggest that BOLA3 plays a crucial role in the biogenesis of iron-sulfur clusters necessary for proper function of respiratory chain and 2-oxoacid dehydrogenase complexes. We conclude that broad sequencing approaches combined with appropriate prioritization filters and experimental validation enable efficient molecular diagnosis and have the potential to discover new disease loci. AU - Haack, T.B. AU - Rolinski, B.* AU - Haberberger, B. AU - Zimmermann, F.* AU - Schum, J. AU - Strecker, V.* AU - Graf, E. AU - Athing, U.* AU - Hoppen, T.* AU - Wittig, I.* AU - Sperl, W.* AU - Freisinger, P.* AU - Mayr, J.A.* AU - Strom, T.M. AU - Meitinger, T. AU - Prokisch, H. C1 - 11158 C2 - 30526 SP - 55-62 TI - Homozygous missense mutation in BOLA3 causes multiple mitochondrial dysfunctions syndrome in two siblings. JO - J. Inherit. Metab. Dis. VL - 36 IS - 1 PB - Springer PY - 2013 SN - 0141-8955 ER - TY - JOUR AB - Brown-Vialetto-Van Laere syndrome (BVVLS [MIM 211530]) is a rare neurological disorder characterized by infancy onset sensorineural deafness and ponto-bulbar palsy. Mutations in SLC52A3 (formerly C20orf54), coding for riboflavin transporter 2 (hRFT2), have been identified as the molecular genetic correlate in several individuals with BVVLS. Exome sequencing of just one single case revealed that compound heterozygosity for two pathogenic mutations in the SLC52A2 gene coding for riboflavin transporter 3 (hRFT3), another member of the riboflavin transporter family, is also associated with BVVLS. Overexpression studies confirmed that the gene products of both mutant alleles have reduced riboflavin transport activities. While mutations in SLC52A3 cause decreased plasma riboflavin levels, concordant with a role of SLC52A3 in riboflavin uptake from food, the SLC52A2-mutant individual had normal plasma riboflavin concentrations, a finding in line with a postulated function of SLC52A2 in riboflavin uptake from blood into target cells. Our results contribute to the understanding of human riboflavin metabolism and underscore its role in the pathogenesis of BVVLS, thereby providing a rational basis for a high-dose riboflavin treatment. AU - Haack, T.B. AU - Makowski, C.* AU - Yao, Y.* AU - Graf, E. AU - Hempel, M.* AU - Wieland, T. AU - Tauer, U.* AU - Ahting, U.* AU - Mayr, J.A.* AU - Freisinger, P.* AU - Yoshimatsu, H.* AU - Inui, K.* AU - Strom, T.M. AU - Meitinger, T. AU - Yonezawa, A.* AU - Prokisch, H. C1 - 11156 C2 - 30525 SP - 943-948 TI - Impaired riboflavin transport due to missense mutations in SLC52A2 causes Brown-Vialetto-Van Laere syndrome. JO - J. Inherit. Metab. Dis. VL - 35 IS - 6 PB - Springer PY - 2012 SN - 0141-8955 ER -