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Molecular Genetics and Metabolism

Stephan C J Huijbregts, Annet M Bosch, Quirine A Simons, Rianne Jahja, Martijn C G J Brouwers, Leo M J De Sonneville, Maaike C De Vries, Floris C Hofstede, Carla E M Hollak, Mirian C H Janssen, Janneke G Langendonk, M Estela Rubio-Gozalbo, Jaap J Van der Meere, Ans T Van der Ploeg, Francjan J Van Spronsen
The aim of this study was to examine Health-Related Quality of Life (HRQoL) of patients with Phenylketonuria (PKU) in three different age groups and to investigate the impact of metabolic control and tetrahydrobiopterin (BH4) treatment on HRQoL of these patients. Participants were 90 early-treated patients aged 7 to 40 years (M = 21.0, SD = 10.1) and 109 controls aged 7 to 40.8 years (M = 19.4, SD = 8.6). HRQoL was assessed with the (generic) TNO-AZL questionnaires. Overall, good HRQoL was reported for children below 12 years of age, although they were judged to be less autonomic than their healthy counterparts...
July 7, 2018: Molecular Genetics and Metabolism
Marco Trinchera, Rossella Parini, Rossella Indellicato, Ruben Domenighini, Fabio dall'Olio
Among the numerous congenital disorders of glycosylation concerning glycoproteins, only a single mutation in ganglioside biosynthesis had been reported until a few years ago: one in the ST3GAL5 gene, encoding GM3 synthase. More recently, additional mutations in the same gene were reported, together with several distinct mutations in the B4GALNT1 gene, encoding GM2/GD2/GA2 synthase. Patients suffering from ST3GAL5 deficiency present a devastating syndrome characterized by early onset and dramatic neurological and cognitive impairment, sometimes associated with dyspigmentation and an increased blood lactate concentration...
June 28, 2018: Molecular Genetics and Metabolism
Shahzeb Hassan, Grisel Lopez, Barbara K Stubblefield, Nahid Tayebi, Ellen Sidransky
Autosomal resessive Mendelian disorders usually result from two inherited disease-causing mutations. However, this is not always the case. Focusing on Gaucher disease, which results from mutations in GBA1, we found that more comprehensive genotyping revealed important exceptions. For example, patients with uniparental disomy or new mutations do not inherit a mutation from each parent. Furthermore, we identified patients found to carry more than one GBA1 mutation on the same allele. It is essential to examine the entire GBA1 gene in order to establish an accurate genotype...
June 28, 2018: Molecular Genetics and Metabolism
Noémie Remacle, Patrick Forny, Hong-Phuc Cudré-Cung, Mary Gonzalez-Melo, Sónia do Vale-Pereira, Hugues Henry, Tony Teav, Hector Gallart-Ayala, Olivier Braissant, Matthias Baumgartner, Diana Ballhausen
BACKGROUND: Methylmalonic aciduria (MMAuria) is an inborn error of metabolism leading to neurological deterioration. In this study, we used 3D organotypic brain cell cultures derived from embryos of a brain-specific Mut-/- (brain KO) mouse to investigate mechanisms leading to brain damage. We challenged our in vitro model by a catabolic stress (temperature shift). RESULTS: Typical metabolites for MMAuria as well as a massive NH4+ increase were found in the media of brain KO cultures...
June 18, 2018: Molecular Genetics and Metabolism
Matthew C Reed, Capucine Schiffer, Simon Heales, Atul B Mehta, Derralynn A Hughes
Gaucher disease (GD) is an inherited disorder in which mutations in the GBA1 gene lead to deficient β-glucocerebrosidase activity and accumulation of its substrate glucosylceramide. Bone disease is present in around 84% of GD patients, ranging from bone loss including osteopenia and osteonecrosis to abnormal bone remodelling in the form of Erlenmeyer flask formation. The range of severity and variety of types of bone disease found in GD patients indicate the involvement of several mechanisms. Here we investigate the effects of exogenous sphingolipids on osteoclasts, osteoblasts, plasma cells and mesenchymal stem cells (MSC) and the interactions between these cell types...
June 14, 2018: Molecular Genetics and Metabolism
Valentina Brancaleoni, Francesca Granata, Pasquale Missineo, Silvia Fustinoni, Giovanna Graziadei, Elena Di Pierro
Alterations in the ferrochelatase gene (FECH) are the basis of the phenotypic expressions in erythropoietic protoporphyria. The phenotype is due to the presence of a mutation in the FECH gene associated in trans to the c.315-48 T > C variant in the intron 3. The latter is able to increase the physiological quota of alternative splicing events in the intron 3. Other two variants in the FECH gene (c.1-252A > G and c.68-23C > T) have been found to be associated to the intron 3 variant in some populations and together, they constitute a haplotype (ACT/GTC), but eventually, their role in the alternative splicing event has never been elucidated...
June 13, 2018: Molecular Genetics and Metabolism
Christoph Wanner, Michael Arad, Ralf Baron, Alessandro Burlina, Perry M Elliott, Ulla Feldt-Rasmussen, Victor V Fomin, Dominique P Germain, Derralynn A Hughes, Ana Jovanovic, Ilkka Kantola, Aleš Linhart, Renzo Mignani, Lorenzo Monserrat, Mehdi Namdar, Albina Nowak, João-Paulo Oliveira, Alberto Ortiz, Maurizio Pieroni, Marco Spada, Anna Tylki-Szymańska, Camilla Tøndel, Miguel Viana-Baptista, Frank Weidemann, Max J Hilz
BACKGROUND: Fabry disease, an inherited lysosomal storage disorder, causes multi-organ pathology resulting in substantial morbidity and a reduced life expectancy. Although Fabry disease is an X-linked disorder, both genders may be affected, but generally to a lesser extent in females. The disease spectrum ranges from classic early-onset disease to non-classic later-onset phenotypes, with complications occurring in multiple organs or being confined to a single organ system depending on the stage of the disease...
June 12, 2018: Molecular Genetics and Metabolism
Lilly S Parr, Ganesh Sriram, Ramin Nazarian, Lola Rahib, Katrina M Dipple
Glycerol kinase (GK) is a multifunctional enzyme located at the interface of carbohydrate and fat metabolism. It contributes to both central carbon metabolism and adipogenesis; specifically, through its role as the ATP-stimulated translocation promoter (ASTP). GK overexpression leads to increased ASTP activity and increased fat storage in H4IIE cells. We performed metabolic flux analysis in human GK-overexpressing H4IIE cells and found that overexpressing cells had significantly altered fluxes through central carbon and lipid metabolism including increased flux through the pentose phosphate pathway and increased production of lipids...
June 12, 2018: Molecular Genetics and Metabolism
Alexandra Latini, Lucila de Bortoli da Silva, Débora da Luz Scheffer, Ananda Christina Staats Pires, Filipe José de Matos, Renata T Nesi, Karina Ghisoni, Roberta de Paula Martins, Paulo Alexandre de Oliveira, Rui D Prediger, Marisa Ghersi, Laura Gabach, Mariela Fernanda Pérez, Susana Rubiales-Barioglio, Rita Raisman-Vozari, Raymond Mongeau, Laurence Lanfumey, Aderbal Silva Aguiar
Tetrahydrobiopterin (BH4) is synthesized by the combined action of three metabolic pathways, namely de novo synthesis, recycling, and salvage pathways. The best-known function of BH4 is its mandatory action as a natural cofactor of the aromatic amino acid hydroxylases and nitric oxide synthases. Thus, BH4 is essential for the synthesis of nitric oxide, a retrograde neurotransmitter involved in learning and memory. We investigated the effect of BH4 (4-4000 pmol) intracerebroventricular administration on aversive memory, and on BH4 metabolism in the hippocampus of rodents...
June 11, 2018: Molecular Genetics and Metabolism
Harvey L Levy, Christineh N Sarkissian, Raymond C Stevens, Charles R Scriver
Phenylketonuria (PKU) is a genetic inborn error in metabolism that impacts many people globally, with profound individual and societal consequences when left untreated. The journey of phenylalanine ammonia lyase (PAL) from plant enzyme to enzyme substitution therapy for PKU is a fascinating story that illustrates the importance of collaboration between basic scientists and industry in the drug development process. The story begins with the curiosity of plant physiologists about the origin of lignin, a polymer involved in maintaining the rigidity of plants...
June 9, 2018: Molecular Genetics and Metabolism
Giovanna Menduti, Elisa Biamino, Roberta Vittorini, Serena Vesco, Maria Paola Puccinelli, Francesco Porta, Concetta Capo, Sara Leo, Bianca Maria Ciminelli, Federico Iacovelli, Marco Spada, Mattia Falconi, Patrizia Malaspina, Luisa Rossi
Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare autosomal recessive metabolic disorder of GABA catabolism. SSADH is a mitochondrial homotetrameric enzyme encoded by ALDH5A1 gene. We report the molecular characterization of ALDH5A1 gene in an Italian SSADHD patient, showing heterozygosity for four missense mutations: c.526G>A (p.G176R), c.538C>T (p.H180Y), c.709G>T (p.A237S) and c.1267A>T (p.T423S), the latter never described so far. The patient inherited c.526A in cis with c.538T from the mother and c...
June 2, 2018: Molecular Genetics and Metabolism
Fan Yi, Xinying Hong, Arun Babu Kumar, Chengli Zong, Geert-Jan Boons, C Ronald Scott, Frantisek Turecek, Bruce H Robinson, Michael H Gelb
BACKGROUND: With ongoing efforts to develop improved treatments for Sanfilippo Syndrome Type A (MPS-IIIA), a disease caused by the inability to degrade heparan sulfate in lysosomes, we sought to develop an enzymatic activity assay for the relevant enzyme, sulfamidase, that uses dried blood spots (DBS). METHODS: We designed and synthesized a new sulfamidase substrate that can be used to measure sulfamidase activity in DBS using liquid chromatography-tandem mass spectrometry (LC-MS/MS)...
May 23, 2018: Molecular Genetics and Metabolism
Shaukat A Khan, Robert W Mason, Roberto Giugliani, Kenji Orii, Toshiyuki Fukao, Yasuyuki Suzuki, Seiji Yamaguchi, Hironori Kobayashi, Tadao Orii, Shunji Tomatsu
To explore the correlation between glycosaminoglycan (GAG) levels and mucopolysaccharidosis (MPS) type, we have evaluated the GAG levels in blood of MPS II, III, IVA, and IVB and urine of MPS IVA, IVB, and VI by tandem mass spectrometry. Dermatan sulfate (DS), heparan sulfate (HS), keratan sulfate (KS; mono-sulfated KS, di-sulfated KS), and the ratio of di-sulfated KS in total KS were measured. Patients with untreated MPS II had higher levels of DS and HS in blood while untreated MPS III had higher levels of HS in blood than age-matched controls...
May 17, 2018: Molecular Genetics and Metabolism
Irene Slavc, Jessica L Cohen-Pfeffer, Sridharan Gururangan, Jeanne Krauser, Daniel A Lim, Marcos Maldaun, Christoph Schwering, Adam J Shaywitz, Manfred Westphal
For decades, intracerebroventricular (ICV), or intraventricular, devices have been used in the treatment of a broad range of pediatric and adult central nervous system (CNS) disorders. Due to the limited permeability of the blood brain barrier, diseases with CNS involvement may require direct administration of drugs into the brain to achieve full therapeutic effect. A recent comprehensive literature review on the clinical use and complications of ICV drug delivery revealed that device-associated complication rates are variable, and may be as high as 33% for non-infectious complications and 27% for infectious complications...
May 16, 2018: Molecular Genetics and Metabolism
Hira Peracha, Kazuki Sawamoto, Lauren Averill, Heidi Kecskemethy, Mary Theroux, Mihir Thacker, Kyoko Nagao, Christian Pizarro, William Mackenzie, Hironori Kobayashi, Seiji Yamaguchi, Yasuyuki Suzuki, Kenji Orii, Tadao Orii, Toshiyuki Fukao, Shunji Tomatsu
Mucopolysaccharidosis IVA (MPS IVA, Morquio A syndrome) is an autosomal recessive disorder caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase. Deficiency of this enzyme leads to the accumulation of specific glycosaminoglycans (GAGs), chondroitin-6-sulfate (C6S) and keratan sulfate (KS), which are mainly synthesized in the cartilage. Therefore, the substrates are stored primarily in the cartilage and its extracellular matrix (ECM), leading to a direct impact on bone development and successive systemic skeletal spondylepiphyseal dysplasia...
May 15, 2018: Molecular Genetics and Metabolism
Muriel Girard, Aurélia Poujois, Monique Fabre, Florence Lacaille, Dominique Debray, Marlène Rio, François Fenaille, Sophie Cholet, Coralie Ruel, Elizabeth Caussé, Janick Selves, Laure Bridoux-Henno, France Woimant, Thierry Dupré, Sandrine Vuillaumier-Barrot, Nathalie Seta, Laurent Alric, Pascale de Lonlay, Arnaud Bruneel
Congenital disorders of glycosylation (CDG) linked to defects in Golgi apparatus homeostasis constitute an increasing part of these rare inherited diseases. Among them, COG-CDG, ATP6V0A2-CDG, TMEM199-CDG and CCDC115-CDG have been shown to disturb Golgi vesicular trafficking and/or lumen pH acidification. Here, we report 3 new unrelated cases of CCDC115-CDG with emphasis on diagnosis difficulties related to strong phenotypic similarities with mitochondriopathies, Niemann-Pick disease C and Wilson Disease. Indeed, while two individuals clinically presented with early and severe liver fibrosis and cirrhosis associated with neurological symptoms, the other one "only" showed isolated and late severe liver involvement...
May 9, 2018: Molecular Genetics and Metabolism
C R Ferreira, S M I Goorden, A Soldatos, H M Byers, J M M Ghauharali-van der Vlugt, F S Beers-Stet, C Groden, C D van Karnebeek, W A Gahl, F M Vaz, X Jiang, H J Vernon
Patients with primary serine biosynthetic defects manifest with intellectual disability, microcephaly, ichthyosis, seizures and peripheral neuropathy. The underlying pathogenesis of peripheral neuropathy in these patients has not been elucidated, but could be related to a decrease in the availability of certain classical sphingolipids, or to an increase in atypical sphingolipids. Here, we show that patients with primary serine deficiency have a statistically significant elevation in specific atypical sphingolipids, namely deoxydihydroceramides of 18-22 carbons in acyl length...
May 7, 2018: Molecular Genetics and Metabolism
J Pérez-López, M Moltó-Abad, C Muñoz-Delgado, M Morales-Conejo, L Ceberio-Hualde, M Del Toro
BACKGROUND: Enzyme replacement therapy (ERT) has been shown to decrease urine glycosaminoglycans (uGAGs) and liver and spleen volumes, and to improve clinical symptoms in mucopolysaccharidosis type II (MPS-II) patients. METHODS: A systematic search of the literature, from inception to August 2017, was conducted to identify randomized trials or observational studies including ≥1 MPS-II patients with ERT initiated in adult age (≥16 years) and evaluating ERT efficacy...
April 30, 2018: Molecular Genetics and Metabolism
Marco Spada, Ralf Baron, Perry M Elliott, Bruno Falissard, Max J Hilz, Lorenzo Monserrat, Camilla Tøndel, Anna Tylki-Szymańska, Christoph Wanner, Dominique P Germain
BACKGROUND: Fabry disease is caused by a deficiency of the lysosomal enzyme α-galactosidase, resulting in progressive accumulation of globotriaosylceramide (GL-3). The disease can manifest early during childhood and adolescence. Enzyme replacement therapy (ERT) with recombinant human α-galactosidase is the first specific treatment for Fabry disease and has been available in Europe since 2001. This paper presents the findings of a systematic literature review of clinical outcomes with ERT in paediatric patients with Fabry disease...
April 26, 2018: Molecular Genetics and Metabolism
C P Howson, B Cedergren, R Giugliani, P Huhtinen, C D Padilla, C S Palubiak, M D Santos, I V D Schwartz, B L Therrell, A Umemoto, J Wang, X Zeng, X Zhao, N Zhong, E R B McCabe
Newborn screening (NBS) prevents morbidity and mortality by screening babies for selected disorders in the first days of life so that early diagnosis and treatment can be initiated. Congenital disorders impact an estimated 8 million or 6% of annual births worldwide, and of the top five that contribute 25% to the global burden of these disorders, three can be identified and managed by NBS. There are determined pockets of activity in Latin America, Sub-Saharan Africa, and the Asia Pacific region, where partnerships among government, non-governmental organizations, academia, the private sector and civil society are developing novel NBS programs that are both saving lives and preventing disability in those who survive...
April 25, 2018: Molecular Genetics and Metabolism
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