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Molecular Genetics and Metabolism

Laura A Adang, David B Frank, Ahmed Gilani, Asako Takanohashi, Nicole Ulrick, Abigail Collins, Zachary Cross, Csaba Galambos, Guy Helman, Usama Kanaan, Stephanie Keller, Dawn Simon, Omar Sherbini, Brian D Hanna, Adeline L Vanderver
While pulmonary hypertension (PH) is a potentially life threatening complication of many inflammatory conditions, an association between Aicardi Goutières syndrome (AGS), a rare genetic cause of interferon (IFN) overproduction, and the development of PH has not been characterized to date. We analyzed the cardiac function of individuals with AGS enrolled in the Myelin Disorders Bioregistry Project using retrospective chart review (n = 61). Additional prospective echocardiograms were obtained when possible (n = 22)...
September 7, 2018: Molecular Genetics and Metabolism
Simon Körver, Magda Vergouwe, Carla E M Hollak, Ivo N van Schaik, Mirjam Langeveld
BACKGROUND: Fabry disease (FD) is a rare lysosomal storage disorder that might result in, amongst other complications, early stroke and white matter lesions (WMLs). More insight in WMLs in FD could clarify the role of WMLs in the disease presentation and prognosis in FD. In this systematic review we assessed the prevalence, severity, location and course of WMLs in FD. We also systematically reviewed the evidence on the relation between WMLs, disease characteristics and clinical parameters...
September 5, 2018: Molecular Genetics and Metabolism
Francesca Granata, Manuel Mendez, Valentina Brancaleoni, Francisco J Castelbon, Giovanna Graziadei, Paolo Ventura, Elena Di Pierro
Genetic variants in promoters and alternative-splicing lesions require to be experimentally tested in order to validate them as causatives of a disease. The digital PCR (dPCR) approach, which is an alternative to the classical qPCR, is an innovative and a more sensitive method for the detection and quantification of nucleic acids. In the present study, we identified four HMBS gene mutations affecting the ubiquitous isoform of porphobilinogen deaminase (PBGD) and established a dPCR protocol which would be able to detect the different transcripts of this gene...
September 5, 2018: Molecular Genetics and Metabolism
Susan A Berry, Jerry Vockley, Alexander A Vinks, Min Dong, George A Diaz, Shawn E McCandless, Wendy E Smith, Cary O Harding, Roberto Zori, Can Ficicioglu, Uta Lichter-Konecki, Renee Perdok, Beth Robinson, Robert J Holt, Nicola Longo
INTRODUCTION: Glycerol phenylbutyrate (GPB) is approved in the US and EU for the chronic management of patients ≥2 months of age with urea cycle disorders (UCDs) who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. GPB is a pre-prodrug, hydrolyzed by lipases to phenylbutyric acid (PBA) that upon absorption is beta-oxidized to the active nitrogen scavenger phenylacetic acid (PAA), which is conjugated to glutamine (PAGN) and excreted as urinary PAGN (UPAGN)...
September 4, 2018: Molecular Genetics and Metabolism
A Serrano Russi, S Donoghue, A Boneh, R Manara, A B Burlina, A P Burlina
Three young patients with glutaric aciduria type I (age 6-23 years) of different ethnic origins, treated for their metabolic disease since early childhood, presented with malignant central nervous system tumors. We recommend continuing clinical follow-up, including monitoring of neurological manifestations and neuroradiological findings, in all patients with glutaric aciduria type I beyond early childhood, especially if adherence to diet is poor or the treatment was not started neonatally.
August 27, 2018: Molecular Genetics and Metabolism
Steven F Dobrowolski, Irina L Tourkova, Lisa J Robinson, Cassandra Secunda, Kayla Spridik, Harry C Blair
Osteopenia is observed in some patients affected by phenylalanine hydroxylase (PAH) deficient phenylketonuria (PKU). Bone density studies, in diverse PKU patient cohorts, have demonstrated bone disease is neither fully penetrant nor uniform in bone density loss. Biochemical assessment has generated a muddled perspective regarding mechanisms of the PKU bone phenotype where the participation of hyperphenylalaninemia remains unresolved. Osteopenia is realized in the Pahenu2 mouse model of classical PKU; although, characterization is incomplete...
August 27, 2018: Molecular Genetics and Metabolism
Natrujee Wiwattanadittakul, Morgan Prust, William Davis Gaillard, An Massaro, Gilbert Vezina, Tammy N Tsuchida, Andrea L Gropman
BACKGROUND: Continuous EEG studies demonstrate that neonates with seizures due to cerebral pathology, such as hypoxia ischemia, exhibit predominantly electrographic seizures (i.e. those only detected with EEG because they lack clinical features). Previous small case series demonstrate EEG changes and seizures during hyperammonemia associated with inborn errors of metabolism (IEM) but there are no reports utilizing continuous EEG in these conditions. OBJECTIVE: To characterize seizures and evaluate the utility of continuous EEG recording during hyperammonemia due to inborn errors of metabolism...
August 24, 2018: Molecular Genetics and Metabolism
Xuntian Jiang, Rohini Sidhu, Joseph J Orsini, Nicole Y Farhat, Forbes D Porter, Elizabeth Berry-Kravis, Jean E Schaffer, Daniel S Ory
BACKGROUND: Niemann-Pick disease type C1 (NPC1) is a rare, neurodegenerative cholesterol storage disorder. Diagnostic delay of >5 years is common due to the rarity of the disease and non-specific early symptoms. To improve diagnosis and facilitate early intervention, we previously developed a newborn screening assay based on newly identified plasma bile acid biomarkers. Because the newborn screen had been validated using dried blood spots (DBS) from already diagnosed NPC1 patients, an unanswered question was whether the screen would be able to detect individuals with NPC1 at birth...
August 24, 2018: Molecular Genetics and Metabolism
Tatiana Yuzyuk, Bijina Balakrishnan, Elizabeth L Schwarz, Irene De Biase, Judith Hobert, Nicola Longo, Rong Mao, Kent Lai, Marzia Pasquali
Impaired activity of galactose-1-phosphate uridyltransferase (GALT) causes classic galactosemia (OMIM 230400), characterized by the accumulation of galactose-1-phosphate (GAL1P) in patients' red blood cells (RBCs). Our recent study demonstrated a correlation between RBC GAL1P and long-term outcomes in galactosemia patients. Here, we analyze biochemical and molecular results in 77 classic galactosemia patients to evaluate the association between GALT genotypes and GAL1P concentration in RBCs. Experimental data from model organisms were also included to assess the correlation between GAL1P and predicted residual activity of each genotype...
August 23, 2018: Molecular Genetics and Metabolism
Roberto Zori, Janet A Thomas, Natasha Shur, William B Rizzo, Celeste Decker, Orli Rosen, Mingjin Li, Becky Schweighardt, Kevin Larimore, Nicola Longo
BACKGROUND: Phenylketonuria (PKU) is caused by a deficiency in phenylalanine hydroxylase enzyme activity that leads to phenylalanine (Phe) accumulation in the blood and brain. Elevated blood Phe levels are associated with complications in adults, including neurological, psychiatric, and cognitive issues. Even with nutrition and pharmacological management, the majority of adults with PKU do not maintain blood Phe levels at or below guideline recommended levels. Pegvaliase, PEGylated recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL), converts Phe to trans-cinnamic acid and ammonia, and is an investigational enzyme substitution therapy to lower blood Phe in adults with PKU...
August 23, 2018: Molecular Genetics and Metabolism
Fabio Nascimbeni, Elena Cassinerio, Annalisa Dalla Salda, Irene Motta, Serena Bursi, Salvatore Donatiello, Vincenzo Spina, Maria Domenica Cappellini, Francesca Carubbi
BACKGROUND & AIMS: Long-term liver-related complications of Gaucher disease (GD) include cirrhosis, portal hypertension and hepatocellular carcinoma. Although liver fibrosis is the main determinant of adverse liver-related clinical outcomes, it has rarely been evaluated in previously published cohorts of GD patients. We aimed at: assessing the prevalence of significant liver fibrosis in a cohort of patients with type 1 GD; identifying its predictors among GD-related variables, enzyme replacement therapy (ERT) and metabolic features...
August 11, 2018: Molecular Genetics and Metabolism
Mei-Ling Bermúdez, Matthew R Skelton, Mary Beth Genter
Mitochondrial dysfunction plays a central role in the pathogenesis of neurodegenerative diseases such as Parkinson's disease (PD). This study was designed to determine whether the dipeptide carnosine, which has been shown to protect against oxidative stress and mitochondrial dysfunction, would provide a beneficial effect on mitochondrial function in the Thy1-aSyn mouse model of PD. Thy1-aSyn mice, which overexpress wild-type human alpha-synuclein (aSyn), exhibit progressive non-motor and motor deficits as early as 2 months of age...
August 10, 2018: Molecular Genetics and Metabolism
Brian W Bigger, David J Begley, Daniela Virgintino, Alexey V Pshezhetsky
Mucopolysaccharidosis (MPS) disorders are caused by deficiencies in lysosomal enzymes, leading to impaired glycosaminoglycan (GAG) degradation. The resulting GAG accumulation in cells and connective tissues ultimately results in widespread tissue and organ dysfunction. The seven MPS types currently described are heterogeneous and progressive disorders, with somatic and neurological manifestations depending on the type of accumulating GAG. Heparan sulfate (HS) is one of the GAGs stored in patients with MPS I, II, and VII and the main GAG stored in patients with MPS III...
August 10, 2018: Molecular Genetics and Metabolism
Xinying Hong, Michael H Gelb
Globotriaosylsphingosine (lyso-Gb3) is a well-established biomarker for diagnosis and prognosis of Fabry disease. This biomarker is measured in biological samples by liquid chromatography-tandem mass spectrometry using an internal standard. The ideal internal standard is a variant of lyso-Gb3 substituted with heavy isotopes, but the total synthesis of such a compound is very labor intensive. In this report, we describe a simple, one-step synthesis of lyso-Gb3 labeled with carbon-13 in all of the galactosyl carbons...
August 10, 2018: Molecular Genetics and Metabolism
Mohammed Almannai, Julia Wang, Hongzheng Dai, Ayman W El-Hattab, Eissa A Faqeih, Mohammed A Saleh, Ali Al Asmari, Ali H Alwadei, Yaser I Aljadhai, Amal AlHashem, Brahim Tabarki, Matthew A Lines, Dorothy K Grange, Ruba Benini, Abdulaziz S Alsaman, Adel Mahmoud, Panagiotis Katsonis, Olivier Lichtarge, Lee-Jun C Wong
An increasing number of mitochondrial diseases are found to be caused by pathogenic variants in nuclear encoded mitochondrial aminoacyl-tRNA synthetases. FARS2 encodes mitochondrial phenylalanyl-tRNA synthetase (mtPheRS) which transfers phenylalanine to its cognate tRNA in mitochondria. Since the first case was reported in 2012, a total of 21 subjects with FARS2 deficiency have been reported to date with a spectrum of disease severity that falls between two phenotypes; early onset epileptic encephalopathy and a less severe phenotype characterized by spastic paraplegia...
July 29, 2018: Molecular Genetics and Metabolism
Simran Madan, Bettina Kron, Zixue Jin, George Al Shamy, Philippe M Campeau, Qin Sun, Shan Chen, Leela Cherian, Yuqing Chen, Elda Munivez, Ming-Ming Jiang, Claudia Robertson, Clay Goodman, Rajiv R Ratan, Brendan Lee
Arginine is a semi-essential amino acid which serves as a substrate for nitric oxide (NO) production by nitric oxide synthase (NOS) and a precursor for various metabolites including ornithine, creatine, polyamines, and agmatine. Arginase competes with nitric oxide synthase for substrate arginine to produce orthinine and urea. There is contradictory evidence in the literature on the role of nitric oxide in the pathophysiology of traumatic brain injury (TBI). These contradictory perspectives are likely due to different NOS isoforms - endothelial (eNOS), inducible (iNOS) and neuronal (nNOS) which are expressed in the central nervous system...
July 25, 2018: Molecular Genetics and Metabolism
Meryl Waldman, Joan C Han, Daniela P Reyes-Capo, Joy Bryant, Kathryn A Carson, Baris Turkbey, Peter Choyke, Jürgen K Naggert, William A Gahl, Jan D Marshall, Meral Gunay-Aygun
Alström Syndrome is a ciliopathy associated with obesity, insulin resistance/type 2 diabetes mellitus, cardiomyopathy, retinal degeneration, hearing loss, progressive liver and kidney disease, and normal cognitive function. ALMS1, the protein defective in this disorder, localizes to the cytoskeleton, microtubule organizing center, as well as the centrosomes and ciliary basal bodies and plays roles in formation and maintenance of cilia, cell cycle regulation, and endosomal trafficking. Kidney disease in this disorder has not been well characterized...
July 24, 2018: Molecular Genetics and Metabolism
L R Ranganath, M Khedr, A M Milan, A S Davison, A T Hughes, J L Usher, S Taylor, N Loftus, A Daroszewska, E West, A Jones, M Briggs, M Fisher, M McCormick, S Judd, S Vinjamuri, R Griffin, E E Psarelli, T F Cox, N Sireau, J P Dillon, J M Devine, G Hughes, J Harrold, G J Barton, J C Jarvis, J A Gallagher
QUESTION: Does Nitisinone prevent the clinical progression of the Alkaptonuria? FINDINGS: In this observational study on 39 patients, 2 mg of daily nitisinone inhibited ochronosis and significantly slowed the progression of AKU over a three-year period. MEANING: Nitisinone is a beneficial therapy in Alkaptonuria. BACKGROUND: Nitisinone decreases homogentisic acid (HGA), but has not been shown to modify progression of Alkaptonuria (AKU)...
July 24, 2018: Molecular Genetics and Metabolism
Noboru Tanaka, Sachiho Kida, Masafumi Kinoshita, Hideto Morimoto, Tadao Shibasaki, Katsuhiko Tachibana, Ryuji Yamamoto
Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is a lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS), an enzyme that catabolizes glycosaminoglycans (GAGs) including heparan sulfate (HS) and dermatan sulfate (DS). GAG accumulation leads to severe neurological and somatic impairments. At present, the most common treatment for MPS II is intravenous enzyme replacement therapy; however, the inability of recombinant IDS to cross the blood-brain barrier (BBB) restricts therapeutic efficacy for neurological manifestations...
July 23, 2018: Molecular Genetics and Metabolism
Kevin J O'Brien, Wendy J Introne, Orhan Akal, Tulay Akal, Adrian Barbu, Melissa P McGowan, Melissa A Merideth, Samuel L Seward, William A Gahl, Bernadette R Gochuico
PURPOSE: Limited information is available regarding chronic treatment with pirfenidone, an anti-fibrotic drug. Effects of long-term open-label pirfenidone were evaluated in a small cohort with Hermansky-Pudlak syndrome (HPS), a rare autosomal recessive disorder with highly penetrant pulmonary fibrosis. RESULTS: Three patients with HPS pulmonary fibrosis treated with open-label pirfenidone and twenty-one historical controls randomized to placebo were studied at a single center...
July 23, 2018: Molecular Genetics and Metabolism
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