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Molecular Genetics and Metabolism

Martino L di Salvo, Mario Mastrangelo, Isabel Nogués, Manuela Tolve, Alessandro Paiardini, Carla Carducci, Davide Mei, Martino Montomoli, Angela Tramonti, Renzo Guerrini, Roberto Contestabile, Vincenzo Leuzzi
No abstract text is available yet for this article.
March 14, 2018: Molecular Genetics and Metabolism
Patricia L Hall, Christina Lam, John J Alexander, Ghazia Asif, Gerard T Berry, Carlos Ferreira, Hudson H Freeze, William A Gahl, Kim K Nickander, Jon D Sharer, Caroline M Watson, Lynne Wolfe, Kimiyo M Raymond
N-glycanase deficiency (NGLY1 deficiency, NGLY1-CDDG), the first autosomal recessive congenital disorder of N-linked deglycosylation (CDDG), is caused by pathogenic variants in NGLY1. The majority of affected individuals have been identified using exome or genome sequencing. To date, no reliable, clinically available biomarkers have been identified. Urine oligosaccharide analysis was included as part of a routine evaluation for possible biomarkers in patients with confirmed NGLY1-CDDG. During the qualitative review of oligosaccharide profiles by an experienced laboratory director an abnormal analyte with a proposed structure of Neu5Ac1Hex1GlcNAc1-Asn was identified in NGLY1-CDDG patient urine samples...
March 10, 2018: Molecular Genetics and Metabolism
Alberto Ortiz, Dominique P Germain, Robert J Desnick, Juan Politei, Michael Mauer, Alessandro Burlina, Christine Eng, Robert J Hopkin, Dawn Laney, Aleš Linhart, Stephen Waldek, Eric Wallace, Frank Weidemann, William R Wilcox
Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene leading to deficient α-galactosidase A activity, glycosphingolipid accumulation, and life-threatening complications. Phenotypes vary from the "classic" phenotype, with pediatric onset and multi-organ involvement, to later-onset, a predominantly cardiac phenotype. Manifestations are diverse in female patients in part due to variations in residual enzyme activity and X chromosome inactivation patterns. Enzyme replacement therapy (ERT) and adjunctive treatments can provide significant clinical benefit...
February 28, 2018: Molecular Genetics and Metabolism
Anna Tylki-Szymańska, Paulina Szymańska-Rożek, Piotr Hasiński, Agnieszka Ługowska
Deficiency of beta-glucocerebrosidase (GBA) leads to Gaucher disease (GD), an inherited disorder characterised by storage of glucosylceramide (GlcCer) in lysosomes of tissue macrophages. Macrophages activated by accumulated GlcCer secrete chitotriosidase. Plasma chitotriosidase activity is significantly elevated in patients with active GD and has been suggested to indicate total body Gaucher cell load. There are two biomarkers used to assess the severity of GD - chitotriosidase has been measured for over 20 years, and deacylated GlcCer, known as glucosylsphingosine (GlcSph) is thought to be even more adequate, as it is almost a direct storage substrate...
February 27, 2018: Molecular Genetics and Metabolism
Hong Li, Heather M Byers, Alicia Diaz-Kuan, Miriam B Vos, Patricia L Hall, Silvia Tortorelli, Rani Singh, Matthew B Wallenstein, Meredith Allain, David P Dimmock, Ryan M Farrell, Shawn McCandless, Michael J Gambello
Hereditary fructose intolerance (HFI) is an autosomal recessive disorder caused by aldolase B (ADOLB) deficiency resulting in an inability to metabolize fructose. The toxic accumulation of intermediate fructose-1-phosphate causes multiple metabolic disturbances, including postprandial hypoglycemia, lactic acidosis, electrolyte disturbance, and liver/kidney dysfunction. The clinical presentation varies depending on the age of exposure and the load of fructose. Some common infant formulas contain fructose in various forms, such as sucrose, a disaccharide of fructose and glucose...
February 27, 2018: Molecular Genetics and Metabolism
Jocelyn M Bischof, Rachel Wevrick
Excess fat mass is a cardinal feature of Prader-Willi syndrome (PWS) that is recapitulated in the Magel2-null mouse model of this genetic disorder. There is a pressing need for drugs that can prevent or treat obesity in children with PWS. Recently, a clinical study of a controlled release form of the benzothiadiazine derivative diazoxide demonstrated improved metabolic parameters and decreased fat mass in obese children and adults with PWS. We tested whether chronic diazoxide administration can reduce fat mass and improve metabolism in mice lacking MAGEL2, a gene inactivated in PWS...
February 27, 2018: Molecular Genetics and Metabolism
Roan Louw, Izelle Smuts, Kimmey-Li Wilsenach, Lindi-Maryn Jonck, Maryke Schoonen, Francois H van der Westhuizen
BACKGROUND: Coenzyme Q10 (CoQ10 ) is an important component of the mitochondrial respiratory chain (RC) and is critical for energy production. Although the prevalence of CoQ10 deficiency is still unknown, the general consensus is that the condition is under-diagnosed. The aim of this study was to retrospectively investigate CoQ10 deficiency in frozen muscle specimens in a cohort of ethnically diverse patients who received muscle biopsies for the investigation of a possible RC deficiency (RCD)...
February 23, 2018: Molecular Genetics and Metabolism
Erzsebet Polyak, Julian Ostrovsky, Min Peng, Stephen D Dingley, Mai Tsukikawa, Young Joon Kwon, Shana E McCormack, Michael Bennett, Rui Xiao, Christoph Seiler, Zhe Zhang, Marni J Falk
Oxidative stress is a known contributing factor in mitochondrial respiratory chain (RC) disease pathogenesis. Yet, no efficient means exists to objectively evaluate the comparative therapeutic efficacy or toxicity of different antioxidant compounds empirically used in human RC disease. We postulated that pre-clinical comparative analysis of diverse antioxidant drugs having suggested utility in primary RC disease using animal and cellular models of RC dysfunction may improve understanding of their integrated effects and physiologic mechanisms, and enable prioritization of lead antioxidant molecules to pursue in human clinical trials...
February 23, 2018: Molecular Genetics and Metabolism
Christian Hendriksz, Saikat Santra, Simon A Jones, Tarekegn Geberhiwot, Lynne Jesaitis, Brian Long, Yulan Qi, Sara M Hawley, Celeste Decker
Elosulfase alfa is an enzyme replacement therapy for Morquio A syndrome (mucopolysaccharidosis IVA), a multisystemic progressive lysosomal storage disorder. This report includes the primary treatment outcomes and immunogenicity profile of elosulfase alfa in patients with Morquio A syndrome from 2 sequential studies, MOR-002 (ClinicalTrials.govNCT00884949) and MOR-100 (NCT01242111), representing >5 years of clinical study data. MOR-002 was an open-label, single-arm phase 1/2 study that evaluated the pharmacokinetics, safety, immunogenicity, and preliminary efficacy of 3 sequential doses of elosulfase alfa (0...
February 19, 2018: Molecular Genetics and Metabolism
Sergei M Danilov, Victoria E Tikhomirova, Roman Metzger, Irina A Naperova, Tatiana M Bukina, Ozlem Goker-Alpan, Nahid Tayebi, Nurshat M Gayfullin, David E Schwartz, Larisa M Samokhodskaya, Olga A Kost, Ellen Sidransky
BACKGROUND: Gaucher disease is characterized by the activation of splenic and hepatic macrophages, accompanied by dramatically increased levels of angiotensin-converting enzyme (ACE). To evaluate the source of the elevated blood ACE, we performed complete ACE phenotyping using blood, spleen and liver samples from patients with Gaucher disease and controls. METHODS: ACE phenotyping included 1) immunohistochemical staining for ACE; 2) measuring ACE activity with two substrates (HHL and ZPHL); 3) calculating the ratio of the rates of substrate hydrolysis (ZPHL/HHL ratio); 4) assessing the conformational fingerprint of ACE by evaluating the pattern of binding of monoclonal antibodies to 16 different ACE epitopes...
February 17, 2018: Molecular Genetics and Metabolism
Marie Joncquel-Chevalier Curt, Marie-Adélaïde Bout, Monique Fontaine, Isabelle Kim, Guillemette Huet, Soumeya Bekri, Gilles Morin, Stéphanie Moortgat, Alexandre Moerman, Jean-Marie Cuisset, David Cheillan, Joseph Vamecq
Creatine transporter is currently the focus of renewed interest with emerging roles in brain neurotransmission and physiology, and the bioenergetics of cancer metastases. We here report on amendments of a standard creatine uptake assay which might help clinical chemistry laboratories to extend their current range of measurements of creatine and metabolites in body fluids to functional enzyme explorations. In this respect, short incubation times and the use of a stable-isotope-labeled substrate (D3 -creatine) preceded by a creatine wash-out step from cultured fibroblast cells by removal of fetal bovine serum (rich in creatine) from the incubation medium are recommended...
February 16, 2018: Molecular Genetics and Metabolism
Matthew A Summers, Emily R Vasiljevski, Kathy Mikulec, Lauren Peacock, David G Little, Aaron Schindeler
Neurofibromatosis Type 1 (NF1) is a common autosomal dominant genetic disorder While NF1 is primarily associated with predisposition for tumor formation, muscle weakness has emerged as having a significant impact on quality of life. NF1 inactivation is linked with a canonical upregulation Ras-MEK-ERK signaling. This in this study we tested the capacity of the small molecule MEK inhibitor PD0325901 to influence the intramyocellular lipid accumulation associated with NF1 deficiency. Established murine models of tissue specific Nf1 deletion in skeletal muscle (Nf1MyoD -/- ) and limb mesenchyme (Nf1Prx1 -/- ) were tested...
February 16, 2018: Molecular Genetics and Metabolism
M Boyer, M Sowa, I Di Meo, S Eftekharian, M R Steenari, V Tiranti, J E Abdenur
Ethylmalonic encephalopathy (EE) is a devastating neurodegenerative disease caused by mutations in the ETHE1 gene critical for hydrogen sulfide (H2 S) detoxification. Patients present in infancy with hypotonia, developmental delay, diarrhea, orthostatic acrocyanosis and petechiae. Biochemical findings include elevated C4, C5 acylcarnitines and lactic and ethylmalonic acid (EMA) in body fluids. Current treatment modalities include metronidazole and N-acetylcysteine (NAC) to lower the production and promote detoxification of toxic H2 S...
February 14, 2018: Molecular Genetics and Metabolism
Monique Fontaine, Isabelle Kim, Anne-Frédérique Dessein, Karine Mention-Mulliez, Dries Dobbelaere, Claire Douillard, Guilhem Sole, Manuel Schiff, Roland Jaussaud, Caroline Espil-Taris, Audrey Boutron, Wim Wuyts, Cécile Acquaviva, Christine Vianey-Saban, Dominique Roland, Marie Joncquel-Chevalier Curt, Joseph Vamecq
Carnitine palmitoyltransferase type 2 (CPT2) deficiency, a mitochondrial fatty acid oxidation disorder (MFAOD), is a cause of myopathy in its late clinical presentation. As for other MFAODs, its diagnosis may be evocated when blood acylcarnitine profile is abnormal. However, a lack of abnormalities or specificity in this profile is not exclusive of CPT2 deficiency. Our retrospective study reports clinical and biological data in a cohort of 11 patients with circulating acylcarnitine profile unconclusive enough for a specific diagnosis orientation...
February 12, 2018: Molecular Genetics and Metabolism
Paul Harmatz, Chester B Whitley, Raymond Y Wang, Mislen Bauer, Wenjie Song, Christine Haller, Emil Kakkis
BACKGROUND: Drug development for ultra-rare diseases is challenging because small sample sizes and heterogeneous study populations hamper the ability of randomized, placebo-controlled trials with a single primary endpoint to demonstrate valid treatment effects. METHODS: To overcome these challenges, a novel Blind Start design was utilized in a study of vestronidase alfa in mucopolysaccharidosis VII (Sly syndrome), an ultra-rare lysosomal disease, that demonstrates the strengths of this approach in a challenging drug-development setting...
February 12, 2018: Molecular Genetics and Metabolism
Stefano Schiaffino
Large scale whole-exome sequence studies have revealed that a number of individuals from different populations have predicted loss-of-function of different genes due to nonsense, frameshift, or canonical splice-site mutations. Surprisingly, many of these mutations do not apparently show the deleterious phenotypic consequences expected from gene knockout. These homozygous null mutations, when confirmed, can provide insight into human gene function and suggest novel approaches to correct gene dysfunction, as the lack of the expected disease phenotype may reflect the existence of modifier genes that reveal potential therapeutic targets...
February 10, 2018: Molecular Genetics and Metabolism
Kyoko Nagao, Thierry Morlet, Elizabeth Haley, Jennifer Padilla, Julianne Nemith, Robert W Mason, Shunji Tomatsu
BACKGROUND: Hearing impairment is a common problem in patients with mucopolysaccharidosis IV (MPS IV) throughout their life. Many of the adult patients with MPS IV exhibit permanent or severe hearing loss. However, there has been no systematic review of detailed audiological test results in MPS IV. MATERIALS AND METHODS: Fourteen individuals with MPS IV (13 MPS IVA and 1 MPS IVB; aged between 12 and 38 years old) participated in the current study. We obtained auditory neurophysiological responses (auditory brainstem responses and otoacoustic emissions test) in addition to pure-tone audiometry and middle ear function tests (tympanometry and acoustic reflexes)...
February 8, 2018: Molecular Genetics and Metabolism
Apolline Imbard, Nuria Garcia Segarra, Marine Tardieu, Pierre Broué, Juliette Bouchereau, Samia Pichard, Hélène Ogier de Baulny, Abdelhamid Slama, Charlotte Mussini, Guy Touati, Marie Danjoux, Pauline Gaignard, Hannes Vogel, François Labarthe, Manuel Schiff, Jean-François Benoist
BACKGROUND AND OBJECTIVES: Patients affected with methylmalonic acidemia (MMA) and propionic acidemia (PA) exhibit diverse long-term complications and poor outcome. Liver disease is not a reported complication. The aim of this study was to characterize and extensively evaluate long-term liver involvement in MMA and PA patients. PATIENTS AND METHODS: We first describe four patients who had severe liver involvement during the course of their disease. Histology showed fibrosis and/or cirrhosis in 3 patients...
February 7, 2018: Molecular Genetics and Metabolism
Jörn Oliver Sass, Sema Kalkan Uçar, Clara D M van Karnebeek
No abstract text is available yet for this article.
February 5, 2018: Molecular Genetics and Metabolism
Rebecca D Ganetzky, Marni J Falk
BACKGROUND: Intravenous (IV) arginine has been reported to ameliorate acute metabolic stroke symptoms in adult patients with Mitochondrial Encephalopathy with Lactic Acidosis and Stroke-like Episodes (MELAS) syndrome, where its therapeutic benefit is postulated to result from arginine acting as a nitric oxide donor to reverse vasospasm. Further, reduced plasma arginine may occur in mitochondrial disease since the biosynthesis of arginine's precursor, citrulline, requires ATP. Metabolic strokes occur across a wide array of primary mitochondrial diseases having diverse molecular etiologies that are likely to share similar pathophysiologic mechanisms...
February 2, 2018: Molecular Genetics and Metabolism
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