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methylmalonic aciduria

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
D-J Reijngoud
Patients with an inborn error of metabolism (IEM) are deficient of an enzyme involved in metabolism, and as a consequence metabolism reprograms itself to reach a new steady state. This new steady state underlies the clinical phenotype associated with the deficiency. Hence, we need to know the flux of metabolites through the different metabolic pathways in this new steady state of the reprogrammed metabolism. Stable isotope technology is best suited to study this. In this review the progress made in characterizing the altered metabolism will be presented...
January 9, 2018: Journal of Inherited Metabolic Disease
Ding An, Jessica L Schneller, Andrea Frassetto, Shi Liang, Xuling Zhu, Ji-Sun Park, Matt Theisen, Sue-Jean Hong, Jenny Zhou, Raj Rajendran, Becca Levy, Rebecca Howell, Gilles Besin, Vladimir Presnyak, Staci Sabnis, Kerry E Murphy-Benenato, E Sathyajith Kumarasinghe, Timothy Salerno, Cosmin Mihai, Christine M Lukacs, Randy J Chandler, Lin T Guey, Charles P Venditti, Paolo G V Martini
Isolated methylmalonic acidemia/aciduria (MMA) is a devastating metabolic disorder with poor outcomes despite current medical treatments. Like other mitochondrial enzymopathies, enzyme replacement therapy (ERT) is not available, and although promising, AAV gene therapy can be limited by pre-existing immunity and has been associated with genotoxicity in mice. To develop a new class of therapy for MMA, we generated a pseudoU-modified codon-optimized mRNA encoding human methylmalonyl-CoA mutase (hMUT), the enzyme most frequently mutated in MMA, and encapsulated it into biodegradable lipid nanoparticles (LNPs)...
December 19, 2017: Cell Reports
Marwa Maalej, Amel Tej, Jihène Bouguila, Samia Tilouche, Senda Majdoub, Boudour Khabou, Mouna Tabbebi, Rahma Felhi, Marwa Ammar, Emna Mkaouar-Rebai, Leila Keskes, Lamia Boughamoura, Faiza Fakhfakh
Deficiency of the mitochondrial enzyme succinyl COA ligase (SUCL) is associated with encephalomyopathic mtDNA depletion syndrome and methylmalonic aciduria. This disorder is caused by mutations in both SUCL subunits genes: SUCLG1 (α subnit) and SUCLA2 (β subnit). We report here, two Tunisian patients belonging to a consanguineous family with mitochondrial encephalomyopathy, hearing loss, lactic acidosis, hypotonia, psychomotor retardation and methylmalonic aciduria. Mutational analysis of SUCLG1 gene showed, for the first time, the presence of c...
January 8, 2018: Biochemical and Biophysical Research Communications
S Brasil, A Briso-Montiano, A Gámez, J Underhaug, M I Flydal, L Desviat, B Merinero, M Ugarte, A Martinez, B Pérez
No abstract text is available yet for this article.
February 2018: Biochimica et Biophysica Acta
Z J Gao, Q Jiang, Q Chen, K M Xu, Z Q Liu, X B Chen, X L Chen
Objective: To analyze the clinical and genetic features of 15 cases with intellectual disability or developmental delay (ID/DD) complicated with congenital nystagmus. Method: The clinical characteristics and the results of laboratory tests, images and genetics of 15 patients with ID/DD complicated with congenital nystagmus, confirmed by gene diagnosis in the Department of Neurology, Children's Hospital Affiliated to Capital Institute of Pediatrics from March 2015 to October 2016, were retrospectively analyzed...
November 2, 2017: Zhonghua Er Ke za Zhi. Chinese Journal of Pediatrics
Lenaig Abily-Donval, Stéphanie Torre, Aurélie Samson, Bénédicte Sudrié-Arnaud, Cécile Acquaviva, Anne-Marie Guerrot, Jean-François Benoist, Stéphane Marret, Soumeya Bekri, Abdellah Tebani
Methylmalonyl-CoA epimerase (MCE) converts d-methylmalonyl-CoA epimer to l-methylmalonyl-CoA epimer in the propionyl-CoA to succinyl-CoA pathway. Only seven cases of MCE deficiency have been described. In two cases, MCE deficiency was combined with sepiapterin reductase deficiency. The reported clinical pictures of isolated MCE are variable, with two asymptomatic patients and two other patients presenting with metabolic acidosis attacks. For combined MCE and sepiapterin reductase deficiency, the clinical picture is dominated by neurologic alterations...
November 1, 2017: International Journal of Molecular Sciences
Liu Miao, Rui-Xing Yin, Feng Huang, Wu-Xian Chen, Xiao-Li Cao, Jin-Zhen Wu
AIM: This study aimed to detect the association of the mevalonate kinase (MVK) and methylmalonic aciduria (cobalamin deficiency) cblB type (MMAB) gene variants, their haplotypes, and gene-environment (G×E) interactions on serum lipid levels and the risk of coronary heart disease (CHD) and ischemic stroke (IS) in a Chinese Han population. METHODS: Genotyping of the rs3759387, rs7134594, rs877710 and rs9593 SNPs in 846 CHD and 869 IS patients and 847 healthy controls was performed by PCR-RFLP and Sanger sequencing...
September 22, 2017: Oncotarget
Liu Miao, Rui-Xing Yin, Shang-Ling Pan, Shuo Yang, De-Zhai Yang, Wei-Xiong Lin
Maonan ethnic group is a relatively conservative and isolated minority in China. Little is known about the association of the mevalonate kinase (MVK), methylmalonic aciduria (cobalamin deficiency) cblB type (MMAB) single nucleotide polymorphisms (SNPs) and serum lipid levels. This study aimed to determine the association between four SNPs in the MVK/MMAB and serum lipid levels. Genotyping of the rs3759387, rs877710, rs7134594 and rs9593 SNPs was performed in 1264 Maonan subjects and 1251 Han participants. Allele and genotype frequencies of the selected SNPs were different between the two populations (P < 0...
September 19, 2017: Oncotarget
X Q Liu, H Yan, J X Qiu, C Y Zhang, J G Qi, X Zhang, H J Xiao, Y L Yang, Y H Chen, J B DU
OBJECTIVE: To deepen our understanding of Methylmalonic aciduria (MMA) associated pulmonary hypertension (PH) by analyzing the characteristics of clinical presentation, pulmonary high resolusion CT(HRCT), treatment response and gene mutation. METHODS: This study includes 15 cases of pediatric patients with MMA associated PH diagnosed and treated in Peking University First Hospital pediatric department between May 2012 and May 2016 with symptoms of PH as their leading presentation...
October 18, 2017: Beijing da Xue Xue Bao. Yi Xue Ban, Journal of Peking University. Health Sciences
Fang Hong, Xinwen Huang, Yu Zhang, Jianbin Yang, Fan Tong, Huaqing Mao, Xiaolei Huang, Xuelian Zhou, Rulai Yang, Zhengyan Zhao
OBJECTIVE: To analyze the results and follow up data of screening for newborn organic aciduria in Zhejiang province. METHODS: The results and follow-up data of 1 861 262 newborns from Zhejiang province undergoing screening for organic aciduria during January 2009 and December 2016 were retrospectively analyzed. The acylcarnitine spectrum in urine samples was detected by tandem mass spectrum (MS/MS) and the positive patients were confirmed by urine gas chromatography mass spectrometry and/or gene analysis...
May 25, 2017: Zhejiang da Xue Xue Bao. Yi Xue Ban, Journal of Zhejiang University. Medical Sciences
Tomas S Aleman, Camila V Ventura, Milena M Cavalcanti, Leona W Serrano, Anastasia Traband, Akosua A Nti, Adriana L Gois, Vasco Bravo-Filho, Thayze T Martins, Charles W Nichols, Mauricio Maia, Rubens Belfort
Importance: A better pathophysiologic understanding of the neurodevelopmental abnormalities observed in neonates exposed in utero to Zika virus (ZIKV) is needed to develop treatments. The retina as an extension of the diencephalon accessible to in vivo microcopy with spectral-domain optical coherence tomography (SD-OCT) can provide an insight into the pathophysiology of congenital Zika syndrome (CZS). Objective: To quantify the microstructural changes of the retina in CZS and compare these changes with those of cobalamin C (cblC) deficiency, a disease with potential retinal maldevelopment...
October 1, 2017: JAMA Ophthalmology
Natario L Couser, Daniel S Marchuk, Laurie D Smith, Alexandra Arreola, Kathleen A Kaiser-Rogers, Joseph Muenzer, Arti Pandya, Muge Gucsavas-Calikoglu, Cynthia M Powell
Mitochondrial DNA depletion syndrome 5 (MIM 612073) is a rare autosomal recessive disorder caused by homozygous or compound heterozygous pathogenic variants in the beta subunit of the succinate-CoA ligase gene located within the 13q14 band. We describe two siblings of Hispanic descent with SUCLA2-related mitochondrial depletion syndrome (encephalomyopathic form with methylmalonic aciduria); the older sibling is additionally affected with trisomy 21. SUCLA2 sequencing identified homozygous p.Arg284Cys pathogenic variants in both patients...
July 27, 2017: American Journal of Medical Genetics. Part A
Victoria Fettelschoss, Patricie Burda, Corinne Sagné, David Coelho, Corinne De Laet, Seraina Lutz, Terttu Suormala, Brian Fowler, Nicolas Pietrancosta, Bruno Gasnier, Beat Bornhauser, D Sean Froese, Matthias R Baumgartner
Vitamin B12 (cobalamin (Cbl)), in the cofactor forms methyl-Cbl and adenosyl-Cbl, is required for the function of the essential enzymes methionine synthase and methylmalonyl-CoA mutase, respectively. Cbl enters mammalian cells by receptor-mediated endocytosis of protein-bound Cbl followed by lysosomal export of free Cbl to the cytosol and further processing to these cofactor forms. The integral membrane proteins LMBD1 and ABCD4 are required for lysosomal release of Cbl, and mutations in the genes LMBRD1 and ABCD4 result in the cobalamin metabolism disorders cblF and cblJ...
July 14, 2017: Journal of Biological Chemistry
Tanja Plessl, Céline Bürer, Seraina Lutz, Wyatt W Yue, Matthias R Baumgartner, D Sean Froese
Mutations in the human MMAA gene cause the metabolic disorder cblA-type methylmalonic aciduria (MMA), although knowledge of the mechanism of dysfunction remains lacking. MMAA regulates the incorporation of the cofactor adenosylcobalamin (AdoCbl), generated from the MMAB adenosyltransferase, into the destination enzyme methylmalonyl-CoA mutase (MUT). This function of MMAA depends on its GTPase activity, which is stimulated by an interaction with MUT. Here, we present 67 new patients with cblA-type MMA, identifying 19 novel mutations...
August 2017: Human Mutation
Giacomo M Bacci, Maria A Donati, Elisabetta Pasquini, Francis Munier, Catia Cavicchi, Amelia Morrone, Andrea Sodi, Vittoria Murro, Nuria Garcia Segarra, Claudio Defilippi, Leonardo Bussolin, Roberto Caputo
PURPOSE: To describe the retinal structure of a group of patients affected by methylmalonic aciduria with homocystinuria cblC type, caused by mutations in the MMACHC gene, using spectral domain optical coherence tomography (SD-OCT). METHODS: Young patients (n = 11, age 0-74 months) with cblC disease, detected by newborn screening or clinically diagnosed within 40 days of life, underwent molecular analysis and complete ophthalmic examination, including fundus photography and SD-OCT...
December 2017: Acta Ophthalmologica
Filipa Dias Costa, Rita Moinho, Sandra Ferreira, Paula Garcia, Luísa Diogo, Isabel Gonçalves, Carla Pinto
INTRODUCTION: Pediatric acute liver failure (ALF) due to inherited metabolic diseases (IMD) is a rare life-threatening condition with a poor prognosis. Early intervention may be lifesaving. OBJECTIVE: To describe clinical presentation, investigation and outcomes of ALF related to IMD in young children. MATERIAL AND METHODS: Retrospective review of the medical records of children aged up to 24 months, admitted to a tertiary pediatric and neonatal Intensive Care Unit during a 27-year period, fulfilling the ALF criteria, with documented metabolic etiology...
April 11, 2017: Anales de Pediatría: Publicación Oficial de la Asociación Española de Pediatría (A.E.P.)
Emmanuel Scalais, Elise Osterheld, Christiane Weitzel, Linda De Meirleir, Frederic Mataigne, Geert Martens, Tamim H Shaikh, Curtis R Coughlin, Hung-Chun Yu, Michael Swanson, Marisa W Friederich, Gunter Scharer, Daniel Helbling, Jamie Wendt-Andrae, Johan L K Van Hove
BACKGROUND: Autosomal recessive or X-linked inborn errors of intracellular cobalamin metabolism can lead to methylmalonic aciduria and homocystinuria. In neonates, both increased cerebrospinal fluid glycine and cerebrospinal fluid/plasma glycine ratio are biochemical features of nonketotic hyperglycinemia. METHODS: We describe a boy presenting in the neonatal period with hypotonia, tonic, clonic, and later myoclonic seizures, subsequently evolving into refractory epilepsy and severe neurocognitive impairment...
January 7, 2017: Pediatric Neurology
Jordan Chu, Mihaela Pupavac, David Watkins, Xia Tian, Yanming Feng, Stella Chen, Remington Fenter, Victor W Zhang, Jing Wang, Lee-Jun Wong, David S Rosenblatt
No abstract text is available yet for this article.
March 2017: Molecular Genetics and Metabolism
Li-Yong Wu, Hong An, Jia Liu, Jie-Ying Li, Yue Han, Ai-Hong Zhou, Fen Wang, Jian-Ping Jia
No abstract text is available yet for this article.
February 20, 2017: Chinese Medical Journal
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