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Molecular Genetics and Metabolism

Carlos R Ferreira, David Cassiman, Nenad Blau
Inherited metabolic diseases account for about one third of pediatric patients with hepatomegaly, acute liver failure, cirrhosis or cholestasis. Specifically for pediatric acute liver failure, they account for 10-15% of cases, with a mortality of 22-65%. The percentage of acute liver failure caused by an inherited metabolic disease in children <2-3 years of age is even higher, ranging from a third to half of all cases. Metabolic liver disease accounts for 8-13% of all pediatric liver transplantations. Despite this high burden of disease, underdiagnosis remains common...
April 12, 2019: Molecular Genetics and Metabolism
Uma Ramaswami, Daniel G Bichet, Lorne A Clarke, Gabriela Dostalova, Alejandro Fainboim, Andreas Fellgiebel, Cassiano M Forcelini, Kristina An Haack, Robert J Hopkin, Michael Mauer, Behzad Najafian, C Ronald Scott, Suma P Shankar, Beth L Thurberg, Camilla Tøndel, Anna Tylki-Szymanska, Bernard Bénichou, Frits A Wijburg
BACKGROUND: Fabry disease is a rare, X-linked, lifelong progressive lysosomal storage disorder. Severely deficient α-galactosidase A activity in males is associated with the classic phenotype with early-onset, multisystem manifestations evolving to vital organ complications during adulthood. We assessed the ability of 2 low-dose agalsidase beta regimens to lower skin, plasma, and urine globotriaosylceramide (GL-3) levels, and influence clinical manifestations in male pediatric Fabry patients...
April 3, 2019: Molecular Genetics and Metabolism
Isabelle Schmutz, Vidhya Jagannathan, Florian Bartenschlager, Veronika M Stein, Achim D Gruber, Tosso Leeb, Martin L Katz
The neuronal ceroid lipofuscinoses (NCLs) are lysosomal storage disorders characterized by progressive neurodegeneration and declines in neurological functions. Pathogenic sequence variants in at least 13 genes underlie different forms of NCL, almost all of which are recessively inherited. To date 13 sequence variants in 8 canine orthologs of human NCL genes have been found to occur in 11 dog breeds in which they result in progressive neurological disorders similar to human NCLs. Canine NCLs can serve as models for preclinical evaluation of therapeutic interventions for these disorders...
March 27, 2019: Molecular Genetics and Metabolism
Nastassja Himmelreich, Riccardo Montioli, Mariarita Bertoldi, Carla Carducci, Vincenzo Leuzzi, Corinne Gemperle, Todd Berner, Keith Hyland, Beat Thöny, Georg F Hoffmann, Carla B Voltattorni, Nenad Blau
Aromatic-l-amino acid decarboxylase (AADC) deficiency is an ultra-rare inherited autosomal recessive disorder characterized by sharply reduced synthesis of dopamine as well as other neurotransmitters. Symptoms, including hypotonia and movement disorders (especially oculogyric crisis and dystonia) as well as autonomic dysfunction and behavioral disorders, vary extensively and typically emerge in the first months of life. However, diagnosis is difficult, requiring analysis of metabolites in cerebrospinal fluid, assessment of plasma AADC activity, and/or DNA sequence analysis, and is frequently delayed for years...
March 27, 2019: Molecular Genetics and Metabolism
Carlos R Ferreira, Georg F Hoffmann, Nenad Blau
About a third of patients with inherited metabolic diseases with neurologic involvement suffer from a movement disorder, in the form of ataxia, hyperkinetic movements, or hypokinetic-rigid syndrome. We reviewed and updated the list of known metabolic etiologies associated with various types of movement disorders, and found approximately 200 relevant inborn errors of metabolism. This represents the first of a series of articles attempting to create and maintain a comprehensive list of clinical and metabolic differential diagnoses according to system involvement...
March 26, 2019: Molecular Genetics and Metabolism
Shinya Iwasawa, Atsuo Kikuchi, Yoichi Wada, Natsuko Arai-Ichinoi, Osamu Sakamoto, Gen Tamiya, Shigeo Kure
Galactosemia is a metabolic disorder that affects the appropriate metabolism of β-D-galactose. Deficiencies in three of the enzymes of the Leloir pathway, namely, GALT, GALK1, or GALE, are characterized as type I, II, and III galactosemia, respectively. Recently, we reported a novel type of galactosemia (type IV galactosemia) due to biallelic GALM mutations. Genetic diagnosis is indispensable for diagnosing GALM deficiency because no biochemical diagnosis method has been established. Given that apparently pathogenic variants in GALM are found in public variant databases, we presumed the presence of pathogenic variants that have not been reported...
March 18, 2019: Molecular Genetics and Metabolism
Hanneke A Haijes, Maria van der Ham, Johan Gerrits, Peter M van Hasselt, Hubertus C M T Prinsen, Monique G M de Sain-van der Velden, Nanda M Verhoeven-Duif, Judith J M Jans
BACKGROUND: For inborn errors of metabolism (IEM), metabolomics is performed for three main purposes: 1) development of next generation metabolic screening platforms, 2) identification of new biomarkers in predefined patient cohorts and 3) for identification of new IEM. To date, plasma, urine and dried blood spots are used. We anticipate that cerebrospinal fluid (CSF) holds additional - valuable - information, especially for IEM with neurological involvement. To expand metabolomics to CSF, we here tested whether direct-infusion high-resolution mass spectrometry (DI-HRMS) based non-quantitative metabolomics could correctly capture the biochemical profile of patients with an IEM in CSF...
March 15, 2019: Molecular Genetics and Metabolism
Mariana Anosov, Ruth Birk
BACKGROUND: Bardet-Biedl syndrome (BBS) is an autosomal recessive ciliopathy, presenting with early obesity onset. The etiology of BBS obesity involves both central and peripheral defects, through mechanisms mostly yet to be deciphered. We previously showed BBS4 expression in adipogenesis, peaking at day 3 of differentiation. Obesity is characterized by cellular stress which promotes pathological consequences. AIMS: We set out to test a possible role of BBS4 in adipocyte endoplasmic reticulum (ER) stress-induced unfolding protein response (UPR)...
March 15, 2019: Molecular Genetics and Metabolism
Hiroko Yanagisawa, Mohammad Arif Hossain, Takashi Miyajima, Kazuaki Nagao, Toshiyuki Miyashita, Yoshikatsu Eto
Lysosomes are an essential organ for cellular metabolism and play an important role in autophagy. We examined the association between methylation and autophagy in a severely affected female patient with Fabry disease, which is caused by mutation of the GLA gene on the X chromosome, and her two sisters, who had few symptoms. We confirmed autophagic flux by LC3 turnover assay using fibroblasts from each sister. In the severe female patient, autophagic flux showed abnormal while her two sisters with few symptoms had normal autophagic flux, revealing the direct relationship between symptoms and autophagic flux...
March 7, 2019: Molecular Genetics and Metabolism
Herbert L Bonkovsky, Natalia Dixon, Sean Rudnick
The acute hepatic porphyrias include four disorders: acute intermittent porphyria [AIP], hereditary coproporphyria [HCP], variegate porphyria [VP], and the rare porphyria due to severe deficiency of ALA dehydratase [ADP]. In the USA, AIP is the most severe and most often symptomatic. AIP, HCP, and VP are due to autosomal dominant genetic abnormalities, in which missense, nonsense, or other mutations of genes of normal hepatic heme biosynthesis, in concert with other environmental, nutritional, hormonal and genetic factors, may lead to a critical deficiency of heme, the end-product of the pathway, in a small but critical 'regulatory pool' within hepatocytes...
March 6, 2019: Molecular Genetics and Metabolism
E Jurecki, K Ueda, D Frazier, F Rohr, A Thompson, C Hussa, L Obernolte, B Reineking, A M Roberts, S Yannicelli, Y Osara, A Stembridge, P Splett, R H Singh
No abstract text is available yet for this article.
March 4, 2019: Molecular Genetics and Metabolism
Nathalie Kaiser, Matthias Gautschi, Lenka Bosanska, Fabian Meienberg, Matthias R Baumgartner, Giatgen A Spinas, Michel Hochuli
BACKGROUND: Regular carbohydrate intake to avoid hypoglycemia is the mainstay of dietary treatment in glycogen storage disease type I (GSDI). The aim of this study was to evaluate the quality of dietary treatment and glycemic control in a cohort of GSDI patients, in relation to the presence of typical long-term complications. METHODS: Data of 25 patients (22 GSD subtype Ia and 3 GSDIb, median age 20y) from the Swiss hepatic glycogen storage disease registry was analyzed cross-sectionally...
February 28, 2019: Molecular Genetics and Metabolism
Femke Molema, Florian Gleich, Peter Burgard, Ans T van der Ploeg, Marshall L Summar, Kimberly A Chapman, Allan M Lund, Dimitris Rizopoulos, Stefan Kölker, Monique Williams
BACKGROUND AND AIM: Patients with methylmalonic acidemia (MMA) and propionic acidemia (PA) and urea cycle disorders (UCD), treated with a protein restricted diet, are prone to growth failure. To obtain optimal growth and thereby efficacious protein incorporation, a diet containing the essential and functional amino acids for growth is necessary. Optimal growth will result in improved protein tolerance and possibly a decrease in the number of decompensations. It thus needs to be determined if amino acid deficiencies are associated with the growth retardation in these patient groups...
February 25, 2019: Molecular Genetics and Metabolism
Davide Tonduti, Giana Izzo, Stefano D'Arrigo, Daria Riva, Isabella Moroni, Giovanna Zorzi, Vanessa Cavallera, Anna Pichiecchio, Carla Uggetti, Pierangelo Veggiotti, Simona Orcesi, Luisa Chiapparini, Cecilia Parazzini
BACKGROUND: Aicardi-Goutières syndrome (AGS) is a rare genetic leukoencephalopathy related to inappropriate activation of type I interferon. Neuroradiological findings are typically characterized by white matter abnormalities, cerebral atrophy and cerebral calcification. The disease usually manifests itself during the first year of life in the form of an initial "encephalitic-like" phase followed by a chronic phase of stabilization of the neurological signs. Recently new therapeutic strategies have been proposed aimed at blocking the abnormal activation of the interferon cascade...
February 25, 2019: Molecular Genetics and Metabolism
Hiroaki Sasa, Munehiko Nagao, Koichi Kino
Fabry disease is a rare X-linked inherited multisystem disorder resulting from deficiency of the lysosomal enzyme alpha-galactosidase A. Currently, specific therapies, including enzyme replacement therapies, are available for Fabry disease, but clinical trials provide limited information on long-term safety and effectiveness. Agalsidase alfa was approved in Japan in 2006. The post-marketing surveillance study of all patients receiving agalsidase alfa to evaluate its long-term safety and effectiveness as a mandatory condition for its approval had been conducted for 8 years (from February 2007 to March 2015)...
February 20, 2019: Molecular Genetics and Metabolism
Simona E Bianconi, Dylan I Hammond, Nicole Y Farhat, An Dang Do, Kisha Jenkins, Antony Cougnoux, Kyle Martin, Forbes D Porter
Niemann-Pick disease, type C (NPC) is a neurodegenerative lysosomal storage disease affecting the visceral organs and the central nervous system. The age of initial presentation varies from fetal to adult onset, although childhood onset is most common. The life expectancy for the full spectrum of NPC patients is not well defined, and it is unknown if current supportive care impacts the natural history. In order to assess age of death for a large cohort of NPC patients, we "crowd-sourced" age and year of death from information posted on disease support group website memorial walls...
February 15, 2019: Molecular Genetics and Metabolism
Manuel Johanns, Samanta Kviklyte, Sheng-Ju Chuang, Katrien Corbeels, Roxane Jacobs, Gaëtan Herinckx, Didier Vertommen, Olivier Schakman, Thibaut Duparc, Patrice D Cani, Caroline Bouzin, Harriet Andersén, Mohammad Bohlooly-Y, Bart Van der Schueren, Jan Oscarsson, Mark H Rider
We previously investigated whether inhibition of AMP-metabolizing enzymes could enhance AMP-activated protein kinase (AMPK) activation in skeletal muscle for the treatment of type 2 diabetes. Soluble 5'-nucleotidase II (NT5C2) hydrolyzes IMP and its inhibition could potentially lead to a rise in AMP to activate AMPK. In the present study, we investigated effects of NT5C2 deletion in mice fed a normal-chow diet (NCD) or a high-fat diet (HFD). On a NCD, NT5C2 deletion did not result in any striking metabolic phenotype...
February 14, 2019: Molecular Genetics and Metabolism
Neil Smith, Nicola Longo, Keith Levert, Keith Hyland, Nenad Blau
Tetrahydrobiopterin (BH4 ) is the natural cofactor of aromatic amino acid hydroxylases and essential for degradation of phenylalanine and synthesis of catecholamines and serotonin. It can be synthesized either de novo from GTP or through the salvage pathway from sepiapterin. Sepiapterin, a natural precursor of BH4 , is a more stable molecule and is transported more efficiently across cellular membranes, thus having potentially significant advantage over BH4 as a pharmacological agent for diseases associated with BH4 -deficient conditions...
February 10, 2019: Molecular Genetics and Metabolism
Geneviève Morrow, Natacha Dreumont, Maxime Bourrelle-Langlois, Vincent Roy, Robert M Tanguay
Hereditary tyrosinemia type 1 (HT1), the most severe disease of the tyrosine catabolic pathway, is caused by a deficiency of fumarylacetoacetate hydrolase (FAH). More than 90 disease-causing variants have been identified in the fah gene. We investigated the molecular defect in a patient who presented atypical symptoms for the disease. No immunoreactive FAH was found in the liver and RNA analysis by RT-PCR suggested the presence of splicing mutations. Indeed, the patient was revealed to be a compound heterozygote for IVS6-1 g- > t and two new variants, namely p...
February 7, 2019: Molecular Genetics and Metabolism
N Guffon, A Tylki-Szymanska, L Borgwardt, A M Lund, M Gil-Campos, R Parini, J B Hennermann
Alpha-mannosidosis is an ultra-rare progressive lysosomal storage disorder caused by deficiency of alpha-mannosidase. Timely diagnosis of the disease has the potential to influence patient outcomes as preventive therapies can be initiated at an early stage. However, no internationally-recognised algorithm is currently available for the diagnosis of the disease. With the aim of developing a diagnostic algorithm for alpha-mannosidosis an international panel of experts met to reach a consensus by applying the nominal group technique...
January 31, 2019: Molecular Genetics and Metabolism
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