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Molecular Genetics and Metabolism

R Feldmann, J Osterloh, S Onon, J Fromm, F Rutsch, J Weglage
BACKGROUND: The long-term prognosis of early treated phenylketonuria (PKU) is still under discussion. Aim of this controlled long-term study was to assess the neurological and neuropsychological outcome in adult patients with early-treated PKU. METHODS: We investigated 35 patients with early-treated classical PKU aged 29 to 51 years (mean age 41 years) and 18 healthy controls matched for age and socioeconomic status. Patients and controls were assessed for their intelligence quotient (IQ), attention and information-processing abilities...
December 26, 2018: Molecular Genetics and Metabolism
Jianbing Zhang, Iqbal Hamza
Coordination of iron acquisition and heme synthesis is required for effective erythropoiesis. The small teleost zebrafish (Danio rerio) is an ideal vertebrate animal model to replicate various aspects of human physiology and provides an efficient and cost-effective way to model human pathophysiology. Importantly, zebrafish erythropoiesis largely resembles mammalian erythropoiesis. Gene discovery by large-scale forward mutagenesis screening has identified key components in heme and iron metabolism. Reverse genetic screens, using morpholino-knockdown and CRISPR/Cas9, coupled with the genetic tractability of the developing embryo have further accelerated functional studies...
December 24, 2018: Molecular Genetics and Metabolism
Filippo Pinto E Vairo, Bruna Cristine Chwal, Silvana Perini, Maria Angélica Pires Ferreira, Ana Carolina de Freitas Lopes, Jonas Alex Morales Saute
Menkes disease is a rare X-linked neurodegenerative disorder caused by defect in copper metabolism. Parenteral copper supplementation has been used as a potential disease-modifying treatment of Menkes disease for decades. However, recent evidence suggests its efficacy only when treatment is started within days after birth, which also has important implications related to the techniques that enable early diagnosis. We aim at proposing a guideline for prenatal and neonatal diagnosis and for disease-modifying treatment of Menkes disease, guided by a systematic review of the literature, and built in conjunction with medical experts, methodologists and patient representatives...
December 11, 2018: Molecular Genetics and Metabolism
Rocio Rius, Lisa G Riley, Yiran Guo, Minal Menezes, Alison G Compton, Nicole J Van Bergen, Velimir Gayevskiy, Mark J Cowley, Beryl B Cummings, Louisa Adams, Carolyn Ellaway, David R Thorburn, Hakon Hakonarson, John Christodoulou
BACKGROUND: In almost half of patients with acute liver failure the cause is unknown, making targeted treatment and decisions about liver transplantation a challenge. Monogenic disorders may contribute to a significant proportion of these undiagnosed patients, and so the incorporation of technologies such as next generation sequencing (NGS) in the clinic could aid in providing a definitive diagnosis. However, this technology may present a major challenge in interpretation of sequence variants, particularly those in non-coding regions...
December 11, 2018: Molecular Genetics and Metabolism
Elin Storjord, Jim A Dahl, Anne Landsem, Judith K Ludviksen, Marlene B Karlsen, Bård O Karlsen, Ole-L Brekke
BACKGROUND: Lifestyle factors, including a low intake of carbohydrates, dieting, alcohol consumption, cigarette smoking and stress are some of the possible triggers of attacks in acute intermittent porphyria (AIP). The influence of lifestyle factors, including energy intake, diet and alcohol consumption on the biochemical disease activity in AIP and biochemical nutritional markers were examined. METHODS: A case-control study with 50 AIP cases and 50 controls matched for age, sex and place of residence was performed...
December 10, 2018: Molecular Genetics and Metabolism
Stephanie C M Nijmeijer, Thirsa Conijn, Phillis Lakeman, Lidewij Henneman, Frits A Wijburg, Lotte Haverman
BACKGROUND: A substantial number of severely debilitating and often ultimately fatal inborn errors of metabolism (IEMs) still lack an effective disease-modifying treatment. Informing couples before a pregnancy about an increased risk of having a child with an inherited disorder is now feasible by preconception expanded carrier screening (ECS). While knowledge about carrier status enhances reproductive autonomy, it may also result in ethical dilemmas. The purpose of this study was to assess the attitudes of the general Dutch population towards preconception ECS and to investigate which factors influence these attitudes...
December 10, 2018: Molecular Genetics and Metabolism
Chester B Whitley, Suresh Vijay, Bert Yao, Mercé Pineda, Geoff J M Parker, Sandra Rojas-Caro, Xiaoping Zhang, Yang Dai, Amy Cinar, Gillian Bubb, Kiran C Patki, Maria L Escolar
Mucopolysaccharidosis IIIB is caused by a marked decrease in N-acetyl-α-d-glucosaminidase (NAGLU) enzyme activity, which leads to the accumulation of heparan sulfate in key organs, progressive brain atrophy, and neurocognitive decline. In this open-label study, 11 eligible patients aged 2 to <12 years (developmental age ≥ 1 year) were sequentially allocated to recombinant human NAGLU enzyme (SBC-103) in 3 staggered- and escalating-dose groups (0.3 mg/kg [n = 3], 1.0 mg/kg [n = 4], or 3...
December 6, 2018: Molecular Genetics and Metabolism
Joseph J Chin, Babak Behnam, Mariska Davids, Prashant Sharma, Wadih M Zein, Camille Wang, Xenia Chepa-Lotrea, William Brian Gallantine, Camilo Toro, David R Adams, Cynthia J Tifft, William A Gahl, May Christine V Malicdan
CLN6 is a transmembrane protein located in the endoplasmic reticulum that is involved in lysosomal acidification. Mutations in CLN6 cause late-infantile neuronal ceroid lipofuscinosis (LINCL), and teenage and adult onset NCL without visual impairment. Here we describe two pediatric patients with LINCL from unrelated families who were evaluated at the National Institutes of Health. Both children exhibited typical phenotypes associated with LINCL except that they lacked the expected visual impairment. Whole exome sequencing identified novel biallelic mutations in CLN6, i...
December 3, 2018: Molecular Genetics and Metabolism
Makiko Yasuda, Brenden Chen, Robert J Desnick
The inborn errors of heme biosynthesis, the Porphyrias, include eight major disorders resulting from loss-of-function (LOF) or gain-of-function (GOF) mutations in eight of the nine heme biosynthetic genes. The major sites of heme biosynthesis are the liver and erythron, and the underlying pathophysiology of each of these disorders depends on the unique biochemistry, cell biology, and genetic mechanisms in these tissues. The porphyrias are classified into three major categories: 1) the acute hepatic porphyrias (AHPs), including Acute Intermittent Porphyria (AIP), Hereditary Coproporphyria (HCP), Variegate Porphyria (VP), and 5-Aminolevlulinic Acid Dehydratase Deficient Porphyria (ADP); 2) a hepatic cutaneous porphyria, Porphyria Cutanea Tarda (PCT); and 3) the cutaneous erythropoietic porphyrias, Congenital Erythropoietic Porphyria (CEP), Erythropoietic Protoporphyria (EPP), and X-Linked Protoporphyria (XLP)...
November 30, 2018: Molecular Genetics and Metabolism
Melissa Wasserstein, Carlo Dionisi-Vici, Roberto Giugliani, Wuh-Liang Hwu, Olivier Lidove, Zoltan Lukacs, Eugen Mengel, Pramod K Mistry, Edward H Schuchman, Margaret McGovern
BACKGROUND: Acid sphingomyelinase deficiency (ASMD), a rare lysosomal storage disease, results from mutations in SMPD1, the gene encoding acid sphingomyelinase (ASM). As a result, sphingomyelin accumulates in multiple organs including spleen, liver, lung, bone marrow, lymph nodes, and in the most severe form, in the CNS and peripheral nerves. Clinical manifestations range from rapidly progressive and fatal infantile neurovisceral disease, to less rapidly progressing chronic neurovisceral and visceral forms that are associated with significant morbidity and shorter life span due to respiratory or liver disease...
November 29, 2018: Molecular Genetics and Metabolism
Yedidyah Weiss, Brenden Chen, Makiko Yasuda, Irina Nazarenko, Karl E Anderson, Robert J Desnick
Porphyria Cutanea Tarda (PCT) is a cutaneous porphyria that results from the hepatic inhibition of the heme biosynthetic enzyme uroporphyrinogen decarboxylase (UROD), and can occur either in the absence or presence of an inherited heterozygous UROD mutation (PCT subtypes 1 and 2, respectively). A heterozygous UROD mutation causes half-normal levels of UROD activity systemically, which is a susceptibility factor but is not sufficient alone to cause type 2 PCT. In both Types 1 and 2 PCT, the cutaneous manifestations are precipitated by additional factors that lead to generation of an inhibitor that more profoundly reduces hepatic UROD activity...
November 28, 2018: Molecular Genetics and Metabolism
Stephan Döring, Jessica Seeßle, Hongying Gan-Schreier, Bahador Javaheri, Li Jiao, Yuting Cheng, Sabine Tuma-Kellner, Gerhard Liebisch, Thomas Herrmann, Wolfgang Stremmel, Walee Chamulitrat
Fatty acid transport protein4 (FATP4) is upregulated in acquired and central obesity and its polymorphisms are associated with blood lipids and insulin resistance. Patients with FATP4 mutations and mice with global FATP4 deletion exhibit skin abnormalities characterized as ischthyosis prematurity syndrome (IPS). Cumulating data have shown that an absence of FATP4 increases the levels of cellular triglycerides (TG). However, FATP4 role and consequent lipid and TG metabolism in the hepatocyte is still elusive...
November 23, 2018: Molecular Genetics and Metabolism
Ryan Thomas, Allison R Kermode
Small-molecule- enzyme enhancement therapeutics (EETs) have emerged as attractive agents for the treatment of lysosomal storage diseases (LSDs), a broad group of genetic diseases caused by mutations in genes encoding lysosomal enzymes, or proteins required for lysosomal function. The underlying enzyme deficiencies characterizing LSDs cause a block in the stepwise degradation of complex macromolecules (e.g. glycosaminoglycans, glycolipids and others), such that undegraded or partially degraded substrates progressively accumulate in lysosomal and non-lysosomal compartments, a process leading to multisystem pathology via primary and secondary mechanisms...
November 22, 2018: Molecular Genetics and Metabolism
Michael J Przybilla, Li Ou, Alexandru-Flaviu Tăbăran, Xuntian Jiang, Rohini Sidhu, Pamela J Kell, Daniel S Ory, M Gerard O'Sullivan, Chester B Whitley
Deficiencies in the lysosomal hydrolase β-galactosidase (β-gal) lead to two distinct diseases: the skeletal disease Morquio syndrome type B, and the neurodegenerative disease GM1-gangliosidosis. Utilizing CRISPR-Cas9 genome editing, the mouse β-gal encoding gene, Glb1, was targeted to generate both models of β-gal deficiency in a single experiment. For Morquio syndrome type B, the common human missense mutation W273L (position 274 in mice) was introduced into the Glb1 gene (Glb1W274L ), while for GM1-gangliosidosis, a 20 bp mutation was generated to remove the catalytic nucleophile of β-gal (β-gal-/- )...
November 22, 2018: Molecular Genetics and Metabolism
S J van der Veen, A B P van Kuilenburg, C E M Hollak, P H P Kaijen, J Voorberg, M Langeveld
BACKGROUND: Treatment of Fabry disease (FD) with recombinant alpha-galactosidase A (r-αGAL A) is complicated by the formation of anti-drug antibodies in the majority of male patients with the classical disease phenotype. Detailed information regarding antibody subtypes, onset and persistence of antibody development and their effect on treatment efficacy is sparse. METHODS: A retrospective study was carried out in 39 male patients with classical FD, treated with either agalsidase-alfa or agalsidase-beta (mean follow up of 10 years)...
November 17, 2018: Molecular Genetics and Metabolism
Christos Chinopoulos, Spyros Batzios, Lambertus P van den Heuvel, Richard Rodenburg, Roel Smeets, Hans R Waterham, Marjolein Turkenburg, Jos P Ruiter, Ronald J A Wanders, Judit Doczi, Gergo Horvath, Arpad Dobolyi, Euthymia Vargiami, Ron A Wevers, Dimitrios Zafeiriou
Succinate-CoA ligase (SUCL) is a heterodimer consisting of an alpha subunit encoded by SUCLG1, and a beta subunit encoded by either SUCLA2 or SUCLG2 catalyzing an ATP- or GTP-forming reaction, respectively, in the mitochondrial matrix. The deficiency of this enzyme represents an encephalomyopathic form of mtDNA depletion syndromes. We describe the fatal clinical course of a female patient with a pathogenic mutation in SUCLG1 (c.626C > A, p.Ala209Glu) heterozygous at the genomic DNA level, but homozygous at the transcriptional level...
November 16, 2018: Molecular Genetics and Metabolism
Elizabeth Braunlin, Kelly Miettunen, Troy Lund, Mark Luquette, Paul Orchard
BACKGROUND: Hematopoietic cell transplantation (HCT) is accepted therapy for severe mucopolysaccharidosis type I (MPS IH). With implementation of newborn screening (NBS) for MPS I in the US, HCT may now occur earlier than 1-2 years of age and it might be assumed that cardiac issues will be fewer. To examine this hypothesis, we reviewed our records for any MPS IH infant who underwent HCT at ≤6 months of age. STUDY PATIENTS: Pre- and (most recent) post-HCT cardiac echos and clinical courses were reviewed in all infants with MPS IH undergoing HCT at ≤6 months of age...
November 13, 2018: Molecular Genetics and Metabolism
Frank Weidemann, Meinrad Beer, Martina Kralewski, Justyna Siwy, Christoph Kampmann
BACKGROUND: Initiation of enzyme replacement therapy (ERT) early in the Fabry disease course may facilitate better outcomes than in patients with advanced disease. Early diagnosis is often hindered by the heterogeneous nature of signs and symptoms, and by the presentation of atypical phenotypes. METHODS: The Sophisticated Assessment of Disease Burden in Patients with Fabry Disease study (SOPHIA;, NCT01210196) evaluated clinical and diagnostic assessments for early detection of Fabry-related organ pathology in ERT-naïve patients with mild FD symptoms...
November 12, 2018: Molecular Genetics and Metabolism
Gang Peng, Christina A de Fontnouvelle, Gregory M Enns, Tina M Cowan, Hongyu Zhao, Curt Scharfe
Analysis of California newborn screening (NBS) data revealed a high prevalence of Hispanic infants testing positive for methylmalonic acidemia (MMA), a trend seen for both true- and false-positive cases. Here we show that Hispanic infants have significantly higher levels of MMA screening markers than non-Hispanics. Preterm birth and increased birth weight were found to be associated with elevated MMA marker levels but could not entirely explain these differences. While the preterm birth rate was higher in Blacks than Hispanics, Black infants had on average the lowest MMA marker levels...
November 10, 2018: Molecular Genetics and Metabolism
R Francisco, D Marques-da-Silva, S Brasil, C Pascoal, V Dos Reis Ferreira, E Morava, J Jaeken
Congenital disorders of glycosylation (CDG) are a rapidly growing family of genetic diseases that currently includes some 130 different types. CDG diagnosis is a challenge, not only because of this large number but also because of the huge clinical heterogeneity even within a number of CDG. In addition, the classical screening test, serum transferrin isoelectrofocusing, is only positive in about 60% of CDG, and can even become negative in some CDG particularly in PMM2-CDG, the most frequent N-glycosylation defect...
November 9, 2018: Molecular Genetics and Metabolism
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