3,672 results match your criteria Molecular Genetics and Metabolism [Journal]


Regulation and tissue-specific expression of δ-aminolevulinic acid synthases in non-syndromic sideroblastic anemias and porphyrias.

Mol Genet Metab 2019 Jan 23. Epub 2019 Jan 23.

INSERM U1149, CNRS ERL 8252, Centre de Recherche sur l'inflammation, Université Paris Diderot, site Bichat, Sorbonne Paris Cité, France, 16 rue Henri Huchard, 75018 Paris, France; Laboratory of Excellence, GR-Ex, Paris, France; AP-HP, HUPNVS, Centre Français des Porphyries, Hôpital Louis Mourier, Colombes, France. Electronic address:

Recently, new genes and molecular mechanisms have been identified in patients with porphyrias and sideroblastic anemias (SA). They all modulate either directly or indirectly the δ-aminolevulinic acid synthase (ALAS) activity. ALAS, is encoded by two genes: the erythroid-specific (ALAS2), and the ubiquitously expressed (ALAS1). Read More

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http://dx.doi.org/10.1016/j.ymgme.2019.01.015DOI Listing
January 2019

Murine models of the human porphyrias: Contributions toward understanding disease pathogenesis and the development of new therapies.

Mol Genet Metab 2019 Jan 18. Epub 2019 Jan 18.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

Mouse models of the human porphyrias have proven useful for investigations of disease pathogenesis and to facilitate the development of new therapeutic approaches. To date, mouse models have been generated for all major porphyrias, with the exception of X-linked protoporphyria (XLP) and the ultra rare 5-aminolevulinic acid dehydratase deficient porphyria (ADP). Mouse models have been generated for the three autosomal dominant acute hepatic porphyrias, acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP). Read More

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http://dx.doi.org/10.1016/j.ymgme.2019.01.007DOI Listing
January 2019
2 Reads

The ability of an LC-MS/MS-based erythrocyte GALT enzyme assay to predict the phenotype in subjects with GALT deficiency.

Mol Genet Metab 2019 Jan 22. Epub 2019 Jan 22.

Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States. Electronic address:

Background: GALT deficiency is a rare genetic disorder of carbohydrate metabolism. Due to the decreased activity or absence of the enzyme galactose-1-phosphate uridylyltransferase (GALT), cells from affected individuals are unable to metabolize galactose normally. Lactose consumption in the newborn period could potentially lead to a lethal disease process with multi-organ involvement. Read More

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http://dx.doi.org/10.1016/j.ymgme.2019.01.016DOI Listing
January 2019
1 Read

Psychosocial issues in erythropoietic protoporphyria - the perspective of parents, children, and young adults: A qualitative study.

Mol Genet Metab 2019 Jan 26. Epub 2019 Jan 26.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States. Electronic address:

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare photodermatoses, generally presenting in childhood with severe and painful phototoxicity. EPP has been reported to negatively affect quality of life (QoL), but there is limited information on the psychosocial issues faced by patients and families. To address this, an online focus group study was conducted to explore the perspective of parents of children with EPP, and young adults and children with EPP. Read More

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http://dx.doi.org/10.1016/j.ymgme.2019.01.023DOI Listing
January 2019

Mild inborn errors of metabolism in commonly used inbred mouse strains.

Mol Genet Metab 2019 Jan 24. Epub 2019 Jan 24.

Department of Genetics and Genomic Sciences, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, Box 1498, New York, NY 10029, USA. Electronic address:

Inbred mouse strains are a cornerstone of translational research but paradoxically many strains carry mild inborn errors of metabolism. For example, α-aminoadipic acidemia and branched-chain ketoacid dehydrogenase deficiency are known in C57BL/6J mice. Using RNA sequencing, we now reveal the causal variants in Dhtkd1 and Bckdhb, and the molecular mechanism underlying these metabolic defects. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S10967192183071
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http://dx.doi.org/10.1016/j.ymgme.2019.01.021DOI Listing
January 2019
2 Reads
2.625 Impact Factor

The mitochondrial heme metabolon: Insights into the complex(ity) of heme synthesis and distribution.

Mol Genet Metab 2019 Jan 17. Epub 2019 Jan 17.

Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, United States; Biomedical and Health Sciences Institute, University of Georgia, Athens, GA 30602, United States; Augusta University-University of Georgia, Medical Partnership, Athens, GA 30602, United States. Electronic address:

Heme is an essential cofactor in metazoans that is also toxic in its free state. Heme is synthesized by most metazoans and must be delivered to all cellular compartments for incorporation into a variety of hemoproteins. The heme biosynthesis enzymes have been proposed to exist in a metabolon, a protein complex consisting of interacting enzymes in a metabolic pathway. Read More

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http://dx.doi.org/10.1016/j.ymgme.2019.01.006DOI Listing
January 2019

The nuclear background influences the penetrance of the near-homoplasmic m.1630 A > G MELAS variant in a symptomatic proband and asymptomatic mother.

Mol Genet Metab 2019 Jan 25. Epub 2019 Jan 25.

Department of Anatomy and Cell Biology, George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA. Electronic address:

In this study, we report the metabolic consequences of the m.1630 A > G variant in fibroblasts from the symptomatic proband affected with the mitochondrial encephalomyopathy lactic acidosis and stroke-like episode Syndrome and her asymptomatic mother. By long-range PCR followed by massively parallel sequencing of the mitochondrial genome, we accurately measured heteroplasmy in fibroblasts from the proband (89. Read More

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http://dx.doi.org/10.1016/j.ymgme.2019.01.022DOI Listing
January 2019
4 Reads

Erythropoietic Protoporphyria and X-Linked Protoporphyria: pathophysiology, genetics, clinical manifestations, and management.

Authors:
Manisha Balwani

Mol Genet Metab 2019 Jan 24. Epub 2019 Jan 24.

Department of Genetics and Genomic Sciences and Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States. Electronic address:

Erythropoietic Protoporphyria (EPP) and X-linked Protoporphyria (XLP) are rare, genetic photodermatoses resulting from defects in enzymes of the heme-biosynthetic pathway. EPP results from the partial deficiency of ferrochelatase, and XLP results from gain-of-function mutations in erythroid specific ALAS2. Both disorders result in the accumulation of erythrocyte protoporphyrin, which is released in the plasma and taken up by the liver and vascular endothelium. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S10967192183064
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http://dx.doi.org/10.1016/j.ymgme.2019.01.020DOI Listing
January 2019
2 Reads

Recessive GM3 synthase deficiency: Natural history, biochemistry, and therapeutic frontier.

Mol Genet Metab 2019 Jan 21. Epub 2019 Jan 21.

Clinic for Special Children, Strasburg, PA, USA. Electronic address:

GM3 synthase, encoded by ST3GAL5, initiates synthesis of all downstream cerebral gangliosides. Here, we present biochemical, functional, and natural history data from 50 individuals homozygous for a pathogenic ST3GAL5 c.862C>T founder allele (median age 8. Read More

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http://dx.doi.org/10.1016/j.ymgme.2019.01.013DOI Listing
January 2019
2 Reads

Trps1 transcription factor regulates mineralization of dental tissues and proliferation of tooth organ cells.

Mol Genet Metab 2019 Jan 23. Epub 2019 Jan 23.

Center for Craniofacial Regeneration, Dept. of Oral Biology, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Dental Medicine, Pittsburgh, PA, USA. Electronic address:

Mutations of the TRPS1 gene cause trichorhinophalangeal syndrome (TRPS), a skeletal dysplasia with dental abnormalities. TRPS dental phenotypes suggest that TRPS1 regulates multiple aspects of odontogenesis, including the tooth number and size. Previous studies delineating Trps1 expression throughout embryonic tooth development in mice detected strong Trps1 expression in dental mesenchyme, preodontoblasts, and dental follicles, suggesting that TRPS dental phenotypes result from abnormalities in early developmental processes. Read More

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http://dx.doi.org/10.1016/j.ymgme.2019.01.014DOI Listing
January 2019

Ammonium accumulation and chemokine decrease in culture media of Gcdh 3D reaggregated brain cell cultures.

Mol Genet Metab 2019 Jan 18. Epub 2019 Jan 18.

Pediatric Metabolic Disease Unit, Department of Pediatrics, Lausanne University Hospital, Chemin de Mont-Paisible 18, 1011 Lausanne, Switzerland. Electronic address:

Glutaric Aciduria type I (GA-I) is caused by mutations in the GCDH gene. Its deficiency results in accumulation of the key metabolites glutaric acid (GA) and 3-hydroxyglutaric acid (3-OHGA) in body tissues and fluids. Present knowledge on the neuropathogenesis of GA-I suggests that GA and 3-OHGA have toxic properties on the developing brain. Read More

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http://dx.doi.org/10.1016/j.ymgme.2019.01.009DOI Listing
January 2019

Congenital erythropoietic porphyria: Recent advances.

Mol Genet Metab 2018 Dec 27. Epub 2018 Dec 27.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America. Electronic address:

Congenital erythropoietic porphyria (CEP) is a rare autosomal recessive disorder characterized by photosensitivity and by hematologic abnormalities in affected individuals. CEP is caused by mutations in the uroporphyrinogen synthase (UROS) gene. In three reported cases, CEP has been associated with a specific X-linked GATA1 mutation. Read More

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http://dx.doi.org/10.1016/j.ymgme.2018.12.008DOI Listing
December 2018
4 Reads

Swallowing dysfunction in patients with nephropathic cystinosis.

Mol Genet Metab 2019 Jan 22. Epub 2019 Jan 22.

Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands. Electronic address:

Introduction: Nephropathic cystinosis is a rare autosomal recessive lysosomal storage disorder caused by mutations in the CTNS gene. Patients with nephropathic cystinosis suffer not only from renal disease but have also other systemic complications like myopathy and swallowing dysfunction. Dysphagia for solid food is mentioned in patients with cystinosis, but in clinical practice swallowing investigations are only performed when the patient has complaints. Read More

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http://dx.doi.org/10.1016/j.ymgme.2019.01.011DOI Listing
January 2019
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Porphyria cutanea tarda: Recent update.

Authors:
Ashwani K Singal

Mol Genet Metab 2019 Jan 18. Epub 2019 Jan 18.

Department of Medicine, Division of Gastroenterology and Hepatology, University of Alabama at Birmingham, Birmingham, AL, United States. Electronic address:

Porphyria cutanea tarda (PCT) is the most common human porphyria, due to hepatic deficiency of uroporphyrinogen decarboxylase (UROD), which is acquired in the presence of iron overload and various susceptibility factors, such as alcohol abuse, smoking, hepatitis C virus (HCV) infection, HIV infection, iron overload with HFE gene mutations, use of estrogens, and UROD mutation. Patients with familial or type II PCT due to autosomal dominant UROD mutation also require other susceptibility factors, as the disease phenotype requires hepatic UROD deficiency to below 20% of normal. PCT clinically manifests with increased skin fragility and blistering skin lesions on sun exposed areas. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S10967192183057
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http://dx.doi.org/10.1016/j.ymgme.2019.01.004DOI Listing
January 2019
4 Reads

Ketogenic and anaplerotic dietary modifications ameliorate seizure activity in Drosophila models of mitochondrial encephalomyopathy and glycolytic enzymopathy.

Mol Genet Metab 2019 Jan 17. Epub 2019 Jan 17.

Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Pittsburgh Institute for Neurodegenerative Diseases (PIND), University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.

Seizures are a feature not only of the many forms of epilepsy, but also of global metabolic diseases such as mitochondrial encephalomyopathy (ME) and glycolytic enzymopathy (GE). Modern anti-epileptic drugs (AEDs) are successful in many cases, but some patients are refractory to existing AEDs, which has led to a surge in interest in clinically managed dietary therapy such as the ketogenic diet (KD). This high-fat, low-carbohydrate diet causes a cellular switch from glycolysis to fatty acid oxidation and ketone body generation, with a wide array of downstream effects at the genetic, protein, and metabolite level that may mediate seizure protection. Read More

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http://dx.doi.org/10.1016/j.ymgme.2019.01.008DOI Listing
January 2019

GLRX5 mutations impair heme biosynthetic enzymes ALA synthase 2 and ferrochelatase in Human congenital sideroblastic anemia.

Mol Genet Metab 2019 Jan 7. Epub 2019 Jan 7.

INSERM U1149, Centre de Recherche sur l'inflammation (CRI), Paris, France; Université Paris Diderot, site Bichat, Sorbonne Paris cité, DHU UNITY, Paris, France; Laboratory of excellence GR-Ex, Paris, France. Electronic address:

Non-syndromic microcytic congenital sideroblastic anemia (cSA) is predominantly caused by defective genes encoding for either ALAS2, the first enzyme of heme biosynthesis pathway or SLC25A38, the mitochondrial importer of glycine, an ALAS2 substrate. Herein we explored a new case of cSA with two mutations in GLRX5, a gene for which only two patients have been reported so far. The patient was a young female with biallelic compound heterozygous mutations in GLRX5 (p. Read More

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http://dx.doi.org/10.1016/j.ymgme.2018.12.012DOI Listing
January 2019
1 Read
2.625 Impact Factor

WORLDSymposium™ 2019 Program.

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Mol Genet Metab 2019 Feb 29;126(2):S7-S16. Epub 2018 Dec 29.

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http://dx.doi.org/10.1016/j.ymgme.2018.12.015DOI Listing
February 2019

WORLDSymposium™ 2019 Introduction.

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Mol Genet Metab 2019 Feb 31;126(2):S2-S6. Epub 2018 Dec 31.

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http://dx.doi.org/10.1016/j.ymgme.2018.12.014DOI Listing
February 2019

Early-onset of symptoms and clinical course of Pompe disease associated with the c.-32-13 T > G variant.

Mol Genet Metab 2019 Feb 23;126(2):106-116. Epub 2018 Aug 23.

Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, 905 S. LaSalle street, GSRB1, Durham, NC, USA. Electronic address:

Background: Individuals with late-onset Pompe disease (LOPD) and the common c.-32-13 T > G variant are widely thought to have milder, adult-onset disease. This belief, and the consequent low suspicion of clinical involvement in children, has led to delays in diagnosis and treatment initiation in patients with early onset of symptoms. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S10967192183028
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http://dx.doi.org/10.1016/j.ymgme.2018.08.009DOI Listing
February 2019
8 Reads

Mutations in the mitochondrial complex I assembly factor NDUFAF6 cause isolated bilateral striatal necrosis and progressive dystonia in childhood.

Mol Genet Metab 2019 Jan 5. Epub 2019 Jan 5.

Department of Child Neurology, Hospital Vall d'Hebron - Institut de Recerca (VHIR), Barcelona, Spain; CIBERER, Centro de Investigaciones Biomédicas en Red de Enfermedades Raras, Madrid, Spain; Faculty of Medicine, Universitat Autónoma de Barcelona, Unitat Docent Vall d'Hebrón, Spain. Electronic address:

Aim: To perform a deep phenotype characterisation in a pedigree of 3 siblings with Leigh syndrome and compound heterozygous NDUFAF6 mutations.

Method: A multi-gene panel of childhood-onset basal ganglia neurodegeneration inherited conditions was analysed followed by functional studies in fibroblasts.

Results: Three siblings developed gait dystonia in infancy followed by rapid progression to generalised dystonia and psychomotor regression. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S10967192183069
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http://dx.doi.org/10.1016/j.ymgme.2019.01.001DOI Listing
January 2019
2 Reads

Sex differences in vascular reactivity in mesenteric arteries from a mouse model of acute intermittent porphyria.

Mol Genet Metab 2019 Jan 7. Epub 2019 Jan 7.

Section on Gastroenterology & Hepatology, Wake Forest University/NC Baptist Medical Center, Winston-Salem, NC, USA. Electronic address:

Background And Aims: Acute intermittent porphyria (AIP) results from a partial deficiency of porphobilinogen deaminase (PBGD). Symptomatic AIP patients, most of whom are women, experience acute attacks characterized by severe abdominal pain and abrupt increases in blood pressure. Here, we characterized the reactivity of mesenteric arteries from male and female AIP mice with ~30% of normal PBGD activity and wild type C57BL/6 mice. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S10967192183058
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http://dx.doi.org/10.1016/j.ymgme.2019.01.005DOI Listing
January 2019
2 Reads

Identification of nucleolar protein NOM1 as a novel nuclear IGF1R-interacting protein.

Mol Genet Metab 2019 Jan 4. Epub 2019 Jan 4.

Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; Yoran Institute for Human Genome Research, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address:

The insulin-like growth factor-1 receptor (IGF1R) mediates the biological actions of both IGF1 and IGF2. In recent years, evidence has accumulated showing that, in addition to its classical cell-surface distribution, IGF1R translocates to cell nucleus via an apparently SUMO-1-dependent mechanism. While the role of IGF1R in nucleus has not yet been settled, available information suggests that the nuclear receptor displays activities usually linked to transcription factors, including DNA binding and transcription regulation. Read More

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http://dx.doi.org/10.1016/j.ymgme.2019.01.002DOI Listing
January 2019

Computational disease model of phenobarbital-induced acute attacks in an acute intermittent porphyria mouse model.

Mol Genet Metab 2018 Dec 21. Epub 2018 Dec 21.

Pharmacometrics & Systems Pharmacology Research Unit, Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.

Introduction: Acute intermittent porphyria (AIP) is characterized by hepatic over-production of the heme precursors when aminolevulinic acid (ALA)-synthase 1 is induced by endogenous or environmental factors. The aim of this study was to develop a semi-mechanistic computational model to characterize urine accumulation of heme precursors during acute attacks based on experimental pharmacodynamics data and support the development of new therapeutic strategies.

Methods: Male AIP mice received recurrent phenobarbital challenge starting on days 1, 9, 16 and 30. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S10967192183057
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http://dx.doi.org/10.1016/j.ymgme.2018.12.009DOI Listing
December 2018
6 Reads

Program and Abstracts WORLDSymposium 2019* 15th Annual Research Meeting.

Authors:

Mol Genet Metab 2019 Feb 29;126(2):S1. Epub 2018 Dec 29.

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http://dx.doi.org/10.1016/j.ymgme.2018.12.013DOI Listing
February 2019

Final results of the phase 1/2, open-label clinical study of intravenous recombinant human N-acetyl-α-d-glucosaminidase (SBC-103) in children with mucopolysaccharidosis IIIB.

Mol Genet Metab 2019 Feb 6;126(2):131-138. Epub 2018 Dec 6.

Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. Electronic address:

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. Read More

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http://dx.doi.org/10.1016/j.ymgme.2018.12.003DOI Listing
February 2019

Zebrafish as a model system to delineate the role of heme and iron metabolism during erythropoiesis.

Mol Genet Metab 2018 Dec 24. Epub 2018 Dec 24.

Department of Animal & Avian Sciences and Department of Cell Biology & Molecular Genetics, University of Maryland, College Park, MD 20742, USA. Electronic address:

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. Read More

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http://dx.doi.org/10.1016/j.ymgme.2018.12.007DOI Listing
December 2018

RNA-Seq analysis in an avian model of maternal phenylketonuria.

Mol Genet Metab 2019 Jan 6;126(1):23-29. Epub 2018 Sep 6.

Department of Biology, University of Central Oklahoma, Edmond, OK, USA. Electronic address:

Cardiac malformations (CVMs) are a leading cause of infant morbidity and mortality. CVMs are particularly prevalent when the developing fetus is exposed to high levels of phenylalanine in-utero in mothers with Phenylketonuria. Yet, elucidating the underlying molecular mechanism leading to CVMs has proven difficult. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S10967192183025
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http://dx.doi.org/10.1016/j.ymgme.2018.09.003DOI Listing
January 2019
4 Reads

Neurocognitive functioning in adults with phenylketonuria: Report of a 10-year follow-up.

Mol Genet Metab 2018 Dec 26. Epub 2018 Dec 26.

University of Münster, Department of Pediatrics, Albert-Schweitzer-Campus 1, 48149 Münster, Germany.

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. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S10967192183060
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http://dx.doi.org/10.1016/j.ymgme.2018.12.011DOI Listing
December 2018
5 Reads

Early detection of organ involvement in Fabry disease by biomarker assessment in conjunction with LGE cardiac MRI: results from the SOPHIA study.

Mol Genet Metab 2019 Feb 12;126(2):169-182. Epub 2018 Nov 12.

Zentrum für Kinder- und Jugendmedizin der Universitätsmedizin Mainz, Mainz, Germany. Electronic address:

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; ClinicalTrials. Read More

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http://dx.doi.org/10.1016/j.ymgme.2018.11.005DOI Listing
February 2019

Recent advances on porphyria genetics: Inheritance, penetrance & molecular heterogeneity, including new modifying/causative genes.

Mol Genet Metab 2018 Nov 30. Epub 2018 Nov 30.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States. Electronic address:

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). Read More

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http://dx.doi.org/10.1016/j.ymgme.2018.11.012DOI Listing
November 2018
2 Reads

A systematic review and evidence-based guideline for diagnosis and treatment of Menkes disease.

Mol Genet Metab 2019 Jan 11;126(1):6-13. Epub 2018 Dec 11.

Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Neurology Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Internal Medicine Department, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Postgraduate program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. Electronic address:

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. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S10967192183041
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http://dx.doi.org/10.1016/j.ymgme.2018.12.005DOI Listing
January 2019
5 Reads

Lifestyle factors including diet and biochemical biomarkers in acute intermittent porphyria: Results from a case-control study in northern Norway.

Mol Genet Metab 2018 Dec 10. Epub 2018 Dec 10.

Department of Laboratory Medicine, Nordland Hospital Trust, Bodø, Norway; Institute of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway.

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. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S10967192183052
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http://dx.doi.org/10.1016/j.ymgme.2018.12.006DOI Listing
December 2018
2 Reads

Attitudes of the general population towards preconception expanded carrier screening for autosomal recessive disorders including inborn errors of metabolism.

Mol Genet Metab 2019 Jan 10;126(1):14-22. Epub 2018 Dec 10.

Amsterdam UMC, University of Amsterdam, Psychosocial Department, Emma Children's Hospital, Meibergdreef 9, Amsterdam, Netherlands. Electronic address:

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. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S10967192183055
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http://dx.doi.org/10.1016/j.ymgme.2018.12.004DOI Listing
January 2019
6 Reads

Cryptic intronic NBAS variant reveals the genetic basis of recurrent liver failure in a child.

Mol Genet Metab 2019 Jan 11;126(1):77-82. Epub 2018 Dec 11.

Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia. Electronic address:

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. Read More

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http://dx.doi.org/10.1016/j.ymgme.2018.12.002DOI Listing
January 2019

Novel mutations in CLN6 cause late-infantile neuronal ceroid lipofuscinosis without visual impairment in two unrelated patients.

Mol Genet Metab 2019 Feb 3;126(2):188-195. Epub 2018 Dec 3.

NIH Undiagnosed Diseases Program, Common Fund, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States; Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States. Electronic address:

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. Read More

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http://dx.doi.org/10.1016/j.ymgme.2018.12.001DOI Listing
February 2019
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2.625 Impact Factor

Enzyme enhancement therapeutics for lysosomal storage diseases: Current status and perspective.

Mol Genet Metab 2019 Feb 22;126(2):83-97. Epub 2018 Nov 22.

Department of Biological Sciences, Simon Fraser University, 8888 University Dr., Burnaby B.C. V5A 1S6, Canada. Electronic address:

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. Read More

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http://dx.doi.org/10.1016/j.ymgme.2018.11.011DOI Listing
February 2019
2 Reads

Intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A: A phase IIb randomized trial.

Mol Genet Metab 2019 Feb 24;126(2):121-130. Epub 2018 Oct 24.

Shire, Lexington, MA, USA. Electronic address:

Background: Sanfilippo syndrome type A (mucopolysaccharidosis type IIIA) is a lysosomal disorder wherein deficient heparan-N-sulfatase (HNS) activity results in the accumulation of heparan sulfate in the central nervous system and is associated with progressive neurodegeneration in early childhood. We report on the efficacy, pharmacokinetics, safety, and tolerability of intrathecal (IT) administration of recombinant human HNS (rhHNS) from a phase IIb randomized open-label trial.

Methods: Twenty-one patients, randomized 1:1:1 to rhHNS IT 45 mg administered every 2 weeks (Q2W), every 4 weeks (Q4W), or no treatment, were assessed for amelioration in neurocognitive decline as determined by the Bayley Scales of Infant and Toddler Development®, Third Edition. Read More

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http://dx.doi.org/10.1016/j.ymgme.2018.10.006DOI Listing
February 2019
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Comprehensive behavioral and biochemical outcomes of novel murine models of GM1-gangliosidosis and Morquio syndrome type B.

Mol Genet Metab 2019 Feb 22;126(2):139-150. Epub 2018 Nov 22.

Gene Therapy Center, Department of Pediatrics, University of Minnesota, Minneapolis, MN, United States; Molecular, Cellular, Developmental Biology, and Genetics Graduate Program, University of Minnesota, Minneapolis, MN, United States. Electronic address:

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 (Glb1), while for GM1-gangliosidosis, a 20 bp mutation was generated to remove the catalytic nucleophile of β-gal (β-gal). Read More

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http://dx.doi.org/10.1016/j.ymgme.2018.11.002DOI Listing
February 2019

Hematopoietic cell transplantation for severe MPS I in the first six months of life: The heart of the matter.

Mol Genet Metab 2019 Feb 13;126(2):117-120. Epub 2018 Nov 13.

Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, United States.

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. Read More

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http://dx.doi.org/10.1016/j.ymgme.2018.11.007DOI Listing
February 2019
5 Reads

Recommendations for clinical monitoring of patients with acid sphingomyelinase deficiency (ASMD).

Mol Genet Metab 2019 Feb 29;126(2):98-105. Epub 2018 Nov 29.

Stony Brook University, School of Medicine, Stony Brook, NY, USA.

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. Read More

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http://dx.doi.org/10.1016/j.ymgme.2018.11.014DOI Listing
February 2019
3 Reads

Porphyria cutanea tarda and hepatoerythropoietic porphyria: Identification of 19 novel uroporphyrinogen III decarboxylase mutations.

Mol Genet Metab 2018 Nov 28. Epub 2018 Nov 28.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

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. Read More

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http://dx.doi.org/10.1016/j.ymgme.2018.11.013DOI Listing
November 2018
3 Reads

Elevation of blood lipids in hepatocyte-specific fatty acid transport 4-deficient mice fed with high glucose diets.

Mol Genet Metab 2019 Jan 23;126(1):30-38. Epub 2018 Nov 23.

Department of Internal Medicine IV, University of Heidelberg Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Electronic address:

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). Read More

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https://linkinghub.elsevier.com/retrieve/pii/S10967192183055
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http://dx.doi.org/10.1016/j.ymgme.2018.11.010DOI Listing
January 2019
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Novel mutations in the mitochondrial complex I assembly gene NDUFAF5 reveal heterogeneous phenotypes.

Mol Genet Metab 2019 Jan 8;126(1):53-63. Epub 2018 Nov 8.

Division of Metabolic Disorders, CHOC Children's Hospital, Orange, CA 92868, USA; Department of Pediatrics, University of California Irvine, Orange, CA 92868, USA. Electronic address:

Primary mitochondrial complex I deficiency is the most common defect of the mitochondrial respiratory chain. It is caused by defects in structural components and assembly factors of this large protein complex. Mutations in the assembly factor NDUFAF5 are rare, with only five families reported to date. Read More

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http://dx.doi.org/10.1016/j.ymgme.2018.11.001DOI Listing
January 2019
14 Reads

Antibodies against recombinant alpha-galactosidase A in Fabry disease: Subclass analysis and impact on response to treatment.

Mol Genet Metab 2019 Feb 17;126(2):162-168. Epub 2018 Nov 17.

Amsterdam UMC, University of Amsterdam, Department of Endocrinology and Metabolism, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. Electronic address:

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). Read More

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http://dx.doi.org/10.1016/j.ymgme.2018.11.008DOI Listing
February 2019

Mutated SUCLG1 causes mislocalization of SUCLG2 protein, morphological alterations of mitochondria and an early-onset severe neurometabolic disorder.

Mol Genet Metab 2019 Jan 16;126(1):43-52. Epub 2018 Nov 16.

1st Department of Pediatrics, "Hippokratio" General Hospital, Aristotle University, Thessaloniki, Greece. Electronic address:

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. Read More

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http://dx.doi.org/10.1016/j.ymgme.2018.11.009DOI Listing
January 2019
11 Reads

The challenge of CDG diagnosis.

Mol Genet Metab 2019 Jan 9;126(1):1-5. Epub 2018 Nov 9.

CDG & Allies - Professionals and Patient Associations International Network (CDG & Allies - PPAIN), Portugal; Center for Metabolic Diseases, UZ and KU Leuven, Leuven, Belgium. Electronic address:

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. Read More

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http://dx.doi.org/10.1016/j.ymgme.2018.11.003DOI Listing
January 2019
9 Reads

Congenital erythropoietic porphyria and erythropoietic protoporphyria: Identification of 7 uroporphyrinogen III synthase and 20 ferrochelatase novel mutations.

Mol Genet Metab 2018 Aug 31. Epub 2018 Aug 31.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address:

The erythropoietic porphyrias are inborn errors of heme biosynthesis with prominent cutaneous manifestations. They include autosomal recessive Congenital Erythropoietic Porphyria (CEP) due to loss-of-function (LOF) mutations in the Uroporphyrinogen III Synthase (UROS) gene, Erythropoietic Protoporphyria (EPP) due to LOF mutations in the ferrochelatase (FECH) gene, and X-Linked Protoporphyria (XLP) due to gain-of-function mutations in the terminal exon of the Aminolevulinic Acid Synthase 2 (ALAS2) gene. During the 11-year period from 01/01/2007 through 12/31/2017, the Mount Sinai Porphyrias Diagnostic Laboratory provided molecular diagnostic testing for one or more of these disorders in 628 individuals, including 413 unrelated individuals. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S10967192183048
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http://dx.doi.org/10.1016/j.ymgme.2018.08.015DOI Listing
August 2018
11 Reads

Elevated methylmalonic acidemia (MMA) screening markers in Hispanic and preterm newborns.

Mol Genet Metab 2019 Jan 10;126(1):39-42. Epub 2018 Nov 10.

Department of Genetics, Yale University School of Medicine, New Haven, CT, United States. Electronic address:

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. Read More

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http://dx.doi.org/10.1016/j.ymgme.2018.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361520PMC
January 2019

Bone manifestations in neuronopathic Gaucher disease while receiving high-dose enzyme replacement therapy.

Mol Genet Metab 2019 Feb 9;126(2):157-161. Epub 2018 Nov 9.

Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA. Electronic address:

Avascular necrosis (AVN), one type of bone infarction, is a major irreversible complication of Gaucher disease (GD). In this report, two pediatric patients with GD type 3, homozygous for the L483P pathogenic variant (formerly L444P), developed AVN despite treatment on long-term, high-dose enzyme replacement therapy (ERT). ERT was initiated in both patients, who had intact spleens, shortly after diagnosis with an initial dramatic response. Read More

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http://dx.doi.org/10.1016/j.ymgme.2018.11.004DOI Listing
February 2019
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Next generation sequencing of RNA reveals novel targets of resveratrol with possible implications for Canavan disease.

Mol Genet Metab 2019 Jan 22;126(1):64-76. Epub 2018 Oct 22.

Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, Denmark. Electronic address:

Resveratrol (RSV) is a small compound first identified as an activator of sirtuin 1 (SIRT1), a key factor in mediating the effects of caloric restriction. Since then, RSV received great attention for its widespread beneficial effects on health and in connection to many diseases. RSV improves the metabolism and the mitochondrial function, and more recently it was shown to restore fatty acid β-oxidation (FAO) capacities in patient fibroblasts harboring mutations with residual enzyme activity. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S10967192183049
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http://dx.doi.org/10.1016/j.ymgme.2018.10.004DOI Listing
January 2019
6 Reads