Journals Journal of Inherited Metabolic...

Journal of Inherited Metabolic Disease
Bernd C Schwahn, Francjan van Spronsen, Albert Misko, Julija Pavaine, Victoria Holmes, Ronen Spiegel, Guenter Schwarz, Flora Wong, Alistair Horman, James Pitt, Jörn Oliver Sass, Charlotte Lubout
Sulfite intoxication is the hallmark of four ultrarare disorders that are caused by impaired sulfite oxidase activity due to genetic defects in the synthesis of the molybdenum cofactor or of the apoenzyme sulfite oxidase. Delays on the diagnosis of these disorders are common and have been caused by their unspecific presentation of acute neonatal encephalopathy with high early mortality, followed by the evolution of dystonic cerebral palsy and also by the lack of easily available and reliable diagnostic tests...
April 16, 2024: Journal of Inherited Metabolic Disease
Sema Kalkan Uçar, Yasemin Atik Altınok, Yelda Mansuroglu, Ebru Canda, Havva Yazıcı, Merve Yoldaş Çelik, Fehime Erdem, Ayşe Yüksel Yanbolu, Zülal Ülger, Mahmut Çoker
Dietary lipid manipulation has recently been proposed for managing glycogen storage disease (GSD) type IIIa. This study aimed to evaluate the myopathic, cardiac, and metabolic status, physical activity, growth, and dietary compliance of a personalized diet high in protein and fat for 24 months. Of 31 patients with type IIIa GSD, 12 met the inclusion criteria. Of these, 10 patients (mean age 11.2 ± 7.4 years) completed the study. Patients were prescribed a personalized high-protein, high-fat diet, comprising 3...
April 16, 2024: Journal of Inherited Metabolic Disease
Melanie B Gillingham, Dongseok Choi, Ashley Gregor, Nida Wongchaisuwat, Danielle Black, Hannah L Scanga, Ken K Nischal, Jose-Alain Sahel, Georgianne Arnold, Jerry Vockley, Cary O Harding, Mark E Pennesi
Long chain 3-hydroxyacyl-CoA dehydrogenase (LCHADD) is the only fatty acid oxidation disorder to develop a progressive chorioretinopathy resulting in vision loss; newborn screening (NBS) for this disorder began in the United States around 2004. We compared visual outcomes among 40 participants with LCHADD or trifunctional protein deficiency diagnosed symptomatically to those who were diagnosed via NBS or a family history. Participants completed ophthalmologic testing including measures of visual acuity, electroretinograms (ERG), fundal imaging, contrast sensitivity, and visual fields...
April 16, 2024: Journal of Inherited Metabolic Disease
Wladimir Mauhin, Gaelle Dzangue-Tchoupou, Damien Amelin, Aurélien Corneau, Foudil Lamari, Yves Allenbach, Bertrand Dussol, Vanessa Leguy-Seguin, Pauline D'Halluin, Marie Matignon, François Maillot, Kim-Heang Ly, Gérard Besson, Marjolaine Willems, Fabien Labombarda, Agathe Masseau, Christian Lavigne, Didier Lacombe, Hélène Maillard, Olivier Lidove, Olivier Benveniste
Fabry disease (FD) is an X-linked disease characterized by an accumulation of glycosphingolipids, notably of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lysoGb3) leading to renal failure, cardiomyopathy, and cerebral strokes. Inflammatory processes are involved in the pathophysiology. We investigated the immunological phenotype of peripheral blood mononuclear cells in Fabry patients depending on the clinical phenotype, treatment, Gb3, and lysoGb3 levels and the presence of anti-drug antibodies (ADA)...
April 16, 2024: Journal of Inherited Metabolic Disease
Alexandra Klein, Katharina Klug, Maximilian Breyer, Julia Grüner, Vijay Krishna Medala, Peter Nordbeck, Christoph Wanner, Eva Klopocki, Nurcan Üçeyler
Fabry disease (FD) is an X-linked multiorgan disorder caused by variants in the alpha-galactosidase A gene (GLA). Depending on the variant, disease phenotypes range from benign to life-threatening. More than 1000 GLA variants are known, but a link between genotype and phenotype in FD has not yet been established for all. p.A143T, p.D313Y, and p.S126G are frequent examples of variants of unknown significance (VUS). We have investigated the potential pathogenicity of these VUS combining clinical data with data obtained in human cellular in vitro systems...
April 15, 2024: Journal of Inherited Metabolic Disease
Sara Mazzini, Sai Yadnik, Inge Timmers, Estela Rubio-Gozalbo, Bernadette M Jansma
Classical galactosaemia (CG) is a hereditary disease in galactose metabolism that despite dietary treatment is characterized by a wide range of cognitive deficits, among which is language production. CG brain functioning has been studied with several neuroimaging techniques, which revealed both structural and functional atypicalities. In the present study, for the first time, we compared the oscillatory dynamics, especially the power spectrum and time-frequency representations (TFR), in the electroencephalography (EEG) of CG patients and healthy controls while they were performing a language production task...
April 10, 2024: Journal of Inherited Metabolic Disease
Earnest J P Daniel, Andrew C Edmondson, Yair Argon, Hind Alsharhan, Christina Lam, Hudson H Freeze, Miao He
ALG3-CDG is a rare congenital disorder of glycosylation (CDG) with a clinical phenotype that includes neurological manifestations, transaminitis, and frequent infections. The ALG3 enzyme catalyzes the first step of endoplasmic reticulum (ER) luminal glycan extension by adding mannose from Dol-P-Man to Dol-PP-Man5 GlcNAc2 (Man5) forming Dol-PP-Man6. Such glycan extension is the first and fastest cellular response to ER stress, which is deficient in ALG3-CDG. In this study, we provide evidence that the unfolded protein response (UPR) and ER-associated degradation activities are increased in ALG3-CDG patient-derived cultured skin fibroblasts and there is constitutive activation of UPR mediated by the IRE1-α pathway...
April 10, 2024: Journal of Inherited Metabolic Disease
J J Wedman, O C M Sibon, E Mastantuono, A Iuso
Coenzyme A (CoA) is an essential cofactor required for over a hundred metabolic reactions in the human body. This cofactor is synthesized de novo in our cells from vitamin B5, also known as pantothenic acid, a water-soluble vitamin abundantly present in vegetables and animal-based foods. Neurodegenerative disorders, cancer, and infectious diseases have been linked to defects in de novo CoA biosynthesis or reduced levels of this coenzyme. There is now accumulating evidence that CoA limitation is a critical pathomechanism in cardiac dysfunction too...
April 9, 2024: Journal of Inherited Metabolic Disease
J J A van den Dorpel, M J Mackenbach, M H G Dremmen, W M C van der Vlugt, D Rizopoulos, P A van Doorn, A T van der Ploeg, R Muetzel, N A M E van der Beek, J M P van den Hout
The aim of this longitudinal cohort study, is to provide more insight into the pattern of brain abnormalities, and possible consequences for cognitive functioning, in patients with classic infantile Pompe disease. We included 19 classic infantile Pompe patients (median age last assessment 8.9 years, range 1.5-22.5 years; 5/19 CRIM negative), treated with ERT. Using MR imaging of the brain (T1, T2, and FLAIR acquisitions), we classified progression of brain abnormalities on a 12-point rating scale at multiple time points throughout follow-up...
April 8, 2024: Journal of Inherited Metabolic Disease
Henry H C Lee, Itay Tokatly Latzer, Mariarita Bertoldi, Guangping Gao, Phillip L Pearl, Mustafa Sahin, Alexander Rotenberg
Neurodevelopment is a highly organized and complex process involving lasting and often irreversible changes in the central nervous system. Inherited disorders of neurotransmission (IDNT) are a group of genetic disorders where neurotransmission is primarily affected, resulting in abnormal brain development from early life, manifest as neurodevelopmental disorders and other chronic conditions. In principle, IDNT (particularly those of monogenic causes) are amenable to gene replacement therapy via precise genetic correction...
April 6, 2024: Journal of Inherited Metabolic Disease
Anna T Reischl-Hajiabadi, Elena Schnabel, Florian Gleich, Katharina Mengler, Martin Lindner, Peter Burgard, Roland Posset, Svenja Lommer-Steinhoff, Sarah C Grünert, Eva Thimm, Peter Freisinger, Julia B Hennermann, Johannes Krämer, Gwendolyn Gramer, Dominic Lenz, Stine Christ, Friederike Hörster, Georg F Hoffmann, Sven F Garbade, Stefan Kölker, Ulrike Mütze
The current German newborn screening (NBS) panel includes 13 inherited metabolic diseases (IMDs). In addition, a NBS pilot study in Southwest Germany identifies individuals with propionic acidemia (PA), methylmalonic acidemia (MMA), combined and isolated remethylation disorders (e.g., cobalamin [cbl] C and methylenetetrahydrofolate reductase [MTHFR] deficiency), cystathionine β-synthase (CBS) deficiency, and neonatal cbl deficiency through one multiple-tier algorithm. The long-term health benefits of screened individuals are evaluated in a multicenter observational study...
April 2, 2024: Journal of Inherited Metabolic Disease
A M J van Wegberg, J C van der Weerd, U F H Engelke, K L M Coene, R Jahja, S J L Bakker, S C J Huijbregts, R A Wevers, M R Heiner-Fokkema, F J van Spronsen
Recent studies in PKU patients identified alternative biomarkers in blood using untargeted metabolomics. To test the added clinical value of these novel biomarkers, targeted metabolomics of 11 PKU biomarkers (phenylalanine, glutamyl-phenylalanine, glutamyl-glutamyl-phenylalanine, N-lactoyl-phenylalanine, N-acetyl-phenylalanine, the dipeptides phenylalanyl-phenylalanine and phenylalanyl-leucine, phenylalanine-hexose conjugate, phenyllactate, phenylpyruvate, and phenylacetate) was performed in stored serum samples of the well-defined PKU patient-COBESO cohort and a healthy control group...
March 31, 2024: Journal of Inherited Metabolic Disease
Fanny Mochel
The field of inherited metabolic diseases (IMD) has initially emerged and developed over decades in pediatric departments. Still, today, about 50% of patients with IMD are adults, and adult metabolic medicine (AMM) is getting more structured at national and international levels. There are several domains in which pediatricians can learn from AMM. First, long-term evolution of IMD patients, especially those treated since childhood, is critical to determine nutritional and neuropsychiatric outcomes in adults so that these outcomes can be better monitored, and patient care adjusted as much as possible from childhood...
March 23, 2024: Journal of Inherited Metabolic Disease
Jun Kido, Georgios Makris, Saikat Santra, Johannes Häberle
Citrin deficiency is an autosomal recessive disorder caused by a defect of citrin resulting from mutations in SLC25A13. The clinical manifestation is very variable and comprises three types: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD: OMIM 605814), post-NICCD including failure to thrive and dyslipidemia caused by citrin deficiency, and adult-onset type II citrullinemia (CTLN2: OMIM 603471). Frequently, NICCD can run with a mild clinical course and manifestations may resolve in the post-NICCD...
March 19, 2024: Journal of Inherited Metabolic Disease
Natalia Alexandra Julia-Palacios, Oya Kuseyri Hübschmann, Mireia Olivella, Roser Pons, Gabriella Horvath, Thomas Lücke, Cheuk-Wing Fung, Suet-Na Wong, Elisenda Cortès-Saladelafont, M Mar Rovira-Remisa, Yılmaz Yıldız, Saadet Mercimek-Andrews, Birgit Assmann, Galina Stevanović, Filippo Manti, Heiko Brennenstuhl, Sabine Jung-Klawitter, Kathrin Jeltsch, H Serap Sivri, Sven F Garbade, Àngels García-Cazorla, Thomas Opladen
The objective of the study is to evaluate the evolving phenotype and genetic spectrum of patients with succinic semialdehyde dehydrogenase deficiency (SSADHD) in long-term follow-up. Longitudinal clinical and biochemical data of 22 pediatric and 9 adult individuals with SSADHD from the patient registry of the International Working Group on Neurotransmitter related Disorders (iNTD) were studied with in silico analyses, pathogenicity scores and molecular modeling of ALDH5A1 variants. Leading initial symptoms, with onset in infancy, were developmental delay and hypotonia...
March 18, 2024: Journal of Inherited Metabolic Disease
Melissa A Walker, Shuqiang Li, Kenneth J Livak, Amel Karaa, Catherine J Wu, Vamsi K Mootha
T cells have been shown to maintain a lower percentage (heteroplasmy) of the pathogenic m.3243A>G variant (MT-TL1, associated with maternally inherited diabetes and deafness [MIDD] and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes [MELAS]). The mechanism(s) underlying this purifying selection, however, remain unknown. Here we report that purified patient memory CD4+ T cells have lower bulk m.3243A>G heteroplasmy compared to naïve CD4+ T cells. In vitro activation of naïve CD4+ m...
March 18, 2024: Journal of Inherited Metabolic Disease
Robert Hegarty, Richard J Thompson
Acute liver failure (ALF) is a rare, rapidly evolving, clinical syndrome with devastating consequences where definitive treatment is by emergency liver transplantation. Establishing a diagnosis can be challenging and, historically, the cause of ALF was unidentified in up to half of children. However, recent technological and clinical advances in genomic medicine have led to an increasing proportion being diagnosed with monogenic aetiologies of ALF. The conditions encountered include a diverse group of inherited metabolic disorders each with prognostic and treatment implications...
March 18, 2024: Journal of Inherited Metabolic Disease
B P Norman, H Sutherland, P J M Wilson, D A Rutland, A M Milan, A T Hughes, A S Davison, M Khedr, J C Jarvis, J A Gallagher, G Bou-Gharios, L R Ranganath
Altered activity of specific enzymes in phenylalanine-tyrosine (phe-tyr) metabolism results in incomplete breakdown of various metabolite substrates in this pathway. Increased biofluid concentration and tissue accumulation of the phe-tyr pathway metabolite homogentisic acid (HGA) is central to pathophysiology in the inherited disorder alkaptonuria (AKU). Accumulation of metabolites upstream of HGA, including tyrosine, occurs in patients on nitisinone, a licenced drug for AKU and hereditary tyrosinaemia type 1, which inhibits the enzyme responsible for HGA production...
March 15, 2024: Journal of Inherited Metabolic Disease
François Feillet, Can Ficicioglu, Florian B Lagler, Nicola Longo, Ania C Muntau, Alberto Burlina, Friedrich K Trefz, Francjan J van Spronsen, Jean-Baptiste Arnoux, Kristin Lindstrom, Joshua Lilienstein, Gillian E Clague, Richard Rowell, Barbara K Burton
Infants born to mothers with phenylketonuria (PKU) may develop congenital abnormalities because of elevated phenylalanine (Phe) levels in the mother during pregnancy. Maintenance of blood Phe levels between 120 and 360 μmol/L reduces risks of birth defects. Sapropterin dihydrochloride helps maintain blood Phe control, but there is limited evidence on its risk-benefit ratio when used during pregnancy. Data from the maternal sub-registries-KAMPER (NCT01016392) and PKUDOS (NCT00778206; PKU-MOMs sub-registry)-were collected to assess the long-term safety and efficacy of sapropterin in pregnant women in a real-life setting...
March 3, 2024: Journal of Inherited Metabolic Disease
Murtadha L Al-Saady, Hristina Galabova, Daphne H Schoenmakers, Shanice Beerepoot, Caroline Lindemans, Peter M van Hasselt, Marjo S van der Knaap, Nicole I Wolf, Petra J W Pouwels
Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disorder characterized by arylsulfatase A (ASA) deficiency, leading to sulfatide accumulation and myelin degeneration in the central nervous system. While primarily considered a white matter (WM) disease, gray matter (GM) is also affected in MLD, and hematopoietic stem cell transplantation (HSCT) may have limited effect on GM atrophy. We cross-sectionally and longitudinally studied GM volumes using volumetric MRI in a cohort of 36 (late-infantile, juvenile and adult type) MLD patients containing untreated and HSCT treated subjects...
March 2, 2024: Journal of Inherited Metabolic Disease
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