Jorge Román Corona-Rivera, Iván Martínez-Duncker, Eva Morava, Wasantha Ranatunga, Roberta Salinas-Marin, Ana María González-Jaimes, Katia Alejandra Castillo-Reyes, Christian Peña-Padilla, Lucina Bobadilla-Morales, Alfredo Corona-Rivera, Mireya Orozco-Vela, Sinhue Alejandro Brukman-Jiménez
The trafficking protein particle (TRAPP) complex is a multisubunit protein complex that functions as a tethering factor involved in intracellular trafficking. TRAPPC11, a crucial subunit of this complex, is associated with pathogenic variants that cause a spectrum of disease, which can range from a limb girdle muscular dystrophy (LGMD) to developmental disability with muscle disease, movement disorder and global developmental delay (GDD)/intellectual disability (ID), or even a congenital muscular dystrophy (CMD)...
March 28, 2024: Molecular Genetics and Metabolism
Sarah H Elsea, Arthur L Beaudet
No abstract text is available yet for this article.
March 25, 2024: Molecular Genetics and Metabolism
Karen Sanders, Dawn Peck, Gisele Bentz Pino, April Studinski Jones, Amy White, Dimitar Gavrilov, Dietrich Matern, Devin Oglesbee, Matthew Schultz, Silvia Tortorelli, Patricia L Hall
Creatine transporter deficiency has been described with normal or uninformative levels of creatine and creatinine in plasma, while urine has been the preferred specimen type for biochemical diagnosis. We report a cohort of untreated patients with creatine transporter deficiency and abnormal plasma creatine panel results, characterized mainly by markedly decreased plasma creatinine. We conclude that plasma should be considered a viable specimen type for the biochemical diagnosis of this disorder, and abnormal results should be followed up with further confirmatory testing...
March 24, 2024: Molecular Genetics and Metabolism
Friedrich Trefz, Georg Frauendienst-Egger, Gerald Dienel, Claire Cannet, Brigitte Schmidt-Mader, Dorothea Haas, Nenad Blau, Nastassja Himmelreich, Manfred Spraul, Peter Freisinger, Steven Dobrowolski, Daniela Berg, Andrea Pilotto
Despite numerous studies in human patients and animal models for phenylketonuria (PKU; OMIM#261600), the pathophysiology of PKU and the underlying causes of brain dysfunction and cognitive problems in PKU patients are not well understood. In this study, lumbar cerebral spinal fluid (CSF) was obtained immediately after blood sampling from early-treated adult PKU patients who had fasted overnight. Metabolite and amino acid concentrations in the CSF of PKU patients were compared with those of non-PKU controls...
March 23, 2024: Molecular Genetics and Metabolism
Soumeya Bekri, Annette Bley, Heather A Brown, Charlotte Chanson, Heather J Church, Michael H Gelb, Xinying Hong, Nils Janzen, David C Kasper, Thomas Mechtler, Georgina Morton, Simona Murko, Petra Oliva, Abdellah Tebani, Teresa H Y Wu
Newborn screening (NBS) for metachromatic leukodystrophy (MLD) is based on first-tier measurement of sulfatides in dried blood spots (DBS) followed by second-tier measurement of arylsulfatase A in the same DBS. This approach is very precise with 0-1 false positives per ∼30,000 newborns tested. Recent data reported here shows that the sulfatide molecular species with an α-hydroxyl, 16‑carbon, mono-unsaturated fatty acyl group (16:1-OH-sulfatide) is superior to the original biomarker 16:0-sulfatide in reducing the number of first-tier false positives...
March 22, 2024: Molecular Genetics and Metabolism
Koenraad Veys, Mohamed A Elmonem, Lambert van den Heuvel, William A Gahl, Elena Levtchenko
BACKGROUND: Cystine-depleting therapy in nephropathic cystinosis is currently monitored via the white blood cell cystine assay, although its application and usefulness are limited by practical and technical issues. Therefore, alternative biomarkers that are widely available, more economical and less technically demanding, while reliably reflecting long-term adherence to cysteamine treatment, are desirable. Recently, we proposed chitotriosidase enzyme activity as a potential novel biomarker for the therapeutic monitoring of cysteamine treatment in cystinosis...
March 21, 2024: Molecular Genetics and Metabolism
Laura Ann Adang, Anjana Sevagamoorthy, Omar Sherbini, Jamie L Fraser, Joshua L Bonkowsky, Francesco Gavazzi, Russel D'Aiello, Nicholson B Modesti, Emily Yu, Sylvia Mutua, Emma Kotes, Justine Shults, Ariel Vincent, Lisa T Emrick, Stephanie Keller, Keith P Van Haren, Sarah Woidill, Isabella Barcelos, Amy Pizzino, Johanna L Schmidt, Florian Eichler, Ali Fatemi, Adeline Vanderver
Growing interest in therapeutic development for rare diseases necessitate a systematic approach to the collection and curation of natural history data that can be applied consistently across this group of heterogenous rare diseases. In this study, we discuss the challenges facing natural history studies for leukodystrophies and detail a novel standardized approach to creating a longitudinal natural history study using existing medical records. Prospective studies are uniquely challenging for rare diseases. Delays in diagnosis and overall rarity limit the timely collection of natural history data...
March 18, 2024: Molecular Genetics and Metabolism
Lucia Santoro, Graziella Cefalo, Fabrizio Canalini, Silvia Rossi, Maurizio Scarpa
Alpha-mannosidosis is an ultra-rare lysosomal disease that is caused by variants of the MAN2B1 gene on chromosome 19p13. These variants result in faulty or absent alpha-mannosidase in lysosomes, which leads to intracellular accumulation of mannose-containing oligosaccharides. Diagnosis of alpha-mannosidosis is often delayed, in part because of the rarity of the disease, its gradual onset and heterogeneity of presentation, but also because of the similarity of many signs and symptoms of the disease to those of other lysosomal diseases...
March 14, 2024: Molecular Genetics and Metabolism
Andrea Jáñez Pedrayes, Daisy Rymen, Bart Ghesquière, Peter Witters
Congenital disorders of glycosylation (CDG) are a large family of rare disorders affecting the different glycosylation pathways. Defective glycosylation can affect any organ, with varying symptoms among the different CDG. Even between individuals with the same CDG there is quite variable severity. Associating specific symptoms to deficiencies of certain glycoproteins or glycolipids is thus a challenging task. In this review, we focus on the glycosphingolipid (GSL) synthesis pathway, which is still rather unexplored in the context of CDG, and outline the functions of the main GSLs, including gangliosides, and their role in the central nervous system...
March 5, 2024: Molecular Genetics and Metabolism
Itay Tokatly Latzer, Mariarita Bertoldi, Nenad Blau, Melissa L DiBacco, Sarah H Elsea, Àngels García-Cazorla, K Michael Gibson, Andrea L Gropman, Ellen Hanson, Carolyn Hoffman, Kathrin Jeltsch, Natalia Juliá-Palacios, Ina Knerr, Henry H C Lee, Patrizia Malaspina, Alice McConnell, Thomas Opladen, Mari Oppebøen, Alexander Rotenberg, Mark Walterfang, Lee Wang-Tso, Ron A Wevers, Jean-Baptiste Roullet, Phillip L Pearl
Succinic semialdehyde dehydrogenase deficiency (SSADHD) (OMIM #271980) is a rare autosomal recessive metabolic disorder caused by pathogenic variants of ALDH5A1. Deficiency of SSADH results in accumulation of γ-aminobutyric acid (GABA) and other GABA-related metabolites. The clinical phenotype of SSADHD includes a broad spectrum of non-pathognomonic symptoms such as cognitive disabilities, communication and language deficits, movement disorders, epilepsy, sleep disturbances, attention problems, anxiety, and obsessive-compulsive traits...
March 4, 2024: Molecular Genetics and Metabolism
Jennifer Goldstein, Amanda Thomas-Wilson, Emily Groopman, Vimla Aggarwal, Simona Bianconi, Raquel Fernandez, Kim Hart, Nicola Longo, Nicole Liang, Daniel Reich, Heidi Wallis, Meredith Weaver, Sarah Young, Saadet Mercimek-Andrews
Cerebral creatine deficiency syndromes (CCDS) are inherited metabolic phenotypes of creatine synthesis and transport. There are two enzyme deficiencies, guanidinoacetate methyltransferase (GAMT), encoded by GAMT and arginine-glycine amidinotransferase (AGAT), encoded by GATM, which are involved in the synthesis of creatine. After synthesis, creatine is taken up by a sodium-dependent membrane bound creatine transporter (CRTR), encoded by SLC6A8, into all organs. Creatine uptake is very important especially in high energy demanding organs such as the brain, and muscle...
March 2, 2024: Molecular Genetics and Metabolism
Allysa M Kuypers, Kimber Evers-van Vliet, Anita MacDonald, Kirsten Ahring, David Abeln, Suzanne Ford, Sanne Hildebrandt-Karlsen, Francjan J van Spronsen, M Rebecca Heiner-Fokkema
INTRODUCTION: Phenylketonuria (PKU) requires regular phenylalanine monitoring to ensure optimal outcome. However, home sampling methods used for monitoring suffer high pre-analytical variability, inter-laboratory variability and turn-around-times, highlighting the need for alternative methods of home sampling or monitoring. METHODS: A survey was distributed through email and social media to (parents of) PKU patients and professionals working in inherited metabolic diseases in Denmark, The Netherlands, and United Kingdom regarding satisfaction with current home sampling methods and expectations for future point-of-care testing (POCT)...
February 29, 2024: Molecular Genetics and Metabolism
Sarah Donoghue, Jordan Wright, Anne K Voss, Paul J Lockhart, David J Amor
The Mendelian disorders of chromatin machinery (MDCMs) represent a distinct subgroup of disorders that present with neurodevelopmental disability. The chromatin machinery regulates gene expression by a range of mechanisms, including by post-translational modification of histones, responding to histone marks, and remodelling nucleosomes. Some of the MDCMs that impact on histone modification may have potential therapeutic interventions. Two potential treatment strategies are to enhance the intracellular pool of metabolites that can act as substrates for histone modifiers and the use of medications that may inhibit or promote the modification of histone residues to influence gene expression...
February 27, 2024: Molecular Genetics and Metabolism
Michael H Gelb, Dietrich Matern, Matthew Ellinwood, Amy Gaviglio
No abstract text is available yet for this article.
February 24, 2024: Molecular Genetics and Metabolism
Erru Yang, Eliza Kruger, David Yin, Kieran Mace, Meghan Tierney, Noelle Liao, Emily Cibelli, Dan Drozd, Nathan Ross, Kathleen L Deering, Peter Herout, Qing Harshaw, Alicia Shillington, Nina Thomas, Deborah Marsden, Amy Kritzer, Jerry Vockley
Major clinical events (MCEs) related to long-chain fatty acid oxidation disorders (LC-FAOD) in triheptanoin clinical trials include inpatient or emergency room (ER) visits for three major clinical manifestations: rhabdomyolysis, hypoglycemia, and cardiomyopathy. However, outcomes data outside of LC-FAOD clinical trials are limited. The non-interventional cohort LC-FAOD Odyssey study examines data derived from US medical records and patient reported outcomes to quantify LC-FAOD burden according to management strategy including MCE frequency and healthcare resource utilization (HRU)...
February 23, 2024: Molecular Genetics and Metabolism
Shannon J Babcock, Sander M Houten, Melanie B Gillingham
Fatty acid oxidation disorders (FAODs) are a family of rare, genetic disorders that affect any part of the fatty acid oxidation pathway. Patients present with severe phenotypes, such as hypoketotic hypoglycemia, cardiomyopathy, and rhabdomyolysis, and currently manage these symptoms by the avoidance of fasting and maintaining a low-fat, high-carbohydrate diet. Because knowledge about FAODs is limited due to the small number of patients, rodent models have been crucial in learning more about these disorders, particularly in studying the molecular mechanisms involved in different phenotypes and in evaluating treatments for patients...
February 23, 2024: Molecular Genetics and Metabolism
Teresa H Y Wu, Heather A Brown, Heather J Church, Christopher J Kershaw, Rebekah Hutton, Christine Egerton, James Cooper, Karen Tylee, Rebecca N Cohen, David Gokhale, Dipak Ram, Georgina Morton, Michael Henderson, Brian W Bigger, Simon A Jones
Metachromatic leukodystrophy (MLD) is a devastating rare neurodegenerative disease. Typically, loss of motor and cognitive skills precedes early death. The disease is characterised by deficient lysosomal arylsulphatase A (ARSA) activity and an accumulation of undegraded sulphatide due to pathogenic variants in the ARSA gene. Atidarsagene autotemcel (arsa-cel), an ex vivo haematopoietic stem cell gene therapy was approved for use in the UK in 2021 to treat early-onset forms of pre- or early-symptomatic MLD. Optimal outcomes require early diagnosis, but in the absence of family history this is difficult to achieve without newborn screening (NBS)...
February 20, 2024: Molecular Genetics and Metabolism
Laura E MacMullen, Ibrahim George-Sankoh, Katelynn Stanley, Elizabeth M McCormick, Colleen C Muraresku, Amy Goldstein, Zarazuela Zolkipli-Cunningham, Marni J Falk
PURPOSE: Optimizing individualized clinical care in heterogeneous rare disorders, such as primary mitochondrial disease (PMD), will require gaining more comprehensive and objective understanding of the patient experience by longitudinally tracking quantifiable patient-specific outcomes and integrating subjective data with clinical data to monitor disease progression and targeted therapeutic effects. METHODS: Electronic surveys of patient (and caregiver) reported outcome (PRO) measures were administered in REDCap within clinical domains commonly impaired in patients with PMD in the context of their ongoing routine care, including quality of life, fatigue, and functional performance...
February 16, 2024: Molecular Genetics and Metabolism
Bibiche den Hollander, Marion M Brands, Ilse J M Nijhuis, Lous J A E Doude van Troostwijk, Peter van Essen, Ageeth H Hofsteenge, Bart G Koot, Annelieke R Müller, Laura A Tseng, Erik S G Stroes, Peter M van de Ven, Albert Wiegman, Clara D M van Karnebeek
RATIONALE: Lipoprotein lipase (LPL) deficiency, a rare inherited metabolic disorder, is characterized by high triglyceride (TG) levels and life-threatening acute pancreatitis. Current treatment for pediatric patients involves a lifelong severely fat-restricted diet, posing adherence challenges. Volanesorsen, an EMA-approved RNA therapy for adults, effectively reduces TG levels by decreasing the production of apolipoprotein C-III. This 96-week observational open-label study explores Volanesorsen's safety and efficacy in a 13-year-old female with LPL deficiency...
February 13, 2024: Molecular Genetics and Metabolism
Isabella Peixoto de Barcelos, Sarah Woidill, Francesco Gavazzi, Nicholson B Modesti, Anjana Sevagamoorthy, Adeline Vanderver, Laura Adang
OBJECTIVE: Aicardi Goutières Syndrome (AGS) is a genetic interferonopathy associated with multisystemic heterogeneous disease and neurologic dysfunction. AGS includes a broad phenotypic spectrum which is only partially explained by genotype. To better characterize this variability, we will perform a systematic analysis of phenotypic variability in familial cases of AGS. METHODS: Among thirteen families, twenty-six siblings diagnosed with AGS were identified from the Myelin Disorders and Biorepository Project (MDBP) at the Children's Hospital of Philadelphia...
February 13, 2024: Molecular Genetics and Metabolism
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