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Start Over Author "Poms, M" Topic hyperammonemia
2 results on '"Poms, M"'

1. Father-to-daughter transmission in late-onset OTC deficiency: an underestimated mechanism of inheritance of an X-linked disease.

Author

Siri B, Olivieri G, Lepri FR, Poms M, Goffredo BM, Commone A, Novelli A, Häberle J, and Dionisi-Vici C

Subjects
Male, Infant, Newborn, Humans, Female, Nuclear Family, Heterozygote, Fathers, Ornithine Carbamoyltransferase genetics, Ornithine Carbamoyltransferase Deficiency Disease genetics, Ornithine Carbamoyltransferase Deficiency Disease diagnosis, Hyperammonemia genetics
Abstract

Background: Ornithine Transcarbamylase Deficiency (OTCD) is an X-linked urea cycle disorder characterized by acute hyperammonemic episodes. Hemizygous males are usually affected by a severe/fatal neonatal-onset form or, less frequently, by a late-onset form with milder disease course, depending on the residual enzymatic activity. Hyperammonemia can occur any time during life and patients could remain non- or mis-diagnosed due to unspecific symptoms. In heterozygous females, clinical presentation varies based on the extent of X chromosome inactivation. Maternal transmission in X-linked disease is the rule, but in late-onset OTCD, due to the milder phenotype of affected males, paternal transmission to the females is possible. So far, father-to-daughter transmission of OTCD has been reported only in 4 Japanese families., Results: We identified in 2 Caucasian families, paternal transmission of late-onset OTCD with severe/fatal outcome in affected males and 1 heterozygous female. Furthermore, we have reassessed the pedigrees of other published reports in 7 additional families with evidence of father-to-daughter inheritance of OTCD, identifying and listing the family members for which this transmission occurred., Conclusions: Our study highlights how the diagnosis and pedigree analysis of late-onset OTCD may represent a real challenge for clinicians. Therefore, the occurrence of paternal transmission in OTCD should not be underestimated, due to the relevant implications for disease inheritance and risk of recurrence., (© 2023. The Author(s).)

Published
2024
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2. The first knock-in rat model for glutaric aciduria type I allows further insights into pathophysiology in brain and periphery

Author

Véronique Rüfenacht, Johannes A. Mayr, Michele Costanzo, Johannes Häberle, Søren W Gersting, Margherita Ruoppolo, Noémie Remacle, Clothilde Roux, Martin Poms, Madalena Barroso, Marianna Caterino, René G. Feichtinger, Hong-Phuc Cudré-Cung, Mary Gonzalez Melo, Olivier Braissant, Cristina Cudalbu, Diana Ballhausen, Gonzalez Melo, M, Remacle, N, Cudré-Cung, Hp, Roux, C, Poms, M, Cudalbu, C, Barroso, M, Gersting, Sw, Feichtinger, Rg, Mayr, Ja, Costanzo, M, Caterino, M, Ruoppolo, M, Rüfenacht, V, Häberle, J, Braissant, O, Ballhausen, D., University of Zurich, and Ballhausen, Diana

Subjects
0301 basic medicine, 1303 Biochemistry, Arginine, Endocrinology, Diabetes and Metabolism, 030105 genetics & heredity, Biochemistry, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, organic-acids, Hyperammonemia, Microglial activation, Gene Knock-In Techniques, Gliosis, Glutaryl-CoA Dehydrogenase, Chemistry, Brain Diseases, Metabolic, Brain, food-intake, Pathophysiology, 1310 Endocrinology, Diabetes and Metabolism, 2712 Endocrinology, Diabetes and Metabolism, Urea cycle, astrogliosis, medicine.medical_specialty, mice, Normal diet, mouse model, 610 Medicine & health, Creatine, energy-metabolism, Astrogliosi, pipecolic acid, 03 medical and health sciences, 1311 Genetics, Internal medicine, 1312 Molecular Biology, Genetics, medicine, Animals, Humans, Molecular Biology, Amino Acid Metabolism, Inborn Errors, Lysine, lysine metabolism, Glutaric aciduria, natural-history, Glutaric aciduria type I, mutations, medicine.disease, Rats, Cerebral organic aciduria, Lysine degradation, Disease Models, Animal, 10036 Medical Clinic, Inborn error of metabolism, 030217 neurology & neurosurgery, Metabolism, Inborn Errors
Abstract

Glutaric aciduria type I (GA-I, OMIM # 231670) is an inborn error of metabolism caused by a deficiency of glutaryl-CoA dehydrogenase (GCDH). Patients develop acute encephalopathic crises (AEC) with striatal injury most often triggered by catabolic stress. The pathophysiology of GA-I, particularly in brain, is still not fully understood. We generated the first knock-in rat model for GA-I by introduction of the mutation p.R411W, the rat sequence homologue of the most common Caucasian mutation p.R402W, into the Gcdh gene of Sprague Dawley rats by CRISPR/CAS9 technology. Homozygous Gcdhki/ki rats revealed a high excretor phenotype, but did not present any signs of AEC under normal diet (ND). Exposure to a high lysine diet (HLD, 4.7%) after weaning resulted in clinical and biochemical signs of AEC. A significant increase of plasmatic ammonium concentrations was found in Gcdhki/ki rats under HLD, accompanied by a decrease of urea concentrations and a concomitant increase of arginine excretion. This might indicate an inhibition of the urea cycle. Gcdhki/ki rats exposed to HLD showed highly diminished food intake resulting in severely decreased weight gain and moderate reduction of body mass index (BMI). This constellation suggests a loss of appetite. Under HLD, pipecolic acid increased significantly in cerebral and extra-cerebral liquids and tissues of Gcdhki/ki rats, but not in WT rats. It seems that Gcdhki/ki rats under HLD activate the pipecolate pathway for lysine degradation. Gcdhki/ki rat brains revealed depletion of free carnitine, microglial activation, astroglyosis, astrocytic death by apoptosis, increased vacuole numbers, impaired OXPHOS activities and neuronal damage. Under HLD, Gcdhki/ki rats showed imbalance of intra-and extracellular creatine concentrations and indirect signs of an intracerebral ammonium accumulation. We successfully created the first rat model for GA-I. Characterization of this Gcdhki/ki strain confirmed that it is a suitable model not only for the study of pathophysiological processes, but also for the development of new ther-apeutic interventions. We further brought up interesting new insights into the pathophysiology of GA-I in brain and periphery., (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

Published
2021

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