المؤلفون: Bilal M; Department of Pathology and Laboratory Medicine, The Aga Khan University Hospital, Karachi, Pakistan., Jafri L; Department of Pathology and Laboratory Medicine, The Aga Khan University Hospital, Karachi, Pakistan., Majid H; Department of Pathology and Laboratory Medicine, The Aga Khan University Hospital, Karachi, Pakistan., Khan AH; Department of Pathology and Laboratory Medicine, The Aga Khan University Hospital, Karachi, Pakistan., Ahmed S; Department of Pathology and Laboratory Medicine, The Aga Khan University Hospital, Karachi, Pakistan.

المصدر: Journal of the College of Physicians and Surgeons--Pakistan : JCPSP [J Coll Physicians Surg Pak] 2024 Jun; Vol. 34 (6), pp. 646-649.

نوع المنشور: Journal Article; Observational Study

بيانات الدورية: Publisher: College of Physicians and Surgeons Pakistan Country of Publication: Pakistan NLM ID: 9606447 Publication Model: Print Cited Medium: Internet ISSN: 1681-7168 (Electronic) Linking ISSN: 1022386X NLM ISO Abbreviation: J Coll Physicians Surg Pak Subsets: MEDLINE

مواضيع طبية MeSH: Amino Acid Metabolism, Inborn Errors*/diagnosis , Amino Acid Metabolism, Inborn Errors*/genetics , Glutaryl-CoA Dehydrogenase*/deficiency , Glutaryl-CoA Dehydrogenase*/genetics , Brain Diseases, Metabolic*/diagnosis , Brain Diseases, Metabolic*/genetics, Humans ; Pakistan ; Male ; Female ; Child, Preschool ; Infant ; Magnetic Resonance Imaging ; Infant, Newborn ; Brain/pathology ; Brain/diagnostic imaging

مستخلص: Objective: To evaluate the clinical, radiological, and biochemical features of glutaric aciduria Type 1 (GA1) patients identified through urine organic acid testing at a biochemical genetics laboratory (BGL) in Pakistan.
Study Design: Observational study. Place and Duration of the Study: Department of Pathology and Laboratory Medicine, The Aga Khan University Hospital, Karachi, Pakistan, from January 2013 to December 2022.
Methodology: Medical charts and urine organic acid (UOA) chromatograms of the patients presenting at the BGL from January 2013 to December 2022 were reviewed. Brain imaging was obtained where available. Variables were noted as per the objective and descriptive statistics were obtained.
Results: GA1 was found in 64 (0.4%) patients out of a total of 16,094 UOA requests for high-risk screening cases. The age of diagnosis ranged between one month and three years. The brain MRI findings revealed characteristic abnormalities such as cerebral atrophy, expanded CSF spaces, white matter abnormalities, and a distinct bat wings appearance, in cohesion with the results of biochemical testing.
Conclusion: Sixty-four cases of GA1 from a single centre indicate a high frequency of the disorder in Pakistan. Late diagnosis emphasises the need for increased clinical awareness and preferably newborn screening to ensure optimal outcomes.
Key Words: Glutaric aciduria Type 1 (GA1), Brain imaging, UOA analysis, Glutaryl-CoA dehydrogenase (GCDH), Pakistan.

SCR Disease Name: Glutaric Acidemia I

المؤلفون: Elola Pastor AI; Centro de Salud Mieres-Sur, Mieres. Asturias, Spain. Electronic address: anaisabel.elola@sespa.es., Prieto García B; Unidad de Bioquímica Clínica, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain., Díaz Martín JJ; Sección de Gastroenterología y Nutrición Pediátrica, Hospital Universitario Central de Asturias, Universidad de Oviedo, Oviedo, Asturias, Spain.

المصدر: Anales de pediatria [An Pediatr (Engl Ed)] 2024 May; Vol. 100 (5), pp. 318-324. Date of Electronic Publication: 2024 May 06.

نوع المنشور: Journal Article; Observational Study

بيانات الدورية: Publisher: Elsevier Country of Publication: Spain NLM ID: 101765626 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2341-2879 (Electronic) Linking ISSN: 23412879 NLM ISO Abbreviation: An Pediatr (Engl Ed) Subsets: MEDLINE

مواضيع طبية MeSH: Neonatal Screening*/methods , Glutaryl-CoA Dehydrogenase*/deficiency , Amino Acid Metabolism, Inborn Errors*/diagnosis , Brain Diseases, Metabolic*/diagnosis, Humans ; Infant, Newborn ; Retrospective Studies ; Male ; Female ; Tandem Mass Spectrometry ; Glutarates/blood ; Gestational Age ; Carnitine/analogs & derivatives

مستخلص: Introduction: . Neonatal screening of glutaric aciduria type 1 (GA-1) has brought radical changes in the course and outcomes of this disease. This study analyses the outcomes of the first 5 years (2015-2019) of the AGA1 neonatal screening programme in our autonomous community.
Material: . We conducted an observational, descriptive and retrospective study. All neonates born between January 1, 2015 and December 31, 2019 that participated in the neonatal screening programme were included in the study. The glutarylcarnitine (C5DC) concentration in dry blood spot samples was measured by means of tandem mass spectrometry applying a cut-off point of 0.25 µmol/L.
Results: . A total of 30 120 newborns underwent screening. We found differences in the C5DC concentration based on gestational age, type of feeding and hours of life at sample collection. These differences were not relevant for screening purposes. There were no differences between neonates with weights smaller and greater than 1500 g. Screening identified 2 affected patients and there were 3 false positives. There were no false negatives. The diagnosis was confirmed by genetic testing. Patients have been in treatment since diagnosis and have not developed encephalopathic crises in the first 4 years of life.
Conclusions: . Screening allowed early diagnosis of two cases of GA-1 in the first 5 years since its introduction in our autonomous community. Although there were differences in C5DC levels based on gestational age, type of feeding and hours of life at blood extraction, they were not relevant for screening.
(Copyright © 2024 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.)

SCR Disease Name: Glutaric Acidemia I

المؤلفون: Sabi EM; Clinical Biochemistry Unit, Pathology Department, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia., AlMogren M; Metabolomics Section, Department of Clinical Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh 11211, KSA, Saudi Arabia., Sebaa R; Department of Medical Laboratories, College of Applied Medical Sciences, Shaqra University, Shaqra 11961, Saudi Arabia., Sumaily KM; Clinical Biochemistry Unit, Pathology Department, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia., AlMalki R; Metabolomics Section, Department of Clinical Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh 11211, KSA, Saudi Arabia., Mujamammi AH; Clinical Biochemistry Unit, Pathology Department, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia., Abdel Rahman AM; Metabolomics Section, Department of Clinical Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh 11211, KSA, Saudi Arabia; The Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. Electronic address: aabdelraman46@kfshrc.edu.sa.

المصدر: Clinica chimica acta; international journal of clinical chemistry [Clin Chim Acta] 2024 Apr 15; Vol. 557, pp. 117861. Date of Electronic Publication: 2024 Mar 13.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: Elsevier Country of Publication: Netherlands NLM ID: 1302422 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-3492 (Electronic) Linking ISSN: 00098981 NLM ISO Abbreviation: Clin Chim Acta Subsets: MEDLINE

مواضيع طبية MeSH: Brain Diseases, Metabolic*/diagnosis , Brain Diseases, Metabolic*/genetics , Brain Diseases, Metabolic*/therapy , Amino Acid Metabolism, Inborn Errors*/diagnosis , Amino Acid Metabolism, Inborn Errors*/genetics, Glutaryl-CoA Dehydrogenase/*deficiency, Humans ; Infant, Newborn ; Glutaryl-CoA Dehydrogenase/genetics ; Biomarkers ; Metabolomics

مستخلص: Background: Glutaric aciduria type-1 (GA-1) is a rare metabolic disorder due to glutaryl coenzyme A dehydrogenase deficiency, causing elevated levels of glutaryl-CoA and its derivatives. GA-1 exhibits symptoms like macrocephaly, developmental delays, and movement disorders. Timely diagnosis through genetic testing and newborn screening is crucial. However, in some cases, transiently elevated level of glutarylcarnitine (C5DC) challenges accurate diagnosis, highlighting the need for alternative diagnostic methods, like mass spectrometry-based untargeted metabolomics, to identify additional biomarkers for distinguishing falsely suspected GA-1 from healthy newborns.
Methodology: DBS samples from falsely suspected GA-1 newborns (n = 47) and matched control were collected through the NBS program. Untargeted metabolomics using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) was performed to enable biomarker and pathway investigations for significantly altered metabolites.
Results: 582 and 546 were up- and down-regulated metabolites in transient GA-1. 155 endogenous metabolites displayed significant variations compared to the control group. Furthermore, our data identified novel altered metabolic biomarkers, such as N-palmitoylcysteine, heptacarboxyporphyrin, 3-hydroxylinoleoylcarnitine, and monoacylglyceride (MG) (0:0/20:1/0:0), along with perturbed metabolic pathways like sphingolipid and thiamine metabolism associated with the transient elevated C5DC levels in DBS samples.
Conclusions: A distinct metabolic pattern linked to the transient C5DC elevation in newborns was reported to enhance the prediction of the falsely positive cases, which could help avoiding unnecessary medical treatments and minimizing the financial burdens in the health sector.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)

SCR Disease Name: Glutaric Acidemia I

المؤلفون: Chauvet E; Pediatric Neurology Unit, Pediatric Subspecialties Service, Children's Hospital, Geneva University Hospitals, Geneva, Switzerland., Ribeiro D; Pediatric Radiology Unit, Radiology Service, Children's Hospital, Geneva University Hospitals, Geneva, Switzerland., Kern I; Pediatric Nephrology and Metabolism Unit, Pediatric Subspecialties Service, Children's Hospital, Geneva University Hospitals, Geneva, Switzerland., Fluss J; Pediatric Neurology Unit, Pediatric Subspecialties Service, Children's Hospital, Geneva University Hospitals, Geneva, Switzerland.

المصدر: Journal of inherited metabolic disease [J Inherit Metab Dis] 2024 Mar; Vol. 47 (2), pp. 217-219. Date of Electronic Publication: 2024 Feb 07.

نوع المنشور: Case Reports; Journal Article

بيانات الدورية: Publisher: Wiley Country of Publication: United States NLM ID: 7910918 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1573-2665 (Electronic) Linking ISSN: 01418955 NLM ISO Abbreviation: J Inherit Metab Dis Subsets: MEDLINE

مواضيع طبية MeSH: Amino Acid Metabolism, Inborn Errors*/complications , Amino Acid Metabolism, Inborn Errors*/diagnosis , Brain Diseases, Metabolic* , Glutaryl-CoA Dehydrogenase*/deficiency , Odontoid Process* , Spinal Cord Diseases*, Child, Preschool ; Female ; Humans ; Muscle Hypotonia

مستخلص: We report the case of a Syrian female refugee with late diagnosis of glutaric aciduria type 1 characterised by massive axial hypotonia and quadriplegia who only started adequate diet upon arrival in Switzerland at the age of 4 years, after a strenuous migration journey. Soon after arrival, she died from an unexpected severe upper cervical myelopathy, heralded by acute respiratory distress after a viral infection. This was likely due to repeated strains on her hypotonic neck and precipitated by an orthotopic os odontoideum who led to atlanto-axial subluxation. This case reminds us not to omit handling patients with insufficient postural control and hypotonia with great care to avoid progressive cervical myelopathy.
(© 2024 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

SCR Disease Name: Glutaric Acidemia I

المؤلفون: Barroso M; University Children's Research, UCR@Kinder-UKE, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Gertzen M; Department of Molecular Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, 80337 Munich, Germany.; Psychiatry and Psychotherapy, Faculty of Medicine, University of Augsburg, 86156 Augsburg, Germany., Puchwein-Schwepcke AF; Department of Molecular Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, 80337 Munich, Germany.; Department of Pediatric Neurology and Developmental Medicine, University of Basel Children's Hospital, 4056 Basel, Switzerland., Preisler H; Department of Molecular Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, 80337 Munich, Germany., Sturm A; Department of Molecular Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, 80337 Munich, Germany., Reiss DD; Department of Molecular Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, 80337 Munich, Germany.; Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, 81377 Munich, Germany., Danecka MK; University Children's Research, UCR@Kinder-UKE, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Muntau AC; University Children's Research, UCR@Kinder-UKE, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.; University Children's Hospital, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany., Gersting SW; University Children's Research, UCR@Kinder-UKE, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.

المصدر: International journal of molecular sciences [Int J Mol Sci] 2023 Aug 24; Vol. 24 (17). Date of Electronic Publication: 2023 Aug 24.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

مواضيع طبية MeSH: Glutaryl-CoA Dehydrogenase*/chemistry , Glutaryl-CoA Dehydrogenase*/genetics , Amino Acid Metabolism, Inborn Errors*/enzymology , Amino Acid Metabolism, Inborn Errors*/genetics , Brain Diseases, Metabolic*/enzymology , Brain Diseases, Metabolic*/genetics, Protein Folding ; Mutation, Missense ; Protein Domains ; Humans ; Enzyme Stability ; Solubility

مستخلص: Glutaric acidemia type 1 (GA1) is a neurotoxic metabolic disorder due to glutaryl-CoA dehydrogenase (GCDH) deficiency. The high number of missense variants associated with the disease and their impact on GCDH activity suggest that disturbed protein conformation can affect the biochemical phenotype. We aimed to elucidate the molecular basis of protein loss of function in GA1 by performing a parallel analysis in a large panel of GCDH missense variants using different biochemical and biophysical methodologies. Thirteen GCDH variants were investigated in regard to protein stability, hydrophobicity, oligomerization, aggregation, and activity. An altered oligomerization, loss of protein stability and solubility, as well as an augmented susceptibility to aggregation were observed. GA1 variants led to a loss of enzymatic activity, particularly when present at the N-terminal domain. The reduced cellular activity was associated with loss of tetramerization. Our results also suggest a correlation between variant sequence location and cellular protein stability ( p < 0.05), with a more pronounced loss of protein observed with variant proximity to the N-terminus. The broad panel of variant-mediated conformational changes of the GCDH protein supports the classification of GA1 as a protein-misfolding disorder. This work supports research toward new therapeutic strategies that target this molecular disease phenotype.

SCR Disease Name: Glutaric Acidemia I

المؤلفون: Barzi M; Y.T. and Alice Chen Center for Genetics and Genomics, Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA., Johnson CG; Center for Cell and Gene Therapy, Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX 77030, USA., Chen T; Y.T. and Alice Chen Center for Genetics and Genomics, Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA., Rodriguiz RM; Department of Psychiatry and Behavioral Sciences, Cell Biology and Neurobiology, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC 27710, USA., Hemmingsen M; Y.T. and Alice Chen Center for Genetics and Genomics, Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA., Gonzalez TJ; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA., Rosales A; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA., Beasley J; Y.T. and Alice Chen Center for Genetics and Genomics, Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA., Peck CK; Biochemical Genetics Laboratory, Children's Hospital Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Ma Y; Y.T. and Alice Chen Center for Genetics and Genomics, Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA., Stiles AR; Y.T. and Alice Chen Center for Genetics and Genomics, Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA., Wood TC; Biochemical Genetics Laboratory, Children's Hospital Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Maeso-Diaz R; Department of Medicine, Division of Gastroenterology, Duke University Medical Center, Durham, NC 27710, USA., Diehl AM; Department of Medicine, Division of Gastroenterology, Duke University Medical Center, Durham, NC 27710, USA., Young SP; Y.T. and Alice Chen Center for Genetics and Genomics, Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA., Everitt JI; Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA., Wetsel WC; Department of Psychiatry and Behavioral Sciences, Cell Biology and Neurobiology, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC 27710, USA., Lagor WR; Department of Integrative Physiology, Baylor College of Medicine, Houston, TX 77030, USA., Bissig-Choisat B; Y.T. and Alice Chen Center for Genetics and Genomics, Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA., Asokan A; Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA.; Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.; Department of Biomedical Engineering (BME) at the Duke University Pratt School of Engineering, Duke University Medical Center, Durham, NC 27710, USA.; Duke Cancer Center, Duke University Medical Center, Durham, NC 27710, USA., El-Gharbawy A; Y.T. and Alice Chen Center for Genetics and Genomics, Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA., Bissig KD; Y.T. and Alice Chen Center for Genetics and Genomics, Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.; Department of Medicine, Division of Gastroenterology, Duke University Medical Center, Durham, NC 27710, USA.; Department of Biomedical Engineering (BME) at the Duke University Pratt School of Engineering, Duke University Medical Center, Durham, NC 27710, USA.; Duke Cancer Center, Duke University Medical Center, Durham, NC 27710, USA.; Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.

المصدر: Science translational medicine [Sci Transl Med] 2023 Apr 19; Vol. 15 (692), pp. eadf4086. Date of Electronic Publication: 2023 Apr 19.

نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

بيانات الدورية: Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101505086 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1946-6242 (Electronic) Linking ISSN: 19466234 NLM ISO Abbreviation: Sci Transl Med Subsets: MEDLINE

مواضيع طبية MeSH: Glutaryl-CoA Dehydrogenase*/genetics , Glutaryl-CoA Dehydrogenase*/metabolism , Lysine*/metabolism, Animals ; Mice ; Mice, Knockout ; Liver/metabolism

مستخلص: Glutaric aciduria type I (GA-1) is an inborn error of metabolism with a severe neurological phenotype caused by the deficiency of glutaryl-coenzyme A dehydrogenase (GCDH), the last enzyme of lysine catabolism. Current literature suggests that toxic catabolites in the brain are produced locally and do not cross the blood-brain barrier. In a series of experiments using knockout mice of the lysine catabolic pathway and liver cell transplantation, we uncovered that toxic GA-1 catabolites in the brain originated from the liver. Moreover, the characteristic brain and lethal phenotype of the GA-1 mouse model was rescued by two different liver-directed gene therapy approaches: Using an adeno-associated virus, we replaced the defective Gcdh gene or we prevented flux through the lysine degradation pathway by CRISPR deletion of the aminoadipate-semialdehyde synthase ( Aass ) gene. Our findings question the current pathophysiological understanding of GA-1 and reveal a targeted therapy for this devastating disorder.

SCR Disease Name: Glutaric Acidemia I

المؤلفون: Paria P; Pediatric Neurology Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India. Electronic address: docpradip10@gmail.com., Saini AG; Pediatric Neurology Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India. Electronic address: doc.arushi@gmail.com., Attri S; Pediatric Biochemistry Division, Department of Pediatrics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India. Electronic address: attrisavi@yahoo.co.in., Kaur R; Pediatric Biochemistry Division, Department of Pediatrics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India. Electronic address: rajdeep1389@gmail.com., Malhi P; Child Psychology Division, Department of Pediatrics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India. Electronic address: pmalhi18@hotmail.com., Didwal G; Pediatric Biochemistry Division, Department of Pediatrics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India. Electronic address: gunjan276@gmail.com., Kasinathan A; Pediatric Neurology Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India. Electronic address: cerebratelife@gmail.com., Bhatia P; In-charge Pediatric Hematology & Pediatric Molecular Hematology Laboratory, Pediatric Hematology-Oncology Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India. Electronic address: prateekbhatia16@gmail.com., Sahu JK; Pediatric Neurology Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India. Electronic address: jsh2003@gmail.com., Suthar R; Pediatric Neurology Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India. Electronic address: drrenusuthar@gmail.com., Saini L; Pediatric Neurology Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India. Electronic address: drlokeshsaini@gmail.com., Vyas S; Department of Radiodiagnosis, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India. Electronic address: sameer574@yahoo.co.in., Panigrahi I; Genetics & Metabolic Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India. Electronic address: inupan@yahoo.com., Sankhyan N; Pediatric Neurology Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India. Electronic address: drnsankhyan@yahoo.co.in.

المصدر: European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society [Eur J Paediatr Neurol] 2022 Jul; Vol. 39, pp. 49-58. Date of Electronic Publication: 2022 May 24.

نوع المنشور: Journal Article; Observational Study

بيانات الدورية: Publisher: Saunders Country of Publication: England NLM ID: 9715169 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1532-2130 (Electronic) Linking ISSN: 10903798 NLM ISO Abbreviation: Eur J Paediatr Neurol Subsets: MEDLINE

مواضيع طبية MeSH: Amino Acid Metabolism, Inborn Errors*/enzymology , Amino Acid Metabolism, Inborn Errors*/genetics , Brain Diseases, Metabolic*/enzymology , Brain Diseases, Metabolic*/genetics , Glutaryl-CoA Dehydrogenase*/chemistry , Glutaryl-CoA Dehydrogenase*/deficiency , Glutaryl-CoA Dehydrogenase*/genetics, Child ; Cross-Sectional Studies ; Humans ; Quality of Life

مستخلص: Aim: To evaluate the pathogenic variants in GCDH gene and to assess the neurodevelopmental outcomes in children with Glutaric aciduria type 1 (GA-1).
Method: Cross-sectional observational study between January 2019 and June 2020 in consecutive North Indian children with a clinical and biochemical suspicion of GA-1. Variants in the coding regions of GCDH gene were identified through Sanger sequencing. Neurodevelopmental and quality of life assessment was done using standardized scales.
Results: 24 children with GA-1 were identified. The median age at diagnosis was 12 months and the median delay in diagnosis was 3 months. Genetic analysis was done in 14 cases. It revealed 12 variants (11 missense and one nonsense) from 13 patients. Most of the pathogenic variants were in exon 9 and exon 5. Three novel variants were identified in three patients: two missense variants c.169G > A (p.Glu57Lys), c.1048T > C (p.Cys350Arg) and one nonsense variant c.331C > T (p.Lys111Ter). On neurodevelopmental assessment, majority of children with GA-1 were non ambulatory (62.5%), had limited hand skills (58.3%) and impaired communication (58.3%). Overall, poor global development was noted in 43.7%. A pre-existing developmental delay was significantly associated with impaired communication skills (p = 0.03), and the number of episodes of encephalopathy were significantly associated with impaired gross motor skill (p = 0.02). Presence of encephalopathy was significantly associated with poor performance in social emotional (p = 0.01) and cognitive (p = 0.03) domains of Developmental Profile-III scale and development of severe dystonia (p = 0.01).
Conclusion: Our findings highlight the clinical, biochemical, radiological and genetic spectrum of GA-1 in children in North India and report the presence of novel pathogenic variations.
(© 2022 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.)

SCR Disease Name: Glutaric Acidemia I

المؤلفون: Mateu-Bosch A; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.; Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain., Segur-Bailach E; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.; Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain., García-Villoria J; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.; Section of Inborn Errors of Metabolism-IBC, Biochemial and Molecular Genetics Department, Hospital Clinic de Barcelona, Barcelona, Spain.; Inherited Metabolic Diseases and Muscle Disorders' Research Group, Barcelona, Spain., Gea-Sorlí S; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain., Ruiz I; Unitat de Biologia Cel·lular i Genètica Mèdica, Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, 08193, Spain., Del Rey J; Unitat de Biologia Cel·lular i Genètica Mèdica, Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, 08193, Spain., Camps J; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.; Unitat de Biologia Cel·lular i Genètica Mèdica, Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, 08193, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain., Guitart-Mampel M; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.; Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.; Inherited Metabolic Diseases and Muscle Disorders' Research Group, Barcelona, Spain., Garrabou G; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.; Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.; Inherited Metabolic Diseases and Muscle Disorders' Research Group, Barcelona, Spain., Tort F; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.; Inherited Metabolic Diseases and Muscle Disorders' Research Group, Barcelona, Spain., Ribes A; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.; Inherited Metabolic Diseases and Muscle Disorders' Research Group, Barcelona, Spain., Fillat C; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. cfillat@recerca.clinic.cat.; Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona (UB), Barcelona, Spain. cfillat@recerca.clinic.cat.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain. cfillat@recerca.clinic.cat.

المصدر: Gene therapy [Gene Ther] 2024 Jan; Vol. 31 (1-2), pp. 12-18. Date of Electronic Publication: 2023 Nov 20.

نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't

بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 9421525 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5462 (Electronic) Linking ISSN: 09697128 NLM ISO Abbreviation: Gene Ther Subsets: MEDLINE

مواضيع طبية MeSH: Lysine*/genetics , Neuroblastoma* , Amino Acid Metabolism, Inborn Errors* , Brain Diseases, Metabolic*, Humans ; Animals ; Mice ; Glutaryl-CoA Dehydrogenase/genetics ; Glutaryl-CoA Dehydrogenase/metabolism ; Mice, Knockout ; Genetic Therapy

مستخلص: Glutaric Aciduria type I (GA1) is a rare neurometabolic disorder caused by mutations in the GDCH gene encoding for glutaryl-CoA dehydrogenase (GCDH) in the catabolic pathway of lysine, hydroxylysine and tryptophan. GCDH deficiency leads to increased concentrations of glutaric acid (GA) and 3-hydroxyglutaric acid (3-OHGA) in body fluids and tissues. These metabolites are the main triggers of brain damage. Mechanistic studies supporting neurotoxicity in mouse models have been conducted. However, the different vulnerability to some stressors between mouse and human brain cells reveals the need to have a reliable human neuronal model to study GA1 pathogenesis. In the present work we generated a GCDH knockout (KO) in the human neuroblastoma cell line SH-SY5Y by CRISPR/Cas9 technology. SH-SY5Y-GCDH KO cells accumulate GA, 3-OHGA, and glutarylcarnitine when exposed to lysine overload. GA or lysine treatment triggered neuronal damage in GCDH deficient cells. SH-SY5Y-GCDH KO cells also displayed features of GA1 pathogenesis such as increased oxidative stress vulnerability. Restoration of the GCDH activity by gene replacement rescued neuronal alterations. Thus, our findings provide a human neuronal cellular model of GA1 to study this disease and show the potential of gene therapy to rescue GCDH deficiency.
(© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

SCR Disease Name: Glutaric Acidemia I

المؤلفون: Tibelius A; Institute of Human Genetics, Heidelberg University, 69120 Heidelberg, Germany., Evers C; Institute of Human Genetics, Heidelberg University, 69120 Heidelberg, Germany., Oeser S; Institute of Human Genetics, Heidelberg University, 69120 Heidelberg, Germany., Rinke I; Institute of Human Genetics, Heidelberg University, 69120 Heidelberg, Germany., Jauch A; Institute of Human Genetics, Heidelberg University, 69120 Heidelberg, Germany., Hinderhofer K; Institute of Human Genetics, Heidelberg University, 69120 Heidelberg, Germany.

المصدر: Genes [Genes (Basel)] 2023 Dec 14; Vol. 14 (12). Date of Electronic Publication: 2023 Dec 14.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: MDPI Country of Publication: Switzerland NLM ID: 101551097 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4425 (Electronic) Linking ISSN: 20734425 NLM ISO Abbreviation: Genes (Basel) Subsets: MEDLINE

مواضيع طبية MeSH: Brain Diseases, Metabolic*/diagnosis, Humans ; Glutaryl-CoA Dehydrogenase ; Phenotype ; Genotype

مستخلص: Glutaric aciduria type 1 (GA-1) is a rare but treatable autosomal-recessive neurometabolic disorder of lysin metabolism caused by biallelic pathogenic variants in glutaryl-CoA dehydrogenase gene ( GCDH ) that lead to deficiency of GCDH protein. Without treatment, this enzyme defect causes a neurological phenotype characterized by movement disorder and cognitive impairment. Based on a comprehensive literature search, we established a large dataset of GCDH variants using the Leiden Open Variation Database (LOVD) to summarize the known genotypes and the clinical and biochemical phenotypes associated with GA-1. With these data, we developed a GCDH -specific variation classification framework based on American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines. We used this framework to reclassify published variants and to describe their geographic distribution, both of which have practical implications for the molecular genetic diagnosis of GA-1. The freely available GCDH -specific LOVD dataset provides a basis for diagnostic laboratories and researchers to further optimize their knowledge and molecular diagnosis of this rare disease.

SCR Disease Name: Glutaric Acidemia I

المؤلفون: Vijan A; From the Departments of Radiology of Tata Memorial Hospital, Dr Ernest Borges Rd, Parel East, Mumbai, Maharashtra 40012, India (A.V.); University of British Columbia, Vancouver, British Columbia, Canada (P.K.); Peter MacCallum Cancer Centre, Melbourne, Australia (A.N.M.); and Bai Jerbai Wadia Hospital for Children, Mumbai, India (F.G.)., Khoshpouri P; From the Departments of Radiology of Tata Memorial Hospital, Dr Ernest Borges Rd, Parel East, Mumbai, Maharashtra 40012, India (A.V.); University of British Columbia, Vancouver, British Columbia, Canada (P.K.); Peter MacCallum Cancer Centre, Melbourne, Australia (A.N.M.); and Bai Jerbai Wadia Hospital for Children, Mumbai, India (F.G.)., Murphy AN; From the Departments of Radiology of Tata Memorial Hospital, Dr Ernest Borges Rd, Parel East, Mumbai, Maharashtra 40012, India (A.V.); University of British Columbia, Vancouver, British Columbia, Canada (P.K.); Peter MacCallum Cancer Centre, Melbourne, Australia (A.N.M.); and Bai Jerbai Wadia Hospital for Children, Mumbai, India (F.G.)., Gala F; From the Departments of Radiology of Tata Memorial Hospital, Dr Ernest Borges Rd, Parel East, Mumbai, Maharashtra 40012, India (A.V.); University of British Columbia, Vancouver, British Columbia, Canada (P.K.); Peter MacCallum Cancer Centre, Melbourne, Australia (A.N.M.); and Bai Jerbai Wadia Hospital for Children, Mumbai, India (F.G.).

المصدر: Radiographics : a review publication of the Radiological Society of North America, Inc [Radiographics] 2023 Nov; Vol. 43 (11), pp. e230114.

نوع المنشور: Journal Article

بيانات الدورية: Publisher: Radiological Society of North America Country of Publication: United States NLM ID: 8302501 Publication Model: Print Cited Medium: Internet ISSN: 1527-1323 (Electronic) Linking ISSN: 02715333 NLM ISO Abbreviation: Radiographics Subsets: MEDLINE

مواضيع طبية MeSH: Amino Acid Metabolism, Inborn Errors*/diagnostic imaging , Brain Diseases, Metabolic*/diagnostic imaging, Humans ; Glutaryl-CoA Dehydrogenase

SCR Disease Name: Glutaric Acidemia I