bims-meglyc 2023-04-30 papers

on Metabolic disorders affecting glycosylation

Issue of 2023–04–30
eight papers selected by
Silvia Radenkovic, Frontiers in Congenital Disorders of Glycosylation Consortium

Congenital disorders of glycosylation and infantile epilepsy.
Clinical and biochemical footprints of inherited metabolic diseases. XII. Immunological defects.
The Hexosamine Biosynthesis Pathway: Regulation and Function.
Clinical Presentation of a Patient with a Congenital Disorder of Glycosylation, Type IIs (ATP6AP1), and Liver Transplantation.
Infants with Congenital Diseases Identified through Newborn Screening-United States, 2018-2020.
Understanding neural development and diseases using CRISPR screens in human pluripotent stem cell-derived cultures.
Implementation of Newborn Screening for Conditions in the United States First Recommended during 2010-2018.
Genetic Screening Reveals Heterogeneous Clinical Phenotypes in Patients with Dilated Cardiomyopathy and Troponin T2 Variants.

Epilepsy Behav. 2023 Apr 20. pii: S1525-5050(23)00133-6. [Epub ahead of print]142 109214

Congenital disorders of glycosylation and infantile epilepsy.

Hsiu-Fen Lee, Ching-Shiang Chi.

  Congenital disorders of glycosylation (CDG) are a group of rare inherited metabolic disorders caused by defects in various defects of protein or lipid glycosylation pathways. The symptoms and signs of CDG usually develop in infancy. Epilepsy is commonly observed in CDG individuals and is often a presenting symptom. These epilepsies can present across the lifespan, share features of refractoriness to antiseizure medications, and are often associated with comorbid developmental delay, psychomotor regression, intellectual disability, and behavioral problems. In this review, we discuss CDG and infantile epilepsy, focusing on an overview of clinical manifestations and electroencephalographic features. Finally, we propose a tiered approach that will permit a clinician to systematically investigate and identify CDG earlier, and furthermore, to provide genetic counseling for the family.

Keywords:  Congenital disorders of glycosylation; Epilepsy; Infants

DOI:  https://doi.org/10.1016/j.yebeh.2023.109214
Mol Genet Metab. 2023 Apr 17. pii: S1096-7192(23)00212-3. [Epub ahead of print]139(1): 107582

Clinical and biochemical footprints of inherited metabolic diseases. XII. Immunological defects.

Lonneke de Boer, Alessandra Cambi, Lilly M Verhagen, Paola de Haas, Clara D M van Karnebeek, Nenad Blau, Carlos R Ferreira.

  Immunological problems are increasingly acknowledged manifestations in many inherited metabolic diseases (IMDs), ranging from exaggerated inflammation, autoimmunity and abnormal cell counts to recurrent microbial infections. A subgroup of IMDs, the congenital disorders of glycosylation (CDG), includes CDG types that are even classified as primary immunodeficiencies. Here, we reviewed the list of metabolic disorders reported to be associated with various immunological defects and identified 171 IMDs accompanied by immunological manifestations. Most IMDs are accompanied by immune dysfunctions of which immunodeficiency and infections, innate immune defects, and autoimmunity are the most common abnormalities reported in 144/171 (84%), 44/171 (26%) and 33/171 (19%) of IMDs with immune system involvement, respectively, followed by autoinflammation 17/171 (10%). This article belongs to a series aiming at creating and maintaining a comprehensive list of clinical and metabolic differential diagnoses according to organ system involvement.

Keywords:  Autoimmunity; Immune defect; Immunodeficiency; Inherited metabolic disorders

DOI:  https://doi.org/10.1016/j.ymgme.2023.107582
Genes (Basel). 2023 Apr 18. pii: 933. [Epub ahead of print]14(4):

The Hexosamine Biosynthesis Pathway: Regulation and Function.

Alysta Paneque, Harvey Fortus, Julia Zheng, Guy Werlen, Estela Jacinto.

  The hexosamine biosynthesis pathway (HBP) produces uridine diphosphate-N-acetyl glucosamine, UDP-GlcNAc, which is a key metabolite that is used for N- or O-linked glycosylation, a co- or post-translational modification, respectively, that modulates protein activity and expression. The production of hexosamines can occur via de novo or salvage mechanisms that are catalyzed by metabolic enzymes. Nutrients including glutamine, glucose, acetyl-CoA, and UTP are utilized by the HBP. Together with availability of these nutrients, signaling molecules that respond to environmental signals, such as mTOR, AMPK, and stress-regulated transcription factors, modulate the HBP. This review discusses the regulation of GFAT, the key enzyme of the de novo HBP, as well as other metabolic enzymes that catalyze the reactions to produce UDP-GlcNAc. We also examine the contribution of the salvage mechanisms in the HBP and how dietary supplementation of the salvage metabolites glucosamine and N-acetylglucosamine could reprogram metabolism and have therapeutic potential. We elaborate on how UDP-GlcNAc is utilized for N-glycosylation of membrane and secretory proteins and how the HBP is reprogrammed during nutrient fluctuations to maintain proteostasis. We also consider how O-GlcNAcylation is coupled to nutrient availability and how this modification modulates cell signaling. We summarize how deregulation of protein N-glycosylation and O-GlcNAcylation can lead to diseases including cancer, diabetes, immunodeficiencies, and congenital disorders of glycosylation. We review the current pharmacological strategies to inhibit GFAT and other enzymes involved in the HBP or glycosylation and how engineered prodrugs could have better therapeutic efficacy for the treatment of diseases related to HBP deregulation.

Keywords:  GFAT1; GFAT2; Gfpt1; O-GlcNAcylation; UDP-GlcNAc; glucosamine; glycosylation; hexosamine biosynthesis pathway; metabolism; protein folding

DOI:  https://doi.org/10.3390/genes14040933
Int J Mol Sci. 2023 Apr 18. pii: 7449. [Epub ahead of print]24(8):

Clinical Presentation of a Patient with a Congenital Disorder of Glycosylation, Type IIs (ATP6AP1), and Liver Transplantation.

Natalia Semenova, Olga Shatokhina, Olga Shchagina, Elena Kamenec, Andrey Marakhonov, Anna Degtyareva, Natalia Taran, Tatiana Strokova.

  The congenital disorder of glycosylation type IIs (ATP6AP1-CDG; OMIM# 300972) is a rare X-linked recessive complex syndrome characterized by liver dysfunction, recurrent bacterial infections, hypogammaglobulinemia, and defective glycosylation of serum proteins. Here, we examine the case of a 1-year-old male patient of Buryat origin, who presented with liver dysfunction. At the age of 3 months, he was hospitalized with jaundice and hepatosplenomegaly. Whole-exome sequencing identified the ATP6AP1 gene missense variant NM_001183.6:c.938A>G (p.Tyr313Cys) in the hemizygous state, which was previously reported in a patient with immunodeficiency type 47. At the age of 10 months, the patient successfully underwent orthotopic liver transplantation. After the transplantation, the use of Tacrolimus entailed severe adverse effect (colitis with perforation). Replacing Tacrolimus with Everolimus led to improvement. Previously reported patients demonstrated abnormal N- and O-glycosylation, but these data were collected without any specific treatment. In contrast, in our patient, isoelectric focusing (IEF) of serum transferrin was performed only after the liver transplant and showed a normal IEF pattern. Thus, liver transplantation could be a curative option for patients with ATP6AP1-CDG.

Keywords:  ATP6AP1; X-linked primary immunodeficiency; cholestasis; liver transplantation

DOI:  https://doi.org/10.3390/ijms24087449
Int J Neonatal Screen. 2023 Apr 13. pii: 23. [Epub ahead of print]9(2):

Infants with Congenital Diseases Identified through Newborn Screening-United States, 2018-2020.

Amy Gaviglio, Sarah McKasson, Sikha Singh, Jelili Ojodu.

  Newborn screening (NBS) is a state or territory-based public health system that screens newborns for congenital diseases that typically do not present with clinical symptoms at birth but can cause significant mortality and morbidity if not detected or treated quickly. NBS continues to be one of the most successful public health interventions in the US, providing early detection and intervention to all infants. The increase in overall birth prevalence of core Recommended Uniform Screening Panel (RUSP) diseases detected via dried blood spot (DBS) specimens from 2015-2017 (17.50-18.31 per 10,000) to 2018-2020 (20.07 per 10,000), as reported into the APHL NewSTEPs database, affirms the importance and impact of NBS programs. This report presents aggregate numbers and birth prevalence of diseases detected by DBS on the RUSP from 2018-2020, including data from fifty US states and two territories.

Keywords:  birth prevalence; newborn screening; rare disease

DOI:  https://doi.org/10.3390/ijns9020023
Front Cell Dev Biol. 2023 ;11 1158373

Understanding neural development and diseases using CRISPR screens in human pluripotent stem cell-derived cultures.

Mai Ahmed, Julien Muffat, Yun Li.

  The brain is arguably the most complex part of the human body in form and function. Much remains unclear about the molecular mechanisms that regulate its normal and pathological physiology. This lack of knowledge largely stems from the inaccessible nature of the human brain, and the limitation of animal models. As a result, brain disorders are difficult to understand and even more difficult to treat. Recent advances in generating human pluripotent stem cells (hPSCs)-derived 2-dimensional (2D) and 3-dimensional (3D) neural cultures have provided an accessible system to model the human brain. Breakthroughs in gene editing technologies such as CRISPR/Cas9 further elevate the hPSCs into a genetically tractable experimental system. Powerful genetic screens, previously reserved for model organisms and transformed cell lines, can now be performed in human neural cells. Combined with the rapidly expanding single-cell genomics toolkit, these technological advances culminate to create an unprecedented opportunity to study the human brain using functional genomics. This review will summarize the current progress of applying CRISPR-based genetic screens in hPSCs-derived 2D neural cultures and 3D brain organoids. We will also evaluate the key technologies involved and discuss their related experimental considerations and future applications.

Keywords:  CRISPR; genetic screens; human pluripotent stem cell (hPSC); neurodevelopment; neurological disease; organoids

DOI:  https://doi.org/10.3389/fcell.2023.1158373
Int J Neonatal Screen. 2023 Apr 06. pii: 20. [Epub ahead of print]9(2):

Implementation of Newborn Screening for Conditions in the United States First Recommended during 2010-2018.

Sikha Singh, Jelili Ojodu, Alex R Kemper, Wendy K K Lam, Scott D Grosse.

  The Recommended Uniform Screening Panel (RUSP) is the list of conditions recommended by the US Secretary of Health and Human Services for inclusion in state newborn screening (NBS). During 2010-2022, seven conditions were added to the RUSP: severe combined immunodeficiency (SCID) (2010), critical congenital heart disease (CCHD) (2011), glycogen storage disease, type II (Pompe) (2015), mucopolysaccharidosis, type I (MPS I) (2016), X-linked adrenoleukodystrophy (X-ALD) (2016), spinal muscular atrophy (SMA) (2018), and mucopolysaccharidosis, type II (MPS II) (2022). The adoption of SCID and CCHD newborn screening by programs in all 50 states and three territories (Washington, D.C.; Guam; and Puerto Rico) took 8.6 and 6.8 years, respectively. As of December 2022, 37 programs screen for Pompe, 34 for MPS I, 32 for X-ALD, and 48 for SMA. The pace of implementation based on the average additional number of NBS programs per year was most rapid for SMA (11.3), followed by CCHD (7.8), SCID (6.2), MPS I (5.4), Pompe (4.9), and X-ALD (4.7).

Keywords:  new conditions; newborn screening; public health

DOI:  https://doi.org/10.3390/ijns9020020
J Pers Med. 2023 Mar 31. pii: 611. [Epub ahead of print]13(4):

Genetic Screening Reveals Heterogeneous Clinical Phenotypes in Patients with Dilated Cardiomyopathy and Troponin T2 Variants.

Angelika Weis, Svenja Krueck, Gregor Dombrowsky, Anne Schänzer, Christian Jux, Anselm Uebing, Inga Voges, Marc-Phillip Hitz, Stefan Rupp.

   BACKGROUND: Cardiomyopathies (CMs) are a heterogeneous and severe group of diseases that shows a highly variable cardiac phenotype and an incidence of app. 1/100.000. Genetic screening of family members is not yet performed routinely.
PATIENTS AND METHODS: Three families with dilated cardiomyopathy (DCM) and pathogenic variants in the troponin T2, Cardiac Type (TNNT2) gene were included. Pedigrees and clinical data of the patients were collected. The reported variants in the TNNT2 gene showed a high penetrance and a poor outcome, with 8 of 16 patients dying or receiving heart transplantation. The age of onset varied from the neonatal period to the age of 52. Acute heart failure and severe decompensation developed within a short period in some patients.
CONCLUSION: Family screening of patients with DCM improves risk assessment, especially for individuals who are currently asymptomatic. Screening contributes to improved treatment by enabling practitioners to set appropriate control intervals and quickly begin interventional measures, such as heart failure medication or, in selected cases, pulmonary artery banding.

Keywords:  TNNT2; cardiomyopathy; dilated cardiomyopathy; genetic screening; troponin T2

DOI:  https://doi.org/10.3390/jpm13040611