bims-meglyc 2023-04-23 papers

on Metabolic disorders affecting glycosylation

Issue of 2023–04–23
23 papers selected by
Silvia Radenkovic, Frontiers in Congenital Disorders of Glycosylation Consortium

The First Congenital Disorders of Glycosylation Patient (Fetus) with Homozygous COG5 c.95T>G Variant.
Abnormal expression of lysosomal glycoproteins in patients with congenital disorders of glycosylation.
Insights into the regulation of cellular Mn2+ homeostasis via TMEM165.
Syndromic forms of congenital hyperinsulinism.
A Rare Case of Cerebrotendinous Xanthomatosis Associated With a Mutation on COG8 Gene.
How has CRISPR transformed therapeutic drug discovery?
Human brain microphysiological systems in the study of neuroinfectious disorders.
GlycoMME, a Markov modeling platform for studying N-glycosylation biosynthesis from glycomics data.
Normalization of hepatic ChREBP activity does not protect against liver disease progression in a mouse model for Glycogen Storage Disease type Ia.
Randomized controlled trial data for successful new drug application for rare diseases in the United States.
Single-cell genomics meets human genetics.
Cardiomyocyte-fibroblast crosstalk in the postnatal heart.
The Role of Large Animal Models in Cardiac Regeneration Research Using Human Pluripotent Stem Cell-Derived Cardiomyocytes.
Advancing cell therapy for neurodegenerative diseases.
Machine learning to examine the genetic underpinnings of cardiac fibrosis at scale.
Central role of cardiac fibroblasts in myocardial fibrosis of diabetic cardiomyopathy.
Biomarker discovery in galactosemia: Metabolomics with UPLC/HRMS in dried blood spots.
Genetics of Inborn Errors of Immunity in highly consanguineous Middle Eastern and North African populations.
Heart-brain axis: Association of congenital heart abnormality and brain diseases.
The Epilepsy Phenotype of ST3GAL3-related Developmental and Epileptic Encephalopathy.
Brain CoA and Acetyl CoA Metabolism in Mechanisms of Neurodegeneration.
Rescue of glutaric aciduria type I in mice by liver-directed therapies.
News in diagnostics and treament of cardiomyopathies.

Mol Syndromol. 2023 Apr;14(2): 181-183

The First Congenital Disorders of Glycosylation Patient (Fetus) with Homozygous COG5 c.95T>G Variant.

Murat Buyukdogan, Veysel Sabri Hancer, Ayhan Sucak.

   Introduction: Congenital disorders of glycosylation (CDG) are autosomal recessive hereditary genetic disorders characterized by abnormal glycosylation of N-linked oligosaccharides.
Case Presentation: In this research, prenatal testing (24th week of pregnancy) revealed findings like polyhydramnios, hydrocephaly, abnormal facial features/shape, brain morphology abnormality, spina bifida, vertebral column abnormality, macrocephaly, scoliosis, micrognathia, abnormal kidney morphology, short fetal femur length, and short fetal humerus length in the fetus. Whole-exome sequencing was performed; the COG5 gene has shown a pathogenic variant.
Discussion: Homozygous patients have never been seen before in the literature for COG5-CDG. We demonstrate the first CDG patient at fetus stage with homozygous COG5 c.95T>G variant.

Keywords:  COG5; Congenital disorder of glycosylation; Fetus; Mutation; Prenatal testing

DOI:  https://doi.org/10.1159/000527221
BMC Res Notes. 2023 Apr 17. 16(1): 53

Abnormal expression of lysosomal glycoproteins in patients with congenital disorders of glycosylation.

Sahar Sabry, Noura R Eissa, Maha S Zaki.

   OBJECTIVE: The study of the impact of some inherited defects in glycosylation on the biosynthesis of some lysosomal glycoproteins. Results description: Whole-exome sequencing revealed a homozygous variant; 428G > A; p. (R143K) in SRD5A3 in one patient and a heterozygous one c.46G > A p. (Gly16Arg) in SLC35A2 in the other patient. Both variants were predicted to be likely pathogenic. Lysosome-associated membrane glycoprotein 2 (LAMP2) immunodetection in both cases showed a truncated form of the protein. Cystinosin (CTN) protein appeared as normal and truncated forms in both patients in ratios of the mature to truncated forms of CTN were lower than the control. The levels of the truncated forms of both cellular proteins were higher in the SRD5A3-CDG case compared to the SLC35A2-CDG case. The tetrameric form of cathepsin C (CTSC) was expressed at low levels in both cases with congenital disorder of glycosylation (CDG). SLC35A2-CDG patient had one extra-unknown band while SRD5A3-CDG patient had a missing band of CTSC forms. The expression patterns of lysosomal glycoproteins could be different between different types of CDG.

Keywords:  Cathepsin C; Congenital disorders of glycosylation; Cystinosin; Lysosome-associated membrane; Lysosomes; Total leukocytes

DOI:  https://doi.org/10.1186/s13104-023-06314-1
Biochim Biophys Acta Mol Basis Dis. 2023 Apr 14. pii: S0925-4439(23)00083-2. [Epub ahead of print] 166717

Insights into the regulation of cellular Mn2+ homeostasis via TMEM165.

Dorothée Vicogne, Nicolas Beauval, Zoé Durin, Delphine Allorge, Kateryna Kondratska, Aurélien Haustrate, Natasha Prevarskaya, Vladimir Lupashin, Dominique Legrand, François Foulquier.

  Golgi cation homeostasis is known to be crucial for many cellular processes including vesicular fusion events, protein secretion, as well as for the activity of Golgi glycosyltransferases and glycosidases. TMEM165 was identified in 2012 as the first cation transporter related to human glycosylation diseases, namely the Congenital Disorders of Glycosylation (CDG). Interestingly, divalent manganese (Mn) supplementation has been shown to suppress the observed glycosylation defects in TMEM165-deficient cell lines, thus suggesting that TMEM165 is involved in cellular Mn homeostasis. This paper demonstrates that the origin of the Golgi glycosylation defects arises from impaired Golgi Mn homeostasis in TMEM165-depleted cells. We show that Mn supplementation fully rescues the Mn content in the secretory pathway/organelles of TMEM165-depleted cells and hence the glycosylation process. Strong cytosolic and organellar Mn accumulations can also be observed in TMEM165- and SPCA1-depleted cells upon incubation with increasing Mn concentrations, thus demonstrating the crucial involvement of these two proteins in cellular Mn homeostasis. Interestingly, our results show that the cellular Mn homeostasis maintenance in control cells is correlated with the presence of TMEM165 and that the Mn-detoxifying capacities of cells, through the activity of SPCA1, rely on the Mn-induced degradation mechanism of TMEM165. Finally, this paper highlights that TMEM165 is essential in secretory pathway/organelles Mn homeostasis maintenance to ensure both Golgi glycosylation enzyme activities and cytosolic Mn detoxification.

Keywords:  CDG; Glycosylation; Golgi; Manganese; SPCA1; TMEM165

DOI:  https://doi.org/10.1016/j.bbadis.2023.166717
Front Endocrinol (Lausanne). 2023 ;14 1013874

Syndromic forms of congenital hyperinsulinism.

Martin Zenker, Klaus Mohnike, Katja Palm.

  Congenital hyperinsulinism (CHI), also called hyperinsulinemic hypoglycemia (HH), is a very heterogeneous condition and represents the most common cause of severe and persistent hypoglycemia in infancy and childhood. The majority of cases in which a genetic cause can be identified have monogenic defects affecting pancreatic β-cells and their glucose-sensing system that regulates insulin secretion. However, CHI/HH has also been observed in a variety of syndromic disorders. The major categories of syndromes that have been found to be associated with CHI include overgrowth syndromes (e.g. Beckwith-Wiedemann and Sotos syndromes), chromosomal and monogenic developmental syndromes with postnatal growth failure (e.g. Turner, Kabuki, and Costello syndromes), congenital disorders of glycosylation, and syndromic channelopathies (e.g. Timothy syndrome). This article reviews syndromic conditions that have been asserted by the literature to be associated with CHI. We assess the evidence of the association, as well as the prevalence of CHI, its possible pathophysiology and its natural course in the respective conditions. In many of the CHI-associated syndromic conditions, the mechanism of dysregulation of glucose-sensing and insulin secretion is not completely understood and not directly related to known CHI genes. Moreover, in most of those syndromes the association seems to be inconsistent and the metabolic disturbance is transient. However, since neonatal hypoglycemia is an early sign of possible compromise in the newborn, which requires immediate diagnostic efforts and intervention, this symptom may be the first to bring a patient to medical attention. As a consequence, HH in a newborn or infant with associated congenital anomalies or additional medical issues remains a differential diagnostic challenge and may require a broad genetic workup.

Keywords:  Beckwith-Wiedemann syndrome; Costello syndrome; Kabuki syndrome; Sotos syndrome; chromosomal disorders; congenital hyperinsulinism; hyperinsulinemic hypoglycemia

DOI:  https://doi.org/10.3389/fendo.2023.1013874
J Investig Med High Impact Case Rep. 2023 Jan-Dec;11:11 23247096231168109

A Rare Case of Cerebrotendinous Xanthomatosis Associated With a Mutation on COG8 Gene.

Hamed Ghoshouni, Roham Sarmadian, Rana Irilouzadian, Habibe Nejad Biglari, Abolfazl Gilani.

  Cerebrotendinous xanthomatosis (CTX) is a rare hereditary disease described by a mutation in the CYP27A1 gene, which encodes the sterol 27-hydroxylase enzyme involved in the synthesis of bile acid. Accumulation of cholesterol and its metabolite, cholestanol, in multiple body organs causes the symptoms of this disease. In addition, a mutation in the COG8 gene, which encodes a subunit of conserved oligomeric Golgi (COG) complex, causes another rare disorder attributed to type IIh of congenital disorder of glycosylation (CDG). We described a rare case of CTX disorder associated with a mutation on COG8 gene, which presented by unusual symptoms.

Keywords:  CDG type IIh; COG8 gene; CTX disorder; CYP27A1 gene

DOI:  https://doi.org/10.1177/23247096231168109
Biotechniques. 2023 Mar;74(3): 119-121

How has CRISPR transformed therapeutic drug discovery?

Jade Parker.

  The genome is the blueprint for life, and over the past decade, CRISPR has become a very powerful method for editing our genetic makeup. In this article, we will explore the importance of CRISPR in developing breakthrough therapies for monogenic conditions and neurodegenerative diseases, and for enhancing the effectiveness of immuno-oncology.

Keywords:  CRISPR; CRISPR screening; Huntington's; drug discovery; gene-editing; genomics; oncology; translation medicine

DOI:  https://doi.org/10.2144/btn-2023-0020
Exp Neurol. 2023 Apr 13. pii: S0014-4886(23)00093-6. [Epub ahead of print] 114409

Human brain microphysiological systems in the study of neuroinfectious disorders.

Paula Barreras, David Pamies, Thomas Hartung, Carlos A Pardo.

  Microphysiological systems (MPS) are 2D or 3D multicellular constructs able to mimic tissue microenvironments. The latest models encompass a range of techniques, including co-culturing of various cell types, utilization of scaffolds and extracellular matrix materials, perfusion systems, 3D culture methods, 3D bioprinting, organ-on-a-chip technology, and examination of tissue structures. Several human brain 3D cultures or brain MPS (BMPS) have emerged in the last decade. These organoids or spheroids are 3D culture systems derived from induced pluripotent cells or embryonic stem cells that contain neuronal and glial populations and recapitulate structural and physiological aspects of the human brain. BMPS have been introduced recently in the study and modeling of neuroinfectious diseases and have proven to be useful in establishing neurotropism of viral infections, cell-pathogen interactions needed for infection, assessing cytopathological effects, genomic and proteomic profiles, and screening therapeutic compounds. Here we review the different methodologies of organoids used in neuroinfectious diseases including spheroids, guided and unguided protocols as well as microglia and blood-brain barrier containing models, their specific applications, and limitations. The review provides an overview of the models existing for specific infections including Zika, Dengue, JC virus, Japanese encephalitis, measles, herpes, SARS-CoV2, and influenza viruses among others, and provide useful concepts in the modeling of disease and antiviral agent screening.

Keywords:  Brain organoid; Brain spheroid; In-vitro infection; Infection model; Microphysiological system; iPSC

DOI:  https://doi.org/10.1016/j.expneurol.2023.114409
STAR Protoc. 2023 Apr 21. pii: S2666-1667(23)00202-2. [Epub ahead of print]4(2): 102244

GlycoMME, a Markov modeling platform for studying N-glycosylation biosynthesis from glycomics data.

Chenguang Liang, Austin W T Chiang, Nathan E Lewis.

  Variations in N-glycosylation, which is crucial to glycoprotein functions, impact many diseases and the safety and efficacy of biotherapeutic drugs. Here, we present a protocol for using GlycoMME (Glycosylation Markov Model Evaluator) to study N-glycosylation biosynthesis from glycomics data. We describe steps for annotating glycomics data and quantifying perturbations to N-glycan biosynthesis with interpretable models. We then detail procedures to predict the impact of mutations in disease or potential glycoengineering strategies in drug development. For complete details on the use and execution of this protocol, please refer to Liang et al. (2020).1.

Keywords:  Bioinformatics; Biotechnology and bioengineering; Systems biology

DOI:  https://doi.org/10.1016/j.xpro.2023.102244
Cancer Metab. 2023 Apr 21. 11(1): 5

Normalization of hepatic ChREBP activity does not protect against liver disease progression in a mouse model for Glycogen Storage Disease type Ia.

Martijn G S Rutten, Yu Lei, Joanne H Hoogerland, Vincent W Bloks, Hong Yang, Trijnie Bos, Kishore A Krishnamurthy, Aycha Bleeker, Mirjam H Koster, Rachel E Thomas, Justina C Wolters, Hilda van den Bos, Gilles Mithieux, Fabienne Rajas, Adil Mardinoglu, Diana C J Spierings, Alain de Bruin, Bart van de Sluis, Maaike H Oosterveer.

   BACKGROUND: Glycogen storage disease type 1a (GSD Ia) is an inborn error of metabolism caused by a defect in glucose-6-phosphatase (G6PC1) activity, which induces severe hepatomegaly and increases the risk for liver cancer. Hepatic GSD Ia is characterized by constitutive activation of Carbohydrate Response Element Binding Protein (ChREBP), a glucose-sensitive transcription factor. Previously, we showed that ChREBP activation limits non-alcoholic fatty liver disease (NAFLD) in hepatic GSD Ia. As ChREBP has been proposed as a pro-oncogenic molecular switch that supports tumour progression, we hypothesized that ChREBP normalization protects against liver disease progression in hepatic GSD Ia.
METHODS: Hepatocyte-specific G6pc knockout (L-G6pc-/-) mice were treated with AAV-shChREBP to normalize hepatic ChREBP activity.
RESULTS: Hepatic ChREBP normalization in GSD Ia mice induced dysplastic liver growth, massively increased hepatocyte size, and was associated with increased hepatic inflammation. Furthermore, nuclear levels of the oncoprotein Yes Associated Protein (YAP) were increased and its transcriptional targets were induced in ChREBP-normalized GSD Ia mice. Hepatic ChREBP normalization furthermore induced DNA damage and mitotic activity in GSD Ia mice, while gene signatures of chromosomal instability, the cytosolic DNA-sensing cGAS-STING pathway, senescence, and hepatocyte dedifferentiation emerged.
CONCLUSIONS: In conclusion, our findings indicate that ChREBP activity limits hepatomegaly while decelerating liver disease progression and protecting against chromosomal instability in hepatic GSD Ia. These results disqualify ChREBP as a therapeutic target for treatment of liver disease in GSD Ia. In addition, they underline the importance of establishing the context-specific roles of hepatic ChREBP to define its therapeutic potential to prevent or treat advanced liver disease.

Keywords:  Carbohydrate Response Element Binding Protein; Cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING); Glycogen Storage Disease type 1a; Hepatomegaly; Yes Associated Protein

DOI:  https://doi.org/10.1186/s40170-023-00305-3
Orphanet J Rare Dis. 2023 Apr 19. 18(1): 89

Randomized controlled trial data for successful new drug application for rare diseases in the United States.

Yosuke Kubota, Mamoru Narukawa.

   BACKGROUND: Randomized controlled trial (RCT) data have important implications in drug development. However, the feasibility and cost of conducting RCTs lower the motivation for drug development, especially for rare diseases. We investigated the potential factors associated with the need for RCTs in the clinical data package for new drug applications for rare diseases in the United States (US). This study focused on 233 drugs with orphan drug designations approved in the US between April 2001 and March 2021. Univariable and multivariable logistic regression analyses were conducted to investigate the association between the presence or absence of RCTs in the clinical data package for new drug applications.
RESULTS: Multivariable logistic regression analysis showed that the severity of the disease outcome (odds ratio [OR] 5.63, 95% confidence interval [CI] 2.64-12.00), type of drug usage (odds ratio [OR] 2.95, 95% confidence interval [CI] 1.80-18.57), and type of primary endpoint (OR 5.57, 95% CI 2.57-12.06) were associated with the presence or absence of RCTs.
CONCLUSIONS: Our results indicated that the presence or absence of RCT data in the clinical data package for successful new drug application in the US was associated with three factors: severity of disease outcome, type of drug usage, and type of primary endpoint. These results highlight the importance of selecting target diseases and potential efficacy variables to optimize orphan drug development.

Keywords:  Clinical trials; Efficacy endpoint; Logistic regression analysis; Orphan drugs; Randomization; Rare diseases

DOI:  https://doi.org/10.1186/s13023-023-02702-9
Nat Rev Genet. 2023 Apr 21.

Single-cell genomics meets human genetics.

Anna S E Cuomo, Aparna Nathan, Soumya Raychaudhuri, Daniel G MacArthur, Joseph E Powell.

Single-cell genomic technologies are revealing the cellular composition, identities and states in tissues at unprecedented resolution. They have now scaled to the point that it is possible to query samples at the population level, across thousands of individuals. Combining single-cell information with genotype data at this scale provides opportunities to link genetic variation to the cellular processes underpinning key aspects of human biology and disease. This strategy has potential implications for disease diagnosis, risk prediction and development of therapeutic solutions. But, effectively integrating large-scale single-cell genomic data, genetic variation and additional phenotypic data will require advances in data generation and analysis methods. As single-cell genetics begins to emerge as a field in its own right, we review its current state and the challenges and opportunities ahead.

DOI: https://doi.org/10.1038/s41576-023-00599-5
Front Cell Dev Biol. 2023 ;11 1163331

Cardiomyocyte-fibroblast crosstalk in the postnatal heart.

Maria Uscategui Calderon, Brittany A Gonzalez, Katherine E Yutzey.

  During the postnatal period in mammals, the heart undergoes significant remodeling in response to increased circulatory demands. In the days after birth, cardiac cells, including cardiomyocytes and fibroblasts, progressively lose embryonic characteristics concomitant with the loss of the heart's ability to regenerate. Moreover, postnatal cardiomyocytes undergo binucleation and cell cycle arrest with induction of hypertrophic growth, while cardiac fibroblasts proliferate and produce extracellular matrix (ECM) that transitions from components that support cellular maturation to production of the mature fibrous skeleton of the heart. Recent studies have implicated interactions of cardiac fibroblasts and cardiomyocytes within the maturing ECM environment to promote heart maturation in the postnatal period. Here, we review the relationships of different cardiac cell types and the ECM as the heart undergoes both structural and functional changes during development. Recent advances in the field, particularly in several recently published transcriptomic datasets, have highlighted specific signaling mechanisms that underlie cellular maturation and demonstrated the biomechanical interdependence of cardiac fibroblast and cardiomyocyte maturation. There is increasing evidence that postnatal heart development in mammals is dependent on particular ECM components and that resulting changes in biomechanics influence cell maturation. These advances, in definition of cardiac fibroblast heterogeneity and function in relation to cardiomyocyte maturation and the extracellular environment provide, support for complex cell crosstalk in the postnatal heart with implications for heart regeneration and disease mechanisms.

Keywords:  cardiac fibroblast; cardiomyocyte; cell signaling; extracellular matrix; heart regeneration; postnatal heart

DOI:  https://doi.org/10.3389/fcell.2023.1163331
Curr Cardiol Rep. 2023 Apr 19.

The Role of Large Animal Models in Cardiac Regeneration Research Using Human Pluripotent Stem Cell-Derived Cardiomyocytes.

Yuan-Yuan Cheng, Yu-Feng Hu, Patrick Ching-Ho Hsieh.

   PURPOSE OF REVIEW: Heart failure leads to high mortality. The failing myocardium cannot often be rescued as heart regeneration is mostly compromised by disease progress. Stem cell therapy is a strategy under development to replace the impaired myocardium for recovery after heart injury.
RECENT FINDINGS: Many studies have provided evidence of the beneficial effects of pluripotent stem cell-derived cardiomyocyte (CM) implantation into diseased rodent hearts, but there are still many challenges and limitations to replicating the same effects in large animal models for preclinical validation. In this review, we summarize progress in the use of pluripotent stem cell-derived CMs in large animal models based on three key parameters: species selection, cell source, and delivery. Most importantly, we discuss the current limitations and challenges that need to be solved to advance this technology to the translational stage.

Keywords:  Cardiomyocyte implantation; Large animal; Pluripotent stem cell; Preclinical examination

DOI:  https://doi.org/10.1007/s11886-023-01857-y
Cell Stem Cell. 2023 Apr 14. pii: S1934-5909(23)00088-7. [Epub ahead of print]

Advancing cell therapy for neurodegenerative diseases.

Sally Temple.

  Cell-based therapies are being developed for various neurodegenerative diseases that affect the central nervous system (CNS). Concomitantly, the roles of individual cell types in neurodegenerative pathology are being uncovered by genetic and single-cell studies. With a greater understanding of cellular contributions to health and disease and with the arrival of promising approaches to modulate them, effective therapeutic cell products are now emerging. This review examines how the ability to generate diverse CNS cell types from stem cells, along with a deeper understanding of cell-type-specific functions and pathology, is advancing preclinical development of cell products for the treatment of neurodegenerative diseases.

Keywords:  Alzheimer disease; GABAergic neurons; Parkinson disease; age-related macular degeneration; astrocytes; central nervous system; dopaminergic neurons; frontotemporal dementia; microglia; neurodegenerative disease; neurons; oligodendrocytes; organoids; photoreceptors; preclinical studies; progressive supranuclear palsy; retina; retinal pigment epithelium; stem cell therapy; transplantation

DOI:  https://doi.org/10.1016/j.stem.2023.03.017
Nat Genet. 2023 Apr 20.

Machine learning to examine the genetic underpinnings of cardiac fibrosis at scale.

DOI: https://doi.org/10.1038/s41588-023-01369-z
Front Endocrinol (Lausanne). 2023 ;14 1162754

Central role of cardiac fibroblasts in myocardial fibrosis of diabetic cardiomyopathy.

Yanan Cheng, Yan Wang, Ruili Yin, Yongsong Xu, Lijie Zhang, Yuanyuan Zhang, Longyan Yang, Dong Zhao.

  Diabetic cardiomyopathy (DCM), a main cardiovascular complication of diabetes, can eventually develop into heart failure and affect the prognosis of patients. Myocardial fibrosis is the main factor causing ventricular wall stiffness and heart failure in DCM. Early control of myocardial fibrosis in DCM is of great significance to prevent or postpone the progression of DCM to heart failure. A growing body of evidence suggests that cardiomyocytes, immunocytes, and endothelial cells involve fibrogenic actions, however, cardiac fibroblasts, the main participants in collagen production, are situated in the most central position in cardiac fibrosis. In this review, we systematically elaborate the source and physiological role of myocardial fibroblasts in the context of DCM, and we also discuss the potential action and mechanism of cardiac fibroblasts in promoting fibrosis, so as to provide guidance for formulating strategies for prevention and treatment of cardiac fibrosis in DCM.

Keywords:  cardiac fibroblasts; cardiac fibrosis; cardiac myofibroblasts; diabetic cardiomyopathy; disorder of matrix metalloproteinases synthesis; imbalance of extracellular matrix synthesis and degradation

DOI:  https://doi.org/10.3389/fendo.2023.1162754
Front Mol Biosci. 2023 ;10 1154149

Biomarker discovery in galactosemia: Metabolomics with UPLC/HRMS in dried blood spots.

Ahmad N Alodaib, Refat M Nimer, Rowan Alhumaidy, Alaa Alhenaky, Mai Abdel Jabar, Reem H AlMalki, Anas M Abdel Rahman.

  Introduction:Galactosemia (GAL) is a genetic disorder that results in disturbances in galactose metabolism and can lead to life-threatening complications. However, the underlying pathophysiology of long-term complications in GAL remains poorly understood. Methods: In this study, a metabolomics approach using ultra-performance liquid chromatography coupled with high-resolution mass spectrometry was used to investigate metabolomic changes in dried blood spots of 15 patients with GAL and 39 healthy individuals. Results: The study found that 2,819 metabolites underwent significant changes in patients with GAL compared to the control group. 480 human endogenous metabolites were identified, of which 209 and 271 were upregulated and downregulated, respectively. PA (8:0/LTE4) and ganglioside GT1c (d18:0/20:0) metabolites showed the most significant difference between GAL and the healthy group, with an area under the curve of 1 and 0.995, respectively. Additionally, the study identified potential biomarkers for GAL, such as 17-alpha-estradiol-3-glucuronide and 16-alpha-hydroxy DHEA 3-sulfatediphosphate. Conclusion: This metabolomics study deepened the understanding of the pathophysiology of GAL and presented potential biomarkers that might serve as prognostic biomarkers to monitor the progression or support the clinical diagnosis of GAL.

Keywords:  biomarker; dried blood spot; galactosemia; metabolomics; newborn screening (NBS); ultra-performance liquid chromatography

DOI:  https://doi.org/10.3389/fmolb.2023.1154149
Semin Immunol. 2023 Apr 17. pii: S1044-5323(23)00054-4. [Epub ahead of print]67 101763

Genetics of Inborn Errors of Immunity in highly consanguineous Middle Eastern and North African populations.

Hamoud Al-Mousa, Mohamed-Ridha Barbouche.

  Consanguineous marriages in Middle Eastern and North African (MENA) countries are deeply-rooted tradition and highly prevalent resulting into increased prevalence of autosomal recessive diseases including Inborn Errors of Immunity (IEIs). Molecular genetic testing is an important diagnostic tool for IEIs since it provides a definite diagnosis, genotype-phenotype correlation, and guide therapy. In this review, we will discuss the current state and challenges of genomic and variome studies in MENA region populations, as well as the importance of funding advanced genome projects. In addition, we will review the MENA underlying molecular genetic defects of over 2457 patients published with the common IEIs, where autosomal recessive mode of inheritance accounts for 76% of cases with increased prevalence of combined immunodeficiency diseases (50%). The efforts made in the last three decades in terms of international collaboration and of in situ capacity building in MENA region countries led to the discovery of more than 150 novel genes involved in IEIs. Expanding sequencing studies within the MENA will undoubtedly be a unique asset for the IEI genetics which can advance research, and support precise genomic diagnostics and therapeutics.

Keywords:  Agammaglobulinemia; Chronic granulomatous disease; Consanguinity; Genetic; Immune dysregulation; Immunodeficiency; Inborn Errors of Immunity; Middle East; Mutation; North Africa; SCID

DOI:  https://doi.org/10.1016/j.smim.2023.101763
Front Cardiovasc Med. 2023 ;10 1071820

Heart-brain axis: Association of congenital heart abnormality and brain diseases.

Leihao Sha, Yajiao Li, Yunwu Zhang, Yusha Tang, Baichuan Li, Yucheng Chen, Lei Chen.

  Brain diseases are a major burden on human health worldwide, and little is known about how most brain diseases develop. It is believed that cardiovascular diseases can affect the function of the brain, and many brain diseases are associated with heart dysfunction, which is called the heart-brain axis. Congenital heart abnormalities with anomalous hemodynamics are common treatable cardiovascular diseases. With the development of cardiovascular surgeries and interventions, the long-term survival of patients with congenital heart abnormalities continues to improve. However, physicians have reported that patients with congenital heart abnormalities have an increased risk of brain diseases in adulthood. To understand the complex association between congenital heart abnormalities and brain diseases, the paper reviews relevant clinical literature. Studies have shown that congenital heart abnormalities are associated with most brain diseases, including stroke, migraine, dementia, infection of the central nervous system, epilepsy, white matter lesions, and affective disorders. However, whether surgeries or other interventions could benefit patients with congenital heart abnormalities and brain diseases remains unclear because of limited evidence.

Keywords:  atrial septal defect; brain disease; congenital heart abnormality; patent foramen ovale; pulmonary arteriovenous fistula

DOI:  https://doi.org/10.3389/fcvm.2023.1071820
Epilepsia Open. 2023 Apr 17.

The Epilepsy Phenotype of ST3GAL3-related Developmental and Epileptic Encephalopathy.

Robyn Whitney, Puneet Jain, Rajesh RamachandranNair, Kevin C Jones, Hassan Kiani, Mark Tarnopolsky, Brandon Meaney.

   OBJECTIVE: ST3GAL3-related developmental and epileptic encephalopathy (DEE-15) is an autosomal recessive condition characterized by intellectual disability, language and motor impairments, behavioural difficulties, stereotypies and epilepsy. Only a few cases have been reported, and the epilepsy phenotype is not fully elucidated.
METHODS: A retrospective chart review of two siblings with ST3GAL3-related DEE was completed. In addition, we reviewed all published cases of ST3GAL3-related congenital disorder of glycosylation.
RESULTS: Two brothers presented with global developmental delay, motor and language impairment, hypotonia, and childhood-onset seizures. Seizures started between 2.5-5 years and had tonic components. Both siblings had prolonged periods of seizure freedom on carbamazepine. Tremor was present in the younger sibling. Whole exome sequencing revealed two novel pathogenic variants in ST3GAL3, 1) c.302del, p.Phe102Serfs*34 and 2) c.781C>T, p.Arg261*, which were inherited in trans. MRI showed T2 hyperintensities and restricted diffusion in the brainstem and middle cerebellar peduncle in the older sibling, also described in two reported cases. A review of the literature revealed 24 cases of ST3GAL3-related CDG. Twelve cases had information about seizures, and epilepsy was diagnosed in 8 (67%). The median age of seizure onset was 5.5 months. Epileptic spasms were most common (67%). Four children were diagnosed with Infantile Epileptic Spasms syndrome and Lennox Gastaut syndrome (57%). Most children (n=6, 75%) had seizures despite anti-seizure medication treatment.
SIGNIFICANCE: Seizures related to ST3GAL3-related DEE often occur in infancy and may present as epileptic spasms. However, seizure onset may also occur outside of infancy with mixed seizure types and show good response to treatment with prolonged seizure freedom. Tremor may also be uniquely observed in this condition.

Keywords:  ST3GAL3; congenital disorder of glycosylation; developmental and epileptic encephalopathy; genetics; genotype

DOI:  https://doi.org/10.1002/epi4.12747
Biochemistry (Mosc). 2023 Apr;88(4): 466-480

Brain CoA and Acetyl CoA Metabolism in Mechanisms of Neurodegeneration.

Andrey G Moiseenok, Nina P Kanunnikova.

  The processes of biotransformation of pantothenic acid (Pan) in the biosynthesis and hydrolysis of CoA, key role of pantothenate kinase (PANK) and CoA synthetase (CoASY) in the formation of the priority mitochondrial pool of CoA, with a high metabolic turnover of the coenzyme and limited transport of Pan across the blood-brain barrier are considered. The system of acetyl-CoA, a secondary messenger, which is the main substrate of acetylation processes including formation of N-acetyl aspartate and acetylcholine, post-translational modification of histones, predetermines protection of the neurons against degenerative signals and cholinergic neurotransmission. Biochemical mechanisms of neurodegenerative syndromes in the cases of PANK and CoASY defects, and the possibility of correcting of CoA biosynthesis in the models with knockouts of these enzymes have been described. The data of a post-mortem study of the brains from the patients with Huntington's and Alzheimer's diseases are presented, proving Pan deficiency in the CNS, which is especially pronounced in the pathognomonic neurostructures. In the frontal cortex of the patients with Parkinson's disease, combined immunofluorescence of anti-CoA- and anti-tau protein was detected, reflecting CoAlation during dimerization of the tau protein and its redox sensitivity. Redox activity and antioxidant properties of the precursors of CoA biosynthesis were confirmed in vitro with synaptosomal membranes and mitochondria during modeling of aluminum neurotoxicity accompanied by the decrease in the level of CoA in CNS. The ability of CoA biosynthesis precursors to stabilize glutathione pool in neurostructures, in particular, in the hippocampus, is considered as a pathogenetic protection mechanism during exposure to neurotoxins, development of neuroinflammation and neurodegeneration, and justifies the combined use of Pan derivatives (for example, D-panthenol) and glutathione precursors (N-acetylcysteine). Taking into account the discovery of new functions of CoA (redox-dependent processes of CoAlation of proteins, possible association of oxidative stress and deficiency of Pan (CoA) in neurodegenerative pathology), it seems promising to study bioavailability and biotransformation of Pan derivatives, in particular of D-panthenol, 4'-phospho-pantetheine, its acylated derivatives, and compositions with redox pharmacological compounds, are promising for their potential use as etiopathogenetic agents.

Keywords:  Alzheimer’s disease; CoA biosynthesis; CoA-synthetase; acetyl-CoA; acyl-CoA; glutathione; neurodegeneration; oxidative stress; panothenate kinase; pantothenic acid deficiency in the CNS

DOI:  https://doi.org/10.1134/S000629792304003X
Sci Transl Med. 2023 Apr 19. 15(692): eadf4086

Rescue of glutaric aciduria type I in mice by liver-directed therapies.

Mercedes Barzi, Collin G Johnson, Tong Chen, Ramona M Rodriguiz, Madeline Hemmingsen, Trevor J Gonzalez, Alan Rosales, James Beasley, Cheryl K Peck, Yunhan Ma, Ashlee R Stiles, Timothy C Wood, Raquel Maeso-Diaz, Anna Mae Diehl, Sarah P Young, Jeffrey I Everitt, William C Wetsel, William R Lagor, Beatrice Bissig-Choisat, Aravind Asokan, Areeg El-Gharbawy, Karl-Dimiter Bissig.

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.

DOI: https://doi.org/10.1126/scitranslmed.adf4086
Vnitr Lek. 2023 ;69(2): 89-104

News in diagnostics and treament of cardiomyopathies.

Hana Poloczková, Tomáš Honek, Anna Chaloupka, Lukáš Opatřil, Mária Bakošová, Jan Krejčí.

  Cardiomyopathies are defined as myocardial disorders in which the heart muscle is structurally and functionaly abnormal in the absence of a disease sufficient to cause this abnormality such as coronary artery disease, hypertension, valvular or congenital heart disease. According to the phenotype expresion cardiomyopathies are divided into dilated, hypertrophic, restrictive, arrhytmogenic and unclassified cardiomyopathies (noncompaction and tako-tsubo cardiomyopathy). The same phenotypic expression may include etiologically different forms of the disease, and at the same time phenotypic expression may change in many cardiomyopathies in the course of illness. For each type of cardiomyopathy, we further distinguish the familial (genetic) form and the acquired form. The clinical manifestation of the disease includes symptoms of heart failure, with reduced, mildly reduced or preserved ejection fraction, symptoms resulting from a number of arrhythmias and extracardiac symptoms, but in some cases symptoms may not be presented for a relatively long time. The disease can lead to significant morbidity and mortality if not detected and treated early, especially in young people who are frequently affected. Significant developments in diagnostic and treatment methods have led to an improvement in the prognosis of patients with cardiomyopathies in recent years.

Keywords:  SGLT2; cardiac magnetic resonance; cardiomyopathy; genetic testing; heart failure; magnetic resonance

DOI:  https://doi.org/10.36290/vnl.2023.016