bims-meglyc 2023-02-26 papers

on Metabolic disorders affecting glycosylation

Issue of 2023–02–26
fiveteen papers selected by
Silvia Radenkovic, Frontiers in Congenital Disorders of Glycosylation Consortium

N-Glycoprofiling of SLC35A2-CDG: Patient with a Novel Hemizygous Variant.
Rare diseases of epigenetic origin: Challenges and opportunities.
Key priorities in rare neurological diseases. A statement from the Coordinating Panel on Rare Neurological Diseases of the European Academy of Neurology.
Complex neurological and multisystem presentations in mitochondrial disease.
Laboratory and metabolic investigations.
Rare diseases: individually rare, collectively common.
Recent trends in glycoproteomics by characterization of intact glycopeptides.
A Broad Characterization of Glycogen Storage Disease IV Patients: A Clinical, Genetic, and Histopathological Study.
Genetics of Chronic Kidney Disease in Low-Resource Settings.
The Genetics of Intellectual Disability.
Hallmarks of neurodegenerative diseases.
Mendelian inheritance revisited: dominance and recessiveness in medical genetics.
Prime Editing for Human Gene Therapy: Where Are We Now?
The Hepatic Mitochondrial Pyruvate Carrier as a Regulator of Systemic Metabolism and a Therapeutic Target for Treating Metabolic Disease.
Leigh syndrome.

Biomedicines. 2023 Feb 16. pii: 580. [Epub ahead of print]11(2):

N-Glycoprofiling of SLC35A2-CDG: Patient with a Novel Hemizygous Variant.

Rebeka Kodríková, Zuzana Pakanová, Maroš Krchňák, Mária Šedivá, Sergej Šesták, Filip Květoň, Gábor Beke, Anna Šalingová, Katarína Skalická, Katarína Brennerová, Emília Jančová, Peter Baráth, Ján Mucha, Marek Nemčovič.

  Congenital disorders of glycosylation (CDG) are a group of rare inherited metabolic disorders caused by a defect in the process of protein glycosylation. In this work, we present a comprehensive glycoprofile analysis of a male patient with a novel missense variant in the SLC35A2 gene, coding a galactose transporter that translocates UDP-galactose from the cytosol to the lumen of the endoplasmic reticulum and Golgi apparatus. Isoelectric focusing of serum transferrin, which resulted in a CDG type II pattern, was followed by structural analysis of transferrin and serum N-glycans, as well as the analysis of apolipoprotein CIII O-glycans by mass spectrometry. An abnormal serum N-glycoprofile with significantly increased levels of agalactosylated (Hex3HexNAc4-5 and Hex3HexNAc5Fuc1) and monogalactosylated (Hex4HexNAc4 ± NeuAc1) N-glycans was observed. Additionally, whole exome sequencing and Sanger sequencing revealed de novo hemizygous c.461T > C (p.Leu154Pro) mutation in the SLC35A2 gene. Based on the combination of biochemical, analytical, and genomic approaches, the set of distinctive N-glycan biomarkers was characterized. Potentially, the set of identified aberrant N-glycans can be specific for other variants causing SLC35A2-CDG and can distinguish this disorder from the other CDGs or other defects in the galactose metabolism.

Keywords:  SLC35A2-CDG; congenital disorders of glycosylation; glycoprofiling

DOI:  https://doi.org/10.3390/biomedicines11020580
Front Genet. 2023 ;14 1113086

Rare diseases of epigenetic origin: Challenges and opportunities.

Maggie P Fu, Sarah M Merrill, Mehul Sharma, William T Gibson, Stuart E Turvey, Michael S Kobor.

  Rare diseases (RDs), more than 80% of which have a genetic origin, collectively affect approximately 350 million people worldwide. Progress in next-generation sequencing technology has both greatly accelerated the pace of discovery of novel RDs and provided more accurate means for their diagnosis. RDs that are driven by altered epigenetic regulation with an underlying genetic basis are referred to as rare diseases of epigenetic origin (RDEOs). These diseases pose unique challenges in research, as they often show complex genetic and clinical heterogeneity arising from unknown gene-disease mechanisms. Furthermore, multiple other factors, including cell type and developmental time point, can confound attempts to deconvolute the pathophysiology of these disorders. These challenges are further exacerbated by factors that contribute to epigenetic variability and the difficulty of collecting sufficient participant numbers in human studies. However, new molecular and bioinformatics techniques will provide insight into how these disorders manifest over time. This review highlights recent studies addressing these challenges with innovative solutions. Further research will elucidate the mechanisms of action underlying unique RDEOs and facilitate the discovery of treatments and diagnostic biomarkers for screening, thereby improving health trajectories and clinical outcomes of affected patients.

Keywords:  DNA methylation; bioinformatics analysis; chromatin remodeler; epigenetics; histone modification; rare disease

DOI:  https://doi.org/10.3389/fgene.2023.1113086
Eur J Neurol. 2023 Feb 19.

Key priorities in rare neurological diseases. A statement from the Coordinating Panel on Rare Neurological Diseases of the European Academy of Neurology.

Michelangelo Mancuso, Holm Graessner, Marianne de Visser, Anita Arsovska, Kailash Bathia.



Keywords:  awareness; neurogenetics; rare diseases; rare neurological diseases

DOI:  https://doi.org/10.1111/ene.15752
Handb Clin Neurol. 2023 ;pii: B978-0-12-821751-1.00003-8. [Epub ahead of print]194 117-124

Complex neurological and multisystem presentations in mitochondrial disease.

Michelangelo Mancuso.

  Mitochondrial diseases typically involve organs highly dependent on aerobic metabolism and are often progressive with high morbidity and mortality. In the previous chapters of this book, classical mitochondrial phenotypes and syndromes are extensively described. However, these well-known clinical pictures are more the exception rather than the rule in mitochondrial medicine. In fact, more complex, unspecified, incomplete, and/or overlap clinical entities may be even more frequent, with multisystem appearance or progression. In this chapter, we describe some complex neurological presentations, as well as the multisystem manifestations of mitochondrial diseases, ranging from the brain to the other organs.

Keywords:  Cardiomyopathies; Hearing loss; Leukoencephalopathies; Mitochondrial diseases; Multisystem involvement; Parkinsonism; mtDNA

DOI:  https://doi.org/10.1016/B978-0-12-821751-1.00003-8
Handb Clin Neurol. 2023 ;pii: B978-0-12-821751-1.00012-9. [Epub ahead of print]194 167-172

Laboratory and metabolic investigations.

Eva Morava, Devin Oglesbee.

  Clinical variability and substantial overlap between mitochondrial disorders and other genetic disorders and inborn errors make the clinical and metabolic diagnosis of mitochondrial disorders quite challenging. Evaluating specific laboratory markers is essential in the diagnostic process, but mitochondrial disease can be present in the absence of any abnormal metabolic markers. In this chapter, we share the current consensus guidelines for metabolic investigations, including investigations in blood, urine, and the cerebral spinal fluid and discuss different diagnostic approaches. As personal experience might significantly vary and there are different recommendations published as diagnostic guidelines, the Mitochondrial Medicine Society developed a consensus approach based on literature review for metabolic diagnostics in a suspected mitochondrial disease. According to the guidelines, the work-up should include the assessment of complete blood count, creatine phosphokinase, transaminases, albumin, postprandial lactate and pyruvate (lactate/pyruvate ratio when the lactate level is elevated), uric acid, thymidine, amino acids, acylcarnitines in blood, and urinary organic acids (especially screening for 3-methylglutaconic acid). Urine amino acid analysis is recommended in mitochondrial tubulopathies. CSF metabolite analysis (lactate, pyruvate, amino acids, and 5-methyltetrahydrofolate) should be included in the presence of central nervous system disease. We also suggest a diagnostic strategy based on the mitochondrial disease criteria (MDC) scoring system in mitochondrial disease diagnostics; evaluating muscle-, neurologic-, and multisystem involvement, and the presence of metabolic markers and abnormal imaging. The consensus guideline encourages a primary genetic approach in diagnostics and only suggests a more invasive diagnostic approach with tissue biopsies (histology, OXPHOS measurements, etc.) after nonconclusive genetic testing.

Keywords:  3MGA; Alanine; Ethylmalonic acid; Lactic acid; Metabolomics; Methylmalonic acid; Mitochondrial disease criteria; Pyruvate; Thymidine

DOI:  https://doi.org/10.1016/B978-0-12-821751-1.00012-9
Lancet Diabetes Endocrinol. 2023 Mar;pii: S2213-8587(23)00042-6. [Epub ahead of print]11(3): 139

Rare diseases: individually rare, collectively common.

The Lancet Diabetes Endocrinology.

DOI: https://doi.org/10.1016/S2213-8587(23)00042-6
Anal Bioanal Chem. 2023 Feb 22.

Recent trends in glycoproteomics by characterization of intact glycopeptides.

Susy Piovesana, Chiara Cavaliere, Andrea Cerrato, Aldo Laganà, Carmela Maria Montone, Anna Laura Capriotti.

  This trends article provides an overview of the state of the art in the analysis of intact glycopeptides by proteomics technologies based on LC-MS analysis. A brief description of the main techniques used at the different steps of the analytical workflow is provided, giving special attention to the most recent developments. The topics discussed include the need for dedicated sample preparation for intact glycopeptide purification from complex biological matrices. This section covers the common approaches with a special description of new materials and innovative reversible chemical derivatization strategies, specifically devised for intact glycopeptide analysis or dual enrichment of glycosylation and other post-translational modifications. The approaches are described for the characterization of intact glycopeptide structures by LC-MS and data analysis by bioinformatics for spectra annotation. The last section covers the open challenges in the field of intact glycopeptide analysis. These challenges include the need of a detailed description of the glycopeptide isomerism, the issues with quantitative analysis, and the lack of analytical methods for the large-scale characterization of glycosylation types that remain poorly characterized, such as C-mannosylation and tyrosine O-glycosylation. This bird's-eye view article provides both a state of the art in the field of intact glycopeptide analysis and open challenges to prompt future research on the topic.

Keywords:  Enrichment; Glycoproteomics; Intact glycopeptides; Protein glycosylation; Qualitative analysis; Quantitative analysis

DOI:  https://doi.org/10.1007/s00216-023-04592-z
Biomedicines. 2023 Jan 26. pii: 363. [Epub ahead of print]11(2):

A Broad Characterization of Glycogen Storage Disease IV Patients: A Clinical, Genetic, and Histopathological Study.

Matheus Vernet Machado Bressan Wilke, Bibiana Mello de Oliveira, Rodrigo Tzovenos Starosta, Marwan Shinawi, Liang Lu, Mai He, Yamin Ma, Janis Stoll, Carolina Fischinger Moura de Souza, Ana Cecilia Menezes de Siqueira, Sandra Maria Gonçalves Vieira, Carlos Thadeu Cerski, Lilia Farret Refosco, Ida Vanessa Doederlein Schwartz.

  Glycogen storage disease type IV (GSD IV) is an ultra-rare autosomal recessive disease caused by variants in the GBE1 gene, which encodes the glycogen branching enzyme (GBE). GSD IV accounts for approximately 3% of all GSD. The phenotype of GSD IV ranges from neonatal death to mild adult-onset disease with variable hepatic, muscular, neurologic, dermatologic, and cardiac involvement. There is a paucity of literature and clinical and dietary management in GSD IV, and liver transplantation (LT) is described to correct the primary hepatic enzyme defect. Objectives: We herein describe five cases of patients with GSD IV with different ages of onset and outcomes as well as a novel GBE1 variant. Methods: This is a descriptive case series of patients receiving care for GSD IV at Reference Centers for Rare Diseases in Brazil and in the United States of America. Patients were selected based on confirmatory GBE1 genotypes performed after strong clinical suspicion. Results: Pt #1 is a Latin male with the chief complaints of hepatosplenomegaly, failure to thrive, and elevated liver enzymes starting at the age of 5 months. Before LT at the age of two, empirical treatment with corn starch (CS) and high protein therapy was performed with subjective improvement in his overall disposition and liver size. Pt #2 is a 30-month-old Afro-American descent patient with the chief complaints of failure to gain adequate weight, hypotonia, and hepatosplenomegaly at the age of 15 months. Treatment with CS was initiated without overall improvement of the symptoms. Pt #3.1 is a female Latin patient, sister to pt #3.2, with onset of symptoms at the age of 3 months with bloody diarrhea, abdominal distention, and splenomegaly. There was no attempt of treatment with CS. Pt #4 is an 8-year-old male patient of European descent who had his initial evaluation at 12 months, which was remarkable for hepatosplenomegaly, elevated ALT and AST levels, and a moderate dilatation of the left ventricle with normal systolic function that improved after LT. Pt #1, #3.2 and #4 presented with high levels of chitotriosidase. Pt #2 was found to have the novel variant c.826G > C p.(Ala276Pro). Conclusions: GSD IV is a rare disease with different ages of presentation and different cardiac phenotypes, which is associated with high levels of chitotriosidase. Attempts of dietary intervention with CS did not show a clear improvement in our case series.

Keywords:  dietary treatment; glycogen storage disease IV; liver transplantation

DOI:  https://doi.org/10.3390/biomedicines11020363
Semin Nephrol. 2023 Feb 17. pii: S0270-9295(23)00011-6. [Epub ahead of print]42(5): 151314

Genetics of Chronic Kidney Disease in Low-Resource Settings.

Titilayo Ilori, Andreia Watanabe, Kar-Hui Ng, Adaobi Solarin, Aditi Sinha, Rasheed Gbadegesin.

  Advances in kidney genomics in the past 20 years has opened the door for more precise diagnosis of kidney disease and identification of new and specific therapeutic agents. Despite these advances, an imbalance exists between low-resource and affluent regions of the world. Individuals of European ancestry from the United States, United Kingdom, and Iceland account for 16% of the world's population, but represent more than 80% of all genome-wide association studies. South Asia, Southeast Asia, Latin America, and Africa together account for 57% of the world population but less than 5% of genome-wide association studies. Implications of this difference include limitations in new variant discovery, inaccurate interpretation of the effect of genetic variants in non-European populations, and unequal access to genomic testing and novel therapies in resource-poor regions. It also further introduces ethical, legal, and social pitfalls, and ultimately may propagate global health inequities. Ongoing efforts to reduce the imbalance in low-resource regions include funding and capacity building, population-based genome sequencing, population-based genome registries, and genetic research networks. More funding, training, and capacity building for infrastructure and expertise is needed in resource-poor regions. Focusing on this will ensure multiple-fold returns on investments in genomic research and technology.

Keywords:  APOL1; Africa; CKD; Latin America; South Asia; Southeast Asia; genetic testing; genetics; genomic resources imbalance

DOI:  https://doi.org/10.1016/j.semnephrol.2023.151314
Brain Sci. 2023 Jan 30. pii: 231. [Epub ahead of print]13(2):

The Genetics of Intellectual Disability.

Sandra Jansen, Lisenka E L M Vissers, Bert B A de Vries.

  Intellectual disability (ID) has a prevalence of ~2-3% in the general population, having a large societal impact. The underlying cause of ID is largely of genetic origin; however, identifying this genetic cause has in the past often led to long diagnostic Odysseys. Over the past decades, improvements in genetic diagnostic technologies and strategies have led to these causes being more and more detectable: from cytogenetic analysis in 1959, we moved in the first decade of the 21st century from genomic microarrays with a diagnostic yield of ~20% to next-generation sequencing platforms with a yield of up to 60%. In this review, we discuss these various developments, as well as their associated challenges and implications for the field of ID, which highlight the revolutionizing shift in clinical practice from a phenotype-first into genotype-first approach.

Keywords:  genetics; genotype; intellectual disability; next-generation sequencing; phenotype

DOI:  https://doi.org/10.3390/brainsci13020231
Cell. 2023 Feb 16. pii: S0092-8674(22)01575-6. [Epub ahead of print]186(4): 693-714

Hallmarks of neurodegenerative diseases.

David M Wilson, Mark R Cookson, Ludo Van Den Bosch, Henrik Zetterberg, David M Holtzman, Ilse Dewachter.

  Decades of research have identified genetic factors and biochemical pathways involved in neurodegenerative diseases (NDDs). We present evidence for the following eight hallmarks of NDD: pathological protein aggregation, synaptic and neuronal network dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA and RNA defects, inflammation, and neuronal cell death. We describe the hallmarks, their biomarkers, and their interactions as a framework to study NDDs using a holistic approach. The framework can serve as a basis for defining pathogenic mechanisms, categorizing different NDDs based on their primary hallmarks, stratifying patients within a specific NDD, and designing multi-targeted, personalized therapies to effectively halt NDDs.

Keywords:  DNA and RNA defects; cytoskeletal defects; energy homeostasis; hallmarks; inflammation; neurodegeneration; neurodegenerative disease; protein aggregation; proteostasis; synaptic and neuronal network dysfunction

DOI:  https://doi.org/10.1016/j.cell.2022.12.032
Nat Rev Genet. 2023 Feb 20.

Mendelian inheritance revisited: dominance and recessiveness in medical genetics.

Johannes Zschocke, Peter H Byers, Andrew O M Wilkie.

Understanding the consequences of genotype for phenotype (which ranges from molecule-level effects to whole-organism traits) is at the core of genetic diagnostics in medicine. Many measures of the deleteriousness of individual alleles exist, but these have limitations for predicting the clinical consequences. Various mechanisms can protect the organism from the adverse effects of functional variants, especially when the variant is paired with a wild type allele. Understanding why some alleles are harmful in the heterozygous state - representing dominant inheritance - but others only with the biallelic presence of pathogenic variants - representing recessive inheritance - is particularly important when faced with the deluge of rare genetic alterations identified by high throughput DNA sequencing. Both awareness of the specific quantitative and/or qualitative effects of individual variants and the elucidation of allelic and non-allelic interactions are essential to optimize genetic diagnosis and counselling.

DOI: https://doi.org/10.1038/s41576-023-00574-0
Cells. 2023 Feb 07. pii: 536. [Epub ahead of print]12(4):

Prime Editing for Human Gene Therapy: Where Are We Now?

Kelly Godbout, Jacques P Tremblay.

  Gene therapy holds tremendous potential in the treatment of inherited diseases. Unlike traditional medicines, which only treat the symptoms, gene therapy has the potential to cure the disease by addressing the root of the problem: genetic mutations. The discovery of CRISPR/Cas9 in 2012 paved the way for the development of those therapies. Improvement of this system led to the recent development of an outstanding technology called prime editing. This system can introduce targeted insertions, deletions, and all 12 possible base-to-base conversions in the human genome. Since the first publication on prime editing in 2019, groups all around the world have worked on this promising technology to develop a treatment for genetic diseases. To date, prime editing has been attempted in preclinical studies for liver, eye, skin, muscular, and neurodegenerative hereditary diseases, in addition to cystic fibrosis, beta-thalassemia, X-linked severe combined immunodeficiency, and cancer. In this review, we portrayed where we are now on prime editing for human gene therapy and outlined the best strategies for correcting pathogenic mutations by prime editing.

Keywords:  CRISPR/Cas9; gene therapy; genetic diseases; inherited diseases; prime editing

DOI:  https://doi.org/10.3390/cells12040536
Biomolecules. 2023 Jan 31. pii: 261. [Epub ahead of print]13(2):

The Hepatic Mitochondrial Pyruvate Carrier as a Regulator of Systemic Metabolism and a Therapeutic Target for Treating Metabolic Disease.

Kyle S McCommis, Brian N Finck.

  Pyruvate sits at an important metabolic crossroads of intermediary metabolism. As a product of glycolysis in the cytosol, it must be transported into the mitochondrial matrix for the energy stored in this nutrient to be fully harnessed to generate ATP or to become the building block of new biomolecules. Given the requirement for mitochondrial import, it is not surprising that the mitochondrial pyruvate carrier (MPC) has emerged as a target for therapeutic intervention in a variety of diseases characterized by altered mitochondrial and intermediary metabolism. In this review, we focus on the role of the MPC and related metabolic pathways in the liver in regulating hepatic and systemic energy metabolism and summarize the current state of targeting this pathway to treat diseases of the liver. Available evidence suggests that inhibiting the MPC in hepatocytes and other cells of the liver produces a variety of beneficial effects for treating type 2 diabetes and nonalcoholic steatohepatitis. We also highlight areas where our understanding is incomplete regarding the pleiotropic effects of MPC inhibition.

Keywords:  liver; mitochondria; pyruvate

DOI:  https://doi.org/10.3390/biom13020261
Handb Clin Neurol. 2023 ;pii: B978-0-12-821751-1.00015-4. [Epub ahead of print]194 43-63

Leigh syndrome.

Shamima Rahman.

  Leigh syndrome, or subacute necrotizing encephalomyelopathy, was initially recognized as a neuropathological entity in 1951. Bilateral symmetrical lesions, typically extending from the basal ganglia and thalamus through brainstem structures to the posterior columns of the spinal cord, are characterized microscopically by capillary proliferation, gliosis, severe neuronal loss, and relative preservation of astrocytes. Leigh syndrome is a pan-ethnic disorder usually with onset in infancy or early childhood, but late-onset forms occur, including in adult life. Over the last six decades it has emerged that this complex neurodegenerative disorder encompasses more than 100 separate monogenic disorders associated with enormous clinical and biochemical heterogeneity. This chapter discusses clinical, biochemical and neuropathological aspects of the disorder, and postulated pathomechanisms. Known genetic causes, including defects of 16 mitochondrial DNA (mtDNA) genes and approaching 100 nuclear genes, are categorized into disorders of subunits and assembly factors of the five oxidative phosphorylation enzymes, disorders of pyruvate metabolism and vitamin and cofactor transport and metabolism, disorders of mtDNA maintenance, and defects of mitochondrial gene expression, protein quality control, lipid remodeling, dynamics, and toxicity. An approach to diagnosis is presented, together with known treatable causes and an overview of current supportive management options and emerging therapies on the horizon.

Keywords:  Diagnosis; Genetics; History; Leigh syndrome; Neuropathology; Pathomechanisms; Subacute necrotizing encephalomyelopathy; Treatment

DOI:  https://doi.org/10.1016/B978-0-12-821751-1.00015-4