bims-meglyc 2023-11-05 papers

on Metabolic disorders affecting glycosylation

Issue of 2023‒11‒05
seven papers selected by
Silvia Radenkovic, Frontiers in Congenital Disorders of Glycosylation Consortium

Autism Spectrum Disorder in Two Unrelated Patients with Homozygous Variants in Either ALG8 or ALG11.
A Case of Congenital Disorder of Glycosylation Type 1b Presenting as Hyperinsulinemic Hypoglycemia and Failure to Thrive.
SLC3A2 N-glycosylation and Golgi remodeling regulate SLC7A amino acid exchangers and stress mitigation.
Case report: Diagnosis and treatment of DGAT1 deficiency-induced congenital diarrhea in two cases and literature review.
An infant with congenital micrognathia and upper airway obstruction was diagnosed as Hutchinson-Gilford progeria syndrome caused by a novel LMNA mutation: Case report and literature review.
Real-world utilization of guideline-directed genetic testing in inherited cardiovascular diseases.
Mitochondrial dysfunction is associated with hypertrophic cardiomyopathy in Pompe disease-specific induced pluripotent stem cell-derived cardiomyocytes.

Mol Syndromol. 2023 Oct;14(5): 428-432

Autism Spectrum Disorder in Two Unrelated Patients with Homozygous Variants in Either ALG8 or ALG11.

Gozde Uzunyayla-Inci, Ertugrul Kiykim, Tanyel Zubarioglu, Gozde Yesil, Cigdem Aktuglu Zeybek.

  Background: Autism spectrum disorder (ASD) is used to describe individuals with a specific combination of disorders in social communication and repetitive behaviors, highly restricted interests, and/or sensory behavior that begin early in life. The prevalence of ASD has been increasing rapidly in recent years. Pathophysiology of ASDs remains still unclear; however, genetic defects and multifactorial causes have been reported to play an important role in genetic disorders. The prevalence of inborn errors of metabolism (IEM) reported among patients with ASD is 2-5%. The clinical presentation of congenital disorders of glycosylation (CDG) may be in the form of psychiatric disorder only.Case Study: Case 1: a 5-year-old female patient was admitted for investigation of ASD. She had a dysmorphic facial appearance, inverted nipples, abnormal fat distribution, ataxic gait, and autistic features. Her transferrin isoelectric focusing test was compatible with a type 1 CDG pattern. A homozygous variant in ALG8 gene revealed the diagnosis of ALG8-CDG (CDG Type 1H). Case 2: a 2-year-old male patient was admitted with complaints of ASD for investigation of an underlying IEM due to speech delay. Physical examination revealed hypertelorism, small hands, and autistic behavior. Transferrin isoelectric focusing test was also found normal. As a result of the WES, a homozygous variant was detected in ALG11 confirming the diagnosis of CDG type 1p.
Conclusion: CDG should also be considered in the differential diagnosis of autistic patients with dysmorphic findings. The aim of our study was to emphasize that autism should be listed among the neurological findings of CDG.

Keywords:  ALG8-CDG; Autism; Autism spectrum disorder; Congenital disorders of glycosylation; Intellectual disability

DOI:  https://doi.org/10.1159/000530118
JCEM Case Rep. 2023 Sep;1(5): luad109

A Case of Congenital Disorder of Glycosylation Type 1b Presenting as Hyperinsulinemic Hypoglycemia and Failure to Thrive.

Swati Rani, Inderneel Sahai, Madhusmita Misra.

  We describe initial manifestations, approach to diagnosis, and treatment of a patient with congenital disorder of glycosylation type 1b (CDG 1b), previously managed as acetylcarnitine deficiency. A 9-year-old girl initially diagnosed with and treated for acetylcarnitine deficiency at an outside hospital presented with recurrent hypoglycemia, failure to thrive, poor weight gain, and short stature. She had discontinued levocarnitine therapy because of lack of response, and testing with us demonstrated a normal carnitine and acyl carnitine panel and hyperinsulinemic hypoglycemia during a diagnostic fast. Oral diazoxide and hydrochlorothiazide were initiated with resolution of hypoglycemia. She had iron deficiency anemia, but an upper gastrointestinal evaluation was normal. Genetic testing confirmed a diagnosis of CDG 1b caused by deficiency of mannose phosphate isomerase. Oral mannose was started with gradual reduction in and eventual discontinuation of the diazoxide dose. Hypoglycemia in the pediatric age group needs a systematic approach. It is important to raise awareness of CDG 1b, which can present as persistent hyperinsulinemic hypoglycemia. Mannose supplementation can ameliorate clinical symptoms and biochemical abnormalities.

Keywords:  diazoxide; glycosylation; hyperinsulinism; hypoglycemia; mannose

DOI:  https://doi.org/10.1210/jcemcr/luad109
J Biol Chem. 2023 Oct 31. pii: S0021-9258(23)02444-4. [Epub ahead of print] 105416

SLC3A2 N-glycosylation and Golgi remodeling regulate SLC7A amino acid exchangers and stress mitigation.

Cunjie Zhang, Massiullah Shafaq-Zadah, Judy Pawling, Geoffrey G Hesketh, Estelle Dransart, Karina Pacholczyk, Joseph Longo, Anne-Claude Gingras, Linda Z Penn, Ludger Johannes, James W Dennis.

  Proteostasis requires oxidative metabolism (ATP) and mitigation of the associated damage by glutathione, in an increasing dysfunctional relationship with aging. SLC3A2 (4F2hc, CD98) plays a role as a disulfide-linked adaptor to the SLC7A5 and SLC7A11 exchangers which import essential amino acids and cystine while exporting Gln and Glu, respectively. The positions of N-glycosylation sites on SLC3A2 have evolved with the emergence of primates, presumably in synchrony with metabolism. Herein, we report that each of the four sites in SLC3A2 have distinct profiles of Golgi-modified N-glycans. N-glycans at the primate-derived site N381 stabilized SLC3A2 in the galectin-3 lattice against coated-pit endocytosis, while N365, the site nearest the membrane promoted glycolipid-galectin-3 (GL-Lect) driven endocytosis. Our results indicate that surface retention and endocytosis are precisely balanced by the number, position, and remodeling of N-glycans on SLC3A2. Furthermore, proteomics and functional assays revealed an N-glycan-dependent clustering of the SLC3A2*SLC7A5 heterodimer with amino-acid /Na+ symporters (SLC1A4, SLC1A5) that balances branched-chain amino acids and Gln levels, at the expense of ATP to maintain the Na+/K+ gradient. In replete conditions, SLC3A2 interactions require Golgi-modified N-glycans at N365D and N381D, whereas reducing N-glycosylation in the endoplasmic reticulum by fluvastatin treatment promoted the recruitment of CD44 and transporters needed to mitigate stress. Thus, SLC3A2 N-glycosylation and Golgi remodeling of the N-glycans have distinct roles in amino acids import for growth, maintenance, and metabolic stresses.

Keywords:  Amino acids; evolution; galectins; metabolism; transporters N-glycosylation

DOI:  https://doi.org/10.1016/j.jbc.2023.105416
Front Pediatr. 2023 ;11 1253800

Case report: Diagnosis and treatment of DGAT1 deficiency-induced congenital diarrhea in two cases and literature review.

Jian Li, Mei Sun, Jing Guo, Lingfen Xu.

  Introduction: Congenital diarrhea is a rare inherited intestinal disease characterized by persistent and severe diarrhea and malabsorption in the first few weeks after birth, which can be life-threatening. Some congenital diarrheal diseases are associated with mutations in the diacylglycerol acyltransferase 1 (DGAT1) gene.Case descriptions: This study delineated 2 cases of diarrhea and growth retardation, subsequently confirmed as congenital diarrhea via genetic testing, revealing that the etiology involved compound heterozygous mutations in the DGAT1 gene.
Diagnostic assessments: High-MCT milk powder did not obtain an ideal outcome, whereas low-fat diets improved the symptoms of diarrhea and increased the body weigths.
Disscussion: The two cases facilitated our understanding of the clinical features of, and treatments for, patients harboring a DGAT1 mutation and enriched the existing DGAT1 mutation database.

Keywords:  DGAT1 deficiency; congenital diarrhea; diacylglycerol acyltransferase 1 gene; diarrhea; growth retardation; hypoalbuminemia

DOI:  https://doi.org/10.3389/fped.2023.1253800
Heliyon. 2023 Oct;9(10): e20857

An infant with congenital micrognathia and upper airway obstruction was diagnosed as Hutchinson-Gilford progeria syndrome caused by a novel LMNA mutation: Case report and literature review.

Duojiao Xu, Yujiao Guo, Zhan Qi, Chanjuan Hao, Guoxia Yu.

  Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare disease characterized by appearance of premature aging, including the skin, bones, heart, and blood vessels caused by LMNA mutation. In this study, the patient presented with congenital micrognathia and progressively aggravated upper airway obstruction as the initial symptom, which required bilateral mandibular distraction osteogenesis (MDO) surgery intervention. This was not commonly described in the literature, and the primary clinical diagnosis of Pierre Robin sequence (PRS) was made. However, other clinical features included sclerotic skin, dry skin, growth failure, lipoatrophy, joint stiffness, prominent scalp veins, small ear lobes, hair loss, and craniofacial disproportion gradually emerged, the diagnosis of HGPS was preferred when the patient was 5 months old. The genetic testing result with a novel and de novo LMNA mutation (c.1968 + 3_1968+6delGAGT) further confirmed the diagnosis and expanded the clinical and mutational spectrum of HGPS. During the 12-month follow-up period after surgery, the patient no longer suffered dyspnea. Complications of other organs and systems have not happened at the moment. In addition, the pathogenesis, the role of LMNA gene mutation, the progress in clinical treatment, and breakthrough studies about genetic treatment in animals of HGPS are described in the literature review.

Keywords:  Congenital micrognathia; Dyspnea; Hutchinson-Gilford progeria syndrome; LMNA mutation; Mandibular distraction osteogenesis

DOI:  https://doi.org/10.1016/j.heliyon.2023.e20857
Front Cardiovasc Med. 2023 ;10 1272433

Real-world utilization of guideline-directed genetic testing in inherited cardiovascular diseases.

Mauro Longoni, Kanchan Bhasin, Andrew Ward, Donghyun Lee, McKenna Nisson, Sucheta Bhatt, Fatima Rodriguez, Rajesh Dash.

  Background: Cardiovascular disease continues to be the leading cause of death globally. Clinical practice guidelines aimed at improving disease management and positively impacting major cardiac adverse events recommend genetic testing for inherited cardiovascular conditions such as dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), long QT syndrome (LQTS), hereditary amyloidosis, and familial hypercholesterolemia (FH); however, little is known about how consistently practitioners order genetic testing for these conditions in routine clinical practice. This study aimed to assess the adoption of guideline-directed genetic testing for patients diagnosed with DCM, HCM, LQTS, hereditary amyloidosis, or FH.Methods: This retrospective cohort study captured real-world evidence of genetic testing from ICD-9-CM and ICD-10-CM codes, procedure codes, and structured text fields of de-identified patient records in the Veradigm Health Insights Ambulatory EHR Research Database linked with insurance claims data. Data analysis was conducted using an automated electronic health record analysis engine. Patient records in the Veradigm database were sourced from more than 250,000 clinicians serving over 170 million patients in outpatient primary care and specialty practice settings in the United States and linked insurance claims data from public and private insurance providers. The primary outcome measure was evidence of genetic testing within six months of condition diagnosis.
Results: Between January 1, 2017, and December 31, 2021, 224,641 patients were newly diagnosed with DCM, HCM, LQTS, hereditary amyloidosis, or FH and included in this study. Substantial genetic testing care gaps were identified. Only a small percentage of patients newly diagnosed with DCM (827/101,919; 0.8%), HCM (253/15,507; 1.6%), LQTS (650/56,539; 1.2%), hereditary amyloidosis (62/1,026; 6.0%), or FH (718/49,650; 1.5%) received genetic testing.
Conclusions: Genetic testing is underutilized across multiple inherited cardiovascular conditions. This real-world data analysis provides insights into the delivery of genomic healthcare in the United States and suggests genetic testing guidelines are rarely followed in practice.

Keywords:  cardiomyopathy; cardiovascular disease; familial hypercholesterolemia; genetic testing; hereditary amyloidosis; long QT syndrome; practice guidelines; real-world evidence

DOI:  https://doi.org/10.3389/fcvm.2023.1272433
Cell Prolif. 2023 Nov 02. e13573

Mitochondrial dysfunction is associated with hypertrophic cardiomyopathy in Pompe disease-specific induced pluripotent stem cell-derived cardiomyocytes.

Wenjun Huang, Rui Zhou, Congshan Jiang, Jie Wang, Yafei Zhou, Xiaoyan Xu, Tao Wang, Anmao Li, Yanmin Zhang.

Pompe disease (PD) is a rare autosomal recessive disorder that presents with progressive hypertrophic cardiomyopathy. However, the detailed mechanism remains clarified. Herein, PD patient-specific induced pluripotent stem cells were differentiated into cardiomyocytes (PD-iCMs) that exhibited cardiomyopathic features of PD, including decreased acid alpha-glucosidase activity, lysosomal glycogen accumulation and hypertrophy. The defective mitochondria were involved in the cardiac pathology as shown by the significantly decreased number of mitochondria and impaired respiratory function and ATP production in PD-iCMs, which was partially due to elevated levels of intracellular reactive oxygen species produced from depolarized mitochondria. Further analysis showed that impaired fusion and autophagy of mitochondria and declined expression of mitochondrial complexes underlies the mechanism of dysfunctional mitochondria. This was alleviated by supplementation with recombinant human acid alpha-glucosidase that improved the mitochondrial function and concomitantly mitigated the cardiac pathology. Therefore, this study suggests that defective mitochondria underlie the pathogenesis of cardiomyopathy in patients with PD.

DOI: https://doi.org/10.1111/cpr.13573