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TRAPPC9 deficiency is an autosomal recessive disorder mainly associated with intellectual disability (ID), microcephaly, and obesity. Previously, TRAPPC9 deficiency has not been associated with biochemical abnormalities.Exome sequencing was performed in 3 individuals with ID and dysmorphic features. N-Glycosylation analyses were performed in the patients' blood samples to test for possible congenital disorder of glycosylation (CDG). TRAPPC9 gene, TRAPPC9 protein expression, and N-glycosylation markers were assessed in patient fibroblasts. Complementation with wild-type TRAPPC9 and immunofluorescence studies to assess TRAPPC9 expression and localization were performed. The metabolic consequences of TRAPPC9 deficiency were evaluated using tracer metabolomics.All 3 patients carried biallelic missense variants in TRAPPC9 and presented with an N-glycosylation defect in blood, consistent with CDG type I. Extensive investigations in patient fibroblasts corroborated TRAPPC9 deficiency and an N-glycosylation defect. Tracer metabolomics revealed global metabolic changes with several affected glycosylation-related metabolites.We identified 3 TRAPPC9 deficient patients presenting with ID, dysmorphic features, and abnormal glycosylation. On the basis of our findings, we propose that TRAPPC9 deficiency could lead to a CDG (TRAPPC9-CDG). The finding of abnormal glycosylation in these patients is highly relevant for diagnosis, further elucidation of the pathophysiology, and management of the disease.

ATP6AP1-CDG is an X-linked disorder typically characterized by hepatopathy, immunodeficiency and an abnormal type II transferrin glycosylation pattern. Here, we present eleven new patients and clinical updates with biochemical characterization on one previously reported patient. We also document intrafamilial phenotypic variability and atypical presentations, expanding the symptomatology of ATP6AP1-CDG to include dystonia, hepatocellular carcinoma, and lysosomal abnormalities on hepatic histology. Three of our subjects received successful liver transplantation. We performed N-glycan profiling of total and fractionated plasma proteins for six patients and show associations with varying phenotypes, demonstrating potential diagnostic and prognostic value of fractionated N-glycan profiles. The aberrant N-linked glycosylation in purified transferrin and remaining plasma glycoprotein fractions normalized in one patient post hepatic transplant, while the increases of Man4GlcNAc2 and Man5GlcNAc2 in purified immunoglobulins persisted. Interestingly, in the single patient with isolated immune deficiency phenotype, elevated high-mannose glycans were detected on purified immunoglobulins without glycosylation abnormalities on transferrin or the remaining plasma glycoprotein fractions. Given the diverse and often tissue specific clinical presentations and the need of clinical management post hepatic transplant in ATP6AP1-CDG patients, these results demonstrate that fractionated plasma N-glycan profiling could be a valuable tool in diagnosis and disease monitoring.

Congenital disorders of glycosylation (CDGs) form a group of rare diseases characterized by hypoglycosylation. We here report the identification of 16 individuals from nine families who have either inherited or de novo heterozygous missense variants in STT3A, leading to an autosomal-dominant CDG. STT3A encodes the catalytic subunit of the STT3A-containing oligosaccharyltransferase (OST) complex, essential for protein N-glycosylation. Affected individuals presented with variable skeletal anomalies, short stature, macrocephaly, and dysmorphic features; half had intellectual disability. Additional features included increased muscle tone and muscle cramps. Modeling of the variants in the 3D structure of the OST complex indicated that all variants are located in the catalytic site of STT3A, suggesting a direct mechanistic link to the transfer of oligosaccharides onto nascent glycoproteins. Indeed, expression of STT3A at mRNA and steady-state protein level in fibroblasts was normal, while glycosylation was abnormal. In S. cerevisiae, expression of STT3 containing variants homologous to those in affected individuals induced defective glycosylation of carboxypeptidase Y in a wild-type yeast strain and expression of the same mutants in the STT3 hypomorphic stt3-7 yeast strain worsened the already observed glycosylation defect. These data support a dominant pathomechanism underlying the glycosylation defect. Recessive mutations in STT3A have previously been described to lead to a CDG. We present here a dominant form of STT3A-CDG that, because of the presence of abnormal transferrin glycoforms, is unusual among dominant type I CDGs. ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:108 issue:11 pages:2130-2144 ispartof: location:United States status: published

OBJECTIVE: Epalrestat, an aldose reductase inhibitor increases phosphomannomutase (PMM) enzyme activity in a PMM2-congenital disorders of glycosylation (CDG) worm model. Epalrestat also decreases sorbitol level in diabetic neuropathy. We evaluated the genetic, biochemical, and clinical characteristics, including the Nijmegen Progression CDG Rating Scale (NPCRS), urine polyol levels and fibroblast glycoproteomics in patients with PMM2-CDG. METHODS: We performed PMM enzyme measurements, multiplexed proteomics, and glycoproteomics in PMM2-deficient fibroblasts before and after epalrestat treatment. Safety and efficacy of 0.8 mg/kg/day oral epalrestat were studied in a child with PMM2-CDG for 12 months. RESULTS: PMM enzyme activity increased post-epalrestat treatment. Compared with controls, 24% of glycopeptides had reduced abundance in PMM2-deficient fibroblasts, 46% of which improved upon treatment. Total protein N-glycosylation improved upon epalrestat treatment bringing overall glycosylation toward the control fibroblasts' glycosylation profile. Sorbitol levels were increased in the urine of 74% of patients with PMM2-CDG and correlated with the presence of peripheral neuropathy, and CDG severity rating scale. In the child with PMM2-CDG on epalrestat treatment, ataxia scores improved together with significant growth improvement. Urinary sorbitol levels nearly normalized in 3 months and blood transferrin glycosylation normalized in 6 months. INTERPRETATION: Epalrestat improved PMM enzyme activity, N-glycosylation, and glycosylation biomarkers in vitro. Leveraging cellular glycoproteome assessment, we provided a systems-level view of treatment efficacy and discovered potential novel biosignatures of therapy response. Epalrestat was well-tolerated and led to significant clinical improvements in the first pediatric patient with PMM2-CDG treated with epalrestat. We also propose urinary sorbitol as a novel biomarker for disease severity and treatment response in future clinical trials in PMM2-CDG. ANN NEUROL 20219999:n/a-n/a. ispartof: ANNALS OF NEUROLOGY vol:90 issue:6 pages:887-900 ispartof: location:United States status: published

Background: Heimler syndrome (OMIM number #234580 and #616617) is a rare condition comprising sensorineural hearing loss (SNHL), nail abnormalities and amelogenesis imperfecta. In addition, patients with this syndrome can have retinal dystrophies. Heimler syndrome is caused by bi-allelic pathogenic variants in the PEX1 or PEX6 gene. Only few patients with this syndrome have been reported. We hereby describe two siblings with genetically confirmed Heimler syndrome and provide imaging of the ocular phenotype.Materials and methods: The medical records of the siblings were reviewed retrospectively.Results: Both brother and sister were diagnosed with SNHL and amelogenesis imperfecta of the permanent teeth; one of the affected siblings also had nail abnormalities. Both patients presented to the ophthalmology department with suboptimal visual acuity, fundus abnormalities and intraretinal cystoid spaces. Full-field electroretinogram revealed a cone-rod dysfunction. A genetic analysis revealed a homozygous likely pathogenic variant c.3077 T > C (p.Leu1026Pro) in the PEX1 gene in both siblings. The parents are heterozygous carriers of the variant.Conclusion: We recommend performing regular ophthalmic examination in patients with Heimler syndrome since the ophthalmic manifestations can manifest later in life. Our patients presented with cone-rod dystrophy and intraretinal cystoid spaces. Review of the literature shows that the ocular phenotype can be very variable in patients with Heimler syndrome.

BACKGROUND & AIMS Although transient elastography (TE) is used to determine liver stiffness as a surrogate to hepatic fibrosis, the normal range in children is not well defined. We performed a systematic review and individual participant data (IPD) meta-analysis to determine the range of liver stiffness in healthy children and evaluate the influence of important biological parameters. METHODS We pooled data from 10 studies that examined healthy children using TE. We divided 1702 children into two groups: ≥3 years (older group) and

Inborn errors of metabolism (IEMs) are rare diseases caused by a defect in a single enzyme, co-factor, or transport protein. For most IEMs, no effective treatment is available and the exact disease mechanism is unknown. The application of metabolomics and, more specifically, tracer metabolomics in IEM research can help to elucidate these disease mechanisms and hence direct novel therapeutic interventions. In this review, we will describe the different approaches to metabolomics in IEM research. We will discuss the strengths and weaknesses of the different sample types that can be used (biofluids, tissues or cells from model organisms; modified cell lines; and patient fibroblasts) and when each of them is appropriate to use. ispartof: METABOLITES vol:12 issue:5 ispartof: location:Switzerland status: published

[Background]: Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited disorder resulting in extremely elevated low-density lipoprotein cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Current guidance about its management and prognosis stems from small studies, mostly from high-income countries. The objective of this study was to assess the clinical and genetic characteristics, as well as the impact, of current practice on health outcomes of HoFH patients globally., [Methods]: The HoFH International Clinical Collaborators registry collected data on patients with a clinical, or genetic, or both, diagnosis of HoFH using a retrospective cohort study design. This trial is registered with ClinicalTrials.gov, NCT04815005., [Findings]: Overall, 751 patients from 38 countries were included, with 565 (75%) reporting biallelic pathogenic variants. The median age of diagnosis was 12∙0 years (IQR 5∙5–27∙0) years. Of the 751 patients, 389 (52%) were female and 362 (48%) were male. Race was reported for 527 patients; 338 (64%) patients were White, 121 (23%) were Asian, and 68 (13%) were Black or mixed race. The major manifestations of ASCVD or aortic stenosis were already present in 65 (9%) of patients at diagnosis of HoFH. Globally, pretreatment LDL cholesterol levels were 14∙7 mmol/L (IQR 11∙6–18∙4). Among patients with detailed therapeutic information, 491 (92%) of 534 received statins, 342 (64%) of 534 received ezetimibe, and 243 (39%) of 621 received lipoprotein apheresis. On-treatment LDL cholesterol levels were lower in high-income countries (3∙93 mmol/L, IQR 2∙6–5∙8) versus non-highincome countries (9∙3 mmol/L, 6∙7–12∙7), with greater use of three or more lipid-lowering therapies (LLT; highincome 66% vs non-high-income 24%) and consequently more patients attaining guideline-recommended LDL cholesterol goals (high-income 21% vs non-high-income 3%). A first major adverse cardiovascular event occurred a decade earlier in non-high-income countries, at a median age of 24∙5 years (IQR 17∙0–34∙5) versus 37∙0 years (29∙0–49∙0) in high-income countries (adjusted hazard ratio 1∙64, 95% CI 1∙13–2∙38)., [Interpretation]: Worldwide, patients with HoFH are diagnosed too late, undertreated, and at high premature ASCVD risk. Greater use of multi-LLT regimens is associated with lower LDL cholesterol levels and better outcomes. Significant global disparities exist in treatment regimens, control of LDL cholesterol levels, and cardiovascular event-free survival, which demands a critical re-evaluation of global health policy to reduce inequalities and improve outcomes for all patients with HoFH., Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; and European Atherosclerosis Society

Pompe disease is a metabolic disorder caused by a deficiency of the glycogen-hydrolyzing lysosomal enzyme acid α-glucosidase (GAA), which leads to progressive muscle wasting. This autosomal-recessive disorder is the result of disease-associated variants located in the GAA gene. In the present study, we performed extended molecular diagnostic analysis to identify novel disease-associated variants in six suspected Pompe patients from four different families for which conventional diagnostic assays were insufficient. Additional assays, such as a generic-splicing assay, minigene analysis, SNP array analysis, and targeted Sanger sequencing, allowed the identification of an exonic deletion, a promoter deletion, and a novel splicing variant located in the 5' UTR. Furthermore, we describe the diagnostic process for an infantile patient with an atypical phenotype, consisting of left ventricular hypertrophy but no signs of muscle weakness or motor problems. This led to the identification of a genetic mosaicism for a very severe GAA variant caused by a segmental uniparental isodisomy (UPD). With this study, we aim to emphasize the need for additional analyses to detect new disease-associated GAA variants and non-Mendelian genotypes in Pompe disease where conventional DNA diagnostic assays are insufficient. ispartof: MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT vol:17 pages:337-348 ispartof: location:United States status: published

We studied galactose supplementation in SLC35A2-congenital disorder of glycosylation (SLC35A2-CDG), caused by monoallelic pathogenic variants in SLC35A2 (Xp11.23), encoding the endoplasmic reticulum (ER) and Golgi UDP-galactose transporter. Patients present with epileptic encephalopathy, developmental disability, growth deficiency, and dysmorphism. Ten patients with SLC35A2-CDG were supplemented with oral D-galactose for 18 weeks in escalating doses up to 1.5 g/kg/day. Outcome was assessed using the Nijmegen Pediatric CDG Rating Scale (NPCRS, ten patients) and by glycomics (eight patients). SLC35A2-CDG patients demonstrated improvements in overall Nijmegen Pediatric CDG Rating Scale (NPCRS) score (P = 0.008), the current clinical assessment (P = 0.007), and the system specific involvement (P = 0.042) domains. Improvements were primarily in growth and development with five patients resuming developmental progress, which included postural control, response to stimuli, and chewing and swallowing amelioration. Additionally, there were improvements in gastrointestinal symptoms and epilepsy. One patient in our study did not show any clinical improvement. Galactose supplementation improved patients’ glycosylation with decreased ratios of incompletely formed to fully formed glycans (M-gal/disialo, P = 0.012 and monosialo/disialo, P = 0.017) and increased levels of a fully galactosylated N-glycan (P = 0.05). Oral D-galactose supplementation results in clinical and biochemical improvement in SLC35A2-CDG. Galactose supplementation may partially overcome the Golgi UDP-galactose deficiency and improves galactosylation. Oral galactose is well tolerated and shows promise as dietary therapy.

BACKGROUND: Phosphomannomutase 2 deficiency (PMM2-CDG) is the most common congenital disorder of glycosylation (CDG). Hypoglycemia has been reported in various CDG including PMM2-CDG. The frequency and etiology of hypoglycemia in PMM2-CDG are not well studied. METHODS: We conducted a systematic review of the literature on genetically and/or biochemically confirmed PMM2-CDG patients who developed hypoglycemia. Prospective follow-up information on the patients who received diazoxide therapy was collected and evaluated. RESULTS: A total of 165 peer-reviewed articles reporting on 933 PMM2-CDG patients were assessed. Hypoglycemia was specifically mentioned only in 23 of these patients (2.5%). Hyperinsulinism was identified in 10 patients (43% of all hypoglycemic patients). Among these 10 patients, seven were successfully treated with diazoxide. However, most patients remained on therapy longer than a year to stay free of hypoglycemia. CONCLUSION: Hypoglycemia is a rarely reported finding in patients with PMM2-CDG. Diazoxide-responsive hyperinsulinism was found to have a good prognosis on medication in our PMM2-CDG patients with hypoglycemia. No genotype-phenotype correlation was observed with respect to hyperinsulinism. A prospective study should be undertaken to explore the hypothesis that hypoglycemia is underdiagnosed in PMM2-CDG and to evaluate whether hyperinsulinism is always associated with hypoglycemia. ispartof: JIMD Rep vol:51 issue:1 pages:76-81 ispartof: location:United States status: Published online

Vockley, Jerry/0000-0002-8180-6457; Zeybek, Ayse Cigdem Aktuglu/0000-0001-7256-0750; Vockley, Jerry/0000-0002-8180-6457; Oishi, Kimihiko/0000-0001-9446-8912; Derks, Terry/0000-0002-7259-1095 WOS:000507768800001 PubMed ID: 31904027 Purpose Multiple acyl-CoA dehydrogenase deficiency (MADD) is a life-threatening, ultrarare inborn error of metabolism. Case reports described successful D,L-3-hydroxybutyrate (D,L-3-HB) treatment in severely affected MADD patients, but systematic data on efficacy and safety is lacking. Methods A systematic literature review and an international, retrospective cohort study on clinical presentation, D,L-3-HB treatment method, and outcome in MADD(-like) patients. Results Our study summarizes 23 MADD(-like) patients, including 14 new cases. Median age at clinical onset was two months (interquartile range [IQR]: 8 months). Median age at starting D,L-3-HB was seven months (IQR: 4.5 years). D,L-3-HB doses ranged between 100 and 2600 mg/kg/day. Clinical improvement was reported in 16 patients (70%) for cardiomyopathy, leukodystrophy, liver symptoms, muscle symptoms, and/or respiratory failure. D,L-3-HB appeared not effective for neuropathy. Survival appeared longer upon D,L-3-HB compared with historical controls. Median time until first clinical improvement was one month, and ranged up to six months. Reported side effects included abdominal pain, constipation, dehydration, diarrhea, and vomiting/nausea. Median D,L-3-HB treatment duration was two years (IQR: 6 years). D,L-3-HB treatment was discontinued in 12 patients (52%). Conclusion The strength of the current study is the international pooling of data demonstrating that D,L-3-HB treatment can be effective and safe in MADD(-like) patients. Junior Scientific Masterclass from the University of Groningen, University Medical Center Groningen [MD/PhD 15-30, MD/PhD 18-55]; National Institutes of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01-DK78755] The authors thank Katinka A.M. Mulder, legal advisor-research contracts, for her contribution to the realization of the consortium agreement. Pharmaceutical industries did not play any role in this study. The MD/PhD scholarships of W.J.v.R. and E.A.J. are funded by the Junior Scientific Masterclass from the University of Groningen, University Medical Center Groningen (MD/PhD 15-30, MD/PhD 18-55, respectively). J.V. is supported in part by National Institutes of Health (NIH) grant R01-DK78755. The sources of funding had no involvement in the study design; data collection, analysis, and interpretation; reporting of the results; or in the decision to submit the paper for publication.

PMM2-CDG is a rare disease, causing hypoglycosylation of multiple proteins, hence preventing full functionality. So far, no direct genotype-phenotype correlations have been identified. We carried out a retrospective cohort study on 26 PMM2-CDG patients. We collected the identified genotype, as well as continuous variables indicating the disease severity (based on Nijmegen Pediatric CDG Rating Score or NPCRS) and dichotomous variables reflecting the patients' phenotype. The phenotypic effects of patients' genotype were studied using non-parametric and Chi-Square tests. Seventeen different pathogenic variants have been studied. Variants with zero enzyme activity had no significant impact on the Nijmegen score. Pathogenic variants involving the stabilization/folding domain have a significantly lower total NPCRS (p = 0.017): presence of the p.Cys241Ser mutation had a significantly lower subscore 1,3 and NPCRS (p = 0.04) and thus result in a less severe phenotype. On the other hand, variants involving the dimerization domain, p.Pro113Leu and p.Phe119Leu, resulted in a significantly higher NPCRS score (p = 0.002), which indicates a worse clinical course. These concepts give a better insight in the phenotypic prognosis of PMM2-CDG, according to their molecular base. ispartof: GENES vol:12 issue:11 ispartof: location:Switzerland status: published

Fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA, MIM#618278) is a rare clinical condition caused by bi-allelic variants in NHL repeat containing protein 2 (NHLRC2, MIM*618277). Pulmonary disease may be the presenting sign and the few patients reported so far, all deceased in early infancy. Exome sequencing was performed on patients with childhood interstitial lung disease (chILD) and additional neurological features. The chILD-EU register database and an in-house database were searched for patients with NHLRC2 variants and clinical features overlapping FINCA syndrome. Six patients from three families were identified with bi-allelic variants in NHLRC2. Two of these children died before the age of two while four others survived until childhood. Interstitial lung disease was pronounced in almost all patients during infancy and stabilized over the course of the disease with neurodevelopmental delay (NDD) evolving as the key clinical finding. We expand the phenotype of FINCA syndrome to a multisystem disorder with variable severity. FINCA syndrome should also be considered in patients beyond infancy with NDD and a history of distinct interstitial lung disease. Managing patients in registers for rare diseases helps identifying new diagnostic entities and advancing care for these patients. ispartof: CLINICAL GENETICS vol:100 issue:4 pages:453-461 ispartof: location:Denmark status: published

International audience; The mesenchymal conversion of epithelial cells (EMT) has been suggested as a potential contributor in cystic fibrosis (CF) disease progression. Endothelial cells (EndCs), the cells lining blood vessels, express functional CFTR and CFTR impairment promotes endothelial activation and dysfunction. However, if the mesenchymal switch also exists in CF EndCs remains uncharacterized. To understand whether the endothelial-to-mesenchymal transition (EndMT) could occur in CF, we have conducted a transcriptomic meta-analysis of primary CFTR-impaired and patient-derived EndCs, and further compared our results to data from CF epithelial cells (EpCs) where EMT has been demonstrated. As compared to EpCs, we show that CFTR-impaired EndCs display a limited signature of EndMT, and that expression of the mesenchymal inducer Twist1 remained unchanged. Nonetheless, the use of CFTR modulators reduced the expression of mesenchymal markers from CF patient-derived EndCs, suggesting an additional therapeutic added-value next to the known effect on CFTR ion transport.

PMM2-CDG is the most common congenital disorder of glycosylation (CDG), which presents with either a neurologic or multisystem phenotype. Little is known about the longitudinal evolution. We performed data analysis on PMM2-CDG patients’ clinical features according to the Nijmegen CDG severity score and laboratory data. Seventy-five patients (28 males) were followed up from 11.0 ± 6.91 years for an average of 7.4 ± 4.5 years. On a group level, there was no significant evolution in overall clinical severity. There was some improvement in mobility and communication, liver and endocrine function, and strabismus and eye movements. Educational achievement and thyroid function worsened in some patients. Overall, the current clinical function, the system-specific involvement, and the current clinical assessment remained unchanged. On follow-up there was improvement of biochemical variables with (near) normalization of activated partial thromboplastin time (aPTT), factor XI, protein C, antithrombin, thyroid stimulating hormone, and liver transaminases. PMM2-CDG patients show a spontaneous biochemical improvement and stable clinical course based on the Nijmegen CDG severity score. This information is crucial for the definition of endpoints in clinical trials.

Phosphoglucomutase 1 (PGM1) encodes the metabolic enzyme that interconverts glucose-6-P and glucose-1-P. Mutations in PGM1 cause impairment in glycogen metabolism and glycosylation, the latter manifesting as a congenital disorder of glycosylation (CDG). This unique metabolic defect leads to abnormal N-glycan synthesis in the endoplasmic reticulum (ER) and the Golgi apparatus (GA). On the basis of the decreased galactosylation in glycan chains, galactose was administered to individuals with PGM1-CDG and was shown to markedly reverse most disease-related laboratory abnormalities. The disease and treatment mechanisms, however, have remained largely elusive. Here, we confirm the clinical benefit of galactose supplementation in PGM1-CDG-affected individuals and obtain significant insights into the functional and biochemical regulation of glycosylation. We report here that, by using tracer-based metabolomics, we found that galactose treatment of PGM1-CDG fibroblasts metabolically re-wires their sugar metabolism, and as such replenishes the depleted levels of galactose-1-P, as well as the levels of UDP-glucose and UDP-galactose, the nucleotide sugars that are required for ER- and GA-linked glycosylation, respectively. To this end, we further show that the galactose in UDP-galactose is incorporated into mature, de novo glycans. Our results also allude to the potential of monosaccharide therapy for several other CDG. ispartof: American Journal of Human Genetics vol:104 issue:5 pages:835-846 ispartof: location:United States status: Published online

A recent report on long-term dietary mannose supplementation in phosphomannomutase 2 deficiency (PMM2-CDG) claimed improved glycosylation and called for double-blind randomized study of the dietary supplement in PMM2-CDG patients. A lack of efficacy of short-term mannose supplementation in multiple prior reports challenge this study’s conclusions. Additionally, some CDG types have previously been reported to demonstrate spontaneous improvement in glycosylated biomarkers, including transferrin. We have likewise observed improvements in transferrin glycosylation without mannose supplementation. This observation questions the reliability of transferrin as a therapeutic outcome measure in clinical trials for PMM2-CDG. We are concerned that renewed focus on mannose therapy in PMM2-CDG will detract from clinical trials of more promising therapies. Approaches to increase efficiency of clinical trials and ultimately improve patients’ lives requires prospective natural history studies and identification of reliable biomarkers linked to clinical outcomes in CDG. Collaborations with patients and families are essential to identifying meaningful study outcomes. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-021-01751-2.

PMM2-CDG is the most prevalent congenital disorder of glycosylation (CDG) with only symptomatic therapy. Some CDG have been successfully treated with D-galactose. We performed an open-label pilot trial with D-galactose in 9 PMM2-CDG patients. Overall, there was no significant improvement but some milder patients did show positive clinical changes; also there was a trend toward improved glycosylation. Larger placebo-controlled studies are required to determine whether D-galactose could be used as supportive treatment in PMM2-CDG patients.Trial registration ClinicalTrials.gov Identifier: NCT02955264. Registered 4 November 2016, https://clinicaltrials.gov/ct2/show/NCT02955264

PMM2-CDG is the most common congenital disorder of glycosylation (CDG) accounting for almost 65% of known CDG cases affecting N-glycosylation. Abnormalities in N-glycosylation could have a negative impact on many endocrine axes. There is very little known on the effect of impaired N-glycosylation on the hypothalamic-pituitary-adrenal axis function and whether CDG patients are at risk of secondary adrenal insufficiency and decreased adrenal cortisol production. Cortisol and ACTH concentrations were simultaneously measured between 7:44 am to 1 pm in forty-three subjects (20 female, median age 12.8 years, range 0.1 to 48.6 years) participating in an ongoing international, multi-center Natural History study for PMM2-CDG (ClinicalTrials.gov Identifier: NCT03173300). Of the 43 subjects, 11 (25.6%) had cortisol below 5 μg/dl and low to normal ACTH levels, suggestive of secondary adrenal insufficiency. Two of the 11 subjects have confirmed central adrenal insufficiency and are on hydrocortisone replacement and/or stress dosing during illness; 3 had normal and 1 had subnormal cortisol response to ACTH low-dose stimulation test but has not yet been started on therapy; the remaining 5 have upcoming stimulation testing planned. Our findings suggest that patients with PMM2-CDG may be at risk for adrenal insufficiency. Monitoring of morning cortisol and ACTH levels should be part of the standard care in patients with PMM2-CDG. ispartof: MOLECULAR GENETICS AND METABOLISM vol:133 issue:4 pages:397-399 ispartof: location:United States status: published

Atigny et al. raise interesting points in the transcriptomic analysis of CFTR-impaired endothelial cells (ECs) revealing a pro-inflammatory phenotype [1]. Indeed, CFTR impairment in different endothelial models and organisms, and in the absence of concomitant infection, suggests that ECs are an overlooked mediator in the exaggerated pro-inflammatory phenotype observed in cystic fibrosis (CF). Whether endothelial CFTR is involved in other vascular diseases is an intriguing question. Indeed, a recent report indicates a pivotal role of CFTR in pulmonary arterial hypertension (PAH) [2]. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. TREPS has nothing to disclose. Conflict of interest: Siham BOUSFIA has nothing to disclose. Conflict of interest: Dr. Carmeliet has nothing to disclose. Conflict of interest: Dr. Witters has nothing to disclose.

Phosphoglucomutase 1 (PGM1) deficiency is a rare genetic disorder that affects glycogen metabolism, glycolysis, and protein glycosylation. Previously known as GSD XIV, it was recently reclassified as a congenital disorder of glycosylation, PGM1-CDG. PGM1-CDG usually manifests as a multisystem disease. Most patients present as infants with cleft palate, liver function abnormalities and hypoglycemia, but some patients present in adulthood with isolated muscle involvement. Some patients develop life-threatening cardiomyopathy. Unlike most other CDG, PGM1-CDG has an effective treatment option, d-galactose, which has been shown to improve many of the patients' symptoms. Therefore, early diagnosis and initiation of treatment for PGM1-CDG patients are crucial decisions. In this article, our group of international experts suggests diagnostic, follow-up, and management guidelines for PGM1-CDG. These guidelines are based on the best available evidence-based data and experts' opinions aiming to provide a practical resource for health care providers to facilitate successful diagnosis and optimal management of PGM1-CDG patients. ispartof: Journal Of Inherited Metabolic Disease vol:s44 issue:1 pages:148-163 ispartof: location:United States status: published

OBJECTIVES: Since 2005, a New Wilson Index (NWI) ≥11 is used as a predictor of death without transplantation in fulminant Wilson disease (WD). Plasma exchange is advocated as a new treatment modality. METHODS: We present a patient with fulminant WD treated with plasma exchange. All published cases applying plasma exchange for fulminant WD were reviewed systematically. RESULTS: A 14-year-old girl presented with hemolysis and fulminant liver failure. She had no encephalopathy; NWI was 14. As a bridge to transplantation plasma exchange was started immediately. Complete remission was achieved with plasma exchange and later chelation therapy with D-penicillamine. She is now at 3-year transplant-free survival. Literature review identified 37 patients presenting with fulminant WD and NWI ≥11 who were treated with plasma exchange. Seventeen of these patients (ie, 46%) recovered without transplantation. CONCLUSIONS: Multiple case reports and case series demonstrate transplant free survival after plasma exchange and subsequent chelation therapy, despite a NWI ≥11. Plasma exchange affects the clinical course and is a therapeutic option in children and young adults presenting with fulminant WD. ispartof: JOURNAL OF PEDIATRIC GASTROENTEROLOGY AND NUTRITION vol:71 issue:6 pages:720-725 ispartof: location:United States status: published

Cystic fibrosis (CF) is a life-threatening disorder characterised by decreased pulmonary mucociliary and pathogen clearance, and an exaggerated inflammatory response leading to progressive lung damage. CF is caused by bi-allelic pathogenic variants of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a chloride channel. CFTR is expressed in endothelial cells (ECs) and EC dysfunction has been reported in CF patients, but a role for this ion channel in ECs regarding CF disease progression is poorly described.We used an unbiased RNA sequencing approach in complementary models of CFTR silencing and blockade (by the CFTR inhibitor CFTRinh-172) in human ECs to characterise the changes upon CFTR impairment. Key findings were further validatedin vitroandin vivoin CFTR-knockout mice andex vivoin CF patient-derived ECs.Both models of CFTR impairment revealed that EC proliferation, migration and autophagy were downregulated. Remarkably though, defective CFTR function led to EC activation and a persisting pro-inflammatory state of the endothelium with increased leukocyte adhesion. Further validation in CFTR-knockout mice revealed enhanced leukocyte extravasation in lung and liver parenchyma associated with increased levels of EC activation markers. In addition, CF patient-derived ECs displayed increased EC activation markers and leukocyte adhesion, which was partially rescued by the CFTR modulators VX-770 and VX-809.Our integrated analysis thus suggests that ECs are no innocent bystanders in CF pathology, but rather may contribute to the exaggerated inflammatory phenotype, raising the question of whether normalisation of vascular inflammation might be a novel therapeutic strategy to ameliorate the disease severity of CF.

Mannose phosphate isomerase-congenital disorder of glycosylation (MPI-CDG) deficiency is a rare subtype of congenital disorders of protein N-glycosylation. It is characterised by deficiency of MPI caused by pathogenic variants in MPI gene. The manifestation of MPI-CDG is different from other CDGs as the patients suffer dominantly from gastrointestinal and hepatic involvement whereas they usually do not present intellectual disability or neurological impairment. It is also one of the few treatable subtypes of CDGs with proven effect of oral mannose. This article covers a complex review of the literature and recommendations for the management of MPI-CDG with an emphasis on the clinical aspect of the disease. A team of international experts elaborated summaries and recommendations for diagnostics, differential diagnosis, management, and treatment of each system/organ involvement based on evidence-based data and experts' opinions. Those guidelines also reveal more questions about MPI-CDG which need to be further studied.

Background: Most patients with cystic fibrosis (CF) suffer from pancreatic insufficiency (PI), leading to fat malabsorption, malnutrition, abdominal discomfort and impaired growth. Pancreatic enzyme replacement therapy (PERT) is effective, but evidence based guidelines for dose adjustment are lacking. A mobile app for self-management of PERT was developed in the context of the HORIZON 2020 project MyCyFAPP. It contains an algorithm to calculate individual PERT-doses for optimal fat digestion, based on in vitro and in vivo studies carried out in the same project. In addition, the app includes a symptoms diary, educational material, and it is linked to a web tool allowing health care professionals to evaluate patient's data and provide feedback. Methods: A 6-month open label prospective multicenter interventional clinical trial was performed to assess effects of using the app on gastro-intestinal related quality of life (GI QOL), measured by the CF-PedsQL-GI (shortened, CF specific version of the Pediatric Quality of Life Inventory, Gastrointestinal Symptoms Module). Results: One hundred and seventy-one patients with CF and PI between 2 and 18 years were recruited at 6 European CF centers. Self-reported CF-PedsQL-GI improved significantly from month 0 (M0) (84.3, 76.4-90.3) to month 6 (M6) (89.4, 80.35-93.5) (p

Congenital disorders of glycosylation (CDG) are a group of clinically and genetically heterogeneous metabolic disorders. Over 150 CDG types have been described. Most CDG types are ultrarare disorders. CDG types affecting N-glycosylation are the most common type of CDG with emerging therapeutic possibilities. This review is an update on the available therapies for disorders affecting the N-linked glycosylation pathway. In the first part of the review, we highlight the clinical presentation, general principles of management, and disease-specific therapies for N-linked glycosylation CDG types, organized by organ system. The second part of the review focuses on the therapeutic strategies currently available and under development. We summarize the successful (pre-) clinical application of nutritional therapies, transplantation, activated sugars, gene therapy, and pharmacological chaperones and outline the anticipated expansion of the therapeutic possibilities in CDG. We aim to provide a comprehensive update on the treatable aspects of CDG types involving N-linked glycosylation, with particular emphasis on disease-specific treatment options for the involved organ systems; call for natural history studies; and present current and future therapeutic strategies for CDG.

Pompe disease is a metabolic disorder caused by a deficiency of the glycogen-hydrolyzing lysosomal enzyme acid α-glucosidase (GAA), which leads to progressive muscle wasting. This autosomal-recessive disorder is the result of disease-associated variants located in the GAA gene. In the present study, we performed extended molecular diagnostic analysis to identify novel disease-associated variants in six suspected Pompe patients from four different families for which conventional diagnostic assays were insufficient. Additional assays, such as a generic-splicing assay, minigene analysis, SNP array analysis, and targeted Sanger sequencing, allowed the identification of an exonic deletion, a promoter deletion, and a novel splicing variant located in the 5′ UTR. Furthermore, we describe the diagnostic process for an infantile patient with an atypical phenotype, consisting of left ventricular hypertrophy but no signs of muscle weakness or motor problems. This led to the identification of a genetic mosaicism for a very severe GAA variant caused by a segmental uniparental isodisomy (UPD). With this study, we aim to emphasize the need for additional analyses to detect new disease-associated GAA variants and non-Mendelian genotypes in Pompe disease where conventional DNA diagnostic assays are insufficient.

Background Autosomal recessive polycystic kidney disease (ARPKD) with congenital hepatic fibrosis (CHF) causes portal hypertension and its complications. A transjugular intrahepatic portosystemic shunt (TIPSS) could serve as a symptomatic treatment for portal hypertension-related symptoms in these children. Aims To study the effect of TIPSS on portal hypertension, liver and kidney function and the long term complications. Materials and methods We report on 5 children with CHF treated with a TIPSS to manage severe portal hypertension related symptoms. Results Mean follow-up time was 7 years and 2 months. At the end of follow-up there was a reduction of spleen size (p = 0.715) and hypersplenism with a rise in platelet count (p = 0.465). Esophageal varices and ascites disappeared in all patients. Liver and kidney function remained stable. In two patients endotipsitis was suspected and two patients developed an in-stent stenosis. There was no sign of encephalopathy in our patients. Conclusion TIPSS using ePTFE-covered stent is a feasible and effective alternative for surgical portosystemic shunting in children with CHF, also on the long term. It can postpone the need of a liver transplantation but close monitoring remains important for early diagnosis of endotipsitis or stent dysfunction related to stenosis.