Active site variants in STT3A cause a dominant type I congenital disorder of glycosylation with neuromusculoskeletal findings.

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.

Glycosphingolipids in congenital disorders of glycosylation (CDG).

Congenital disorders of glycosylation (CDG) are a large family of rare disorders affecting the different glycosylation pathways. Defective glycosylation can affect any organ, with varying symptoms among the different CDG. Even between individuals with the same CDG there is quite variable severity. Associating specific symptoms to deficiencies of certain glycoproteins or glycolipids is thus a challenging task. In this review, we focus on the glycosphingolipid (GSL) synthesis pathway, which is still rather unexplored in the context of CDG, and outline the functions of the main GSLs, including gangliosides, and their role in the central nervous system. We provide an overview of GSL studies that have been performed in CDG and show that abnormal GSL levels are not only observed in CDG directly affecting GSL synthesis, but also in better known CDG, such as PMM2-CDG. We highlight the importance of studying GSLs in CDG in order to better understand the pathophysiology of these disorders.

Frontiers in congenital disorders of glycosylation consortium, a cross-sectional study report at year 5 of 280 individuals in the natural history cohort.

OBJECTIVE: Our report describes clinical, genetic, and biochemical features of participants with a molecularly confirmed congenital disorder of glycosylation (CDG) enrolled in the Frontiers in Congenital Disorders of Glycosylation (FCDGC) Natural History cohort at year 5 of the study. METHODS: We enrolled individuals with a known or suspected CDG into the FCDGC Natural History Study, a multicenter prospective and retrospective natural history study of all genetic causes of CDG. We conducted a cross-sectional analysis of baseline study visit data from participants with confirmed CDG who were consented into the FCDGC Natural History Study (5U54NS115198) from October 2019 to November 2023. RESULTS: Three hundred thirty-three subjects consented to the FCDGC Natural History Study. Of these, 280 unique individuals had genetic data available that was consistent with a diagnosis of CDG. These 280 individuals were enrolled into the study between October 8, 2019 and November 29, 2023. One hundred forty-one (50.4%) were female, and 139 (49.6%) were male. Mean and median age at enrollment was 10.1 and 6.5 years, respectively, with a range of 0.22 to 71.4 years. The cohort encompassed individuals with disorders of N-linked protein glycosylation (57%), glycosylphosphatidylinositol anchor disorder (GPI anchor) (15%), disorders of Golgi homeostasis, trafficking and transport (12%), dolichol metabolism disorders (5%), disorders of multiple pathways (6%), and other (5%). The most frequent presenting symptom(s) leading to diagnosis were developmental delay/disability (77%), followed by hypotonia (56%) and feeding difficulties (42%). Mean and median time between first related symptom and diagnosis was 2.7 and 0.8 years, respectively. One hundred percent of individuals in our cohort had developmental differences/disabilities at the time of their baseline visit, followed by 97% with neurologic involvement, 91% with gastrointestinal (GI)/liver involvement, and 88% with musculoskeletal involvement. Severity of disease in individuals was scored on the Nijmegen Progression CDG Rating Scale (NPCRS) with 27% of scores categorized as mild, 44% moderate, and 29% severe. Of the individuals with N-linked protein glycosylation defects, 83% of those with data showed a type 1 pattern on carbohydrate deficient transferrin (CDT) analysis including 82/84 individuals with PMM2-CDG, 6% a type 2 pattern, 1% both type 1 and type 2 pattern and 10% a normal or nonspecific pattern. One hundred percent of individuals with Golgi homeostasis and trafficking defects with data showed a type 2 pattern on CDT analysis, while Golgi transport defect showed a type II pattern 73% of the time, a type 1 pattern for 7%, and 20% had a normal or nonspecific pattern. Most of the variants documented were classified as pathogenic or likely pathogenic using ACMG criteria. For the majority of the variants, the predicted molecular consequence was missense followed by nonsense and splice site, and the majority of the diagnoses are inherited in an autosomal recessive pattern but with disorders of all major nuclear inheritance included. DISCUSSION: The FCDGC Natural History Study serves as an important resource to build future research studies, improve clinical care, and prepare for clinical trial readiness. Herein is the first overview of CDG participants of the FCDGC Natural History Study.

Single-cell RNA sequencing of cystic fibrosis liver disease explants reveals endothelial complement activation.

BACKGROUND & AIMS: Cystic fibrosis (CF) is considered a multisystemic disorder in which CF-associated liver disease (CFLD) is the third most common cause of mortality. Currently, no effective treatment is available for CFLD because its pathophysiology is still unclear. Interestingly, CFLD exhibits identical vascular characteristics as non-cirrhotic portal hypertension, recently classified as porto-sinusoidal vascular disorders (PSVD). METHODS: Since endothelial cells (ECs) are an important component in PSVD, we performed single-cell RNA sequencing (scRNA-seq) on four explant livers from CFLD patients to identify differential endothelial characteristics which could contribute to the disease. We comprehensively characterized the endothelial compartment and compared it with publicly available scRNA-seq datasets from cirrhotic and healthy livers. Key gene signatures were validated ex vivo on patient tissues. RESULTS: We found that ECs from CF liver explants are more closely related to healthy than cirrhotic patients. In CF patients we also discovered a distinct population of liver sinusoidal ECs-coined CF LSECs-upregulating genes involved in the complement cascade and coagulation. Finally, our immunostainings further validated the predominant periportal location of CF LSECs. CONCLUSIONS: Our work showed novel aspects of human liver ECs at the single-cell level thereby supporting endothelial involvement in CFLD, and reinforcing the hypothesis that ECs could be a driver of PSVD. Therefore, considering the vascular compartment in CF and CFLD may help developing new therapeutic approaches for these diseases.

Fractionated plasma N-glycan profiling of novel cohort of ATP6AP1-CDG subjects identifies phenotypic association.

ATP6AP1-CDG is an X-linked disorder typically characterized by hepatopathy, immunodeficiency, and an abnormal type II transferrin glycosylation pattern. Here, we present 11 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.

The Metabolic Map into the Pathomechanism and Treatment of PGM1-CDG.

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.

TRAPPC9-CDG: A novel congenital disorder of glycosylation with dysmorphic features and intellectual disability.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Sorbitol Is a Severity Biomarker for PMM2-CDG with Therapeutic Implications.

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.

Cystic fibrosis and alpha-1 antitrypsin deficiency: case report and review of literature.

BACKGROUND: This case report describes a child born with both cystic fibrosis (CF) and alpha-1 antitrypsin deficiency (A1ATD). Both are autosomal recessive inherited diseases, mainly affecting the lungs and the liver. The combination of both diseases together is rare and may lead to a fulminant disease with limited life span. To the best of our knowledge, no case has been reported of a patient born with both diseases. CASE PRESENTATION: After an uneventful pregnancy, a male baby was born with meconium ileus. The suspected diagnosis of CF was confirmed based on the sweat test and genetic analysis. The child developed persisting cholestasis, too severe to be likely caused by CF alone and indicating an associated problem. The diagnosis of A1ATD was established based on clinical suspicion (persisting cholestasis), decreased serum alpha-1 antitrypsin and genetic analysis. Supportive therapy was started, however the boy evolved to rapidly progressive liver disease leading to liver failure which necessitated an infant liver transplantation. CONCLUSIONS: This case illustrates the complexity of care in case of two severe inherited diseases as well as post solid organ transplant care.

Transcriptomic analysis of CFTR-impaired endothelial cells reveals a pro-inflammatory phenotype.

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 validated in vitro and in vivo in CFTR-knockout mice and ex vivo in 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.

Should patients with Phosphomannomutase 2-CDG (PMM2-CDG) be screened for adrenal insufficiency?

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.

Congenital Extrahepatic Portosystemic Shunts (Abernethy Malformation): An International Observational Study.

Congenital extrahepatic portosystemic shunt (CEPS) or Abernethy malformation is a rare condition in which splanchnic venous blood bypasses the liver draining directly into systemic circulation through a congenital shunt. Patients may develop hepatic encephalopathy (HE), pulmonary hypertension (PaHT), or liver tumors, among other complications. However, the actual incidence of such complications is unknown, mainly because of the lack of a protocolized approach to these patients. This study characterizes the clinical manifestations and outcome of a large cohort of CEPS patients with the aim of proposing a guide for their management. This is an observational, multicenter, international study. Sixty-six patients were included; median age at the end of follow-up was 30 years. Nineteen patients (28%) presented HE. Ten-, 20-, and 30-year HE incidence rates were 13%, 24%, and 28%, respectively. No clinical factors predicted HE. Twenty-five patients had benign nodular lesions. Ten patients developed adenomas (median age, 18 years), and another 8 developed HCC (median age, 39 years). Of 10 patients with dyspnea, PaHT was diagnosed in 8 and hepatopulmonary syndrome in 2. Pulmonary complications were only screened for in 19 asymptomatic patients, and PaHT was identified in 2. Six patients underwent liver transplantation for hepatocellular carcinoma or adenoma. Shunt closure was performed in 15 patients with improvement/stability/cure of CEPS manifestations. Conclusion: CEPS patients may develop severe complications. Screening for asymptomatic complications and close surveillance is needed. Shunt closure should be considered both as a therapeutic and prophylactic approach.

Expanding the phenotypic spectrum of FINCA (fibrosis, neurodegeneration, and cerebral angiomatosis) syndrome beyond infancy.

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.

International consensus guidelines for phosphoglucomutase 1 deficiency (PGM1-CDG): Diagnosis, follow-up, and management.

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.

Therapeutic approaches in Congenital Disorders of Glycosylation (CDG) involving N-linked glycosylation: an update.

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.

Clinical and biochemical improvement with galactose supplementation in SLC35A2-CDG.

PURPOSE: 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. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.

Efficacy and safety of D,L-3-hydroxybutyrate (D,L-3-HB) treatment in multiple acyl-CoA dehydrogenase deficiency.

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.

Normal liver stiffness and influencing factors in healthy children: An individual participant data meta-analysis.

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 < 3 years of age (younger group). Univariate and multivariate linear regression models predicting liver stiffness were conducted. RESULTS: After excluding children with obesity, diabetes, or abnormal liver tests, 652 children were analysed. Among older children, mean liver stiffness was 4.45 kPa (95% confidence interval 4.34-4.56), and increased liver stiffness was associated with age, sedation status, and S probe use. In the younger group, the mean liver stiffness was 4.79 kPa (95% confidence interval 4.46-5.12), and increased liver stiffness was associated with sedation status and Caucasian race. In a subgroup analysis, hepatic steatosis on ultrasound was significantly associated with increased liver stiffness. We define a reference range for normal liver stiffness in healthy children as 2.45-5.56 kPa. CONCLUSIONS: We have established TE-derived liver stiffness ranges for healthy children and propose an upper limit of liver stiffness in healthy children to be 5.56 kPa. We have identified increasing age, use of sedation, probe size, and presence of steatosis on ultrasound as factors that can significantly increase liver stiffness.

Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation.

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.

Fulminant Wilson Disease in Children: Recovery After Plasma Exchange Without Transplantation.

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.