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Glucose-6-phosphatase deficiency (G6P deficiency), or glycogen storage disease type I (GSDI), is a group of inherited metabolic diseases, including types Ia and Ib, characterized by poor tolerance to fasting, growth retardation and hepatomegaly resulting from accumulation of glycogen and fat in the liver. Prevalence is unknown and annual incidence is around 1/100,000 births. GSDIa is the more frequent type, representing about 80% of GSDI patients. The disease commonly manifests, between the ages of 3 to 4 months by symptoms of hypoglycemia (tremors, seizures, cyanosis, apnea). Patients have poor tolerance to fasting, marked hepatomegaly, growth retardation (small stature and delayed puberty), generally improved by an appropriate diet, osteopenia and sometimes osteoporosis, full-cheeked round face, enlarged kydneys and platelet dysfunctions leading to frequent epistaxis. In addition, in GSDIb, neutropenia and neutrophil dysfunction are responsible for tendency towards infections, relapsing aphtous gingivostomatitis, and inflammatory bowel disease. Late complications are hepatic (adenomas with rare but possible transformation into hepatocarcinoma) and renal (glomerular hyperfiltration leading to proteinuria and sometimes to renal insufficiency). GSDI is caused by a dysfunction in the G6P system, a key step in the regulation of glycemia. The deficit concerns the catalytic subunit G6P-alpha (type Ia) which is restricted to expression in the liver, kidney and intestine, or the ubiquitously expressed G6P transporter (type Ib). Mutations in the genes G6PC (17q21) and SLC37A4 (11q23) respectively cause GSDIa and Ib. Many mutations have been identified in both genes,. Transmission is autosomal recessive. Diagnosis is based on clinical presentation, on abnormal basal values and absence of hyperglycemic response to glucagon. It can be confirmed by demonstrating a deficient activity of a G6P system component in a liver biopsy. To date, the diagnosis is most commonly confirmed by G6PC (GSDIa) or SLC37A4 (GSDIb) gene analysis, and the indications of liver biopsy to measure G6P activity are getting rarer and rarer. Differential diagnoses include the other GSDs, in particular type III (see this term). However, in GSDIII, glycemia and lactacidemia are high after a meal and low after a fast period (often with a later occurrence than that of type I). Primary liver tumors and Pepper syndrome (hepatic metastases of neuroblastoma) may be evoked but are easily ruled out through clinical and ultrasound data. Antenatal diagnosis is possible through molecular analysis of amniocytes or chorionic villous cells. Pre-implantatory genetic diagnosis may also be discussed. Genetic counseling should be offered to patients and their families. The dietary treatment aims at avoiding hypoglycemia (frequent meals, nocturnal enteral feeding through a nasogastric tube, and later oral addition of uncooked starch) and acidosis (restricted fructose and galactose intake). Liver transplantation, performed on the basis of poor metabolic control and/or hepatocarcinoma, corrects hypoglycemia, but renal involvement may continue to progress and neutropenia is not always corrected in type Ib. Kidney transplantation can be performed in case of severe renal insufficiency. Combined liver-kidney grafts have been performed in a few cases. Prognosis is usually good: late hepatic and renal complications may occur, however, with adapted management, patients have almost normal life span. Disease name and synonyms Glucose-6-phosphatase deficiency or G6P deficiency or glycogen storage disease type I or GSDI or type I glycogenosis or Von Gierke disease or Hepatorenal glycogenosis.

Classical galactosemia (CG) is an inborn error of galactose metabolism. Evidence-based guidelines for the treatment and follow-up of CG are currently lacking, and treatment and follow-up have been demonstrated to vary worldwide. To provide patients around the world the same state-of-the-art in care, members of The Galactosemia Network (GalNet) developed an evidence-based and internationally applicable guideline for the diagnosis, treatment, and follow-up of CG. The guideline was developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. A systematic review of the literature was performed, after key questions were formulated during an initial GalNet meeting. The first author and one of the working group experts conducted data-extraction. All experts were involved in data-extraction. Quality of the body of evidence was evaluated and recommendations were formulated. Whenever possible recommendations were evidence-based, if not they were based on expert opinion. Consensus was reached by multiple conference calls, consensus rounds via e-mail and a final consensus meeting. Recommendations addressing diagnosis, dietary treatment, biochemical monitoring, and follow-up of clinical complications were formulated. For all recommendations but one, full consensus was reached. A 93 % consensus was reached on the recommendation addressing age at start of bone density screening. During the development of this guideline, gaps of knowledge were identified in most fields of interest, foremost in the fields of treatment and follow-up.

Glycogen storage disease type III (GSDIII) is a rare disorder of glycogenolysis due to AGL gene mutations, causing glycogen debranching enzyme deficiency and storage of limited dextrin. Patients with GSDIIIa show involvement of liver and cardiac/skeletal muscle, whereas GSDIIIb patients display only liver symptoms and signs. The International Study on Glycogen Storage Disease (ISGSDIII) is a descriptive retrospective, international, multi-centre cohort study of diagnosis, genotype, management, clinical course and outcome of 175 patients from 147 families (86 % GSDIIIa; 14 % GSDIIIb), with follow-up into adulthood in 91 patients. In total 58 AGL mutations (non-missense mutations were overrepresented and 21 novel mutations were observed) were identified in 76 families. GSDIII patients first presented before the age of 1.5 years, hepatomegaly was the most common presenting clinical sign. Dietary management was very diverse and included frequent meals, uncooked cornstarch and continuous gastric drip feeding. Chronic complications involved the liver (hepatic cirrhosis, adenoma(s), and/or hepatocellular carcinoma in 11 %), heart (cardiac involvement and cardiomyopathy, in 58 % and 15 %, respectively, generally presenting in early childhood), and muscle (pain in 34 %). Type 2 diabetes mellitus was diagnosed in eight out of 91 adult patients (9 %). In adult patients no significant correlation was detected between (non-) missense AGL genotypes and hepatic, cardiac or muscular complications. This study demonstrates heterogeneity in a large cohort of ageing GSDIII patients. An international GSD patient registry is warranted to prospectively define the clinical course, heterogeneity and the effect of different dietary interventions in patients with GSDIII.

Galactokinase (GALK1) deficiency is a rare hereditary galactose metabolism disorder. Beyond cataract, the phenotypic spectrum is questionable. Data from affected patients included in the Galactosemias Network registry were collected to better characterize the phenotype. Observational study collecting medical data of 53 not previously reported GALK1 deficient patients from 17 centers in 11 countries from December 2014 to April 2020. Neonatal or childhood cataract was reported in 15 and 4 patients respectively. The occurrence of neonatal hypoglycemia and infection were comparable with the general population, whereas bleeding diathesis (8.1% versus 2.17–5.9%) and encephalopathy (3.9% versus 0.3%) were reported more often. Elevated transaminases were seen in 25.5%. Cognitive delay was reported in 5 patients. Urinary galactitol was elevated in all patients at diagnosis; five showed unexpected Gal-1-P increase. Most patients showed enzyme activities ≤1%. Eleven different genotypes were described, including six unpublished variants. The majority was homozygous for NM_000154.1:c.82C>A (p.Pro28Thr). Thirty-five patients were diagnosed following newborn screening, which was clearly beneficial. The phenotype of GALK1 deficiency may include neonatal elevation of transaminases, bleeding diathesis, and encephalopathy in addition to cataract. Potential complications beyond the neonatal period are not systematically surveyed and a better delineation is needed.

Glycogen storage disease type Ia (GSDIa) is caused by defective glucose-6-phosphatase, a key enzyme in carbohydrate metabolism. Affected individuals cannot release glucose during fasting and accumulate excess glycogen and fat in the liver and kidney, putting them at risk of severe hypoglycaemia and secondary metabolic perturbations. Good glycaemic/metabolic control through strict dietary treatment and regular doses of uncooked cornstarch (UCCS) is essential for preventing hypoglycaemia and long-term complications. Dietary treatment has improved the prognosis for patients with GSDIa; however, the disease itself, its management and monitoring have significant physical, psychological and psychosocial burden on individuals and parents/caregivers. Hypoglycaemia risk persists if a single dose of UCCS is delayed/missed or in cases of gastrointestinal intolerance. UCCS therapy is imprecise, does not treat the cause of disease, may trigger secondary metabolic manifestations and may not prevent long-term complications. We review the importance of and challenges associated with achieving good glycaemic/metabolic control in individuals with GSDIa and how this should be balanced with age-specific psychosocial development towards independence, management of anxiety and preservation of quality of life (QoL). The unmet need for treatment strategies that address the cause of disease, restore glucose homeostasis, reduce the risk of hypoglycaemia/secondary metabolic perturbations and improve QoL is also discussed.

The aim of the Protocole National De Diagnostic et de Soins/ French National Protocol for Diagnosis and Healthcare (PNDS) is to provide advice for health professionals on the optimum care provision and pathway for patients with glycogen storage disease type III (GSD III).The protocol aims at providing tools that make the diagnosis, defining the severity and different damages of the disease by detailing tests and explorations required for monitoring and diagnosis, better understanding the different aspects of the treatment, defining the modalities and organisation of the monitoring. This is a practical tool, to which health care professionals can refer. PNDS cannot, however, predict all specific cases, comorbidities, therapeutic particularities or hospital care protocols, and does not seek to serve as a substitute for the individual responsibility of the physician in front of his/her patient.

Background The COVID-19 pandemic presented unique challenges for patients with inherited metabolic diseases (IMDs), particularly due to the risk of infection-related metabolic decompensation and disruptions to specialized care. We aimed to assess the impact of COVID-19 infection on the clinical course of patients with IMDs in a National Multicenter Study from the French IMDs Healthcare Network for Rare Diseases. Results This national French study included 317 IMD patients (69 children and 248 adults) with symptomatic or asymptomatic COVID-19 infection between January 2020 and January 2023. Most COVID-19 cases were mild to moderate. The frequency of symptomatic COVID-19 was similar in adults and children (234/248 [94.3%] vs. 56/64 [87.5%], p  = 0.09). Children experienced more frequently metabolic destabilization than adults during a COVID-19 infection (17/67 [25.4%] vs. 33/248 [13.3%], p  = 0.03). Moreover, the proportion of children admitted to the ICU was higher than that of adult patients (5/69 [7.2%] vs. 4/248 [1.6%], p  = 0.04). Temporary suspension or delay of IMD-specific treatment due to COVID-19 was rare, affecting 3/64 (4.7%) children and 13/229 (5.7%) adults. Severe COVID-19 outcomes were uncommon, with only one death in the adult cohort and five cases of long-term sequelae (1 child, 4 adults). Conclusions COVID-19 was generally mild to moderate in IMD patients and caused metabolic decompensation or imbalance in a minority of cases, with only rare interruptions to disease-specific treatment. We observed that COVID-19 more frequently worsened the condition of children with IMD compared to adults in our cohort of patients.

Glycogen storage disorder type III (GSDIII), or debranching enzyme (GDE) deficiency, is a rare metabolic disorder characterized by variable liver, cardiac, and skeletal muscle involvement. GSDIII manifests with liver symptoms in infancy and muscle involvement during early adulthood. Muscle biopsy is mainly performed in patients diagnosed in adulthood, as routine diagnosis relies on blood or liver GDE analysis, followed by AGL gene sequencing. The GSDIII mouse model recapitulate the clinical phenotype in humans, and a nearly full rescue of muscle function was observed in mice treated with the dual AAV vector expressing the GDE transgene. In order to characterize GSDIII muscle morphological spectrum and identify novel disease markers and pathways, we performed a large international multicentric morphological study on 30 muscle biopsies from GSDIII patients. Autophagy flux studies were performed in human muscle biopsies and muscles from GSDIII mice. The human muscle biopsies revealed a typical and constant vacuolar myopathy, characterized by multiple and variably sized vacuoles filled with PAS-positive material. Using electron microscopy, we confirmed the presence of large non-membrane bound sarcoplasmic deposits of normally structured glycogen as well as smaller rounded sac structures lined by a continuous double membrane containing only glycogen, corresponding to autophagosomes. A consistent SQSTM1/p62 decrease and beclin-1 increase in human muscle biopsies suggested an enhanced autophagy. Consistent with this, an increase in the lipidated form of LC3, LC3II was found in patients compared to controls. A decrease in SQSTM1/p62 was also found in the GSDIII mouse model. In conclusion, we characterized the morphological phenotype in GSDIII muscle and demonstrated dysfunctional autophagy in GSDIII human samples. These findings suggest that autophagic modulation combined with gene therapy might be considered as a novel treatment for GSDIII.

Acute bronchiolitis treatment in children and infants is largely supportive, but chest physiotherapy is routinely performed in some countries. In France, national guidelines recommend a specific type of physiotherapy combining the increased exhalation technique (IET) and assisted cough (AC). Our objective was to evaluate the efficacy of chest physiotherapy (IET + AC) in previously healthy infants hospitalized for a first episode of acute bronchiolitis. We conducted a multicenter, randomized, outcome assessor-blind and parent-blind trial in seven French pediatric departments. We recruited 496 infants hospitalized for first-episode acute bronchiolitis between October 2004 and January 2008. Patients were randomly allocated to receive from physiotherapists three times a day, either IET + AC (intervention group, n=246) or nasal suction (NS, control group, n=250). Only physiotherapists were aware of the allocation group of the infant. The primary outcome was time to recovery, defined as 8 hours without oxygen supplementation associated with minimal or no chest recession, and ingesting more than two-thirds of daily food requirements. Secondary outcomes were intensive care unit admissions, artificial ventilation, antibiotic treatment, description of side effects during procedures, and parental perception of comfort. Statistical analysis was performed on an intent-to-treat basis. Median time to recovery was 2.31 days, (95% confidence interval [CI] 1.97-2.73) for the control group and 2.02 days (95% CI 1.96-2.34) for the intervention group, indicating no significant effect of physiotherapy (hazard ratio [HR]=1.09, 95% CI 0.91-1.31, p=0.33). No treatment by age interaction was found (p=0.97). Frequency of vomiting and transient respiratory destabilization was higher in the IET + AC group during the procedure (relative risk [RR]=10.2, 95% CI 1.3-78.8, p=0.005 and RR=5.4, 95% CI 1.6-18.4, p=0.002, respectively). No difference between groups in bradycardia with or without desaturation (RR=1.0, 95% CI 0.2-5.0, p=1.00 and RR=3.6, 95% CI 0.7-16.9, p=0.10, respectively) was found during the procedure. Parents reported that the procedure was more arduous in the group treated with IET (mean difference=0.88, 95% CI 0.33-1.44, p=0.002), whereas there was no difference regarding the assessment of the child's comfort between both groups (mean difference=-0.07, 95% CI -0.53 to 0.38, p=0.40). No evidence of differences between groups in intensive care admission (RR=0.7, 95% CI 0.3-1.8, p=0.62), ventilatory support (RR=2.5, 95% CI 0.5-13.0, p=0.29), and antibiotic treatment (RR=1.0, 95% CI 0.7-1.3, p=1.00) was observed. IET + AC had no significant effect on time to recovery in this group of hospitalized infants with bronchiolitis. Additional studies are required to explore the effect of chest physiotherapy on ambulatory populations and for infants without a history of atopy. ClinicalTrials.gov NCT00125450.

Several lines of evidence indicate that immature oocyte retrieval and subsequent in vitro maturation (IVM) without ovarian stimulation may be a reliable option in assisted reproductive technologies (ART). However, few outcome data are available for children born following this technique. We assessed height and weight development of French children conceived after IVM. All children conceived after IVM at Antoine Beclere Hospital (Clamart, France) and born between June 2003 and October 2008 (n = 38) were included in a prospective cohort study and compared with a control group of children conceived by ICSI without IVM, matched for maternal age, gestational age and singleton/twin pregnancies. Follow-up included clinical examination at one year and a questionnaire completed by parents when the children were two years old (97% follow-up rate). No statistical differences between IVM and control groups were found for boys. Mean weight, height and head circumference at birth were significantly greater for IVM than for ICSI girls (3.236 kg vs 2.701 kg (p = 0.03); 49 cm vs 47 cm (p = 0.01) and 34 cm vs 33 cm (p = 0.04), respectively). At one year, IVM girls remained heavier (mean weight 10.2 kg vs 8.6 kg (p = 0.001)) and taller (76 cm vs 73 cm (p = 0.03)), and there was a two-point difference in BMI between the two groups of girls (18 vs 16 (p = 0.01)). Our results in girls born after IVM should be interpreted with caution. It remains unclear whether the observed sexual dimorphism is due to IVM technology or to maternal characteristics such as underlying infertility in patients with polycystic ovary syndrome (PCOS). Further monitoring of the outcomes of these infants is required.