Background/PurposePhosphoglucomutase-1 deficiency is a subtype of congenital disorders of glycosylation (PGM1-CDG). Previous case-reports in PGM1-CDG patients receiving oral D-galactose (D-gal) showed clinical improvement. So far no systematic in vitro and clinical studies assessed safety and benefits of D-gal supplementation. In a prospective pilot study, we evaluated the effects of oral D-gal in nine patients.Methods/ResultsD-gal supplementation was increased to 1.5 g/kg/day (maximum 50 g/day) in three increments over 18 weeks. Laboratory studies were performed before and during treatment to monitor safety and effect on serum transferrin-glycosylation, coagulation, liver and endocrine function. Additionally, the effect of D-gal on cellular glycosylation was characterized in vitro.Eight patients were compliant with D-gal supplementation. No adverse effects were reported. Abnormal baseline results (ALT/AST/aPTT) improved or normalized already using 1g/kg/day D-gal. Antithrombin-III levels and Transferrin-glycosylation showed significant improvement, and increase in galactosylation and whole glycan content. In vitro studies before treatment showed N-glycan hyposialylation, altered O-linked glycans, abnormal LLO-profile, and abnormal nucleotide-sugars in patient fibroblasts. Most cellular abnormalities improved or normalized following D-gal treatment.ConclusionD-gal increased both UDP-Glc and UDP-gal levels and improved LLO fractions in concert with improved glycosylation in PGM1-CDG. Oral D-gal supplementation is a safe and effective treatment for PGM1-CDG in this pilot study. Transferrin glycosylation and ATIII levels were useful trial end points. Larger, longer duration trials are ongoing.

We established a scoring algorithm to reliably evaluate disease severity in patients with PGM1-CDG on the basis of their clinical history and presentation. We also identified 5 clinical features that are predictors of disease severity; 2 of these features can be evaluated by physical examination, without the need for specific diagnostic testing and thus allow for rapid assessment and initiation of therapy.

Screening by tandem mass spectrometry provides a better outcome for patients at 6 years of age, with fewer deaths and fewer clinically significant disabilities.

HAPO is a 5-year investigator-initiated prospective observational study that will recruit approximately 25000 pregnant women in 10 countries. HAPO utilizes a Central Laboratory for measurement of key metabolic variables, a Clinical Coordinating Center, a Data Coordinating Center, and an independent Data Monitoring Committee. Glucose tolerance is assessed by a 75 g 2-h OGTT at 24-32 weeks' gestation. Results are unblinded to the woman and her caregivers if: fasting plasma glucose >5.8 mmol/l, 2-h plasma glucose >11.1 mmol/l or any plasma glucose <2.5 mmol/l. Random plasma glucose measurement is performed at 34-37 weeks or if symptoms suggest hyperglycemia; results are unblinded for values > or = 8.9 mmol/l. Sociodemographic and health history data are collected via questionnaire and medical record abstraction. Maternal blood is obtained for measurement of serum C-peptide and hemoglobin A1c (HbA(1C)), cord blood for serum C-peptide and plasma glucose, and a capillary specimen is taken between 1 and 2 h following delivery for neonatal plasma glucose. Neonatal anthropometrics are obtained, and follow-up data are collected at 4-6 weeks post-delivery. The primary outcomes to be assessed in relation to maternal glycemia are cesarean delivery, increased fetal size (macrosomia/LGA/obesity), neonatal morbidity (hypoglycemia), and fetal hyperinsulinism.

No abstract

Sulfate is important for mammalian development but is not routinely measured in clinical settings. The renal NaS1 sulfate transporter maintains circulating sulfate levels and is linked to renal sulfate wasting in mice. Some autistic individuals exhibit renal sulfate wasting, but the etiology is yet unknown. We measured plasma and urinary sulfate levels, calculated the fractional excretion index (FEI) of sulfate, and screened for two loss-of-function NaS1 sequence variants (R12X and N174S) in 23 autistic individuals. The FEI sulfate values ranged from 0.13 to 0.50. NaS1 variants were detected in 18 of the 23 individuals (11 heterozygous N174S, four homozygous N174S, two heterozygous R12X, and one individual carried both R12X and N174S). Those individuals with neither sequence variant had FEI sulfate ≤ 0.34, whereas FEI sulfate ≥ 0.35 was found in about 60 % (11 of 18) of individuals that had R12X and/or N174S. This study links renal sulfate wasting with loss-of-function NaS1 sequence variants in humans.

Background:  There is considerable evidence supporting the role of vitamin D deficiency in the pathogenesis of type 1 diabetes mellitus (T1DM). Vitamin D deficiency is also associated with impairment of insulin synthesis and secretion. There have been no formal studies looking at the relationship between 25(OH)‐vitamin D3 and the severity of diabetic ketoacidosis (DKA) in children at presentation with T1DM. Objective:  To determine the relationship between measured 25(OH)‐vitamin D3 levels and the degree of acidosis in children at diagnosis with T1DM. Subjects:  Children presenting with new‐onset T1DM at a tertiary children’s hospital. Methods:  25(OH)‐vitamin D3 and bicarbonate levels were measured in children at presentation with newly diagnosed T1DM. Those with suboptimal 25(OH)‐vitamin D3 levels (<50 nmol/L) had repeat measurements performed without interim vitamin D supplementation. Results:  Fourteen of the 64 children had low 25(OH)‐vitamin D3 levels at presentation, and 12 of these had low bicarbonate levels (<18 mmol/L) (p = 0.001). Bicarbonate explained 20% of the variation in vitamin D level at presentation (partial r2 = 0.20, p < 0.001) and ethnic background a further 10% (partial r2 = 0.10, p = 0.002). The levels of 25(OH)‐vitamin D3 increased in 10 of the 11 children with resolution of the acidosis. Conclusions:  Acid–base status should be considered when interpreting 25(OH)‐vitamin D3 levels in patients with recently diagnosed T1DM. Acidosis may alter vitamin D metabolism, or alternatively, low vitamin D may contribute to a child’s risk of presenting with DKA.

Children presenting with a clinical phenotype consisting of a refractory seizure disorder, ataxia and developmental delay should prompt the consideration of Glucose transporter 1 deficiency syndrome. While the diagnostic test of lumbar puncture is an invasive manoeuvre, the diagnosis provides a viable treatment option, the ketogenic diet. GLUT1-DS displays clinical heterogeneity, but the value of early diagnosis and treatment is demonstrated by our patient cohort.