Summary Background The interest in neonatal screening for lysosomal storage disorders has increased substantially because of newly developed enzyme replacement therapies, the need for early ...diagnosis, and technical advances. We tested for Gaucher's disease, Pompe's disease, Fabry's disease, and Niemann-Pick disease types A and B in an anonymous prospective nationwide screening study that included genetic mutation analysis to assess the practicality and appropriateness of including these disorders in neonatal screening panels. Methods Specimens from dried blood spots of 34 736 newborn babies were collected consecutively from January, 2010 to July, 2010, as part of the national routine Austrian newborn screening programme. Anonymised samples were analysed for enzyme activities of acid β-glucocerebrosidase, α-galactosidase, α-glucosidase, and acid sphingomyelinase by electrospray ionisation tandem mass spectrometry. Genetic mutation analyses were done in samples with suspected enzyme deficiency. Findings All 34 736 samples were analysed successfully by the multiplex screening assay. Low enzyme activities were detected in 38 babies. Mutation analysis confirmed lysosomal storage disorders in 15 of them. The most frequent mutations were found for Fabry's disease (1 per 3859 births), followed by Pompe's disease (1 per 8684), and Gaucher's disease (1 per 17 368). The positive predictive values were 32% (95% CI 16–52), 80% (28–99), and 50% (7–93), respectively. Mutational analysis detected predominantly missense mutations associated with a late-onset phenotype. Interpretation The combined overall proportion of infants carrying a mutation for lysosomal storage disorders was higher than expected. Neonatal screening for lysosomal storage disorders is likely to raise challenges for primary health-care providers. Furthermore, the high frequency of late-onset mutations makes lysosomal storage disorders a broad health problem beyond childhood. Funding Austrian Ministry of Health, Family, and Women.
In a 24-week, randomized, placebo-controlled trial, evolocumab, a fully human anti-PSCK9 monoclonal antibody, was studied in pediatric patients who had heterozygous familial hypercholesterolemia and ...were receiving stable lipid-lowering treatment. Evolocumab reduced the LDL cholesterol level and other lipid variables.
Obesity-associated chronic low-grade inflammation leads to dysregulation of central lipid and glucose metabolism pathways leading to metabolic disorders. MicroRNAs (miRNAs) are known to control ...regulators of metabolic homeostasis. We aimed to assess the relationship of circulating miRNAs with inflammatory modulators and metabolic disorders in pediatric obesity.
From a pediatric cohort with severe obesity (n = 109), clinically thoroughly characterized including diverse routine blood parameters, oral glucose tolerance test, and liver MRI, a panel of 16 circulating miRNAs was quantified using qRT-PCR. Additionally, markers of inflammation TNFα, IL1 receptor antagonist, procalcitonin, CRP, and IL-6 were measured.
Markers of obesity-associated inflammation, TNFα, IL-1Ra, and procalcitonin, all significantly correlated with concentrations of miRNAs 122 and 192. Concentrations of these miRNAs negatively correlated with serum adiponectin and were among those strongly linked to parameters of dyslipidemia and liver function. Moreover, miRNA122 concentrations correlated with HOMA-IR. Several miRNA levels including miRNAs 34a, 93, 122, and 192 were statistically significantly differing between individuals with prediabetes, impaired glucose tolerance, metabolic syndrome, or nonalcoholic fatty liver disease compared to the respective controls. Additionally, miRNA 192 was significantly elevated in metabolically unhealthy obesity.
A miRNA pattern associated with obesity-associated inflammation and comorbidities may be used to distinguish metabolically healthy from unhealthy pediatric patients with obesity. Moreover, these changes in epigenetic regulation could potentially be involved in the etiology of obesity-linked metabolic disease in children and adolescents.
Summary
Background
Eighty percent of adolescents with severe obesity suffer from non‐alcoholic fatty liver disease (NAFLD). Non‐invasive prediction models have been tested in adults, however, they ...performed poorly in paediatric populations.
Objective
This study aimed to investigate novel biomarkers for NAFLD and to develop a score that predicts liver fat in youth with severe obesity.
Methods
From a population with a BMI >97th percentile aged 9‐19 years (n = 68), clinically thoroughly characterized including MRI‐derived proton density fat fraction (MRI‐PDFF), amino acids and acylcarnitines were measured by HPLC‐MS.
Results
In children with NAFLD, higher levels of plasma branched‐chain amino acids (BCAA) were determined. BCAAs correlated with MRI‐PDFF (R = 0.46, p < .01). We identified a linear regression model adjusted for age, sex and pubertal stage consisting of BCAAs, ALT, GGT, ferritin and insulin that predicted MRI‐PDFF (R = 0.75, p < .01). ROC analysis of this model revealed AUCs of 0.85, 0.85 and 0.92 for the detection of any, moderate and severe steatosis, respectively, thus markedly outperforming previously published scores.
Conclusion
BCAAs could be an important link between obesity and other metabolic pathways. A BCAA‐based metabolic score can predict steatosis grade in high‐risk children and adolescents and may provide a feasible alternative to sophisticated methods like MRI or biopsy in the future.
Congenital disorders of glycosylation (CDGs) comprise a large number of inherited metabolic defects that affect the biosynthesis and attachment of glycans. CDGs manifest as a broad spectrum of ...disease, most often including neurodevelopmental and skeletal abnormalities and skin laxity. Two patients with biallelic CSGALNACT1 variants and a mild skeletal dysplasia have been described previously. We investigated two unrelated patients presenting with short stature with advanced bone age, facial dysmorphism, and mild language delay, in whom trio‐exome sequencing identified novel biallelic CSGALNACT1 variants: compound heterozygosity for c.1294G>T (p.Asp432Tyr) and the deletion of exon 4 that includes the start codon in one patient, and homozygosity for c.791A>G (p.Asn264Ser) in the other patient. CSGALNACT1 encodes CSGalNAcT‐1, a key enzyme in the biosynthesis of sulfated glycosaminoglycans chondroitin and dermatan sulfate. Biochemical studies demonstrated significantly reduced CSGalNAcT‐1 activity of the novel missense variants, as reported previously for the p.Pro384Arg variant. Altered levels of chondroitin, dermatan, and heparan sulfate moieties were observed in patients’ fibroblasts compared to controls. Our data indicate that biallelic loss‐of‐function mutations in CSGALNACT1 disturb glycosaminoglycan synthesis and cause a mild skeletal dysplasia with advanced bone age, CSGALNACT1‐CDG.
Congenital disorders of glycosylation (CDGs) comprise a large number of inherited metabolic defects that affect the biosynthesis and attachment of glycans. Four patients with biallelic CSGALNACT1 variants and a mild skeletal dysplasia are now known. Biallelic loss‐of‐function mutations in CSGALNACT1 disturb glycosaminoglycan synthesis and cause a mild skeletal dysplasia with advanced bone age, CSGALNACT1‐CDG
Biallelic loss‐of‐function mutations in the centrosomal pericentrin gene (PCNT) cause microcephalic osteodysplastic primordial dwarfism type II (MOPDII), which is characterized by extreme growth ...retardation, microcephaly, skeletal dysplasia, and dental anomalies. Life expectancy is reduced due to a high risk of cerebral vascular anomalies. Here, we report two siblings with MOPDII and attenuated growth restriction, and pachygyria. Compound heterozygosity for two novel truncated PCNT variants was identified. Both truncated PCNT proteins were expressed in patient's fibroblasts, with a reduced total protein amount compared to control. Patient's fibroblasts showed impaired cell cycle progression. As a novel finding, 20% of patient's fibroblasts were shown to express PCNT comparable to control. This was associated with normal mitotic morphology and normal co‐localization of mutated PCNT with centrosome‐associated proteins γ‐tubulin and centrin 3, suggesting some residual function of truncated PCNT proteins. These data expand the clinical and molecular spectrum of MOPDII and indicate that residual PCNT function might be associated with attenuated growth restriction in MOPDII.
3D free-hand ultrasound (3DFUS) is becoming increasingly popular to assist clinical gait analysis because it is cost- and time-efficient and does not expose participants to radiation. The aim of this ...study was to evaluate its reliability in localizing the anterior superior iliac spine (ASIS) at the pelvis and the hip joint centers (HJC). Additionally, we evaluated its accuracy to get a rough estimation of the potential to use of 3DFUS to segment bony surface. This could offer potential to register medical images to motion capture data in future. To evaluate reliability, a test-retest study was conducted in 16 lean and 19 obese individuals. The locations of the ASIS were determined by manual marker placement (MMP), an instrumented pointer technique (IPT), and with 3DFUS. The HJC location was also determined with 3DFUS. To quantify reliability, intraclass correlation coefficients (ICCs), the standard error of measurement (SEm), among other statistical parameters, were calculated for the identified locations between the test and retest. To assess accuracy, the surface of a human plastic pelvic phantom was segmented with 3DFUS in a distilled water bath in 27 trials and compared to a 3D laser scan of the pelvis. Regarding reliability, the MMP, but especially the IPT showed high reliability in lean (SEm: 2-3 mm) and reduced reliability in obese individuals (SEm: 6-15 mm). Compared to MMP and IPT, 3DFUS presented lower reliability in the lean group (SEm: 2-4 mm vs. 2-8 mm, respectively) but slightly better values in the obese group (SEm: 7-11 mm vs. 6-16 mm, respectively). Correlations between test-retest reliability and torso body fat mass (% of body mass) indicated a moderate to strong relationship for MMP and IPT but only a weak correlation for the 3DFUS approach. The water-bath experiments indicated an acceptable level of 3.5 (1.7) mm of accuracy for 3DFUS in segmenting bone surface. Despite some difficulties with single trials, our data give further rise to the idea that 3DFUS could serve as a promising tool in future to inform marker placement and hip joint center location, especially in groups with higher amount of body fat.
Hyperphosphatemic conditions such as chronic kidney disease are associated with severe muscle wasting and impaired life quality. While regeneration of muscle tissue is known to be reliant on ...recruitment of myogenic progenitor cells, the effects of elevated phosphate loads on this process have not been investigated in detail so far. This study aims to clarify the direct effects of hyperphosphatemic conditions on skeletal myoblast differentiation in a murine in vitro model. C2C12 murine muscle progenitor cells were supplemented with phosphate concentrations resembling moderate to severe hyperphosphatemia (1.4–2.9 mmol/l). Phosphate-induced effects were quantified by RT-PCR and immunoblotting. Immunohistochemistry was performed to count nuclear positive cells under treatment. Cell viability and metabolic activity were assessed by XTT and BrdU incorporation assays. Inorganic phosphate directly induced ERK-phosphorylation in pre-differentiated C2C12 myoblast cells. While phosphate concentrations resembling the upper normal range significantly reduced Myogenin expression (− 22.5%,
p
= 0.015), severe hyperphosphatemic conditions further impaired differentiation (Myogenin − 61.0%,
p
< 0.0001; MyoD − 51.0%;
p
< 0.0001). Analogue effects were found on the protein level (Myogenin − 42.0%,
p
= 0.004; MyoD − 25.7%,
p
= 0.002). ERK inhibition strongly attenuated phosphate-induced effects on Myogenin expression (
p
= 0.002). Metabolic activity was unaffected by the treatments. Our data point to a phosphate-induced inhibition of myoblast differentiation without effects on cell viability. Serum phosphate levels as low as the upper normal serum range significantly impaired marker gene expression in vitro. Investigation of cellular effects of hyperphosphatemia may help to better define serum cutoffs and modify existing treatment approaches of phosphate binders, especially in patients at risk of sarcopenia.
Obesity is associated with many cardiovascular risk factors (CVRF) in childhood. There is an ongoing discussion whether there is a linear relationship between degree of overweight and deterioration ...of CVRFs justifying body mass index (BMI) cut-offs for treatment decisions.
We studied the impact of BMI-SDS on blood pressure, lipids, and glucose metabolism in 76,660 children (aged 5-25 years) subdivided in five groups: overweight (BMI-SDS 1.3 to <1.8), obesity class I (BMI-SDS 1.8 to <2.3), class II (BMI-SDS 2.3-2.8), class III (BMI-SDS > 2.8-3.3), and class IV (BMI-SDS > 3.3). Analyses were stratified by age and sex.
We found a relationship between BMI-SDS and blood pressure, triglycerides, HDL cholesterol, liver enzymes, and the triglycerides-HDL-cholesterol ratio at any age and sex. Many of these associations lost significance when comparing children with obesity classes III and IV: In females < 14 years and males < 12 years triglycerides and glucose parameters did not differ significantly between classes IV and III obesity. Prevalence of dyslipidemia was significantly higher in class IV compared to class III obesity only in females ≥ 14 years and males ≥ 12 years but not in younger children. In girls < 14 years and in boys of any age, the prevalences of type 2 diabetes mellitus did not differ between classes III and IV obesity.
Since a BMI above the highest BMI cut-off was not associated consistently with dyslipidemia and disturbed glucose metabolism in every age group both in boys and girls, measurements of CVRFs instead of BMI cut-off seem preferable to guide different treatment approaches in obesity such as medications or bariatric surgery.
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