Additional evidence on the phenotype produced by combination of CFTR 1677delTA alleles and their relevance in causing CFTR-related disease.

Cystic fibrosis is the most common, life-threatening, autosomal recessive disease in the Caucasian population. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene, which encodes a chloride ion channel expressed on the surface of epithelial cells. There are more than 2000 variants of the cystic fibrosis transmembrane conductance regulator gene reported worldwide. Some of these variants cause classic cystic fibrosis, while others are labeled as variants of unknown significance or variants of varying clinical consequences alleles and associated with atypical disease or cystic fibrosis transmembrane conductance regulator-related disorders. Although these alleles do not directly cause cystic fibrosis, they may predispose compound heterozygous patients to certain clinical phenotypes. Specifically, 1677delTA has been reported as a pathogenic allele in homozygous state or in combination with other cystic fibrosis-causing alleles. However, the L997F allele is considered to be benign or causative of non-classic cystic fibrosis or cystic fibrosis transmembrane conductance regulator-related disorders in combination with other pathogenic alleles. In this case series, we describe three cases with 1677delTA and L997F genotype, and speculate that a co-concurrence of these two alleles in trans does not cause classic cystic fibrosis symptoms; however, because the late-onset of cystic fibrosis is possible in the presence of rare alleles, such as L997F, longer follow-up of these patients and identification of a greater number of adults with 1677delTA/L997F genotype are necessary to make final conclusion about the nature of this genotype.

Genotype-phenotype correlations of cystic fibrosis in siblings compound heterozygotes for rare variant combinations: Review of literature and case report.

Here, we describe a cystic fibrosis (CF) family with affected siblings, two of whom have a combination of I1234V and 1677delTA variants with classic CF features, the third child with a combination of I1234V and L997F variants with atypical CF, and the apparently healthy mother with a combination of 1677delTA and L997F alleles. Interestingly, the sibling with I1234V and L997F variants had normal sweat test results and had a much milder phenotype than the other two siblings with I1234V and 1677delTA variants, suggesting that this combination is causative for atypical CF. The fact that their mother with the combination of 1677delTA and L997F appears to be healthy suggests that the L997F variant causes different phenotypes in different allele combinations. The current cases show that there is a genotype-phenotype correlation in this disease and underline the importance of genotyping individuals with suspected CF to allow prediction of disease severity and effective treatment.

Novel variants and clinical symptoms in four new ALG3-CDG patients, review of the literature, and identification of AAGRP-ALG3 as a novel ALG3 variant with alanine and glycine-rich N-terminus.

ALG3-CDG is one of the very rare types of congenital disorder of glycosylation (CDG) caused by variants in the ER-mannosyltransferase ALG3. Here, we summarize the clinical, biochemical, and genetic data of four new ALG3-CDG patients, who were identified by a type I pattern of serum transferrin and the accumulation of Man5 GlcNAc2 -PP-dolichol in LLO analysis. Additional clinical symptoms observed in our patients comprise sensorineural hearing loss, right-descending aorta, obstructive cardiomyopathy, macroglossia, and muscular hypertonia. We add four new biochemically confirmed variants to the list of ALG3-CDG inducing variants: c.350G>C (p.R117P), c.1263G>A (p.W421*), c.1037A>G (p.N346S), and the intron variant c.296+4A>G. Furthermore, in Patient 1 an additional open-reading frame of 141 bp (AAGRP) in the coding region of ALG3 was identified. Additionally, we show that control cells synthesize, to a minor degree, a hybrid protein composed of the polypeptide AAGRP and ALG3 (AAGRP-ALG3), while in Patient 1 expression of this hybrid protein is significantly increased due to the homozygous variant c.160_196del (g.165C>T). By reviewing the literature and combining our findings with previously published data, we further expand the knowledge of this rare glycosylation defect.

Clinical course & management of childhood nephrotic syndrome in Germany: a large epidemiological ESPED study.

BACKGROUND: Nephrotic syndrome (NS) is one of the most frequent occurring chronic kidney diseases in childhood, despite its rarely occurrence in the general population. Detailed information about clinical data of NS (e.g. average length of stay, complications) as well as of secondary nephrotic syndrome (SNS) is not well known. METHODS: A nationwide ESPED follow-up study presenting the clinical course and management of children with NS in Germany. RESULTS: In course of 2 years, 347 children developed the first onset of NS, hereof 326 patients (93.9%) had a primary NS, and 19 patients had a SNS (missing data in 2 cases), the majority due to a Henoch-Schönlein Purpura. Patients with steroid-resistant NS (SRNS) stayed significantly longer in hospital than children with steroid-sensitive NS (25.2 vs. 13.3 d, p <  0.001). Patients with bacterial/viral infections stayed longer in hospital (24.9 d/19.5d) than children without an infection (14.2 d/14.9 d; p <  0.001; p = 0.016). Additionally, children with urinary tract infections (UTI) (p < 0,001), arterial hypertension (AH) (p < 0.001) and acute renal failure (ARF) (p < 0,001) stayed significantly longer in hospital. Patients with SRNS had frequent complications (p = 0.004), such as bacterial infections (p = 0.013), AH (p < 0.001), UTI (p < 0.001) and ARF (p = 0.007). Children with a focal segmental glomerulosclerosis (FSGS) had significantly more complications (p = 0.04); specifically bacterial infections (p = 0.01), UTI (p = 0.003) and AH (p < 0,001). Steroid-resistance was more common in patients with UTI (p < 0.001) and in patients with ARF (p = 0.007). Furthermore, steroid-resistance (p < 0.001) and FSGS (p < 0.001) were more common in patients with AH. CONCLUSIONS: This nationwide, largest German study presents results on the clinical course of children with NS considering a diverse range of complications that can occur with NS. The establishment of a region-wide and international pediatric NS register would be useful to conduct further diagnostic and therapy studies with the aim to reduce the complication rate and to improve the prognosis of NS, and to compare the data with international cohorts.

The History of Maltose-active Disaccharidases.

The history of maltose-active disaccharidases is closely related to the history of the sugar and starch industry. It began in the 19th century, when a shortage of cane sugar occurred in continental Europe, because Napoleon Bonaparte decreed that no goods could be imported from England to the countries he occupied. Other sugar sources had to be found, and it led to the identification of sugar beets as alternative source of sugar by Marggraf in 1774, to the detection of starch hydrolysis by diluted sulfuric acid by Kirchhoff in 1812, and to the starch digestion enzyme, α-amylase, by Payen in 1833. In the 20th century, Borkström's group in Sweden investigated the absorption of nutrients in human adults by transintubation techniques and found that the luminal concentration of invertase was small compared to that of α-amylase. They speculated that the major locus of this enzyme activity must be in the intestinal cells. Borkström's coworker, Dahlqvist, investigated the maltose-active enzymes in pig intestine, and a second group around Semenza studied the maltase-active enzymes in rabbit intestine. After the first descriptions of congenital sucrase-isomaltase deficiency in 1960 and 1961, the research on disaccharidases increased. Dahlqvist published the first quantitative method to measure these enzymes. Consecutive research led to the discovery of 4 maltases, which were later identified as 2 complex enzymes: the sucrase-isomaltase complex and the maltase-glucoamylase complex. The homology of the 2 enzyme complexes was later determined when the cDNA sequences of the 2 complexes in human intestine were identified.

Chapter 2. ESPGHAN: 50 Years Memories-The Early Years.

Thirty-six founding members from Europe were present in 1968, when the European Society of Paediatric Gastroenterology (ESGA) had its first meeting in Paris. The aim was to create a forum for presentations and discussions of research activities in paediatric gastroenterology in Europe. At the second meeting of ESGA 1969 in Interlaken, an important landmark was set for all gastroenterologists in the world. In this conference, the first ever criteria for "the Diagnosis of Coeliac Disease" (CD) were established. In 1990, the revised criteria for the diagnosis of CD were published. After the introduction of new noninvasive techniques, like tissue transglutaminase 2-antibodies and the HLADQ2/HLADQ8 determinations in blood, "new" criteria for the diagnosis of CD were published in 2012 by the European society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). Close collaboration of ESPGHAN and the North American Society of Paediatric Gastroenterology, Hepatology and Nutrition led to mutual meetings. The first combined meeting was 1978 in Paris, followed by meetings in New York, Amsterdam, Houston, and last in Toulouse. The first World Congress of Paediatric Gastroenterology took place in Boston 2000 followed by congresses in Paris, Iguazu, Taipeh, and Toronto. The creation of specialised committees (Nutrition Committees, GI-Committee, and Hepatology-Committee) enabled the society to elaborate numerous guidelines for standards in the diagnosis and treatment of diseases within the subspecialties. The Journal of Paediatric Gastroenterology and Nutrition, as organ of ESPGHAN and the North American Society of Paediatric Gastroenterology, Hepatology and Nutrition since 1991, serves as the voice for these worldwide accepted guidelines. Growing educational activities with summer schools, the Young Investigator Forum and the creation of working groups have distributed our current knowledge among the younger generation and led to fruitful reports, guidelines, and syllabus. In 1992, ESPGHAN was 1 of the founding 7 members of the United European Gastroenterology Federation (UEGF), which developed into a successful organisation for gastroenterology in Europe. This year we celebrate the 50th anniversary of ESPGHAN at our annual Meeting in Geneva.

Chapter 8. 50 Years of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN): Captivating Witness Reports of a Success Story.

Since the conception of an idea of a few paediatric gastroenterologists in Europe to create a society for Paediatric Gastroenterology in 1967, and its foundation in 1968, half a century has passed. The European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) now celebrates its 50th anniversary and its utmost success in combining clinical and scientific expertise in the fields of paediatric gastroenterology, haepatology, and nutrition. To describe this success story 14 of the still living presidents of ESPGHAN recount their impressions of the steady growth of ESPGHAN with all the historical facets from their own points of view. This historical view of ESPGHAN over the last 5 decades provides personal accounts of the development of all activities and creations of this great European Society. The Society started as a small family of experts in the field into a global working open society involved in a large variety of activities within the subspecialties, becoming a leading organisation in Europe and beyond. This unique view gives also a wonderful insight into the famous clinicians and researchers from all over Europe who have helped in the growth and development of ESPGHAN. By describing all these activities and collaborations it becomes clear that this astonishing pan-European enterprise was achieved by people who put considerable effort and time into the development of this society. Their statements serve as a historical source and reference for future evaluation of the first 50 years of ESPGHAN. In depicting different time episodes, and by assembling all the historical pieces of a puzzle together, the statements help to illustrate how a highly structured society such as ESPGHAN has evolved over the last 50 years, for what it stands for today and what is to be expected in the future.