Jürgen Schaub

Fanconi-Bickel syndrome – the original patient and his natural history, historical steps leading to the primary defect, and a review of the literature

AbstractFanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder of carbohydrate metabolism recently demonstrated to be caused by mutations in Glut2, the gene for the glucose transporter protein 2 expressed in liver, pancreas, intestine and kidney. The disease was first described in a 3-year-old Swiss boy in 1949. Here we report a follow up of this original patient over more than 50 years and show that the typical clinical and laboratory findings of FBS (hepatomegaly secondary to glycogen accumulation, glucose and galactose intolerance, fasting hypoglycaemia, a characteristic proximal tubular nephropathy and severe short stature) persist into adulthood. We further summarize the historical observations that eventually led to the identification of the basic defect of FBS and give an overview of the 82 cases from 70 families in the published literature and from personal communications. Conclusion Although with the first description of a congenital defect of facilitative glucose transport the main steps in the pathophysiology of Fanconi-Bickel syndrome have been elucidated, numerous pathophysiological mechanisms are far from clear and thus encourage the ongoing study of patients with this disorder.

The mutation spectrum of the facilitative glucose transporter gene SLC2A2 (GLUT2) in patients with Fanconi-Bickel syndrome

Abstract. We report a total of 23 novel mutations of the SLC2A2 (GLUT2) gene in 49 patients with a clinical diagnosis of Fanconi-Bickel syndrome (FBS). Molecular genetic analysis has now been performed in more than 50% of the 109 FBS cases from 88 families that we have been able to locate world-wide since the original report in 1949. In these 49 patients, 33 different SLC2A2 mutations (9 missense, 7 nonsense, 10 frameshift, 7 splice-site) have been detected. Thus, our results confirm that mutations of SLC2A2 are the basic defect in patients with FBS. Mutations of SLC2A2 were detected in historical FBS patients in whom some of the characteristic clinical features (hepatorenal glycogen accumulation, glucose and galactose intolerance, fasting hypoglycemia, a characteristic tubular nephropathy) and the effect of therapy were described for the first time. Mutations were also found in patients with atypical clinical signs such as intestinal malabsorption, failure to thrive, the absence of hepatomegaly, or renal hyperfiltration. No single prevalent SLC2A2 mutation was responsible for a significant number of cases. In a high percentage (74%) of FBS patients, the mutation is homozygous, so we conclude that the prevalence of SLC2A2 mutations is relatively low in most populations. No mutational hot spots within SLC2A2 or even within homologous sequences among the genes for facilitative glucose transporters were detected.

Fanconi-Bickel syndrome--a congenital defect of facilitative glucose transport.

Fanconi-Bickel syndrome (FBS, OMIM 227810) is a rare type of glycogen storage disease (GSD). It is caused by homozygous or compound heterozygous mutations within GLUT2, the gene encoding the most important facilitative glucose transporter in hepatocytes, pancreatic beta-cells, enterocytes, and renal tubular cells. To date, 112 patients have been reported in the literature. Most patients have the typical combination of clinical symptoms: hepatomegaly secondary to glycogen accumulation, glucose and galactose intolerance, fasting hypoglycemia, a characteristic tubular nephropathy, and severely stunted growth. In 63 patients, mutation analysis has revealed a total of 34 different GLUT2 mutations with none of them being particularly frequent. No specific therapy is available for FBS patients. Symptomatic treatment is directed towards a stabilization of glucose homeostasis and compensation for renal losses of various solutes. In addition to the clinical and molecular genetic aspects of FBS, this review discusses the pathophysiology of the disease and compares it to recent findings in GLUT2 deficient transgenic animals. An overview is also provided on recently discovered members of the rapidly growing family of facilitative glucose transporters, which are novel candidates for congenital disorders of carbohydrate metabolism.

Molecular genetic basis and prevalence of glycogen storage disease type IIIA in the Faroe Islands.

Glycogen storage disease type IIIA (GSD IIIA) is caused by mutations of the amyloglucosidase gene (AGL). For most populations, none of the AGL mutations described to date is particularly frequent. In this paper, we report that six children with GSD IIIA from the Faroe Islands were found to be homozygous for the novel nonsense mutation c.1222C>T (R408X) of the AGL gene. This mutation is easily detected by restriction enzyme digest with NsiI after mismatch PCR. Investigating five intragenic polymorphisms, we could show that this mutation was always associated with the same haplotype. The c.1222C>T mutation could be detected on two chromosomes of another 50 unselected GSD IIIA patients of other European or North American origin which means that this mutation plays a minor role worldwide. From the fact that we are currently aware of a total of 14 GSD IIIA cases in the Faroese population of 45 000, the observed prevalence is 1 : 3100. While the novel AGL mutation c.1222C>T was not detectable among 198 German newborns, nine out of 272 children from the Faroese neonatal screening program were found to be heterozygous for this mutation. Thus, the calculated prevalence is 1 : 3600 (95% CI 1:700–1:6400). We conclude that due to a founder effect, the Faroe Islands have the highest prevalence of GSD IIIA world-wide. The detection of the molecular defect has facilitated the diagnosis and has offered the opportunity for prenatal diagnosis in this patient group.

Agarose gel isoelectrofocusing of UDP-galactose pyrophosphorylase and galactose-1-phosphate uridyltransferase. Developmental aspect of UDP-galactose pyrophosphorylase.

The uridine diphosphogalactose pyrophosphorylase activity has been determined in human adult and fetal tissues as well as blood of various ages by measurement of UDP-galactose production from gal-1-p and UTP. The highest activity was found from adult liver in which the specific activity was about 5% of the gal-1-p uridyltransferase activity. In general adult tissues had a somewhat higher activity than the corresponding fetal tissues except erythrocytes in which fetuses had a 5-10 times higher activity than adults. From normal blood the pyrophosphorylase activity in erythrocytes decreased with age, but in the case of galactosemia the decrease with age was not distinct. According to agarose gel isoelectrofocusing studies, at least two isozyme forms for UDP-galactose pyrophosphorylase exist with the activity bands between pH 6.0-6.15. The patterns of AGIF bands of pyrophosphorylase varied according to the age of the samples, suggesting the development of the isozyme forms of pyrophosphorylase to be age-dependent. Uridyltransferase, on the other hand, resolved into multiple bands between pH 5.1-5.6 on agarose gels and the patterns varied according to the variants but not to the age. Significance of the decrease in the pyrophosphorylase activity in erythrocytes with age as well as of the difference in AGIF bands between normal and the galactosemic were discussed with regard to the pathology of classical galactosemia.

Molecular analysis in glycogen storage disease 1 non-A: DHPLC detection of the highly prevalent exon 8 mutations of the G6PT1 gene in German patients.

We investigated the molecular basis of glycogen storage disease type 1 non‐A (GSD�1 non‐A) in 21�patients. In addition to 8 novel mutations within the G6PT1 gene (c.250T>A, c.580G>A, c.627C>T, c.653‐4delAG, c.844C>A, c.1071A>C, c.1268G>A, c.1348G>A), we found a remarkably high prevalence of exon 8 mutations in German patients. The c.1211‐2delCT mutation and the c.1184G>T mutation accounted for 32% and 29% of mutant chromosomes, respectively, supporting the hypothesis of a Middle European origin of these two mutations. Together with less common mutations, 79% of German GSD�1 non‐A patients were either homozygous or heterozygous for an exon 8 mutation. In addition to direct sequencing, these exon�8 mutations could be detected by mutation‐specific methods such as the detection of heteroduplex formation on polyacrylamide gel electrophoresis or by the amplification of DNA segments by allele‐specific oligonucleotides. Furthermore, the use of denaturating high performance liquid chromatography (DHPLC) allowed a 100% detection and discrimination of all exon 8 mutations. In conclusion from these results, we recommend the use of either conventional or DHPLC screening as the initial non‐invasive and efficient diagnostic procedure in patients with GSD�1 non‐A from populations with a similar distribution of mutations. Hum Mutat 16:177, 2000.

Fanconi–Bickel syndrome – A congenital defect of the liver-type facilitative glucose transporter

1 Department Pediatricsof of Childrenˇs, University Kiel; 2 Municipal Hospital,Esslingen, Germany; 3 Division of Metabolic and Molecular Diseases, Department ofPediatrics, University Zurichof , Switzerland* Correspondence: University Childrenˇs Hospital, Schwanenweg 20, D-24105 Kiel,GermanyIn 1949, Fanconi and Bickel reported the —rst patient with a rare autosomal reces-sive inborn error of metabolism characterized by hepatorenal glycogen accumula-tion, fasting hypoglycaemia, postprandial hyperglycaemia and hypergalactosaemia,and a Fanconi-type nephropathy with disproportionately severe glucosuria(Fanconi 1949).and Bickel To date, approximately 30 cases of this condition havebeen reported; it has been termed Fanconi¨Bickel syndrome (FBS) et al(Manz1987) (Hug 1987).or glycogen storage disease type XI The latter classi—cation wasbased on the assumption that an enzymatic defect of phosphoglucomutase was theunderlying cause. Recently, however, we were able to show that a congenital defectof the liver-type glucose transporter Glut2 is the basic defect et al(Santer 1997).Here we present a model that shows that a Glut2 defect explains most of the patho-physiological events encountered in this condition.PATIENTS AND METHODSFour patients with characteristic clinical and biochemical features of FBS (includingthe original patient described by Fanconi and Bickel) from 3 families were investi-gated. A mutation screening covering the complete coding sequence of the Glut2gene was performed by polyacrylamide gel electrophoresis of single- and double-stranded PCR products, direct sequencing of samples showing an aberrant patternand conformation of detected mutations by restriction enzyme digest.RESULTS AND DISCUSSIONIn all aƒected individuals a homozygous mutation (*T446¨449, C1213T or C1405T)in the Glut2 gene could be detected. All mutations predict a premature terminationof translation and a loss of glucose transport activity et al(Santer 1997).191

Supplemental Feeding in the First Days of Life – Effects on the Recipient Infant

Aim: Since clinical indications may necessitate the feeding of supplements to newborn infants, the effects of different supplemental feedings on the recipient infants were studied. Methods: Two groups of healthy, term newborn infants (n = 64 in each group) were investigated. The mothers breast-fed their infants, and by indication the babies were additionally fed supplement A (supplementary neonatal formula, 78 kcal/dl) or the traditionally used supplement B (glucosaccharide solution, 100 kcal/dl). The differences in volume and energy intake, weight development and rate of hyperbilirubinemia were assessed in the hospital. The frequency of breast-feeding was evaluated using a structured telephone interview at the ages of 4 and 8 weeks. Results: The energy intake of group B was higher prior to the 3rd day of study (p < 0.05). Afterwards a higher mean intake of human milk, a faster weight gain but a lower frequency of exclusive breast-feeding at discharge were observed in study group A. Hyperbilirubinemia was more frequent in the group B. Fifty-five percent (group A) and 52% (group B) of the participants were exclusively breast-fed at the age of 8 weeks. Conclusions: Despite differences in milk intake and weight gain in the early postpartum period, the breast-feeding patterns at 4 and 8 weeks were not significantly influenced by the use of different supplements.

Acknowledgement to the 2002 Reviewers

Ambrosini, G., Crawley, Australia Azizi, F., Tehran, Iran Baker, P.W., Adelaide, Australia Baumgartner, M., Basel, Switzerland Berg, A., Freiburg, Germany Böhles, H.J., Frankfurt, Germany Bitsch, I., Giessen, Germany Bode, C., Stuttgart, Germany Boeing, H., Bergholz-Rehbrücke, Germany Bretillon, L., Dijon, France Brussaard, J.H., Zeist, The Netherlands Burdan, F., Lublin, Poland Chango, A., Jefferson, USA Cser, A., Budapest, Hungary Cynober, L.A., Paris, France Demirkol, M., Istanbul, Turkey Donaldson, M., Salisbury, USA Elmadfa, I., Vienna, Austria Faist, V., Kiel, Germany Flachowsky, G., Braunschweig, Germany Fogliano, V., Portici, Italy Gazia, N., Assiut, Egypt Genser, D., Vienna, Austria Grandjean, A., Omaha, USA Koletzko, B., Munich, Germany König, J., Vienna, Austria Kosenko, E., Pushchino, Russia Krawinkel, M., Giessen, Germany Lohninger, A., Vienna, Austria Moser, U., Basel, Switzerland Münch, G., Leipzig, Germany Nakamoto, T., New Orleans, USA Nestel, P.J., Melbourne, Australia Niedermüller, H., Vienna, Austria Nogala, M., Poznan, Poland Oliver, P., Palma de Mallorca, Spain Oltersdorf, U., Karlsruhe, Germany Palou, A., Palma de Mallorca, Spain Pedersen, J., Oslo, Norway Pokorny, J., Prague, Czech Republic Pollak, A., Vienna, Austria Prentice, A., Cambridge, UK Remer, T., Dortmund, Germany Renaud, S., Bordeaux, France von Ruecker, A., Bonn, Germany Rust, P., Vienna, Austria Sanchez-Muniz, F., Boston, USA Sanders, T., London, UK Schächinger, V., Frankfurt, Germany Scheppach, W., Würzburg, Germany Schiefermeier, M., Vienna, Austria Simopoulos, A., Washington, USA Sjöström, M., Huddinge, Sweden Stehle, P., Bonn, Germany Steinhart, H., Hamburg, Germany Suetsuna, K., Yamaguchi, Japan Tamura, M., Tsukuba, Japan de Vrese, M., Kiel, Germany Wagner, K.-H., Vienna, Austria Wascher, T., Graz, Austria Wenk, C., Zürich, Switzerland Yoshida, A., Nagoya, Japan Zittermann, A., Bonn, Germany Zunft, J., Bergholz-Rehbrücke, Germany Zwiauer, K. F., St. Pölten, Austria