Fanconi-Bickel Syndrome Research Articles

GLUT1 deficiency and other glucose transporter diseases.

We review the three genetically determined disorders of glucose transport across cell membranes. Diseases such as glucose-galactose malabsorption, Fanconi-Bickel syndrome and De Vivo disease (GLUT1 deficiency syndrome (GLUT1DS)) arise from heritable mutations in transporter-encoding genes that impair monosaccharide uptake, which becomes rate-limiting in tissues where the transporters serve as the main glucose carrier systems. We focus in greater detail on De Vivo disease as a prototype of a brain energy failure syndrome, for which the greatest pathophysiological detail is known, but which presents the most therapeutic challenges. The study of these diseases illustrates fundamental aspects of energetic metabolism, while providing the basis for their diagnosis by simple metabolic screening and for their treatment by dietary modification.

Intestinal glucose transport: Evidence for a membrane traffic–based pathway in humans

Background & Aims: The presence of glucose transporter 2 (GLUT2) molecules in the basolateral membrane of enterocytes has long been considered to be of major importance for intestinal glucose absorption. The aim of this study was to reevaluate the role of GLUT2 in a patient with congenital GLUT2 deficiency (Fanconi-Bickel syndrome, FBS). Methods: Oral mono- and disaccharide tolerance tests including gaschromatographic determination of breath hydrogen concentrations were performed in an FBS patient. For comparison, a patient with a microsomal carbohydrate transport defect, glucose-6-phosphate translocase 1 (G6PT1) deficiency, and a control individual were investigated. Results: No increase in breath hydrogen concentration was found in the GLUT2-deficient patient after a glucose load. In G6PT1 deficiency, basal hydrogen concentrations were repeatedly found to be elevated. Conclusions: From the fact that a GLUT2-deficient patient does not show any impairment of intestinal monosaccharide transport measurable by the hydrogen breath test, we conclude that mechanisms other than facilitative glucose transport by GLUT2 must be involved in the transport of monosaccharides at the basolateral membrane of enterocytes. When relating this observation to the high intestinal expression of human hexokinase, G6PT1, and glucose-6-phosphatase and to our results of oral carbohydrate tolerance tests in a G6PT1-deficient patient, there is evidence that a microsomal membrane traffic-based transport pathway, as recently suggested for GLUT2-deficient animals, also plays a major role in transcellular monosaccharide transport of the human intestine.GASTROENTEROLOGY 2003;124:34-39

Glucose transporter protein syndromes

Publisher Summary The disturbances of carbohydrate homeostasis have interested clinicians and scientists since the recognition of diabetes mellitus. A parallel line of study emerged in the study of patients with recurrent or chronic hypoglycemic syndromes. These studies eventually led to an understanding of fuel-hormonal interrelationships with insulin playing a prominent role. However, this understanding has remained quite incomplete even following the discovery of several gene families that influence carbohydrate homeostasis. These families include the active co-transporters (SGLTs) and the facilitative glucose transporters (GLUTs). The recognition of these two gene families has expanded our understanding of carbohydrate metabolism and introduced new insights into human disease states. Now it is understood that the molecular basis for old conditions, such as the Fanconi-Bickel syndrome, and newer conditions such as the glucose-galactose malabsorption syndrome and the GLUT1 deficiency syndrome. However, understanding of disturbed carbohydrate homeostasis in the setting of diabetes mellitus remains incomplete, and it is expected that there will be further insight into the pathogenesis of this common human condition as we continue to explore the factors that control the movement of glucose across tissue membranes. This chapter focuses on the several clinical conditions that have been associated with documented mutations affecting the two glucose transporter gene families.

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

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.

Single-strand conformation polymorphism analysis of the glucose transporter gene GLUT1 in maturity-onset diabetes of the young.

Maturity-onset diabetes of the young (MODY), an autosomal dominant, early-onset form of type-2 diabetes, is caused by mutations in five different genes all leading to defect(s) in the pancreatic beta cell. However, some patients with this form of diabetes do not bear a mutation in any of the known (MODY1-MODY5) loci, a notion prompting the search for new MODY genes. Clinical and genetic data point toward a defect in beta cell function in the majority of patients with MODY, and partners of the glucose-sensing device are reasonable functional candidates. The high-capacity glucose transporter GLUT2 has the ideal kinetic features for performing this task. However, complete GLUT2 deficiency in humans leads to hepato-renal glycogenosis (Fanconi-Bickel syndrome), and heterozygous GLUT2 mutations apparently behave in a recessive manner. Furthermore, in the human beta cell GLUT1 mRNA is predominant when compared to GLUT2 and glucose influx appears to be largely mediated by this low-Km transporter. Thus, we looked for the presence of sequence variants by polymerase chain reaction and single-strand conformation polymorphism (PCR-SSCP) within the GLUT1 gene in 90 Italian pedigrees negative at the search for mutations in glucokinase (MODY2) and hepatocyte nuclear factor-1alpha (MODY3), the two genes responsible for about 60% of MODY cases in Italian children. We found three already described silent mutations and a new single base deletion in position -173 of the 5' regulatory region. The -173de1A variant, which was detected in the heterozygous or homozygous state in 30.8% of MODY patients examined and is located in a Nuclear Factor Y binding sequence, is not associated with hyperglycemia in affected relatives of MODY probands. In conclusion, it appears from these results that the glucose transporter gene GLUT1 is unlikely to play a major role in the etiology of MODY diabetes.

Glucose transporters: structure, function and consequences of deficiency.

There are two mechanisms for glucose transport across cell membranes. In the intestine and renal proximal tubule, glucose is transported against a concentration gradient by a secondary active transport mechanism in which glucose is cotransported with sodium ions. In all other cells, glucose transport is mediated by one or more of the members of the closely related GLUT family of glucose transporters. The pattern of expression of the GLUT transporters in different tissues is related to the different roles of glucose metabolism in different tissues. Primary defects in glucose transport all appear to be extremely rare and not all possible deficiencies have been identified. Deficiency of the secondary active sodium/glucose transporters result in glucose/galactose malabsorption or congenital renal glycosuria. GLUT1 deficiency produces a seizure disorder with low glucose concentration in cerebrospinal fluid and GLUT2 deficiency is the basis of the Fanconi-Bickel syndrome, which resembles type I glycogen storage disease.

The molecular background of glycogen metabolism disorders.

The molecular pathology of classical glycogen storage disorders, glycogen synthase deficiency and Fanconi-Bickel syndrome is reviewed. The isolation of the respective cDNAs, the chromosomal localization of the genes and the elucidation of the genomic organization enabled mutation analysis in most disorders. The findings have shed light on the multi-protein structure of the glucose-6-phosphatase system, the phosphorylase kinase enzymatic complex and the molecular background of the differential tissue expression in debranching enzyme deficiency. The immediate practical benefit of these studies is our extending ability to predict the outcome of clinical variants and to offer genetic counseling to most families. The elucidation of the tertiary structure of these proteins and their structure-function relationship poses major challenges for the future.

Ｆａｎｃｏｎｉ‐Ｂｉｃｋｅｌ症候群（糖原病ＸＩ型）における腎病変の検討

Fanconi-Bickel症候群 (糖原病XI型) は肝腎でのグリコーゲン蓄積，Fanconi症候群およびガラクトース代謝異常を呈する先天代謝異常疾患である。今回，当科で長期間加療している本症の2例の腎機能および腎組織について報告した。症例1は現在22歳の男性，症例2は現在24歳の女性。症例1は1歳6カ月時に，症例2は4歳時にそれぞれFanconi症候群を伴う糖原病 (欠損酵素不明) と診断された。 2例とも糸球体機能は正常であったが，低身長，腎性くる病，腎性糖尿，汎アミノ酸尿，近位型尿細管性アシドーシス，低リン血症などの近位尿細管障害を認めた。症例1では高カルシウム尿症を認め，10歳時に腎石灰化，20歳時に大脳基底核の石灰化を指摘された。症例2では高カルシウム尿症，腎および頭蓋内の石灰化は認めなかった。症例1の腎生検組織では，尿細管上皮の壊死と石灰化，近位および遠位尿細管とその周囲でのPAS陽性物質の沈着を認めた。一方，症例2の腎生検組織では明らかな尿細管の変化やPAS陽性物質の沈着は認めなかった。2症例ともに臨床的および生化学的にはFanconi-Bickel症候群と診断されるが，腎組織像や高カルシウム尿症の有無など異なる点も多い。ゲノムDNAを用いたglucose transporter 2 (GLUT 2) 遺伝子の検討では，症例1ではTrp 420 stopのホモ接合子異常を認めたが，症例2では異常は検出できなかった。以上のことから，本症候群がGLUT2遺伝子以外の異常によっても生じる可能性が示唆された。

Fanconi-Bickel syndrome--a congenital defect of the liver-type facilitative glucose transporter. SSIEM Award. Society for the Study of Inborn Errors of Metabolism.

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

Erratum: Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome

Erratum: Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome

Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome.

Fanconi-Bickel syndrome (FBS) is a rare autosomal-recessive inborn error of metabolism characterized by hepatorenal glycogen accumulation, Fanconi nephropathy and impaired utilization of glucose and galactose. To date, no underlying enzymatic defect in carbohydrate metabolism has been identified. Therefore, and because of the impairment of both glucose and galactose metabolism, a primary defect of monosaccharide transport across membranes has been suggested. Here we report mutations in the gene encoding the facilitative glucose transporter 2 (GLUT2) in three FBS families, including the original patient described in 1949 by Fanconi and Bickel. Homozygous mutations were found in affected individuals, whereas all parents tested were heterozygous for the respective mutation. Because all detected mutations (delta T446-449, C1251T and C1405T) predict truncated translation products that cannot be expected to have functional monosaccharide transport activity, GLUT2 mutations are probably the cause of FBS.

Fanconi-Bickel-Syndrom

The Fanconi-Bickel syndrome is characterized by tubular dysfunction, impaired metabolism of glucose and galactose and glycogenosis. Up to now the data of nineteen patients have been reported. In the following case firstly an abnormal body composition is described measuring the concentration of Potassium-40 with a Whole Body Radiation Counter. Before therapy an increased value of total body cell mass but no value of total body fat is measured. After therapy body weight increased while cell mass decreased and a value of fat had been observed. Concerning renal parameters a 60 fold elevation of the beta 2-microglobulin-clearance is noted.