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.

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.

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Due to an error, the designation of the GLUT2 mutation of patient 0301 is wrong. C1251T has to be replaced by Cl213T. As the amino-acid code (R301X) was correctly stated, this does not affect the discussion of the results and the conclusions of the paper. We regret this error.