GLYCOGEN STORAGE DISEASE XI
GLYCOGENOSIS, FANCONI TYPE
FANCONI SYNDROME WITH INTESTINAL MALABSORPTION AND GALACTOSE INTOLERANCE
HEPATIC GLYCOGENOSIS WITH FANCONI NEPHROPATHY
PSEUDO-PHLORIZIN DIABETES
HEPATIC GLYCOGENOSIS WITH AMINO ACIDURIA AND GLUCOSURIA
HEPATORENAL GLYCOGENOSIS WITH RENAL FANCONI SYNDROME
FBS
Fanconi-Bickel disease
Bickel-Fanconi glycogenosis
GSD due to GLUT2 deficiency
Glycogenosis due to GLUT2 deficiency
Fanconi-Bickel syndrome is a rare but well-defined clinical entity, inherited in an autosomal recessive mode and characterized by hepatorenal glycogen accumulation, proximal renal tubular dysfunction, and impaired utilization of glucose and galactose (Manz et al., 1987). Because no underlying ...Fanconi-Bickel syndrome is a rare but well-defined clinical entity, inherited in an autosomal recessive mode and characterized by hepatorenal glycogen accumulation, proximal renal tubular dysfunction, and impaired utilization of glucose and galactose (Manz et al., 1987). Because no underlying enzymatic defect in carbohydrate metabolism had been identified and because metabolism of both glucose and galactose is impaired, a primary defect of monosaccharide transport across the membranes had been suggested (Berry et al., 1995; Fellers et al., 1967; Manz et al., 1987; Odievre, 1966). Use of the term glycogenosis type XI introduced by Hug (1987) is to be discouraged because glycogen accumulation is not due to the proposed functional defect of phosphoglucomutase, an essential enzyme in the common degradative pathways of both glycogen and galactose, but is secondary to nonfunctional glucose transport
Fanconi and Bickel (1949) described what they believed to be the first combination of tubular nephropathy and glycogen storage disease in a boy born to consanguineous parents living in a remote valley in the southern Swiss Alps. Because of ...Fanconi and Bickel (1949) described what they believed to be the first combination of tubular nephropathy and glycogen storage disease in a boy born to consanguineous parents living in a remote valley in the southern Swiss Alps. Because of failure to thrive, polydipsia, and constipation at around the age of 6 months, the patient received vitamin D and calcium supplements. At ages 2.7 and 3.7 years he had short stature (-6 SD), a protuberant abdomen, hyperlordosis, excessive hepatomegaly, facial obesity, and generalized osteopenia but no frank rickets. Tubular nephropathy was characterized by excessive glucosuria (mean 10 to 30 g per day, up to 60 g), and moderate hyperphosphaturia in the presence of constant hypophosphatemia, hyperuricemia, hyperaminoaciduria, and intermittent albuminuria. Fanconi and Bickel (1949) observed hypoglycemia and ketonuria in the fasting state and hyperglycemia in the postabsorptive state. Sensitivity was increased to insulin and decreased to adrenaline. Liver biopsy revealed excessive amounts of glycogen with steatosis; hypercholesterolemia and hyperlipidemia were pronounced; no evidence of a secretory defect was present. Gitzelmann (1957) gave a follow-up of the patient reported by Fanconi and Bickel (1949) at age 12 years and described relative resistance to glucagon. At age 52, the patient still lived in the same village and was withdrawn, having spent his life as a shepherd (Steinmann, 1997). He had never had any medication and was consuming a great deal of milk. He was 140 cm in height with an arm span of 150 cm and a weight of 43 kg. His abdomen was moderately prominent, his liver 10 cm below the costal margin. There were no cataracts. Apart from arthrotic changes of the lower back and shoulders, he had no complaints. Blood and urine compounds were characteristic of FBS (Steinmann, 1997). In a comprehensive review published in honor of Professor Bickel's 80th birthday, Santer et al. (1998) summarized the case of the original patient and presented his follow-up over more than 50 years. Rotthauwe et al. (1963) described a 4.5-year-old girl with the typical clinical and chemical features of FBS, including fasting hypoglycemia, glucose and galactose intolerance, and partial resistance to adrenaline and glucagon. In the liver biopsy, Rotthauwe et al. (1963) found that glycogen content was increased to 11 g per 100 g wet weight (normal below 7); glycogen structure was normal, as were the enzyme activities of glucose-6-phosphatase, phosphorylase, and amylo-1,6-glucosidase; and free liver glucose was twice as high as that in rat liver, whereas the other glycolytic metabolites were comparable. Various enzymes and metabolites indicated regular function of glycolysis, hexose-monophosphate shunt, and Krebs cycle in the liver. At autopsy, Rotthauwe et al. (1963) noted liver and kidney weights of 1100 g and 100 g, respectively; the surface of the kidneys was smooth, and glycogen content was increased in the proximal renal tubules. Odievre (1966) described 2 cases in 2 families with similar clinical and chemical findings as those reported by Fanconi and Bickel (1949). He noted fasting hypoglycemia, ketosis, and low blood lactate levels, and after glucose loads, prolonged hyperglycemia, only moderate insulin levels, and high blood lactate levels. After insulin administered subcutaneously or released by intravenous tolbutamide, glucose dropped to very low levels and blood lactate rose; Odievre (1966) concluded that lactic acid was produced by glycolysis of glucose that had been taken up by peripheral tissues rather than by the liver. After oral and intravenous galactose loads there were severe and long-lasting hypergalactosemias. Since after oral and intravenous fructose loads disappearance of this sugar was normal, Odievre (1966) concluded that only utilization of glucose and galactose were impaired. Liver and kidneys were enlarged, and biopsies disclosed excessive glycogen contents in these organs but normal activities of phosphorylase, glucose-6-phosphatase, and amylo-1,6-glucosidase in the liver. Fellers et al. (1967) found in their patient that renal clearance of glucose was equal to or greater than the renal clearance of inulin, which suggested to them an undiscovered renal transport defect; the term pseudo-phlorizin was chosen to attach importance to a mechanism of glucose reabsorption or a defect in glucose transport. Brivet et al. (1983) studied carbohydrate metabolism in a patient with FBS. [1-14C] galactose oxidation was normal in erythrocytes but reduced in fresh minced liver tissue. Data suggested to Brivet et al. (1983) an unidentified defect in galactose transport across the liver cells. Manz et al. (1987) postulated a defect of the diffusion carrier facilitating the influx and efflux of glucose and galactose in the liver and the efflux of glucose and galactose at the basolateral membrane of the proximal tubule, which would lead to high intracellular glucose concentration, inhibition of glycogen degradation, and proximal tubular dysfunction. They also introduced the eponymic designation Fanconi-Bickel syndrome. Manz et al. (1987) compared clinical, functional, and morphologic data from 9 infants, children, and adults with FBS observed from 2 to 25 years with those reported in the literature. The first symptoms were fever, vomiting, growth failure, and rickets at the age of 3 to 10 months. Later the patients presented with dwarfism, protuberant abdomen, hepatomegaly, moon-shaped face, and fat deposition about the shoulders and abdomen. Cutting of the teeth and puberty were retarded. Fractures and pancreatitis were complications. Rickets and osteoporosis later in life were constant features. Cataracts were not present. As determined radiologically by Manz et al. (1987), kidney size and growth related to body height was increased in most patients. Glomerular filtration rate was normal or low normal, and there was no progression to glomerular insufficiency nor deterioration of tubular defects. Manz et al. (1987) observed that glucosuria was the most prominent finding (40 to 200 g per 1.73 m(2), with somewhat lower values during the first year of life), and the ratio of glucose clearance to inulin clearance ranged from 0.59 to 1.0, independent of the blood glucose levels. After an oral load of galactose, tubular reabsorption of galactose was 10% at a serum level of 105 mg/dl. Generalized hyperaminoaciduria, moderate hyperphosphaturia, hyperuricosuria, and hypercalciuria were constant findings, and mild proteinuria was exclusively of tubular origin. Renal bicarbonate threshold was decreased and led to moderate metabolic acidosis. Polyuria, probably due to osmotic diuresis, was a constant finding. Upon renal biopsy, Manz et al. (1987) found normal glomeruli, interstitium, and vessels. By electron microscopy, glycogen accumulation was marked in some but not all proximal tubular cells and seemed to predominate in the straight part of the proximal tubules, and megamitochondria were encountered in these cells. The brush border was normal. Manz et al. (1987) noted that at birth, the liver appeared normal or slightly increased in size in 2 cases, and became greatly enlarged during infancy when hepatomegaly was present in all patients. The liver size and glycogen content were reduced after the institution of an antiketogenic diet. Laboratory findings of Manz et al. (1987) included fasting hypoglycemia and ketonuria; hyperglycemia and hypergalactosemia in the postabsorptive state; hypercholesterolemia and hyperlipidemia; moderately elevated ALP; hypophosphatemia, hyperaminoaciduria, glucosuria, galactosuria, and proteinuria; normal enzymes of galactose and glycogen metabolism; normal fructose metabolism; and normal endocrinologic results. Sanjad et al. (1993) reported large consanguineous family in which several individuals had the characteristic clinical features and laboratory findings of Fanconi-Bickel syndrome in association with markedly reduced liver phosphorylase kinase activity (PHK, see, e.g., 300798). This suggested that Fanconi-Bickel syndrome is genetically heterogeneous and that there may be another subtype of PHK deficiency (possibly associated with a distinctive genotype) that gives rise to hepatorenal glycogenosis. However, Burwinkel et al. (1999) showed that affected members of this family in fact had a homozygous mutation in the GLUT2 gene (P417L; 138160.0005). The affected proline residue is completely conserved in all mammalian glucose permease isoforms and even in bacterial sugar transporters and was believed to be critical for the passage of glucose through the permease. The low PHK activity was thought to be a secondary phenomenon that contributed to the deposition of glycogen in response to the intracellular glucose retention caused by GLUT2 deficiency. Nagai et al. (1988) had also described renal tubular acidosis in a 2.5-year-old Japanese boy with phosphorylase kinase deficiency. In their 8-year-old patient, Berry et al. (1995) described renal glomerular hyperfiltration, microalbuminuria, and diffuse glomerular mesangial expansion resembling incipient diabetic nephropathy and similar to the changes observed in patients with glucose-6-phosphatase deficiency. Santer et al. (2002) demonstrated compound heterozygosity for 2 mutations in the GLUT2 gene (138160.0010 and 138160.0011) in this patient, thus indicating this was a bona fide case of Fanconi-Bickel syndrome and that renal hyperfiltration can be a feature of the disorder. Furthermore, phosphoglucomutase activity was not reduced in this patient, an important finding. Aperia et al. (1981) described a boy and girl, offspring of first-cousin, Turkish-Assyrian parents, who showed poor appetite, slow weight gain, and retarded psychomotor development. Impairment of galactose metabolism was demonstrated by oral galactose load and by galactosemia when milk was given. As in classic galactosemia, Fanconi syndrome was present. However, galactose restriction did not restore renal tubular function or the children's general condition to normal. Galactokinase and galactose-1-phosphate uridyltransferase activities in red cells were normal. A generalized transport defect was suggested. Intestinal malabsorption was indicated by the general appearance (sparse subcutaneous fat, thin limbs, and distended abdomen) and the results of vitamin A and xylose absorption tests. Glucose absorption was normal, however. As the parents refused consent for biopsy, no morphologic studies of gut, liver, or kidney tissue were made. Santer et al. (2002) demonstrated that these sibs were homozygous for a splice site 1-bp insertion in the GLUT2 gene (138160.0009), thus indicating that they represented bona fide cases of FBS. Furthermore, the cases demonstrated that failure to thrive because of intestinal malabsorption can be a presenting sign of FBS in infancy and that hepatomegaly is not a 'conditio sine qua non' for the diagnosis of FBS. Because of galactose intolerance, patients with FBS can be detected by neonatal screening for galactose; this was the case in 3 patients reported by Aperia et al. (1981), Manz et al. (1987), and Muller et al. (1997). Muller et al. (1997) noted that although FBS and galactosemia are clinically and enzymatically easy to distinguish, the 2 share some symptoms; clinicians should therefore be aware of this condition in cases of positive galactosemia screening. The paucity of FBS cases detected by neonatal galactose screening indicates that the disorder is extremely rare
Among the members of the facilitative glucose transporter family, Santer et al. (1997) considered GLUT2 (138160), the 524-amino acid, high-Km isoform expressed in hepatocytes, pancreatic beta cells, and the basolateral membranes of intestinal and renal tubular epithelial cells (Mueckler ...Among the members of the facilitative glucose transporter family, Santer et al. (1997) considered GLUT2 (138160), the 524-amino acid, high-Km isoform expressed in hepatocytes, pancreatic beta cells, and the basolateral membranes of intestinal and renal tubular epithelial cells (Mueckler et al., 1994), to be a candidate gene for the defect in FBS. They identified mutations in the GLUT2 gene in 3 families with FBS (138160.0002-138160.0004), including the patient originally described by Fanconi and Bickel (1949). This original patient carried a homozygous arg301-to-ter (R301X) mutation (138160.0004). Sakamoto et al. (2000) studied 3 Japanese patients with FBS and found 4 novel mutations in the GLUT2 gene, including a splice site mutation, a nonsense mutation, and 2 missense mutations (138160.0012-138160.0015). Several family members who had a heterozygous missense mutation were shown to have glucosuria, but a family member heterozygous for the nonsense mutation did not. Sakamoto et al. (2000) speculated that mutant GLUT2 proteins may have a dominant-negative effect and that heterozygosity for a nonsense mutation may not lead to glucosuria because of selective and efficient degradation of the nonsense mRNA. For additional information about the molecular genetics of the Fanconi-Bickel syndrome, see 138160. Fukumoto et al. (1988) localized the GLUT2 gene to chromosome 3q26.1-q26.3 by somatic cell hybridization and in situ hybridization. Matsutani et al. (1992) positioned the GLUT2 gene on 3q using a (CA)n dinucleotide repeat polymorphism adjacent to the 3-prime end of exon 4a