FANCONI BICKEL SYNDROME PDF

ORPHA Synonym(s). Bickel-Fanconi glycogenosis; Fanconi-Bickel disease; GSD due to GLUT2 deficiency; GSD type 11; GSD type XI; Glycogen storage. Fanconi-Bickel syndrome (FBS) is a rare inherited glycogen storage disease ( GSD) caused by defects in facilitative Glucose Transporter (GLUT2) gene that. NIH Rare Diseases: Fanconi Bickel syndrome (FBS) is a rare condition characterized by the accumulation of a substance called glycogen in different parts of the.

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Renal tubular acidosis RTA encompasses many renal tubular disorders characterized by hyperchloremic metabolic acidosis with a normal anion gap.

Untreated patients usually complain of growth failure, osteoporosis, rickets, nephrolithiasis and eventually afnconi insufficiency. It is a rare inherited disorder of carbohydrate metabolism manifested by huge hepatomegaly [hence it is classified as glycogen storage disease GSD type XI; GSD XI], severe bicksl rickets and failure to thrive due to proximal renal tubular dysfunction leading to glucosuria, phosphaturia, generalized aminoaciduria, bicarbonate wasting and hypophosphatemia.

Many mutant alleles have been described, its exact frequency is unknown and there is no single mutation found more frequently than the others. The presence of consanguinity in affected families suggests an autosomal recessive pattern of inheritance. Two novel mutations have been discovered in two unrelated Egyptian families. The first was two bases deletion, guanine and adenine, c. Glu85fs and the second is mutation in exon6 in splicing acceptor site with intron5 c. Moreover, a new different mutation was described in a 3 year old Indian boy.

Renal tubular acidosis RTA defines many renal tubular disorders characterized by hyperchloremic metabolic acidosis with a normal anion gap. They represent chronic diseases with significant impact on the quality of life of the affected patients when left untreated, possibly leading to growth failure, osteoporosis, rickets, nephrolithiasis and eventually renal insufficiency[ 1 fancoji 6 ].

These disorders may be primary genetic defects of tubular transport mechanisms[ 7 ] or secondary to systemic diseases or adverse drug reactions[ 89 ].

FBS is a rare inherited disorder of carbohydrate metabolism; it is characterized by the association of huge hepatomegaly due to glycogen accumulation hence it is classified as glycogen storage disease GSD type XI; GSD XI by Hug sybdrome al[ 23 ]severe hypophosphatemic rickets and failure to thrive due to proximal renal tubular dysfunction. Proximal renal tubular dysfunction is documented by glucosuria, phosphaturia, generalized aminoaciduria, bicarbonate wasting and hypophosphatemia[ 24 – 28 ].

These findings are the characteristic laboratory evidence of the disease[ 2930 ]. The disorder has been reported from all parts of Europe, Turkey, Israel, Arabian countries. Japan and North America. Many mutant bickek have been described, the exact frequency of the disease or each mutation is not known and there is no reported single mutation found more frequently than the others.

The presence of consanguinity in most of the affected families suggests an autosomal recessive pattern of inheritance[ 2122 ]. 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 substances[ 22 ]. The overall prognosis seems to be favorable; several patients have been reported to have reached adulthood in a stable condition[ 21 ] and the first reports on fertility of female and male patients have recently been published[ 223132 ].

Recently, two novel mutations have been discovered in two unrelated Egyptian families[ 33 ] and another different mutation in an Indian boy aged 3 years[ 34 ]. RTA should be suspected in any patient with hyperchloremic metabolic acidosis and a normal anion gap less than 12 after ruling out other causes of bicarbonate loss e. Thus, in a young infant with diarrhea and underlying RTA, diagnosis may be initially obscured.

In such situations, RTA is further suspected if hyperchloremic metabolic acidosis shows delayed resolution[ 3536 ].

Fanconi-Bickel syndrome as an example of marked allelic heterogeneity

However, acidosis with a high gap more than 20 rules out RTA and suggests added fajconi, whether endogenous lactic acidosis, inborn errors of metabolism or exogenous salicylates ingestion [ 37 ]. Untreated children with RTA have nonspecific symptoms, such as failure to thrive[ 38 ], polydipsia, polyuria, anorexia, vomiting, constipation and restlessness[ 12 ]. There are also signs and symptoms which are more specific to some types of RTA.

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Metabolic bone disease is frequent in Fanconi syndrome secondary to excessive losses of phosphates and calcium, nephrocalcinosis and hypercalciuria are common in patients with distal RTA[ 39 ] and muscle weakness in hypokalemic patients[ 40 ].

Urinary pH may help to distinguish distal from proximal RTA; if less than 5. In recent years, remarkable progress has been made in the unraveling of the molecular pathogenesis of hereditary diseases caused by mutations in genes encoding transporters in renal tubules[ 4546 ]. Proximal RTA is syndroem heterogeneous group of disorders whose genes are dispersed in the human genome[ 47 ]. Fanconi syndrome, the most common prototype of proximal RTA[ 48 ], is part of a systemic disease, mostly autosomal recessive.

Chromosomal mapping of some inherited forms of proximal renal tubular acidosis[ 496970 ].

Clinical diagnosis of FBS should be based on: These mutations represent the first detection of a congenital defect within a whole family of membrane proteins facilitative glucose transporters. Sakamoto et al[ 20 syndrmoe studied 3 Japanese patients with FBS and found 4 novel mutations in the GLUT2 gene, bifkel a splice site mutation, a nonsense mutation and 2 missense mutations.

Several family members who had a heterozygous missense mutation were shown to have glucosuria but a syndrme member heterozygous for the nonsense mutation did not. It was 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[ 55 ].

Later, Santer et al[ 22 ] reported a total of cases from 88 families worldwide who had been diagnosed as FBS. Homozygosity or compound heterozygosity for GLUT2 mutations was found in 49 patients among these cases and 23 novel mutations of the GLUT2 gene were detected.

These mutations were scattered over the whole coding sequence of the GLUT2 buckel and mutations were found in all exons. None of these mutations was particularly frequent, thus making the molecular diagnosis more laborious. It is interesting that most of the GLUT2 mutations were private and confined to a single family.

Of these patients, 12 were Turkish and all had a different mutation[ 55 ]. Since the first report of mutations in the GLUT2 gene[ 56 ], more than 30 different mutations have been identified and most of the reported mutations are confined to a single family[ 55 ].

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Some FBS patients did not have any detected mutations in the protein-coding region of the GLUT2 gene[ 5758 ]; this situation could be explained by the presence of heterozygous long-range deletions which are not detectable with the usually applied PCR-based method[ 58 ].

Recently, two new mutations were detected in two unrelated Egyptian families that presented with cases of FBS[ 33 ]. The first one represents a mutation type causing non-insulin dependent diabetes mellitus and the other 14 types are responsible for FBS with different phenotypes. A thrto-ile substitution was present at equal frequency in diabetic and control populations, whereas a valto-ile substitution was discovered in a single allele of a patient with non-insulin dependent diabetes[ 57 ].

Mueckler et al[ 53 ] tested the effect of these amino acid changes on glucose transport activity by expression of the mutant proteins in Xenopus oocytes. The polymorphism at threonine had no effect on the expression of GLUT protein or the uptake of 2-deoxyglucose. On the other hand, the highly conserved valto-ile amino acid change abolished transport activity of the GLUT2 transporter expressed in Xenopus oocytes. This was the first known dysfunctional mutation in a human facilitative glucose transporter protein.

The presence of the mutation in a diabetic patient suggested that defects in GLUT2 expression may be causally involved in the pathogenesis of non-insulin dependent diabetes mellitus[ 58 ].

Santer et al[ 22 ] stated that the patient reported by Tanizawa et al[ 57 ] was a woman of African American descent with gestational diabetes mellitus and that the mutation was heterozygous.

OMIM Entry – # – FANCONI-BICKEL SYNDROME; FBS

Three allelic variants, all of which are nonsense causing premature termination of protein synthesis[ 21 ]: They were homozygous for a single-base deletion in a stretch of 4 thymine residues positions to in exon 3 causing a frameshift with a premature TGA stop at codon 74 in the same exon, resulting in a truncated protein of 45 regular and 28 aberrant amino acids. The patient was found still alive at the age of 52 years, cm tall but with fannconi clinical and chemical features of FBS.

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A homozygous missense mutation, SLC2A2, PROLEU, was described in a large family with a high degree of consanguinity; it showed several affected individuals of both sexes, markedly reduced liver phosphorylase kinase activity was found in association with the characteristic clinical features and laboratory findings of FBS[ 61 ], thus suggesting that FBS 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.

The affected proline residue is completely conserved in all mammalian glucose permease isoforms and even in bacterial sugar transporters and is believed to be critical for the passage of glucose through the permease. Homozygosity for this mutation was found in 7 syndromw individuals from different branches of that family.

Recently, this mutation has been detected in a third Egyptian family Al-Haggar, personal communication but it is re-enumerated to exon 10 not 9 as in the initial report due to the changes of gene structure. Five allelic variants were described by Santer et al[ 22 ], mostly missense mutations: Byfive allelic variants had been described in Japanese.

Fanfoni nonsense mutation[ 66 ], a homozygous G-to-A transition at nucleotide in exon 9 was found and the four allelic variants published by Sakamoto et al[ 20 ]. They described three missense mutations and the fourth was frameshift: The principal investigator made the mutation analysis for the three Egyptian families, including the two new allelic variants.

Molecular analysis on three Japanese patients found four novel mutations: Recently, Al-Haggar et al[ 33 ] defined three different mutations in three Egyptian families with FBS, one mutation specific for each family. The first two mutations are novel: Glu85fswhich fancconi with an early grave course despite adequate treatment, and the second novel fancpni exists in exon 6 in the splicing acceptor site with intron5 c.

The third mutation had previously been described in Arab families from Saudi Arabia[ 62 ]; a missense mutation C-to-T substitution at c.

The last known mutation had fanconk previously localized in exon 9; however, we re-enumerated it to exon 10 due syndrlme the fact that between exonstwo exons exon 4-a and exon 4-b had been discovered[ 68 ]. In other words, discovery of new exons in a gene should make changes in exon re-numbering. PL mutation can be easily and unambiguously recognized irrespective of syndrlme exon number, especially for experts in this lesion, with no difficulty in locating it within GLUT2 gene.

However, re-numbering its location to exon 10 is highly recommended in subsequent publications, especially those submitted to journals not specialized in the genetics domain, in order to remove any confusion among young researchers. In the three Egyptian families, the following findings are striking: Glu85fs ; 3 Two new mutations were found as well as the third known mutation; and fsnconi All affected cases were homozygous and all the heterozygous individuals were asymptomatic.

These observations should yield the following conclusions: National Center for Biotechnology InformationU. Journal List World J Nephrol v. Published online Jun 6. Author information Article notes Copyright and License information Disclaimer. Al-Haggar M solely contributed to this paper. This article has been cited by other articles in PMC. Abstract Renal tubular acidosis RTA encompasses many renal tubular disorders characterized by hyperchloremic blckel acidosis with a normal anion gap.

Table 1 Chromosomal mapping of some inherited forms of proximal renal tubular acidosis[ 496970 ]. Open in a separate window. Williams and Wilkins; Physiology Bethesda ; Inherited disorders of bickdl renal tubules.

Genetic diseases of acid-base transporters. Antimicrobial-associated renal tubular acidosis. Permeability defect with bicarbonate leak as a mechanism of immune-related distal renal tubular acidosis. Am J Kidney Dis. Renal tubular acidosis syndromes. Renal tubular acidosis in infants and children.