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Clinical Report

Fanconi syndrome with lysinuric protein intolerance

Eleonora Riccio and Antonio Pisani

Department of Public Health, University Federico II, Naples, Italy

Correspondence and offprint requests to:Eleonora Riccio; E-mail: elyriccio@libero.it

AbstractWe present the case of a 9-year-old child with lysinuric protein intolerance and Fanconi syndrome.She was referred to our hospital with a persistent metabolic acidosis and polyuria. Renal investiga-tions revealed all laboratory signs of Fanconi syndrome, with glucosuria, generalized aminoacidur-ia, phosphaturia and severe hypercalciuria. The diagnosis of Fanconi syndrome was conrmed by arenal biopsy that showed extensive lesions of proximal tubular epithelial cells with vacuolation ofthese cells and a sloughing of the brush border.

Keywords: Fanconi syndrome; hyperammonaemia; lysinuric protein intolerance

Introduction

Lysinuric protein intolerance (LPI; OMIM 222700) is a rareautosomal recessive multiorgan disorder in which therenal and intestinal transport of the cationic amino acidslysine, arginine and ornithine is defective [1]. The molecu-lar defect resides in mutations of the SLC7A7 gene, encod-ing for y+ LAT-1, the catalytic light chain subunit of acomplex belonging to the heterodimeric amino acid trans-porter family [2]. The basolateral transport defect is ex-

pressed in the epithelial cells of the intestine and thekidney tubules, hepatocytes and skin broblasts [3],leading to a depletion of their tissue pools and, as a con-sequence, to impaired functioning of the hepatic ureacycle with hyperammonaemic episodes (Figure 1). Most,but not all, of the symptoms of LPI have been linked to asecondary urea cycle derangement due to impaired trans-port of cationic amino acids. Typically, symptoms beginafter weaning with refusal of feeding, vomiting and conse-quent failure to thrive. Hepatosplenomegaly, haemato-logical anomalies and neurological involvement, includinghyperammonaemic coma, are recurrent clinical features[4,5]. Two major complications, pulmonary alveolar pro-teinosis and renal disease, are increasingly observed in LPIpatients [5, 6]. The disease has long been erroneously

considered relatively benign when appropriately treatedwith low-protein diet and L-citrulline supplementation.During the past years, however, other manifestations havesuggested that LPI is not only a urea cycle disorder, butalso a complex multisystem disease with an uncertainoutcome [7], thus considerably modifying the way to viewthis disorder.

We describe the clinical course in a patient with LPI andrenal pathology.

Case report

The patient was diagnosed with LPI at the 7 years ofage; she was born to consanguineous (rst-cousin)healthy parents after three abortions. The patient had abrother who died at the age of 6 years of respiratoryfailure; he was diagnosed with mucopolysaccharidosisbecause of the ndings of delayed psychomotor develop-ment, anorexia, repeated episodes of acute bronchitis,hepatosplenomegaly and pancytopenia. At 6 years, our

patient presented signs and symptoms similar to thoseobserved in her brother: in particular, she was hospitalizedbecause of delayed psychomotor development, vomitingand mild hepatosplenomegaly. The family history andclinical features suggested a diagnosis of metabolicdisease that was then investigated. Complete blood countshowed that mild pancytopenia, renal and hepatic func-tions were normal, lactate was 2.5 mmol/L (normal

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14 mmol/L) with an elevated anion gap of 20.4 (normal3000 mL/day)and renal investigations revealed all laboratory signs ofFanconi syndrome, with glucosuria, generalized aminoaci-duria, phosphaturia and severe hypercalciuria (Table 1).The glomerular ltration rate, evaluated by the creati-

nine clearance (Schwartz equation), was 88 mL/min per1.73 m2 (normal 80120). Echosonography of the kidneywas normal.

To explain the combination of a renal Fanconi syndromeand elevated levels of organic acids in the urine, a renalbiopsy was performed after parental informed consenthad been obtained. Consistent with the existence of aFanconi syndrome, renal biopsy showed extensive lesionsof proximal tubular epithelial cells with a dramatic vac-uolation of these cells and a sloughing of the brushborder. No evidence of immune deposits was shown byimmunouorescence (Figure 2).

Discussion

Renal involvement is a well-known manifestation of LPI.However, its progressive characteristic has recently beenemphasized [9]. Most of the patients present with mildproteinuria and microscopic haematuria for years with-out overt consequences. However, some patients have

Fig. 1. Pathway for the disposal of nitrogen waste products in the urea cycle. Each number represents the following enzymes: 1, carbamylphosphatesynthetase; 2, ornithine carbamyltransferase; 3, argininosuccinate synthetase; 4, argininosuccinate lyase; 5, arginase; 6, N-acetylglutamate synthetase.CoA, co-enzyme A; NH3, ammonia.

Table 1. Laboratory data on admission

Normal range Patient

Serum potassium (mEq/L) 3.65.0 3.3Serum phosphorus (mg/dL) 2.54.3 2.6Serum uric acid (mg/dL) 2.57.5 2.1Serum chloride (mEq/L) 101109 83Serum bicarbonat e ( mmol/ L) 22.026.0 14Anion gap (mEq/L) 12 3 20.4

Proteinuria Negative (

) (+)Urinary pH 4.87.5 6.5Urinary glucose Negative () (3+)

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glomerular dysfunction due to mild glomerulonephritis,whereas others display signs of Fanconi syndrome [9,10].Renal involvement may sometimes progress to end-stagerenal disease requiring dialysis and renal transplantation[9]. Our patient had evidence of a full-blown Fanconi syn-

drome with proximal tubular acidosis. Besides a proximaltubular acidosis, other signs of a complex tubular disorderwere found, i.e. diminished renal reabsorption of phosphate[11], glucose, amino acids and carnitine. The majority ofcases of proximal renal tubular acidosis t into the categoryof generalized tubule dysfunction with the Fanconi syn-drome. This defect can be due either to backleak of solutesvia the paracellular pathway or to a generalized disorderof the apical membrane and its transporters, a disorderof the basolateral Na+, K+-ATPase or a metabolic disorderthat lowers ATP concentration. Electron microscopy of renaltissue showed severe abnormalities in the ultrastructure ofproximal tubular apical membranes. We suggest that this isthe basic disorder causing proximal tubular dysfunction,either through a diminished resorptive area and decreased

availability of transport proteins or through increased back-leak of solutes from the proximal tubular cell. The cause ofthe ultrastructural changes remains to be determined; pos-sible mechanisms are a direct toxic effect of retained meta-bolites on the cell membrane or a generalized disorder incellular energy metabolism [5].

The hypothesis that the accumulation of intracellularlysine in the proximal tubule because of diminished basolat-eral transport might exercise a cytotoxic effect leadingto renal tubular damage [12] has been confuted by theevidence that patients with hyperlysinaemia due to otherdiseases (i.e. 2-aminoadipic semialdehyde synthetase de-ciency), with a similar heavy load on the renal tubular y+LAT-1 system, never develop a renal Fanconi syndrome [13].

Therefore, we consider the intratubular accumulation of

lysine an unlikely candidate for the development of therenal Fanconi syndrome.

It is known that, in LPI, there is a specic defect ofdibasic aminoacid transport, located at the basolateralmembrane of epithelial cells. However, this defect doesnot cause disturbances in other basolateral transportsystems, such as Na+ and K+-ATPase. It is therefore notlikely that it would be the cause of the Fanconi syndrome.

In conclusion, this case demonstrates a rapid develop-ment of a Fanconi syndrome in a child with LPI. The exist-ence and possible cytotoxic effect of intracellular lysine

accumulation in proximal tubular cells deserve furtherattention.

Conict of interest statement. None declared.

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Received for publication: 8.8.14; Accepted in revised form: 22.9.14

Fig. 2. Light microscopy shows proximal tubules with vacuolatedcytoplasm and brush border attenuation.

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