Citron, Lorenzo (2008) Correlazione genotipo-fenotipo in una famiglia a quattro generazioni con malattia di dent tipo 1 ricorrente. [Tesi di dottorato]
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Background . Dent's disease is an X-linked recessive renal proximal tubular disorder. It is usualy characterized by low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis and progressive renal failure. Aminoaciduria, phosphaturia, glycosuria, uricosuria and an acquired impairment of urinary acidification may also occur. At the present time two kinds of Dent's disease are known: Dent's disease-1(OMIN No 300009) and Dent's disease-2 (OMIN No 300555). The first associated with mutations in CLCN5 that encodes the renal chloride channel CIC-5. the progression of the nephropaty into uraemia would occur between the third and fifth decade of life.
Object of the study. The aim of this study is to carry out a metabolic- instrumental survey of the renal calculosis in a family where some members have mutations in the CLCN5 gene.
Material and methods. A patient from clinical pediatrics was admitted to our centre due to a suspected Dent's disease so a molecular analysis was performed and a CLCN5 gene mutation was detected. We created a family tree over four generations, the molecular analysis was performed on 26 out of the generations, the molecular analysis was performed on 26 out of the 52 members of the family. The nephrological clinic followed up a group of 9 patients, from the second and third generation, and carried out a metabolic-instrumental survey of the nephrolitiasis. For each patient we evaluated the creatinine, uric acid, Ca, P, K, Cl, Mg both at the plasmatic level and urinary level, pH hematic (venous).
Furthemore we tested PTH, osteocalcina, vt.D3, bony ALP at the plasmatic level. The 24h urine excretion, oxalate (Ox) and citrate were tested. All patients were studied with renal ultrasonography.
Results. Besides the proband, the mutation was detected also in 7 males out 11 and 11 heterozygotic females out of 15. Six patients out of 9 shoved hyperphosphaturia, hypersodiuria and hyperuricuria was associated with hyperuricemia. In 5/9 patients hypercalciuria and hyperossaluria were detected; in 2/9 hypocitraturia was detected. None of the 9 patients showed hypomagnesiuria or hypomagnesaemia. All patients had a normal level of PTH, osteocalcina and bony ALP, the same was for the clearance of the creatinine. The statistical analysis carried out with t Student's tests between mutaded and non-mutaded patients did not reveal differences as for UCa e UPO4. The linear regression test revealed the following correlations: TmPO4/VFG vs UPO4 (r=-0.82 p=0.006); EFNa/UNa /r=0.77 p=0.013); UNa/UPO4(r=0.73 p=0.023), UCa vs UPO4 (r=0.74 p=0.02), UNa vs UCa (r =0.72 p=0.026). According to the renal ultrasonography 8/9 patients showed bilateral microlithiasis.
Conclusions. None of the members of the 3rd generation had renal failure including the 3 mutated patients. Moreover these patients showed hyperuricemia that didn't seen related to renal involvement. In all the subjects we studied, there was the presence and the bilaterality of the microlithiasis. Although in the 3 subjects there were the distinctive signs of the proximal tubulopathy, from the metabolic survey we detected a picture similar to the typical bilateral relapsing nephrolithiasis.
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