Anderson-Fabry disease (AFd) is a rare X-linked lisosomal storage disorder of glycosphingolipid (GL) metabolism, caused by a deficiency of the activity of alpha-galactosidase A (alpha-gal A). The ...progressive accumulation of GL in tissues results in the clinical manifestations of the disease, that are more evident in hemizygous males, and include characteristic skin lesions (angiokeratomas), neurological symptoms (acroparesthesia), ocular features (cornea verticillata), cardiac involvement (left ventricular enlargement, conduction abnormalities), cerebrovascular manifestations (thromboses, hemorrhage, etc.), and kidney involvement with progression to end-stage renal failure (ESRF). ESRF is a common manifestation in hemizygous males (3rd-5th decade) and death occurs around the 5th decade of life because of severe cardiac and/or cerebrovascular complications. Heterozygous females have an attenuated form of this systemic disease. In the kidney, accumulation of GL occurs in the endothelial cells of every vessel, in the epithelial cells of every tubular segment, and in all kinds of glomerular cells. The broad spectrum of renal lesions is a pathophysiological continuum with progressive impairment in the renal function related to continuous intracellular deposition of GL. Electron microscopic study of renal biopsies shows typical osmiophilic inclusion bodies in the cytoplasm of all kind of renal cells, characterized by concentric lamellation of clear and dark layers (35-50 A of periodicity). ESRF is treated by dialysis and kidney transplantation: neither treatment modifies the progression of the cardiovascular and cerebrovascular lesions due to progressive GL deposition. The outcome of kidney transplantation seems to be similar to that found in other non-diabetic patients, but the survival rate on dialysis is lower than in patients with other causes of ESRF. Nowadays, treatment with enzyme replacement infusion with purified alpha-Gal A, produced by a genetically engineered human cell line or Chinese hamster ovocytes, seems to be effective and safe.
Anderson-Fabry disease is a rare inborn X-linked glycosphingolipid storage disorder in which the deficient activity of the enzyme alfa-galactosidase A (alfa-gal A) leads to the progressive tissular ...accumulation of lipidic molecules which, in turn, cause a protean pattern of multi-organ disfunction. Enzyme replacement therapy has recently become available and has proved to be effective in controlling the disorder. We present and discuss the case of a family with this disease, with special attention to the variability of clinical features and the difficulty of a correct diagnosis.
Anderson-Fabry disease (AFd) is caused by an X-linked inborn error in the glycosphingoLipid metabolic pathway due to an enzymatic defect in a lysosomal hydrolase: alpha-galactosidase A. The defect ...results in the progressive accumulation of neutral glycosphingolipids in most body fluids and several tissues. The clinical manifestations of AFd are related to organ damage and, obviously, are more severe in hemizygous males than in heterozygous females. In the third decade of life, the course of the disease involves severe deterioration of kidney function progressing to end-stage renal failure. All kind of cells of renal structures are filled with glycosphingolipid deposits. Electron microscopic studies document typical intracytoplasmic osmiophilic bodies with a characteristic "zebra" or "onion-skin" appearance due to concentric lamellation of alternating clear and dark layers. Clinical interest in Fabry patients is related to recent advances in treatment with an intravenous specific enzyme to modify the biochemical error of the glycosphingolipid catabolic pathway.
Anderson-Fabry disease (AFd) is a rare X-linked disorder characterized by deficiency of alpha-galactosidase A that leads to systemic accumulation of neutral glycosphingolipids, predominantly ...globotriaosylceramide (Gb3), in body fluids and visceral tissues, including the kidney. End-stage renal failure is a common manifestation in hemizygous males that often occurs by the third to fourth decade of life. Usually transplanted patients exhibit improvement in clinical symptoms of the disease, probably related to the production of alpha-galactosidase A from the grafted kidney, but mainly related to the increase in Gb3 clearance by the functioning kidney, and increased survival of red cells due to the correction of the uremic status with an evident decrease in the production of Gb3 depending from hemolysis. Several Fabry patients with successful kidney graft survived for 10-15 years and died for cardiovascular complications related to the metabolic disease. The loss of grafted kidney is due to rejection, thrombosis or sepsis. An important issue considering renal transplantation in AFd is the recurrence of the disease in the kidney graft; however, no evidence regarding this possibility has occurred up to now. We report herein the ultrastructural study of the urinary sediment of a 35-year-old male Fabry patient with a severe clinical form of the disease with progression to ESRF at age 29, and submitted to renal transplantation at 33 years. Ultrastructural findings of the urinary sediment documented several cells, probably tubular epithelial cells, with typical accumulation of myelinic bodies resulting from intracellular storage of neutral glycosphingolipids. This morphological evidence arises the problem of the possible recurrence of AFd in the kidney graft in patients with severe phenotype of the metabolic disease.
Von Hippel-Lindau (VHL) disease is a rare autosomal dominant disorder characterized by multifocal and bilateral renal cell carcinoma and cysts, retinal angiomas, hemangioblastoma of the central ...nervous system, pheochromocytoma, epididymis cystoadenoma, pancreatic cysts and/or islet cell tumors. However, phenotypic manifestations and clinical outcome are wide ranging including inter and intra-familial patterns. The VHL gene has been localized on chromosome 3 p 25-26 and more than 250 germline mutations have been described. The sensitivity of analytic techniques of VHL gene is close to 100%. It is well known that about 25% of VHL patients present de novo mutations, and first cases function as possible founders of new VHL kindreds. Herein, we report the clinical case of a 45-year-old Caucasian female patient affected by bilateral polycystic kidney disease with two renal carcinomas in both kidneys without lynphoadenopathies. She underwent ophthalmologic surgery at 19 years old because of retinal detachment due to bilateral retinal angiomatosis. Direct gene sequencing showed a deletion-insertion in exon 3, starting from nucleotide 499 of the coding sequence (c.499-504 delinstT) in a heterozygous status; it causes a frame-shift and creates a premature stop at codon 170. The genetic study of the unaffected parents and of the unaffected brother confirmed the diagnosis of de novo VHL disease with the dentification of a new germline mutation, never reported in the literature. The patient showed normal kidney function and she did not show other organ lesions or clinical manifestations of VHL disease. She was successfully submitted to renal parenchymal sparing-surgery. In conclusion, it is important to test for germline mutations in VHL patients with the involvement of one organ or a pair of organs. Once the mutation is found in the proband, all family members can be easily tested for the documented mutation. The early identification of VHL patients is very important for clinical and genetic reasons.
Von Hippel-Lindau (VHL) disease is an autosomal dominant syndrome characterized by germline mutations in the VHL tumor suppressor gene located at chromosome 3p25-26 and pleomorphic clinical picture. ...The major clinical manifestations include retinal angiomas, central nervous system hemangioblastomas, pheopleochromocytoma, pancreatic cysts, epididymal cystoadenomas and renal lesions. Recently, we observed a 58-year-old male patient with macrohematuria and a history of nephrectomy due to renal cell carcinoma (RCC). The patient showed retinal angiomatosis, cerebellar hemangioblastomas, multiple pancreatic cysts, right kidney with polycystic features plus two RCC. The patient's offspring, two females and one male, showed VHL lesions, such as retinal angiomatosis, cerebellar hemangioblastomas and polycystic kidney disease (PKD). The affected family members were screened for mutations in the VHL gene. Data suggested the presence of a deletion encompassing exon 1 of the VHL gene. Early diagnosis of VHL disease in patients and their relatives is important for clinical and geneticreasons. VHL disease patients have an increased incidence of malignant carcinomas and the syndrome can mimic the presentation of other cystic kidney diseases. Early diagnosis and molecular genetic testing of family members is essential to improve the clinical management of patients and to allow an accurate risk assessment in asymptomatic individuals. In conclusion, nephrologists and urologists must carefully evaluate patients with PKD and RCC to confirm or exclude VHL disease, and physicians must play a crucial role in the clinical process of therapeutical decisions and choices for VHL patients.
Molecular genetics has strongly influenced clinical medicine and particularly nephrology. Several gene mutations of single-gene hereditary nephropathies have been recently identified. These data are ...useful to develop methods of diagnosis and treatment, but also to understand the pathogenesis of these particular disorders. In this review we focused on several monogenic hereditary renal diseases inducing nephrotic syndrome and other hereditary diseases with renal involvement and progression towards end-stage renal failure.
