Approach to the evaluation of heritable diseases and update on familial focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is a pathological entity that is a significant cause of morbidity and mortality throughout the world. It is also a significant cause of end-stage renal disease (ESRD). Glomerular disease is the third leading cause of ESRD, and FSGS comprises a significant proportion of this subgroup. Up to 20% of individuals with ESRD have FSGS. It has been reported in patients from varied ethnic backgrounds including individuals who are of Spanish, North American, North European and African descent. The diagnosis of FSGS is based on renal pathology and requires the presence of areas of glomerular sclerosis and tuft collapse that are both focal and segmental. The clinical hallmarks of FSGS include proteinuria, nephrotic syndrome and, frequently, the progressive loss of renal function. At present, there are no consistently reliable treatments for FSGS and response rates to available treatments have been estimated at <30-50%. FSGS has been characterized previously as having primary (idiopathic), secondary and familial forms. In the latter category, both autosomal recessive and dominant inheritance patterns have been reported. Advances in molecular genetics technology and mapping, including high-throughput genotyping for genomic screening, provide powerful tools for the analysis of renal diseases. Genes associated with many familial renal disorders that lead to ESRD have been isolated; these include Alport's nephropathy, familial juvenile nephronophthisis and adult polycystic disease. Recently, the genetic mutation (ACTN4) causing a form of autosomal dominant FSGS (ACTN4) and congenital nephrotic syndromes (NPHS2) have been described. The existence of hereditary forms of FSGS permits the use of molecular genetics techniques to study the pathogenesis of this disorder.