High-quality health care for children with certain inherited nephrotic syndrome
Nephrotic syndrome (NS) is a disorder of the glomerular filtration barrier, a highly specialized tri-layer structure with unique functional properties. Recent advances emanating from the field of molecular genetics have revealed the podocyte as probably the central player in the control of glomerular filtration, more specifically, the cell-cell junction between adjacent podocyte foot processes, namely, the slit diaphragm, has been revealed to be made up of a sophisticated multi-protein complex which dynamically `controls foot process architecture via signaling to the acting cystoskeleton. Key genes that have been identified from the study of inherited nephrotic syndrome include those encoding nephrin, podocin, TRPC6, and α-actinine-4.
NS may be classified by response to steroids, i.e. steroid responsive and steroid resistant, with the possibility that there is a different pathophysiology which confers response to steroid. Most genetic forms of Steroid-Resistant Nephrotic Syndrome (SRNS) represent structural changes in the glomerulus or, more specifically, the podocyte, which are unlikely to respond to current therapy. In total, this only explains a small percentage of total cases.
The nature of the condition and the proportion of familial forms have led to much work on the genetics of NS, with a resultant expansion in the knowledge of genes involved
In a large European cohort of 89 children from 80 families, 66.3% of patients presenting within the first year of life were found to carry a mutation in one of four genes: NPHS1, NPHS2, WT1 and LAMB2
Mutations have been described in phospholipase C epsilon 1 (PLCe1; genetic nomenclature is NPHS3), which belongs to the phospholipase C family and is involved in cleavage resulting in the formation of the second messengers DAG and IP3, thereby activating certain cell signaling cascades. Hinkes et al. described truncating mutations in PLCe1 (NPHS3) leading to isolated (non-syndromic) diffuse mesangial sclerosis (DMS) and missense non-truncating mutations leading to FSGS (1). These mutations are increasingly being recognized as resulting in isolated DMS with rapid progression to ESRD and a poor outcome generally; however there are features which differ from the other hereditary forms of NS (2). The initial study described two of the 14 children reported who responded to immunosuppression (one on steroid, one on cyclosporine). Both of these children presented within the first year of life, and both had siblings similarly affected who had progressed to end stage rapidly
Mitochondrial (mt) cytopathies as a cause of NS are rare, but are very important to recognize as interventional treatment to modify the disease may be possible. Modification of disease progression is potentially possible because the mutations affect the co-enzyme Q10 biosynthesis pathway, and this enzyme can be orally supplemented.
Mutations that cause MELAS (mt myopathy, encephalopathy, lactic acidosis and stroke-like episodes) and coenzyme Q10 (CoQ10) deficiency can also cause FSGS in isolation. In the later case, 3 genes are recognized: COQ2, PDSS2, and recently a third gene COQ6, has been reported in 13 individuals from seven families, causing early onset SRNS and sensorineural deafness. Two of these individuals were treated with COQ10 supplementation orally and appeared to respond with a lowering proteinuria; in one patient, the deafness also improved (3)
Nephrologists still have something to learn about whether patients with certain genetic mutations, such as PLCe1, can respond to immunosuppression. For the rare patient for whom a COQ10 biosynthesis pathway defect is discovered, supplemental enzyme therapy to delay or avoid renal failure could be instituted.
1) Hinkes BG et al. Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, LAMB2). Pediatrics 119:e907-e919
2) Gbadegesin R. et al. (2008) mutations in PLCE1 are a major cause of isolated diffuse mesangial sclerosis (IDMS). Nephrol Dial Transplant 23:1291-1297
3) Heeringa SF, et al. (2011) COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness. J Clin Invest 121:2013-2024