Nephrotic syndrome type 9 (NPHS9) is an autosomal recessive chronic kidney disorder characterized by significant proteinuria resulting in hypoalbuminemia and edema. Onset is in the first or second decade of life. The disorder is steroid treatment-resistant and usually ... Nephrotic syndrome type 9 (NPHS9) is an autosomal recessive chronic kidney disorder characterized by significant proteinuria resulting in hypoalbuminemia and edema. Onset is in the first or second decade of life. The disorder is steroid treatment-resistant and usually progresses to end-stage renal disease requiring transplantation. Renal biopsy shows focal segmental glomerulosclerosis (FSGS) or collapsing FSGS (summary by Ashraf et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of nephrotic syndrome and FSGS, see NPHS1 (256300).
Ashraf et al. (2013) reported 15 patients from 8 unrelated families with steroid-resistant nephrotic syndrome. Disease onset was typically between ages 10 and 20 years, although several had earlier onset, including 1 patient with onset in the first ... Ashraf et al. (2013) reported 15 patients from 8 unrelated families with steroid-resistant nephrotic syndrome. Disease onset was typically between ages 10 and 20 years, although several had earlier onset, including 1 patient with onset in the first year of life. Histology showed focal segmental glomerulosclerosis (FSGS) or collapsing FSGS, and electron microscopy showed effacement of the foot processes of podocytes. One patient was treated with high-dose CoQ10 supplementation, in addition to other medications, which resulted in some clinical improvement in renal function.
In 15 patients from 8 unrelated families with steroid-resistant nephrotic syndrome, Ashraf et al. (2013) identified 11 different mutations in the ADCK4 gene (see, e.g., 615567.0001-615567.0007). All mutations occurred in the homozygous or compound heterozygous state and segregated ... In 15 patients from 8 unrelated families with steroid-resistant nephrotic syndrome, Ashraf et al. (2013) identified 11 different mutations in the ADCK4 gene (see, e.g., 615567.0001-615567.0007). All mutations occurred in the homozygous or compound heterozygous state and segregated with the disorder in the families. The mutation in the first family was found by homozygosity mapping combined with whole-exome sequencing; subsequent mutations were found by whole-exome sequencing in 6 additional families. The final patient was identified from a cohort of 400 individuals with steroid-resistant nephrotic syndrome who underwent next-generation sequencing. Patient-derived cells showed CoQ10 deficiency and reduced mitochondrial respiratory enzyme activity. Ashraf et al. (2013) demonstrated that the ADCK4 protein localizes to the mitochondria and foot processes in podocytes, as well as to proximal tubules and collecting ducts in the kidney. Ashraf et al. (2013) concluded that a loss of ADCK4 function was responsible for the phenotype.