title: Clinical consequences of PKHD1 mutations in 164 patients with autosomal-recessive polycystic kidney disease (ARPKD).
abstract: BACKGROUND
  ARPKD is associated with mutations in the PKHD1 gene on chromosome 6p12. Most cases manifest peri-/neonatally with a high mortality rate in the first month of life while the clinical spectrum of surviving patients is much more variable than generally perceived.
  
  
  METHODS
  We examined the clinical course of 164 neonatal survivors (126 unrelated families) over a mean observation period of 6 years (range 0 to 35 years). PKHD1 mutation screening was done by denaturing high-performance liquid chromatography (DHPLC) for the 66 exons encoding the 4074 aa fibrocystin/polyductin protein.
  
  
  CONCLUSIONS
  This is the first study that reports the long-term outcome of ARPKD patients with defined PKHD1 mutations. The 1- and 10-year survival rates were 85% and 82%, respectively. Chronic renal failure was first detected at a mean age of 4 years. Actuarial renal survival rates [end point defined as start of dialysis/renal transplantation (RTX) or by death due to end-stage renal disease (ESRD)] were 86% at 5 years, 71% at 10 years, and 42% at 20 years. All but six patients (92%) had a kidney length above or on the 97th centile for age. About 75% of the study population developed systemic hypertension. Sequelae of congenital hepatic fibrosis and portal hypertension developed in 44% of patients and were related with age. Positive correlations could further be demonstrated between renal and hepatobiliary-related morbidity suggesting uniform disease progression rather than organ-specific patterns. PKHD1 mutation analysis revealed 193 mutations (70 novel ones; 77% nonconservative missense mutations). No patient carried two truncating mutations corroborating that one missense mutation is indispensable for survival of newborns. We attempted to set up genotype-phenotype correlations and to categorize missense mutations. In 96% of families we identified at least one mutated PKHD1 allele (overall detection rate 76.6%) indicating that PKHD1 mutation screening is a powerful diagnostic tool in patients suspected with ARPKD.
authors.affiliation: Department of Human Genetics, Aachen University, Aachen, Germany. cbergmann@ukaachen.de
authors.forename: Carsten
authors.initials: C
authors.lastname: Bergmann
authors.forename: Jan
authors.initials: J
authors.lastname: Senderek
authors.forename: Ellen
authors.initials: E
authors.lastname: Windelen
authors.forename: Fabian
authors.initials: F
authors.lastname: Küpper
authors.forename: Iris
authors.initials: I
authors.lastname: Middeldorf
authors.forename: Frank
authors.initials: F
authors.lastname: Schneider
authors.forename: Christian
authors.initials: C
authors.lastname: Dornia
authors.forename: Sabine
authors.initials: S
authors.lastname: Rudnik-Schöneborn
authors.forename: Martin
authors.initials: M
authors.lastname: Konrad
authors.forename: Claus P
authors.initials: CP
authors.lastname: Schmitt
authors.forename: Tomas
authors.initials: T
authors.lastname: Seeman
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Neuhaus
authors.forename: Udo
authors.initials: U
authors.lastname: Vester
authors.forename: Jutta
authors.initials: J
authors.lastname: Kirfel
authors.forename: Reinhard
authors.initials: R
authors.lastname: Büttner
authors.forename: Klaus
authors.initials: K
authors.lastname: Zerres
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010641:Phenotype; D017044:Polycystic Kidney, Autosomal Recessive / Q000235:genetics*; D011110:Polymorphism, Genetic; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics*
chemical_list: C451750:PKHD1 protein, human; D011956:Receptors, Cell Surface