Congenital sodium diarrhea is an autosomal recessive disorder of sodium/proton exchange but unrelated to known candidate genes

Background & Aims: Congenital sodium diarrhea (CSD) is caused by defective sodium/proton exchange with only 6 sporadic cases reported. The genetics of the disease have not been established. We studied 5 infants with secretory diarrhea, identified in a circumscribed rural area in Austria, to define t he mode of transmission and the involvement of candidate genes known to enc ode for sodium/proton exchangers (NHEs). Methods: We collected clinical and laboratory data from 5 affected patients, analyzed the pedigrees of their families, and performed homozygosity mapping and multipoint linkage analysi s studies in 4 candidate regions known to contain NHE genes. Results: The d iagnosis of CSD in 4 of 5 patients was based on daily fecal sodium excretio n between 98 and 190 mmol/L, hyponatremia, metabolic acidosis, and low-to-n ormal urinary sodium concentrations. Pedigree analysis of the affected 2 CS D families revealed parental consanguinity and a common single ancestor 5 g enerations ago. Homozygosity mapping and/or multipoint linkage analysis exc luded the NHE1 locus on chromosome 1, NHE2 locus on chromosome 2, NHE3 locu s on chromosome 5, and NHE5 locus on chromosome 16 as potential candidate g enes for CSD in this pedigree. Results on NHE4 were inconclusive because th e precise chromosomal location of this NHE gene in humans is currently unkn own. Conclusions: Our data indicate that CSD is an autosomal recessive diso rder but is not related to mutations in the NHE1, NHE2, NHE3, and NHE5 gene s encoding for currently known sodium/proton exchangers.