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 the mode of transmission and the involvement of candidate genes known to encode 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 analysis studies in 4 candidate regions known to contain NHE genes.
Results: The diagnosis of CSD in 4 of 5 patients was based on daily fecal sodium excretion between 98 and 190 mmol/L, hyponatremia, metabolic acidosis, and low-to-normal urinary sodium concentrations. Pedigree analysis of the affected 2 CSD families revealed parental consanguinity and a common single ancestor 5 generations ago. Homozygosity mapping and/or multipoint linkage analysis excluded the NHE1 locus on chromosome 1, NHE2 locus on chromosome 2, NHE3 locus on chromosome 5, and NHE5 locus on chromosome 16 as potential candidate genes for CSD in this pedigree. Results on NHE4 were inconclusive because the precise chromosomal location of this NHE gene in humans is currently unknown.
Conclusions: Our data indicate that CSD is an autosomal recessive disorder but is not related to mutations in the NHE1, NHE2, NHE3, and NHE5 genes encoding for currently known sodium/proton exchangers.