Diarrhea, Chronic, With Villous Atrophy

A number sign (#) is used with this entry because of evidence that chronic diarrhea with villous atrophy can be caused by deletion/duplication events involving the ND4L (516004), ND5 (516005), and MTCYB (516020) genes.

Clinical Features

Cormier-Daire et al. (1994) described 2 unrelated children with onset of chronic diarrhea and villous atrophy in the first years of life. Elevated plasma lactate concentrations and lactate/pyruvate and ketone body molar ratios suggested a genetic defect of oxidative phosphorylation. Analysis of the mitochondrial respiratory chain showed a complex III deficiency in muscle of both patients. One patient gradually developed diabetes mellitus and showed severe growth retardation, severe renal insufficiency, hypertrichosis, cerebellar ataxia, and bilateral sensorineural deafness. She died at 12 years of age after a prolonged tonic-clonic seizure. The other patient gradually developed retinitis pigmentosa, cerebellar ataxia, pyramidal syndrome, proximal muscle weakness, and sensorineural deafness. Skeletal muscle biopsy provided evidence of ragged-red fibers. She died at 12 years of age.

Molecular Genetics

In 2 unrelated children with chronic diarrhea and villous atrophy, Cormier-Daire et al. (1994) found evidence of heteroplasmic mitochondrial DNA rearrangements that involved deletion and deletion-duplication. Directly repeated sequences (10 and 11 bp, respectively) were present in the wildtype mitochondrial genome at the boundaries of the deletion. Neither parent of either patient had rearranged molecules in circulating lymphocytes. In 1 patient, the deletion extended from nucleotide 10744 in the ND4L gene (516004) to nucleotide 14124 in the ND5 gene (516005). In the other patient, the 4,191-bp deletion extended from 10665 in the ND4L gene to nucleotide 14856 in the cytochrome b gene (MTCYB; 516020).