Abstract 825 Inborn Errors of Metabolism Platform, Monday, 5/3

Cystinosis results from lysosomal cystine accumulation due to a defect in the gene for lysosomal cystine transport (CTNS). The condition presents as three major phenotypes of varying severity: nephropathic, intermediate (late onset), and benign, with some overlap. Forty-six percent of nephropathic patients are homozygous for a 65 kb deletion that terminates between exons 3 and 11 of CTNS. Intermediate cystinosis, a rare variant, is distinguished from the nephropathic form by later onset, milder course, and end-stage renal disease (ESRD) later than ten years. In five patients with an intermediate form of cystinosis, 2 sibs reached ESRD at 14 and 15 years respectively, and were found to be doubly heterozygous for a point mutation (753G→A, W153X, known to result in nephropathic cystinosis when homozygous), and an apparent slice site mutation detected by sequencing the two different sized cDNAs obtained by RT-PCR of their mRNA, showing skipping of exon 11 (also present in their mother). Their fibroblast cystine content is 2.13 and 3.28 nmol/mg protein, normal less than 0.10 typical nephropathic 3.3-5.3. Two Taiwanese sisters, at ages 12 9/12 and 14 2/12 years have creatinines of 3.3 and 1.2 mg/dl, heights of 5th and 20th percentiles respectively, point mutations (1308C→G, N323K, and 710G→A. S125N affecting non-transmembrane regions of CTNS, and mildly elevated fibroblast cystine content (1.1 and 1.2 nmol/mg protein). A male diagnosed with cystinosis at 18 years still has marginally functional kidneys at 36 years (creatinine 2.8). Surprisingly, he is he heterozygous for the 65 kb deletion and a frequently encountered 753G→A, W138X mutation, which is nephropathic when homozygous. His leukocyte cystine content is 1.91 nmol/mg protein, typical nephropathic 4.5±2.3. In the first four patients either conserved or splice site mutations probably permit synthesis of protein with some residual function, milder course, and lower levels of cystine storage. The adult may represent an instance of mosaicism, or the operation of modifying genes which mitigate the effects of CTNS mutations.