Rience recurrent EIARF at various intervals. Serum UA level is normal or only slightly reduced on presentation (due to renal failure) and decreases to less than 1 mg/dl after renal recovery, which usually occurs in all patients. Our patient represents the most severe end of the spectrum of RHUC2 clinical and biochemical characteristics. In fact, SLC2A9 analysis identified two distinct missense mutations (p.PepstatinMedChemExpress Pepstatin A Gly216Arg and p.Arg380Trp); although segregation analysis was not performed, the severe clinical phenotype strongly suggests that they are present in compound heterozygosity. Both missense mutations have already been described in patients with RHUC2, but they have never been identified in combination in a single patient. In previously documented patients, the recessive p.Gly216Arg mutation was either homozygous or in compound heterozygous patients [7], whereas the p.Arg380Trp substitution was observed only in heterozygosity and was therefore classified as a dominant mutation [11,15].Comparison of the clinical and biochemical characteristics of our patient with the other recently reported patients provides new insights into the genotype-phenotype correlation of SLC2A9 mutations associated with UA homeostasis. The p.Arg380Trp substitution was one of the first causal mutations identified in the SLC2A9 gene, being found in heterozygosity in a Japanese mother and her son who had serum UA levels of 1.5 and 2.7 mg/dl respectively, and an FE-UA of 15 [11]. These two patients were PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/26080418 selected from the large database of the personnel of the Japan Maritime Self-Defense Force on the basis of UA levels, and severe clinical manifestations were not recorded. Therefore, this apparently dominant mutation alone is probably insufficient to cause a complete clinical phenotype of the disease, i.e., EIARF and hospitalization (Table 2). The p.Gly216Arg substitution was originally described in a 14-year-old boy in compound heterozygosity with the p.Asn333Ser mutation [7]. The patient presented with EIARF (maximum serum creatinine level of 297 mol/l) following a cross-country run, and his serum UA concentration was consistently below the normal range at 0.67 mg/dl (normal range 2.35?.90 mg/dl), daily urinary UA excretion was 2190 mg (normal range 250?50 mg), and FE-UA was 93 (normal range 4?4 ). The renal recovery was complete, and after the original episode, he had further incidences of mild abdominal pain and mild renal dysfunction following exercise. The p.Gly216Arg mutation was also found in homozygosity in a 12-year-old patient presenting with severe EIARF requiring dialysis, abdominal pain and vomiting. His serum UA was found to be persistently low at 0.5 mg/dl, his urinary UA excretion was 2050 mg/die, and FE-UA was 45.8 ; the patient recovered normal renal function. Both of these patients presented with severe EIARF, similar to our patient; however, their UA levels were higher (0.67 and 0.5 mg/dl vs. 0.1 mg/dl) and the FE-UA was significantly lower (93 and 45.8 vs. >150 ) compared with our patient. Therefore, we can speculate that the p.Arg380Trp substitution most severely impairs the GLUT9 function in comparison with the p.Gly216Arg and p.Asn333Ser mutations, giving our compound heterozygous patient an increased risk of EIARF. To date, several studies have described the clinical and molecular characteristics of different patients with a severe type of RHUC2 caused by compound heterozygous or homozygous loss-of-function mutations in the SLC2A9 gene,.