Endocrine Abstracts

Background: Familial renal glucosuria (FRG) is a rare renal tubular disorder characterized by increased urinary glucose excretion despite normoglycemia. The sodium-glucose cotransporter 2 (SGLT2) is expressed in the proximal renal tubule and is crucial for glucose reabsorption. SLC5A2 is a member of the solute carrier family V transporter genes and encodes for this cotransporter. Mutations in SLC5A2 are the primary cause of FRG.

Case presentation: We report the case of a 44-year-old male who was referred for unexplained glucosuria despite well-controlled diabetes mellitus (with fasting glycemia 138 mg/dl and HbA1c 6,5%) treated with metformin and gliclazide. He was diagnosed with diabetes mellitus at the age of 38. He complained of an unintentional 5-kg weight loss in one year (despite normal appetite) and nycturia. A 24-hour urinary collection revealed overt glucosuria (24,2 g/1,73 m²/24 h) as well as generalized aminoaciduria (hydroxyproline, serine, glycine, alanine, valine, cystine, isoleucine and lysine) and increased uric acid excretion. Renal function was preserved and proteinuria was absent. Whole exome sequencing with analysis of the nephropathy gene panel was performed (with specific attention to the SLC5A2 and HFN1A genes (MODY 3)) and revealed a novel heterozygous c.469-1G>A variant in the SLC5A2 gene. This mutation was classified as class 4 (likely pathogenic) according to the American College of Medical Genetics guidelines. In-silico analysis predicted a possible splice defect. No other pathogenic variants were detected. Familial genetic testing was recommended to the patient and his children.

Discussion: The SLC5A2 gene encodes the kidney-specific low-affinity/high-capacity sodium-glucose cotransporter, SGLT2. Mutations in SLC5A2 are associated with FRG, which is considered to be a benign disorder of proximal tubular glucose transport. FRG can be inherited in an autosomal recessive or autosomal dominant pattern. Individuals with bi-allelic pathogenic variants are considered to have a more severe phenotype than patients who only have a heterozygous variant. Generalized or selective aminoaciduria is a feature of FRG, although it has been suggested that aminoaciduria in this setting is a consequence of the impairment of glucose reabsorption rather than directly related to the SLC5A2 mutation.

Conclusion: We describe a patient with renal glucosuria despite well-controlled diabetes mellitus, associated with a novel heterozygous c.469-1G>A mutation in the SLC5A2 gene. The pathogenesis of aminoaciduria and hyperuricosuria with aberrant renal glucose transport remains to be established.