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Fanconi renotubular syndrome, type 1 (FRTS1; MIM #134600) is an ultrarare autosomal dominant disorder caused by pathogenic variants in the GATM gene, which encodes glycine amidinotransferase that is required for the regeneration of ATP from ADP in cells mitochondria. FRTS1 is characterized by generalized proximal renal tubular dysfunction, manifesting early in life and progressing to ESKD in middle adulthood. Only six missense GATM variants associated with FRTS1 have been reported by now.
The aim of the study was to present two cases with FRTS1 due to novel missense variants in the GATM gene.
Case 1. The girl was born from non-consanguineous parents with birth weight 2740 g and height 49 cm. Family history of kidney disease was negative. The child presented with failure to thrive from the age of 17 months. Lower limb deformities revealed at the age of 5 years. At the first admission at the age of 9 years the girl had short stature (height and weight <3P), full-blown Fanconi syndrome (FS) including polyuria, hypokalemia (3.5 mmol/l), metabolic acidosis (pH 7.32, HCO3- 16 mmol/l), phosphaturia with decreased TmP/eGFR (0.38 mmol/mmol), glycosuria (17 mmol/l), low molecular weight (LMW) proteinuria (urinary β-2 microglobulin level 31.5 mg/L), aminoaciduria and rickets (X-ray: widening of the distal femoral and proximal tibial growth plates). She had high alkaline phosphatase (APL) level (1670 U/L) and decreased eGFR (71.2 ml/min/1.73 m2). Kidney ultrasound showed medullary nephrocalcinosis (NC) grade 2. NGS revealed novel heterozygous variant c.1079T>A in exon 8 in GATM gene. Sanger sequencing and family segregation analysis are pending. The girl has been treated with L-сarnitine, phosphate and potassium supplements, calcitriol and sodium bicarbonate for 8 years. Ongoing therapy has not resulted in the correction of Fanconi syndrome, improvement of growth rate and rickets. By the age of 17 years her eGFR decreased to 38.5 ml/min/1.73 m2.
Case 2. The girl was the first child of unrelated parents without family history of kidney disease. Her birth weight was 3900 g and height 56 cm. At the age of 10 months the child presented with glycosuria (13.3 mmol/l), LMW proteinuria (β-2 microglobulin 15 mg/L), aminoaciduria. Bone deformities appeared in the second year of life. On examination at the age of 2 years the girl had severe dental demineralization, muscle hypotonia, hypokalemia (3.3 mmol/l), metabolic acidosis (pH 7.3, HCO3- 14 mmol/l), hypophosphatemia 0.91 mmol/l with decreased TmP/eGFR (0.4 mmol/mmol), elevated serum APL activity (1181 U/l), eGFR was 95.1 ml/min/1.73 m2. A lower limb X-ray revealed widening of the metaphysis. Kidney ultrasound demonstrated medullary NC grade 1. NGS identified novel heterozygous variant c.1076C>T in exon 8 of GATM gene. Sanger sequencing and family segregation analysis are pending. The girl received L-carnitine, phosphate and potassium supplements, calcitriol and sodium bicarbonate constantly. At the age of 11 years the girl had normal growth and weight (H 75P, W 50P), absence of signs of rickets, medullary NC grade 2 and eGFR 88 ml/min/1.73 m2.
Novel missense variants in the GATM gene associated with FRTS1 were identified in 2 children. These cases demonstrate variability of response to treatment of FS and rates of decline in kidney function which could be explained by different effect of the disease-causing GATM variants on the protein. We recommend to perform testing of GATM variants in all patients with FS even in the absence of kidney failure.