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Abstract: SA-PO528

Autosomal Dominant Fanconi Syndrome and CKD Associated With Glycine Amidinotransferase Mutation: A Rare Genetic Syndrome

Session Information

  • Genetic Diseases: Diagnosis
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

  • 1102 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Portales Castillo, Ignacio A., Massachusetts General Hospital, Boston, Massachusetts, United States
  • Hanna, Patrick, Massachusetts General Hospital, Boston, Massachusetts, United States
  • Lundquist, Andrew L., Massachusetts General Hospital, Boston, Massachusetts, United States
  • Jüppner, Harald, Massachusetts General Hospital, Boston, Massachusetts, United States
  • Traum, Avi, Boston Children's Hospital, Boston, Massachusetts, United States
  • Allegretti, Andrew S., Massachusetts General Hospital, Boston, Massachusetts, United States
Introduction

Chronic kidney disease (CKD) secondary to monoallelic mutations in the gene glycine amidinotransferase (GATM) was reported in 2018, without subsequent patients published in the literature. We now present the case of a female with hereditary Fanconi syndrome, nephrolithiasis and mild CKD, found with a heterozygous GATM mutation.

Case Description

A 27 year-old female from Ecuador presented to the adult nephrology clinic for evaluation of renal tubular acidosis (RTA) and CKD. She was first seen at the pediatric nephrology clinic 10 years earlier for a non-anion gap metabolic acidosis (serum bicarbonate 19 mmol/L) and nephrolithiasis. Work-up at that time revealed CKD stage 2 (GFR of ~60 mL/min), hypokalemia at 3.3 mEq/L and low-normal serum phosphate at ~3.5 mg/dl. Urine pH was 7 with glucosuria, amino aciduria, moderately increased phosphate (FePO4 27%) and calcium excretion (300 mg calcium/24 hours). At the time, potassium citrate was prescribed for suspected type 2 RTA.
During our evaluation at the adult nephrology clinic, serum and urine parameters remained unchanged, except for worsening hypophosphatemia (2.2 mg/dL) with normal 1,25(OH)2 vitamin D of 44 pg/mL and PTH 28 pg/mL. Her family history was notable for a younger sister with RTA and her father with ESRD at age 30. She was referred to the Massachusetts General Hospital Renal Genetics Clinic with a diagnosis of hereditary Fanconi syndrome. Genetic testing revealed a heterozygous variant of uncertain significance (VUS) in the GATM gene (Pro341Leu). In multidisciplinary review, this VUS was strongly suspected to be causative, and was genetically confirmed in her father and sister.

Discussion

Fanconi syndrome and CKD in association with heterozygous mutations in GATM have been described thus far in a single research study. Using a proximal tubular cell model, pathologic GATM mutations caused fibrillary aggregates in the mitochondria, also present in patients’ kidney biopsies. Our patient presents with Fanconi syndrome and nephrolithiasis which was not previously associated with variants in this gene. This case illustrates the value of genetic testing, the importance of access to genetic expertise for interpretation of a VUS and the results hold promise for personalized treatment targeting expression of GATM with creatine.