Presence of mitochondrial dysfunction in a case of Fanconi syndrome with normoglycemic MODY1
Yuko Fujii1, Hideki Matsumura2, Kei Murayama3
1Department of Pediatrics, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki, Osaka, Japan. yuko.fujii@ompu.ac.jp.
Abstract:
Maturity-onset diabetes of the young 1 (MODY1) is characterized by macrosomia and transient hypoglycemia in neonates, in addition to diabetes mellitus (DM). Only patients with MODY1 harboring a pathogenic variant (c.187C > T; p.R63W) in HNF4A are sure to develop Fanconi syndrome (FS). Here we report the successful diagnosis of MODY1 in a patient harboring p.R63W before confirmation of DM-related hyperglycemia after being alerted to the presence of abnormal mitochondria in a kidney-biopsy specimen revealed by electron microscopy. The patient was born at 39 weeks of gestation with macrosomia, elevated levels of liver enzymes, and transient hypoglycemia. At three years of age, proteinuria was found by chance, and further laboratory investigations revealed metabolic acidosis, mild renal dysfunction, hypouricemia, proteinuria, aminoaciduria, and glycosuria. On this basis, we diagnosed the patient as having FS and performed percutaneous renal biopsy. Light microscopy revealed no evidence of proximal tubule disorder, but electron microscopy demonstrated mitochondria with disordered cristae in glomerular podocytes and giant mitochondria in proximal tubules. Mitochondrial nephropathy was suspected, and skin fibroblasts from the patient grown on galactose medium showed decreased oxygen consumption suggestive of mitochondrial dysfunction. Therefore, genetic testing was performed and a pathogenic variant (c.187C > T; p.R63W) in HNF4A was detected. Mitochondrial dysfunction in a Drosophila and murine model of patients with both MODY1 and FS has already been reported, and we detected it in this human MODY1/FS patient on the basis of functional tests and imaging. We believe mitochondrial dysfunction may be involved in the pathogenesis of MODY1/FS.
Insights
Maturity-onset diabetes of the young 1 (MODY1) with Fanconi syndrome (FS) was diagnosed early in a patient with HNF4A gene variant. Electron microscopy revealed abnormal mitochondria, confirming mitochondrial dysfunction in this rare condition.
Area of Science:
- Genetics
- Nephrology
- Endocrinology
Background:
- Maturity-onset diabetes of the young 1 (MODY1) presents with neonatal macrosomia, transient hypoglycemia, and diabetes mellitus (DM).
- Fanconi syndrome (FS) is specifically linked to MODY1 in patients with a pathogenic HNF4A variant (c.187C>T; p.R63W).
- Early diagnosis of MODY1/FS is challenging, often relying on later manifestation of hyperglycemia.
Purpose of the Study:
- To report the successful early diagnosis of MODY1 in a patient with the HNF4A p.R63W variant before overt hyperglycemia.
- To investigate the role of mitochondrial dysfunction in the pathogenesis of MODY1 associated with FS.
Main Methods:
- Kidney biopsy with electron microscopy to identify mitochondrial abnormalities.
- Functional tests on skin fibroblasts (galactose medium) to assess oxygen consumption.
- Genetic testing to detect pathogenic variants in HNF4A.
- Analysis of clinical presentation including neonatal complications and renal function.
Main Results:
- The patient presented with macrosomia, transient hypoglycemia, and later developed FS symptoms (proteinuria, acidosis, hypouricemia, aminoaciduria, glycosuria).
- Electron microscopy revealed disordered mitochondrial cristae and giant mitochondria in renal biopsy specimens.
- Skin fibroblasts showed decreased oxygen consumption, indicating mitochondrial dysfunction.
- Genetic testing confirmed the pathogenic HNF4A variant (c.187C>T; p.R63W).
Conclusions:
- Mitochondrial dysfunction is detectable in patients with MODY1 and FS, supporting its role in the disease's pathogenesis.
- Early identification of mitochondrial abnormalities via kidney biopsy can facilitate the diagnosis of MODY1/FS prior to hyperglycemia.
- This case highlights the importance of considering genetic testing and mitochondrial evaluation in neonates with unexplained macrosomia, hypoglycemia, and renal abnormalities.
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