#4044 FOCAL SEGMENTAL GLOMERULOSCLEROSIS DUE TO A3243G POINT MUTATION IN THE MTDNA CODING FOR TRNALEU(UUR)
Authors: Marchini Michele , Blanco Valentina , Ardini Michela , Panaro Laura , Mocka Sonila , Trezzi Matteo , Chiappini Nadia , Lauria Francesca , Rolla Davide 
Published: June 2023

Abstract

Background and Aims
Mitochondrial Diseases represent a heterogeneous set of maternally inherited diseases that arise by mutations either of the mitochondrial DNA (mtDNA) or in genes of nuclear DNA (nDNA) linked to the cell mitochondrial cross-talk. Many mutations in mtDNA that code for different genes are linked to a wide spectrum of kidney manifestations ranging from focal segmental glomerulosclerosis (FSGS), tubule-interstitial disease (TIN), nephrotic syndrome (NS), and proximal or distal tubulopathy. Renal manifestations of mtDNA disorders are poorly recognized in clinical practice and often misdiagnosed for other conditions like FSGS, Alport Syndrome, steroid-resistant nephrotic syndrome. The guanine for adenine point mutation (A–&gt;G) at position 3243 in the mtDNA has emerged as the most common mutation found in patient with FSGS often accompained by diabetes mellitus and deafness. Focal Segmental Glomerulosclerosis, (FSGS) is the prevalent histologic finding in patients with mtDNA point mutations. Epidemiologic studies have shown that about 1% of diabetic populations in Europe and Japan have this mutation.

Method
A 34-year-old man presented for evaluation with recently diagnosed Type II diabetes mellitus and serum creatinine of 3.9 mg/dL with nephrotic range proteinuria (3.2 gr/die). His family history included Type II diabetes mellitus, chronic kidney disease, coronary artery disease, and hypertension. The patient medical history included hypertension, dyslipidemia, and sensorineural hearing loss which had initially developed during adolescence. Serum creatinine was reportedly elevated years before this presentation, and urinalysis showed mild proteinuria with no microhematuria, white cells, or casts.

Results
On evaluation his blood pressure was 150/90 mmHg, presented mild peripheral leg edema. Laboratory results showed serum creatinine 3.4 mg/dl (eGFR 23 ml/min), HbA1c of 7.2%, albumin 2.8 gr/dL. Urinalysis showed protein (3+), glucose (+1) and no hematuria. Urinary protein-creatinine ratio was 3 mg/g. Serum C3 and C4, immunoglobulins, liver enzymes were normal; autoimmunity tested negative (ANCA, Anti-PLA2r, Anti nuclear antobodies). A kidney biopsy was performed. Light microscopy revealed glomeruli with segmental obliteration of glomerular capillaries by collagenous sclerosis (Fig. 1). Both the Jones methenamine silver stain and Masson's trichrome stain (Fig. 1B, C) showed segmental collagen deposition and sclerosis of glomerular capillaries. Tubular atrophy and fibrosis were also present. Immunofluorescence microscopy was negative. A diagnosis of not otherwise specified focal segmental glomerulosclerosis (NOS FSGS) was made. Interestingly electron microscopy showed mitochondrial abnormalities in the tubular cells. In particular, the cytoplasm of a tubular cell appears to be whiffed by mitochondria of enlarged size and altered shape (Fig. 2). Mithocondria appeared dysmorphic with extensive reduction of mitochondrial cristae (Fig. 2 arrows). The patient was screened for mtDNA mutations and guanine for adenine substitution (A–&gt;G) at position 3243 was detected. The patient received a diagnosis of chronic kidney disease with histological features of FSGS due to an A3243G point mutation in the mtDNA with associated diabetes mellitus and sensorineural deafness.

Conclusion
This case underscores the role of electron microscopy in identifying mithocondrial related nephropathies. Even more important is to evaluate mtDNA mutations in cases with familial FSGS, sensorineural hearing loss, cardiomyopathy and diabetes.