Noninvasive diagnosis of the 3243A>G mitochondrial DNA mutation using urinary epithelial cells

Abstract

The 3243A4G mutation is one of the most frequently observed mutations of mitochondrial DNA (mtDNA), and is associated with numerous clinical presentations including mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), progressive external ophthalmoplegia (PEO) and diabetes and deafness. The routine diagnosis of the 3243A4G mutation in blood is difficult as mutation levels are known to decrease in this tissue over time, while in some patients it may be absent. We have directly compared the levels of the 3243A4G mutation in skeletal muscle, blood and urinary epithelial cells in 18 patients and observed a striking correlation between the mutation load in postmitotic muscle and urinary epithelium, a mitotic tissue. These data strongly support the use of urinary epithelial cells as the tissue of choice in the noninvasive diagnosis of the 3243A4G mutation.

Early Onset of Diabetes Mellitus Accelerates Cognitive Decline in Japanese Patients with Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes

“…The Category B criteria comprise three items: 1) high lactate levels in the plasma and/or cerebrospinal fluid (CSF) or deficiency of mitochondria-related enzyme activities, 2) mitochondrial abnormalities based on a muscle biopsy, and 3) definitive mitochondrial gene mutations (Yatsuga et al 2012). The A3243G mutation was confirmed in peripheral leukocytes, skeletal muscles, or urinary epithelial cells, as previously reported (Suzuki et al 2003;McDonnell et al 2004). Diagnosis of diabetes mellitus was based on the diagnostic criteria of JDS, and the values for glycated hemoglobin (HbA1c) were described with 0.25% added to the 1.02-fold JDS values (Committee of the Japan Diabetes Society on the Diagnostic Criteria of Diabetes Mellitus et al 2010).…”

Maternally inherited mitochondrial DNA disease in consanguineous families

“…This highlights a potential pitfall in screening familial samples for mt-tRNA mutations and the importance of selecting clinically relevant tissues for investigation. 16,17 In our patient, the age of onset, 14 in tandem with combined respiratory chain deficiencies and marked histological abnormalities, was highly suggestive of an mtDNA rather than nuclear genetic abnormality.…”

Mutations in mitochondrially encoded complex I enzyme as the second common cause in a cohort of Chinese patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes

“…Meanwhile, urinary sediment or follicles can be good non-invasive samples for mtDNA mutation screening. 8,18 Also, in order to avoid false negative results when doing whole mtDNA sequencing, muscle or other post-mitotic tissue DNA is highly recommended, especially when we take both the high cost and time consumption of whole mtDNA sequencing into consideration.…”

“…[5][6][7][8][9] The clinical hallmark of MELAS is stroke-like episodes that cause the abrupt onset of focal neurological deficits at a young age. Neuroimaging studies and measurement of blood lactate are useful screening tests for the diagnosis of MELAS, though the definite diagnosis of MELAS relies on the ragged red fibers (RRFs) or strongly succinate dehydrogenase-stained vessels (SSVs) demonstrated by muscle biopsy, or the causative mtDNA mutation confirmed by molecular genetic studies.…”