Contribution of skin immunohistochemistry in the evaluation of nerve fibers in diabetes mellitus type 2

Abstract

SUELY KAZUE NAGAHASHI MARIE** Mitochondrial disorders are a heterogeneous group of diseases characterized by the dysfunction of the oxidative phosphorilation. As the protein complexes of the respiratory chain are coded by both nuclear and mitochondrial genomes, there are additional difficulties on the clinical and diagnostic approaches to those disorders. The RRF detected on muscle biopsy, a hallmark of mitochondrial proliferation, is not always present on those conditions, neither is the increase of lactic acid level. Since the first description of pathogenic mutation of mitochondrial DNA (mtDNA), in 1988, a molecular criteria has been used for the classification of mitochondriopathies. Among 377 patients with clinical diagnosis of mitochondrial disease and patients with maternal inheritance of diabetes mellitus, and patients with maternal risk factors of dementia, followed-up between the period of 1991 to 2001, by our group, 145 met the clinical criteria for MELAS (40cases), MERRF (27 cases), Leigh Syndrome (LS) (32 cases), Kearns-Sayre Syndrome (KSS) (14 cases), and Chronic Progressive External Ophthalmoplegia (CPEO) (32 cases). Measurements of lactic acid level, muscle biopsy, and neuroimaging were performed on the majority of the cases. Molecular analysis were done on all patients looking for 8 point mutations of mtDNA in MELAS, 3 in MERRF, 6 in LS, 1 in KSS/CPEO, and mtDNA rearrangements on KSS/CPEO. A3243G point mutation of mtDNA was detected in 18 cases with MELAS, including 10 asymptomatic proband's family members. A8344G mutation was observed in 5 cases with MERRF; T8993G and T8993C in two cases with LS; 14 different mtDNA deletions in KSS and 11 deletions in CPEO, including 3 multiple deletions. Phenotypic variability was observed in all 5 groups, with overlap of MELAS, MERRF and LS in one patients, and MELAS and LS in another. An autopsy study of MELAS case showed an universal distribution of A3243G mutation on all tissues studied. The neuropathological findings showed a diffuse degeneration of cerebral cortex with neovascularization, a similar picture observed on LS. Surprisingly the neurons were apparently well preserved even when surrounded by degeneration. Atrophy and deep grey matter lesion were the most frequent neuroimaging findings, particularly in KSS and LS, when compared to MELAS and MERRF. The characteristic distribution of lesion on the tegmen of brain stem was observed in KSS and LS, which is similar to the presentation of Wilson's disease. Interestingly, those 3 diseases share a common alteration: mutation in gene coing for the complex V of the respiratory chain. Although the central nervous system is diffusely lesioned on mitochondriopathies, as show the most sensitive diagnostic methods as functional imaging, and immunohistochemical methods, the order, the degree, and the velocity of those alterations seen to present some differences between the groups, as observed in our cases. A careful analysis concerning those parameters could reveal new details for better understanding of the pat...