Conclusion-The most severe clinical phenotype, LS 3243, was associated with the highest proportion of the A3243G mutation as well as the most prominent histological and biochemical abnormalities. (Arch Dis Child 2000;82:407-411)

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Five unrelated patients harboring the A3243G mutation in the mitochondrial DNA (mtDNA) but presenting with different clinical phenotype were studied for their percentage of mutation at the single muscle fiber levels. One patient had a clinically and pathologically defined Leigh syndrome (LS), two showed mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), another showed progressive external ophthalmoplegia (PEO), and the other showed mitochondrial diabetes mellitus (MDM). The mutation load was greater in the muscle from the patient with LS (92%), who showed more than 80% even in the non-ragged red fibers (RRF) and also presented the highest proportion of RRF. The patients with MELAS had lower mutation levels as well as a lower proportion of RRF, and these two parameters were even lower in the PEO and MDM patients. These results were consistent with the concept that differences in the mutation load and in the somatic distribution of the mutation among different cells and tissues are responsible for the differences in phenotypical expression of the disease.

Cytokines have been regarded as effector molecules responsible for beta-cell death and major histocompatibility complex hyperexpression in endocrine pancreas of type I diabetes. However, the mechanism that results in beta-cell-selective destruction has not been elucidated. We demonstrated in this study, using cell lines of transformed mouse beta-cells and alpha-cells, that only pancreatic beta-cells but not alpha-cells produced tumor necrosis factor-alpha when exposed to interleukin-1 beta. Northern blot analysis confirmed the beta-cell-selective expression of tumor necrosis factor-alpha mRNA. Interleukin-1 beta also provoked tumor necrosis factor-alpha mRNA expression in vitro by normal mouse islet cells. Because tumor necrosis factor-alpha has been shown to potentiate beta-cell cytotoxicity of interleukin-1 and interferon-gamma, tumor necrosis factor-alpha produced in situ by beta-cells might be self-destructive. In fact, a low dose of interleukin-1 beta in combination with a low dose of interferon-gamma preferentially injured beta-cells. Hence endogenous tumor necrosis factor-alpha production by beta-cells may be involved in beta-cell-selective destruction in type 1 diabetes.

Graves' disease (GD) is an autoimmune disorder with genetic predisposition. Interferon-gamma (IFN-gamma) is an important mediator of inflammatory and immune responses. The aim of the present study was to investigate whether the polymorphism of IFN-gamma gene is associated with the development of GD or with clinical course during the antithyroid drug therapy. We have studied the CA repeat polymorphisms in the first intron of IFN gamma gene in Japanese patients with GD (n = 162) and healthy control subjects without antithyroid autoantibodies or family history of autoimmune disorders (n = 133). There was no difference in allele frequency of IFN-gamma gene polymorphism between patients with GD and control subjects. However, the allele 4 (15 CA repeats) frequency was significantly greater in patients whose antithyrotropin receptor antibody (TRAb) became negative within 3 years by antithyroid drug treatment than those with consistently positive TRAb for more than 3 years (34.1% vs. 15.7%, chi2 = 8.545, p = 0.0035, pc = 0.049). The in vitro production of IFN-gamma by concanavalin A-stimulated peripheral blood mononuclear cells was significantly smaller in control subjects with the allele 4 compared to those with the other alleles. In conclusions, the CA repeat polymorphism of the IFN-gamma gene might be associated with the outcome of anti-thyroid drug treatment.