Evidence Of Mitochondrial Disease Research Articles

Involvement of mitochondrial dysfunction in pathogenesis of hemophagocytic lymphohistiocytosis

Background: Hemophagocytic lymphohistiocytosis (HLH) is a hyper-inflammatory condition resulting from altered crosstalk between innate and adaptive immune responses. Familial HLH is caused by mutations in several genes whereas the acquired form is associated with infections, rheumatic diseases, malignancies, and inherited metabolic disorders. Case Presentation: We report an infant boy who developed HLH and the potential involvement of mitochondrial DNA in pathogenicity. This patient was with evidence of mitochondrial disease based on neonatal-onset lactic acidosis, elevated lactate in cerebrospinal fluid, a significant lactate peak on magnetic resonance spectroscopy, and generalized reduction of multiple respiratory chain enzyme complex activities. In addition, full mitochondrial genome sequencing only revealed the identification of the homoplasmic m.4325A>G mutation. Subsequently, he presented with a febrile illness complicated by HLH. Conclusion: Elevated levels of lactic acidosis and mitochondrial dysfunction strengthen the involvement of mitochondria in causing secondary HLH in our patient.

Pathology of Mitochondrial Encephalomyopathies

Muscle biopsy provides the best tissue to confirm a mitochondrial cytopathy. Histochemical features often correlate with specific syndromes and facilitate the selection of biochemical and genetic studies. Ragged-red fibres nearly always indicate a combination defect of respiratory complexes I and IV. Increased punctate lipid within myofibers is a regular feature of Kearns-Sayre and PEO, but not of MELAS and MERRF. Total deficiency of succinate dehydrogenase indicates a severe defect in Complex II; total absence of cytochrome-c-oxidase activity in all myofibres correlates with a severe deficiency of Complex IV or of coenzyme-Q10. The selective loss of cytochrome-c-oxidase activity in scattered myofibers, particularly if accompanied by strong succinate dehydrogenase staining in these same fibres, is good evidence of mitochondrial cytopathy and often of a significant mtDNA mutation, though not specific for Complex IV disorders. Glycogen may be excessive in ragged-red zones. Ultrastructure provides morphological evidence of mitochondrial cytopathy, in axons and endothelial cells as well as myocytes. Abnormal axonal mitochondria may contribute to neurogenic atrophy of muscle, a secondary chronic feature. Quantitative determinations of respiratory chain enzyme complexes, with citrate synthase as an internal control, confirm the histochemical impressions or may be the only evidence of mitochondrial disease. Biological and technical artifacts may yield falsely low enzymatic activities. Genetic studies screen common point mutations in mtDNA. The brain exhibits characteristic histopathological alterations in mitochondrial diseases. Skin biopsy is useful for mitochondrial ultrastructure in smooth erector pili muscles and axons; skin fibroblasts may be grown in culture. Mitochondrial alterations occur in many nonmitochondrial diseases and also may be induced by drugs and toxins.

Nucleoside Exposure in the Children of HIV-Infected Women Receiving Antiretroviral Drugs: Absence of Clear Evidence for Mitochondrial Disease in Children Who Died Before 5 Years of Age in Five United States Cohorts

Nucleoside Exposure in the Children of HIV-Infected Women Receiving Antiretroviral Drugs: Absence of Clear Evidence for Mitochondrial Disease in Children Who Died Before 5 Years of Age in Five United States Cohorts

Mitochondrial abnormalities are not invariably present in neurologic syndromes associated with multiple symmetric lipomatosis

Familial multiple symmetric lipomatosis (MSL) associated with neurologic disease has been described in several reports. Recently, MSL has been associated with morphologic changes in skeletal muscle or genetic evidence of mitochondrial DNA (mtDNA) mutations, particularly the base pair (bp) 8,344 MERRF mutation [1,2]. However, it is unclear whether MSL or the associated neurologic disease are invariably associated with such mitochondrial abnormalities, either inherited or acquired. In 1990 we described a familial syndrome of axonal peripheral neuropathy with MSL [3]. Four of seven surviving siblings of one generation (II-2, II-7, II-8, and II-9) were affected Figure 1in Chalk et al [3]). Both parents were deceased, but they had not displayed multiple lipomata. We examined many of our patients' offspring (III-1 to III-8; IV-4 and IV-5) and found no MSL or neuropathy Figure 1in Chalk et al [3]). On the basis of this pedigree, we felt that inheritance was most likely to be on an autosomal recessive basis. However, the recent reports linking MSL with mtDNA abnormalities prompted us to note that our family's pedigree was also consistent with a maternal inheritance pattern. In view of this possibility, we have studied muscle histology and biochemistry and mtDNA extracted from muscle and a lipoma removed at plastic surgery from patient II-9 for evidence of mitochondrial disease. Methods. Cytochrome oxidase and citrate …