Mitochondrial myopathies and encephalomyopathies

Abstract

Defects of mitochondrial metabolism result in a wide variety of human disorders, which can present at any time from infancy to late adulthood and involve virtually any tissue either alone or in combination. Abnormalities of the electron transport and oxidative phosphorylation (OXPHOS) system are probably the most common cause of mitochondrial diseases. Thirteen of the protein subunits of OXPHOS are encoded by mitochondrial DNA (mtDNA) and mutations of this genome are important causes of OXPHOS deficiency. The link between genotype and phenotype with respect to mtDNA mutations is not clear: the same mutation may result in a variety of phenotypes, and the same phenotype may be seen with a variety of different mtDNA mutations. The pathogenesis of mtDNA mutations is unclear although OXPHOS and ATP deficiency, and free radical generation, are thought to contribute to tissue dysfunction. There is now strong evidence for mitochondrial dysfunction in neurodegenerative disorders. In some cases, e.g. Friedreich's ataxia, hereditary spastic paraplegia, this is a result of a mutation of a nuclear gene encoding a mitochondrial protein, whilst in others, e.g. Huntington's disease, amyotrophic lateral sclerosis, the OXPHOS defect is secondary to events induced by a mutation in a nuclear gene encoding a non-mitochondrial protein. In yet a third group, e.g. Parkinson's disease, Alzheimer's disease, the relationship of the mitochondrial defect to aetiology and pathogenesis is unclear.

Hematological Manifestations of Primary Mitochondrial Disorders

“…Additional clinical features include failure to thrive, villous atrophy with chronic diarrhea, lactic acidosis, muscle hypotonia, pancreas dysfunction, and ataxia [23, 24]. With disease progression, hepatomegaly, elevated transaminases, hyperbilirubinemia, exocrine pancreas dysfunction, coagulopathy, growth hormone deficiency, pigmentary retinopathy, or tubular dysfunction with aminoaciduria and glucosuria, including Fanconi’s syndrome may develop [25,26,27]. In single cases there may be visual impairment, tremor, ataxia, proximal muscle weakness, or external ophthalmoplegia.…”

“…In patients who survive beyond infancy, PS evolves into KSS [23, 28]. Bone marrow biopsy at the early stages is characterized by normal cellularity, but vacuolization of the precursor cells [22, 27]. At the later stages bone marrow aspiration may show reduced cell number, vacuolated erythroblasts, myeloblasts, and ringed sideroblasts [18, 22].…”

“…Additional features include mental retardation, deafness, syncope, double vision, fatigue, exercise intolerance, bulbar symptoms such as dysphagia, stroke-like episodes, myopathy with proximal weakness, delayed puberty, primary amenorrhea, diabetes, or lactacidosis [27, 32]. Hematological manifestations of KSS include sideroblastic anemia, megaloblastic anemia, or aplastic anemia (table 4) [33].…”

Mitochondrial Encephalomyopathy inDrosophila

“…Furthermore, mitochondrial dysfunction has been conclusively implicated in nearly every chronic human neurodegenerative disease, including mitochondrial encephalomyopathies, amyotrophic lateral sclerosis, and Huntington's, Alzheimer's, and Parkinson's diseases (Orth and Schapira, 2001;Schon and Manfredi, 2003). Primary mutations in several distinct mitochondrial genes, as well as nuclear genes that encode proteins localized to the mitochondria, are known to cause a variety of related and devastating encephalomyopathies with complex clinical features, including neurological and muscular dysfunction that is often complicated by renal, endocrine, cardiac, and hepatic involvement (for review, see Schapira and Cock, 1999;Hart et al, 2002;DiMauro and Schon, 2003). There are over 150 mutations causing these related diseases and range from point mutations to large deletions.…”

c-MYC apoptotic function is mediated by NRF-1 target genes

“…This ensures that the cell maintains the correct stoichiometry of respiratory complex subunits and a means for their import and correct assembly in the mitochondria (for review, see Poyton and McEwen 1996). A disruption of this critical balance has a detrimental effect, and examples exist of mitochondrial dysfunctions that result from both reduced (for review, see Schapira and Cock 1999) and increased expression of genes involved in mitochondrial function, such as adenine nucleotide translocase-1 (Bauer et al 1999) and the mitochondrial hinge protein (Okazaki et al 1998).…”