Chapter 062. Principles of Human Genetics (Part 22)

Inherited mitochondrial disorders are transmitted in a matrilineal fashion; all children from an affected mother will inherit the disease, but it will not be transmitted from an affected father to his children (Fig. 62-11D ). Alterations in the mtDNA affecting enzymes required for oxidative phosphorylation lead to reduction of ATP supply, generation of free radicals, and induction of apoptosis. Several syndromic disorders arising from mutations in the mitochondrial genome are known in humans and they affect both protein-coding and tRNA genes (Table 62-1 and Table 62-5). The broad clinical spectrum often involves(cardio)myopathies and encephalopathies because of the high dependence...
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Chapter 062. Principles of Human Genetics (Part 22) Chapter 062. Principles of Human Genetics (Part 22) Inherited mitochondrial disorders are transmitted in a matrilineal fashion;all children from an affected mother will inherit the disease, but it will not betransmitted from an affected father to his children (Fig. 62-11D ). Alterations inthe mtDNA affecting enzymes required for oxidative phosphorylation lead toreduction of ATP supply, generation of free radicals, and induction of apoptosis.Several syndromic disorders arising from mutations in the mitochondrial genomeare known in humans and they affect both protein-coding and tRNA genes (Table62-1 and Table 62-5). The broad clinical spectrum often involves(cardio)myopathies and encephalopathies because of the high dependence of thesetissues on oxidative phosphorylation. The age of onset and the clinical course arehighly variable because of the unusual mechanisms of mtDNA transmission,which replicates independently from nuclear DNA. During cell replication, theproportion of wild-type and mutant mitochondria can drift among different cellsand tissues. The resulting heterogeneity in the proportion of mitochondria with andwithout a mutation is referred to as heteroplasmia and underlies the phenotypicvariability that is characteristic of mitochondrial diseases. Table 62-5 Selected Mitochondrial Diseases Disease/Syndrome OMIM # MELAS syndrome: mitochondrial myopathy with 540000encephalopathy, lactacidosis, and stroke Lebers optic atrophy: hereditary optical neuropathy 535000 Kearns-Sayre syndrome (KSS): ophthalmoplegia, pigmental 530000degeneration of the retina, cardiomyopathy MERRF syndrome: myoclonic epilepsy and ragged-red 545000fibers Neurogenic muscular weakness with ataxia and retinitis 551500pigmentosa (NARP) Progressive external ophthalmoplegia (CEOP) 258470 Pearson syndrome (PEAR): bone marrow and pancreatic 557000failure Autosomal dominant inherited mitochondrial myopathy 157640with mitochondrial deletion (ADMIMY) Somatic mutations in cytochrome b gene: exercise 516020intolerance, lactic acidosis, complex III deficiency, muscle pain,ragged-red fibers Acquired somatic mutations in mitochondria are thought to be involved inseveral age-dependent degenerative disorders affecting predominantly muscle andthe peripheral and central nervous system (e.g., Alzheimers and Parkinsonsdisease). Establishing that a mtDNA alteration is causal for a clinical phenotype ischallenging because of the high degree of polymorphism in mtDNA and thephenotypic variability characteristic of these disorders. Certain pharmacologictreatments may have an impact on mitochondria and/or their function. Forexample, treatment with the antiretroviral compound azidothymidine (AZT)causes an acquired mitochondrial myopathy through depletion of muscularmtDNA. Mosaicism Mosaicism refers to the presence of two or more genetically distinct celllines in the tissues of an individual. It results from a mutation that occurs duringembryonic, fetal, or extrauterine development. The developmental stage at whichthe mutation arises will determine whether germ cells and/or somatic cells areinvolved. Chromosomal mosaicism results from non-disjunction at an earlyembryonic mitotic division, leading to the persistence of more than one cell line,as exemplified by some patients with Turner syndrome (Chap. 343). Somaticmosaicism is characterized by a patchy distribution of genetically altered somaticcells. The McCune-Albright syndrome, for example, is caused by activatingmutations in the stimulatory G protein α (Gsα) that occur early in development(Chap. 347). The clinical phenotype varies depending on the tissue distribution ofthe mutation; manifestations include ovarian cysts that secrete sex steroids andcause precocious puberty, polyostotic fibrous dysplasia, café-au-lait skinpigmentation, growth hormone–secreting pituitary adenomas, and hypersecretingautonomous thyroid nodules (Chap. 341).