Mitochondrial myopathies

Genetic testing

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Fig. 24. Mitochondrial myopathies. Bilateral ptosis and ocular divergence due to weakness of the extraocular muscles

Fig. 25. Mitochondrial Myopathy. Typical ragged red fiber seen with trichrome stain (arrows)

Mitochondrial (Mt) myopathies may affect any muscle system in the body, Distribution/anatomy although they are usually limited to skeletal muscle systems. Usually proximal muscles are affected, although extraocular, and distal muscles may also be affected.

In most cases the disorder is slowly progressive. In the adult onset forms of Mt Time course myopathy, the disease is usually very slowly progressive and may be limited to symptoms rather than clinical weakness.

Can occur at any age Onset/age

Mutations in Mt DNA can be classified into three main categories: 1) large scale rearrangements in Mt-DNA, 2) point mutations in tRNAs or rRNAs, and 3) point mutations in protein coding genes. These type of defects generally take one of two forms, firstly deletions or secondly, duplications. In a duplication defect usually patients present as sporadic cases. Often symptoms are mild or absent. In contrast, deletions cause more severe symptoms. The most common and mildest variant is chronic external ophthalmoplegia syndrome (CPEO) (Fig. 24), in which clinical signs and symptoms develop during adulthood and are limited to the eyelids and eye muscles. A more severe variant is Kearns-Sayre syndrome (KSS) which is characterized by significant multisystem involvement starting usually in the second decade, and which includes cardiac conduction defects, diabetes mellitus, cerebellar ataxia, retinitis pigmentosa, increased CSF protein, and multi-focal neurodegeneration. In general Mt deletions lessen with age, and reflect the increase in the proportion of deleted Mt-DNAs developing with age.

Mutations in Mt-DNA protein coating genes include: i) ATP6 mutations: NARP and Leigh syndrome. These patients have a complex phenotype that includes neuropathy, myopathy, ataxia, and retinitis pigmentosa. The age of onset is infancy through early childhood. ii) Cytochrome b mutations and Complex I mutations: subjects may have exercise intolerance, myalgia, and may or may not have myoglobinuria. iii) Complex IV (COX) subunit mutations: several different mutations have been described within this group, resulting in disorders ranging from pure myopathies to multi-system disorders.

Mutations of tRNA and Mutations of tRNA and rRNA include: i) Mt encephalopathy, lactic acidosis and rRNA stroke-like episodes (MELAS): in this disorder there is sudden development of cerebral lesions resembling small vessel strokes, and patients may also have pre-existing migraine headaches and/or seizures. Other associated symptoms include myopathy, ataxia, cardiomyopathy, diabetes mellitus, renal tubular disorders, retinitis pigmentosa, lactic acidosis, and hyperalaninemia. The disease usually starts in the fourth or fifth decade. ii) Myoclonic epilepsy and ragged-red fibers (MERRF): symptoms start in early childhood to adulthood. Clinical findings include myoclonic and/or generalized or focal seizures, cerebellar ataxia, myopathy, corticospinal tract deficits, dementia, optic atrophy, deafness, peripheral neuropathy, cardiomyopathy, multiple symmetric lipomatosis, and renal tubular acidosis. iii) Mitochondrial myopathy and cardiomyopathy: This disorder is associated with a hypertrophic cardiomyopathy, congestive heart failure, bilateral cataracts, insulin-dependent diabetes mellitus, my-opathy of very great severity, and Wolf-Parkinson-White syndrome.

Multiple Mt-DNA deletions: i) this disease is characterized clinically by oph-thalmoparesis and exercise intolerance with onset usually between ages 18 to 48. ii) myoneurogastrointestinal encephalopathy (MNGIE): this disorder is characterized by a progressive external ophthalmoplegia, dementia, myopathy, peripheral neuropathy, and gastrointestinal abnormalities including diarrhea, malabsorption, and weight loss with normal function of the pancreas. iii) Wolfram syndrome (DIDMOAD): this disorder is characterized by diabetes insipidus, insulin-dependent diabetes mellitus, optic neuropathy, and deafness. iv) Autosomal recessive cardiomyopathy with ophthalmoplegia (ARCO): This

Clinical syndrome

Mutations in Mt-DNA protein coating genes

Multiple Mt-DNA deletions disease begins in childhood and is associated with a severe clinical hypertrophic cardiomyopathy and progressive external ophthalmoplegia, and proximal muscle weakness.

In most cases of Mt cytopathy, there is a dysfunction of Mt oxidative phospho- Pathogenesis rylation. Oxidative phosphorylation is dependent on four enzyme complexes (Complexes I to IV) that comprise the electron transport chain, and are necessary for generation of ATP. Both the nuclear and Mt genomes are necessary for generation of the oxidative phosphorylation complexes. Proteins for the eighty structural subunits are encoded in the Mt-DNA, and the remainder by genomic DNA. Thus the disorders can exhibit any mode of inheritance, including maternal, autosomal dominant, recessive, or sporadic.

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