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Clinical Pathological Correlations > Current Correlation > Diagnosis and DiscussionA Head CT performed more than 24 hours of the symptoms onset revealed bilateral hypodensities within the temporal lobes, consistent with subacute infarcts. He also had a long-standing seizure disorder. The admission labs revealed lactic acidosis and mild CK elevation. A muscle biopsy was performed, and tissue was sent to electron microscopy.
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Diagnosis:
Based on the presence of red-ragged fibers on the gomori stain, the lactic acidosis, and a mutation in 3243 A>G of the mitochondrial genome a diagnosis of MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, Stroke-like episodes) was made.
Discussion:
The muscle biopsy revealed size variation of the muscle fibers (slide 1 and 2). Gomori trichrome stain shows massive mitochondrial proliferation as irregular patches under the sarcolemma and in the midst of what has been referred as 'ragged red fibers' (slide 3). A more sensitive detector of the mitochondrial proliferation is the succinate dehydrogenase stain (SDH), which was strongly positive in this case (slide 5). The mitochondrial proliferation also occurs in the endothelial cells of the intramuscular vessels: strongly SDH-reactive vessels (SSVs), which are a common finding in MELAS. The decreased COX stain also favors a mitochondrial myopathy (slide 4). Finally, electron microscopy (EM) showed increased and very abnormal mitochondria with irregular cristae, and occasional inclusions (slide 6).
Patients with MELAS often present with history of intractable migraine headaches, recurrent strokes, and cortical blindness. Some patients can also present with diabetes, endocrine disorders, heart conduction problems, and cardiomyopathy. The prevalence of sensorineural hearing loss is also very significant. Because mitochondria are ubiquitous, every tissue in the body can be affected by mtDNA mutations, and that is the reason why mitochondrial disorders are often multisystemic.
Mitochondrial disorders are almost exclusively maternaly inherited. The pathogenesis of these disorders is unclear; however, impaired production of ATP has a central role. Two other features are also essential about mitochondrial disorders: heteroplasmy and mitotic segregation. Heteroplasmy means that not all the mitochondrial genome copies are affected to the same extent, and, a minimum of 80-90% of mutations in the mitochrondrial load is required to cause clinical dysfunction. Mitotic segregation explains why the proportion of mutant mtDNA in daughter cells may shift and the phenotype changes concurrently.
Other common mitochondrial disoders that can usually enter in the differential diagnosis are: MERRF, Leber-Hereditary Optic Neuropathy (LHON), and Kearns-Sayre Syndrome (KSS). There are some non-mitochondrial myopathies that can harbour red-ragged fibers and include CoQ10 deficiency, inclusion body myopathy, some subtypes of maltase deficiency, and even normal aging.
The role of the mtDNA in the understanding of more common disorders in the clinical practice has invaded the current literature. The formation of reactive oxygen species within the mitochondrias in the pathogenesis of age-related neurodegeneration has generated a role for the experimental use of anti-oxydants for 'aging prevention'. In addition, several mtDNA mutations have been described in a variety of common cancers, including: prostate, breast, melanoma, and colon. The use of mitochondrial DNA has also innovated the forensic identification of cadavers. In summary, mtDNA has created a new paradigm for the understanding of the pathologic basis of disease.
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