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Morphological correlates of mitochondrial dysfunction in children
1Department of Anatomical Pathology, Royal Children's Hospital, Melbourne, Victoria, Australia. chowcw@cryptic.rch.unimelb.edu.au
Insights
Morphological studies reveal key brain and organ changes in children with mitochondrial diseases. Ultrastructural analysis of liver biopsies is crucial for diagnosing mitochondrial dysfunction in pediatric patients.
Area of Science:
- Pediatric Neurology
- Mitochondrial Diseases
- Cell Biology
Background:
- Morphological studies are vital for diagnosing mitochondrial diseases in adults.
- Their utility in pediatric cases requires specific consideration due to differing manifestations.
Purpose of the Study:
- To review the role of morphological investigations in diagnosing pediatric mitochondrial diseases.
- To highlight key morphological findings in various pediatric mitochondrial disorders.
- To emphasize the importance of ultrastructural analysis, particularly in liver biopsies.
Main Methods:
- Review of morphological findings in pediatric patients with suspected mitochondrial dysfunction.
- Analysis of macroscopic, histological, and ultrastructural changes in brain, liver, heart, and intestine.
- Correlation of morphological findings with specific mitochondrial diseases like pyruvate dehydrogenase deficiency, Leigh syndrome, Alpers disease, lethal infantile mitochondrial disease, and Barth syndrome.
Main Results:
- Pediatric patients rarely show ragged-red fibers in muscle biopsies, unlike adults.
- Distinct macroscopic and histological brain abnormalities are observed in conditions like pyruvate dehydrogenase deficiency and Leigh syndrome.
- Ultrastructural changes in mitochondria are prominent in organs like the liver, heart, and intestine, with specific patterns in Alpers and lethal infantile mitochondrial diseases.
- Hepatocyte lipid accumulation and mitochondrial alterations are linked to decreased respiratory chain enzyme activity in the liver.
Conclusions:
- Detailed morphological studies, including brain autopsy and liver biopsies with ultrastructural assessment, are valuable preliminary investigations for suspected pediatric mitochondrial dysfunction.
- Findings should be correlated with clinical features to guide further biochemical and molecular studies.
- Morphological assessment provides essential insights for diagnosing complex pediatric mitochondrial disorders.
Abstract:
Morphological studies have traditionally played a major role in the study of adults with suspected mitochondrial diseases. Here we review their role in the investigation of paediatric patients. The morphological changes may be macroscopic, such as developmental abnormalities of the brain in pyruvate dehydrogenase deficiency, including ectopic inferior olives and the absence of corpus callosum and pyramids. Other changes are histological, such as rarefaction of the neuropil and endothelial prominence in Leigh syndrome, and spongiosis with neuronal loss and gliosis in Alpers disease. The ragged-red fibres typical of mitochondrial disease in adults are only rarely seen in skeletal muscle biopsies from children. On the other hand, dramatic ultrastructural changes involving the mitochondria may be seen in many organs, including the liver, heart and intestine. In Alpers and lethal infantile mitochondrial diseases, the hepatocytes show marked accumulation of small droplets of lipid alternating with densely packed mitochondria with pale matrix and loss of granules. These changes are associated with a marked decrease in respiratory chain enzyme activity in the liver, often without similar decrease in the skeletal muscle or fibroblasts. Enlarged mitochondria with concentric cristae are prominent in the cardiac myocytes in Barth syndrome. For the assessment of children with a suspected disorder of mitochondrial dysfunction, detailed morphological studies of the brain (at autopsy) and of biopsies (especially of the liver), including ultrastructural assessment of the mitochondria, can be a very useful preliminary investigation. The findings should then be correlated with the clinical features and used as a guide for further biochemical and molecular studies, preferably on multiple tissues.