Mitochondrial disorders of DNA polymerase γ dysfunction: from anatomic to molecular pathology diagnosis.

CONTEXT: Primary mitochondrial dysfunction is one of the most common causes of inherited disorders predominantly involving the neuromuscular system. Advances in the molecular study of mitochondrial DNA have changed our vision and our approach to primary mitochondrial disorders. Many of the mitochondrial disorders are caused by mutations in nuclear genes and are inherited in an autosomal recessive pattern. Among the autosomal inherited mitochondrial disorders, those related to DNA polymerase γ dysfunction are the most common and the best studied. Understanding the molecular mechanisms and being familiar with the recent advances in laboratory diagnosis of this group of mitochondrial disorders are essential for pathologists to interpret abnormal histopathology and laboratory results and to suggest further studies for a definitive diagnosis.
OBJECTIVES: To help pathologists better understand the common clinical syndromes originating from mutations in DNA polymerase γ and its associated proteins and use the stepwise approach of clinical, laboratory, and pathologic diagnosis of these syndromes. DATA SOURCES: Review of pertinent published literature and relevant Internet databases.
CONCLUSIONS: Mitochondrial disorders are now better recognized with the development of molecular tests for clinical diagnosis. A cooperative effort among primary physicians, diagnostic pathologists, geneticists, and molecular biologists with expertise in mitochondrial disorders is required to reach a definitive diagnosis.