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Clinical Characteristics and Muscle Pathology in Myopathic Mitochondrial DNA Depletion

Institute for Child Development and Pediatric Neurology Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Dov Soffer, MD

Department of Pathology Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Miriam Kutai, MD

Pediatric Neurology Clinic Haemek Hospital, Afula, Israel

Nathanel Zelnik, MD

Pediatric Neurology and Development Unit Carmel Medical Center, Haifa, Israel

Anne Saada, PhD

Metabolic Disease Unit Shaare Zedek Medical Center, Jerusalem, Israel

Joseph Jossiphov, MD

Department of Pathology Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Glenda Messer, PhD

Department of Pathology Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Avraham Shaag, MSc

Metabolic Disease Unit Shaare Zedek Medical Center, Jerusalem, Israel

Eli Shahar, MD

Child Neurology Unit Rambam Medical Center, Haifa, Israel

Shaul Harel, MD

Institute for Child Development and Pediatric Neurology Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Orly Elpeleg, MD

Metabolic Disease Unit Shaare Zedek Medical Center, Jerusalem, Israel

Four nonrelated children with myopathic mitochondrial DNA depletion are described. Two of them initially had normal motor development and two had mild motor delay. Motor arrest and regression started at age 6 to 21 months. All four had mitochondrial DNA:nuclear DNA ratios reduced to 16 to 22% of the control mean and mutations in their mitochondrial thymidine kinase 2. Muscle pathology was genotype related: homozygosity for a missense mutation at position 181 was associated with severe myopathic changes, including marked variation in muscle fiber size, myofiber necrosis, regeneration, and interstitial fibrosis, whereas homozygosity for a missense mutation at position 90 was associated with essentially normal muscle histology. No ragged red fibers were detected in any study child. Mitochondrial DNA depletion should be considered in children with myopathy, worsening hypotonia, motor regression, and death during infancy or early childhood. The severity of pathologic findings on muscle biopsy is variable and may correlate with specific mutations and thymidine kinase 2 protein residual activity. (J Child Neurol 2002;17:499-504).

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