Neonatal mitochondrial encephaloneuromyopathy due to a defect of mitochondrial protein synthesis

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Abstract

Mitochondrial diseases are clinically and genetically heterogeneous disorders due to primary mutations in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). We studied a male infant with severe congenital encephalopathy, peripheral neuropathy, and myopathy. The patient's lactic acidosis and biochemical defects of respiratory chain complexes I, III, and IV in muscle indicated that he had a mitochondrial disorder while parental consanguinity suggested autosomal recessive inheritance. Cultured fibroblasts from the patient showed a generalized defect of mitochondrial protein synthesis. Fusion of cells from the patient with 143B206 ρ0 cells devoid of mtDNA restored cytochrome c oxidase activity confirming the nDNA origin of the disease. Our studies indicate that the patient has a novel autosomal recessive defect of mitochondrial protein synthesis.

Introduction

Mitochondrial disorders are highly heterogeneous diseases due to mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) mutations that cause defects of oxidative phosphorylation. These disorders are generally multi-systemic and affect highly aerobic post-mitotic tissues, such as muscle and nerve.

MtDNA depends on nuclear genes for its biogenesis and maintenance. In fact, replication, transcription, and translation of mtDNA are entirely regulated by nDNA-encoded genes. Disruptions of these mitochondrial functions generally cause deficiencies of respiratory chain complexes I, III, IV, and V, all of which contain one or more subunits encoded by mtDNA, and have been classified as defects of intergenomic communication [1]. A growing number of autosomal recessive defects of mitochondrial protein synthesis have been identified [2], [3] often as a consequence of consanguinity [4]. Here, we describe the clinical and biochemical features of an infant with a novel neonatal encephaloneuromyopathy caused by a novel defect in mitochondrial protein synthesis.

Section snippets

Cell lines and cultures

Experiments were performed with primary skin cell fibroblasts from the patient and controls. Cells were cultured in glucose Dulbelcco's modified Eagle minimum medium supplemented with 15% fetal bovine serum, 1.2 mM vitamin solution (D-Ca pantothenate 100 mg/L; choline 100 mg/L; folic acid 100 mg/L; inositol 200 mg/L; nicotinamide 100 mg/L; pyridoxal HCl 100 mg/L; riboflavin 10 mg/L; and thiamine–HCl 100 mg/L), 0.6 mM essential amino acids, 1.2 mM non-essential amino acids, 2 mM l-glutamine,

Case report

This 18 day-old male infant of consanguineous Saudi Arabian parents presented with severe neonatal encephalopathy. At birth, the infant was unresponsive, but was successfully resuscitated and intubated. He had little spontaneous limb movement and required mechanical ventilation. Examination revealed prominent tongue fasciculations, bilateral equinus deformities of the feet, and profound hypotonia of arms and legs. Tendon reflexes were absent. On the third day of life, he developed myoclonic

Characterization of the molecular defect and etiology of the disease

Histochemical staining of the patient's fibroblasts revealed severe uniform reduction of COX activity, while SDH activity was normal compared to control cells, indicating that the COX deficiency was probably due to a nDNA defect (Fig. 1A). Biochemical analysis of the patient's fibroblasts showed marked reduction of complex IV activity (0.106 nmol/min/mg protein) corresponding to 11% of activity in normal controls while complex I activity (4.8 nmol/min/mg protein) was 68% and complex III

Discussion

A growing number of patients show multiple respiratory chain enzyme deficiencies, but lack mitochondrial genome mutations and some of these patients have evidence of autosomal inheritance. Obvious “suspects” for these disorders are nDNA-encoded components of the mitochondrial protein-synthesis machinery, which is required for expression of the mtDNA-encoded subunits of mitochondrial complexes I, III, IV, and V [4].

Approximately 150 nDNA genes encode proteins that participate in mitochondrial

Acknowledgments

This research was supported by National Institutes of Health grants NS11766 and HD32062 (M.H), FAPESP (CFB, CHT and MHB), CNPq (CHT), and Marriott Mitochondrial Disorders Clinical Research Fund (MMDCRF)(CFB, CK, SD, MH). We are in debt to Dr. Alexander Tzagoloff (Columbia University) for the in vivo mitochondrial translation labeling experiment.

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