Mitochondrial Ultrastructural Defects in NDUFS3-Related Disorder

Abstract

Complex I, the largest multisubunit enzyme complex of the respiratory chain, has a vital role in the energy production of the cell, and the clinical spectrum of complex I deficiency varies from severe lactic acidosis in infants to muscle weakness in adults. Pathogenic variants of NDUFS3 (constitutes the catalytic core of the complex I) have been reported in a small number of patients with variable phenotypes. We describe a girl with a history of infantile-onset nonepileptic myoclonus, who developed myopathy at the age of 2 years. Next-generation sequencing revealed compound heterozygous for two variants in the NDUSF3 gene. The electron-microscopic study of the skeletal muscle showed an increase in the number of mitochondria inside the myofibers; mitochondria were variably enlarged with some irregularity and were aligned perpendicular to the myofibrils in a stacked-up manner. This is the first description of mitochondrial ultrastructural abnormality in an individual with NDUFS3-related disorder.

Keywords: Complex I; NDUFS3; mitochondria; myoclonus; myopathy.

Figure 1

Light-microscopic findings: All major histochemical stains and reactions, including hematoxylin and eosin (A), Gomori trichrome (B), ATPase at pH 4.6 (C), NADH-TR (D), succinic dehydrogenase (E), and cytochrome oxidase (F) are unremarkable. (Original magnification: ×200)

Figure 2

Electron-microscopic findings: Enlarged and increased numbers of mitochondria stacked up amongst the myofibrils (arrows) are seen. No significant subsarcolemmal accumulation of mitochondria is identified (block arrow). Only a few lipid droplets (arrowheads) are present. (Original magnification: ×2500)