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- ATP, adenosine triphosphate
- CK, creatine kinase
- COX, cytochrome c oxidase
- KSS, Kearns-Sayre syndrome
- mtDNA, mitochondrial DNA
- PEO, progressive external ophthalmoplegia
- RCS, revised Cambridge sequence
Mitochondrial disorders are clinical phenotypes associated with abnormalities of the terminal component of mitochondrial energy metabolism—that is, oxidative phosphorylation. Oxidative phosphorylation is carried out in the inner mitochondrial membrane by the four enzyme complexes (I–IV), of the respiratory chain plus the adenosine triphosphate (ATP) synthase complex (complex V). All these complexes, except complex II, which is entirely nucleus encoded, contain both nucleus and mitochondrion encoded subunits, and their biosynthesis also requires co-operation between the nuclear and mitochondrial genomes. Because of this dual genetic control, oxidative phosphorylation diseases can be due to mutations either in mitochondrial DNA (mtDNA) or nuclear DNA genes. Pathogenic mutations of mitochondrial DNA include either large scale rearrangements, which are usually sporadic, or point mutations and micro-rearrangements, which are usually transmitted through the maternal lineage. However, these concepts have recently been challenged by the identification of one family in which a de novo microdeletion in a mtDNA gene was detected in a patient’s mitochondrial genome, which had clearly been inherited from the proband’s father1 and of a family with a mother to offspring transmission of a single mtDNA deletion.2
We present here a case of maternal transmission of a single heteroplasmic deleted mtDNA species in two subjects, both affected by Kearns-Sayre syndrome (KSS).
A woman with KSS (subject I-1 in fig 1A) died at 48 years of age of respiratory insufficiency. She was the second of four uneventful pregnancies from healthy non-consanguineous parents. At the age of 14 years, she noted the presence of bilateral eyelid ptosis and ophthalmoparesis. Over the following 4 years, both symptoms steadily progressed and she developed bilateral hearing loss, ataxia and proximal limb muscle weakness. At the age of 27 years, she received a heart pacemaker because of several brief episodes of unconsciousness, associated with atrioventricular block of variable severity, …