The genetics of Leigh syndrome and its implications for clinical practice and risk management

Abstract

Leigh syndrome, also referred to as subacute necrotizing encephalomyelopathy, is a severe, early-onset neurodegenerative disorder that is relentlessly progressive and devastating to both the patient and the patient’s family. Attributed to the ultimate failure of the mitochondrial respiratory chain, once it starts, the disease often results in the regression of both mental and motor skills, leading to disability and rapid progression to death. It is a mitochondrial disorder with both phenotypic and genetic heterogeneity. The cause of death is most often respiratory failure, but there are a whole host of complications, including refractory seizures, that may further complicate morbidity and mortality. The symptoms may develop slowly or with rapid progression, usually associated with age of onset. Although the disease is usually diagnosed within the first year of life, it is important to note that recent studies reveal phenotypic heterogeneity, with some patients having evidence of in utero presentation and others having adult-onset symptoms.

Keywords:

• mitochondrial disorder
• neurodegeneration
• multisystemic disease
• oxidative phosphorylation
• mitochondrial DNA
• neuroimaging
• seizures

Acknowledgments

The authors thank the families and patients who have added to their learning and understanding of Leigh syndrome.

Disclosure

RPS has received grants from the National Institutes of Health (7RO1GM75184, 1RC1NS070232-01, 1U54NS078059-01) and Edison Pharmaceuticals, and has also received funds from the Mitochondrial Research Guild at Seattle Children’s Hospital. The authors have no conflicts of interest in this work.