Simple functions such as blinking and breathing are actions that we take for granted. However, for those living with Leigh disease, these normally subconscious body functions can become difficult or even impossible to execute at all. First described in the 1950s by Denis Leigh, a British neuropsychiatrist, Leigh disease is a rare inborn error of metabolism, importantly touching the brain, that affects approximately 1 in 40,000 newborns, with quickly progressing symptoms frequently starting in the first year of life.
Unfortunately, due to the neurodegenerative nature of the disease, the most severe patients living with Leigh disease are often only given a life expectancy of two to three years after their diagnosis. Some patients suffer from slower progressing symptoms and others, although rarely, do not exhibit symptoms until adulthood.
The disease is found to be caused by mutations in one of more than 75 different genes, both in nuclear DNA and mitochondrial DNA. Gene mutations resulting in Leigh disease impact the various proteins and protein complexes involved in the mitochondrial energy generating system.
Particularly affected is the final biochemical pathway involved in energy production, the OXPHOS system. While the exact mechanism remains unclear, cell biological consequences observed in patient derived cells and disease models, such as increased radical production, disturbed redox metabolism, and energy shortness are thought to play an important role in disease pathology.
As Leigh disease can be caused by mutations to both nuclear and mitochondrial DNA, there are multiple ways the disease can be inherited. These include both maternal and autosomal recessive, dominant and X-linked inheritance.
Signs and symptoms of Leigh disease are dictated by the region of the brain most affected by cell dysfunction; for example, deterioration of the brain stem can affect breathing, swallowing, movement and posture. Tragically, children with Leigh disease will often initially gain normal developmental skills only to lose them again. This developmental regression typically occurs after minor childhood illnesses, such as coughs and colds or the flu.
Progressive neurological deterioration associated with Leigh disease is marked by a variety of symptoms including cognitive decline, strabismus (when the eyes are not lined up properly and point in different directions), difficulty swallowing, generalised weakness, hypotonia (lack of muscle tone), clumsiness, tremors, the absence of tendon reflexes, and/or muscle spasms that result in slow, stiff movements of the legs.
Sadly, there is no cure or specific treatment for Leigh disease caused by OXPHOS system defects. Supportive care is provided for symptomatic relief of patient complaints, often requiring the coordinated efforts of specialist teams to ease the specific symptoms for individual patients.