What is Leigh syndrome?
Leigh syndrome (also called Leigh disease and subacute necrotizing encephalomyelopathy) is an under-recognized inherited neurometabolic disorder that affects the central nervous system.
Leigh's disease is a rare inherited neurometabolic disorder that affects the central nervous system. This progressive disorder begins in infants between the ages of three months and two years. Rarely, it occurs in teenagers and adults.
What causes Leigh's disease?
Leigh syndrome can be caused by mutations in any of more than 75 different genes. Most of our genes are made up of DNA in the cell's nucleus (nuclear DNA). Some of our genes are made up of DNA in other cell structures called mitochondria (mitochondrial DNA, or mtDNA). Most people with Leigh syndrome have a mutation in nuclear DNA, and about 20% have a mutation in mtDNA.
Most genes associated with Leigh syndrome are involved in the process of energy production in mitochondria (oxidative phosphorylation). Five protein complexes, named complex I through complex IV, are involved in this process. Many of the gene mutations associated with Leigh syndrome disrupt the function of proteins in these complexes, how the complexes form, or additional steps related to energy production. Researchers believe that impaired oxidative phosphorylation may cause cells to die because they don't have enough energy. The death of brain cells likely contributes to the neurologic features of the condition, while the death of cells in other tissues may lead to additional symptoms in other parts of the body.
What are the symptoms of Leigh's disease?
he symptoms of Leigh syndrome are classically described as beginning in infancy and leading to death within a span of several years.
Symptoms of Leigh's disease usually progress rapidly. The earliest signs may be poor sucking ability, and the loss of head control and motor skills. These symptoms may be accompanied by loss of appetite, vomiting, irritability, continuous crying, and seizures. As the disorder progresses, symptoms may also include generalized weakness, lack of muscle tone, and episodes of lactic acidosis, which can lead to impairment of respiratory and kidney function.
How is Leigh syndrome diagnosed?
Leigh syndrome may be diagnosed by using the following criteria, defined by Rahman et al. in 1996.
1).Progressive neurologic disease with motor and intellectual developmental delay
2). Signs and symptoms of brainstem and/or basal ganglia disease
3). Raised lactate concentration in blood and/or cerebrospinal fluid (CSF)
The presence of one or more of the following:
1). Characteristic features on brain imaging (CT scan or MRI)
2). Typical nervous system tissue changes
3). Typical nervous system tissue changes in a similarly affected sibling
After these criteria are met and a diagnosis of Leigh syndrome is made, molecular genetic testing can then differentiate between mtDNA-associated Leigh syndrome (caused by mutations in mtDNA) and nuclear gene-encoded Leigh syndrome (caused by mutations in nuclear DNA).
A diagnosis of nuclear gene-encoded Leigh syndrome can be made either by identifying a mutation in nuclear DNA, or by excluding the presence of a mutation in mtDNA.
Because not all patients have increased lactate levels, recent studies proposed new diagnostic criteria excluding the raised lactate levels as a prerequisite. The remaining criteria are similar, but add mitochondrial dysfunction as a criterion.
A diagnosis of Leigh-like syndrome may be considered in individuals who do not meet the strict diagnostic criteria but have features resembling Leigh syndrome.
What is the treatment for Leigh's disease?
Treatment of Leigh syndrome is directed toward the specific symptoms present in each person.
The most common treatment for Leigh's disease is thiamine or Vitamin B1. Oral sodium bicarbonate or sodium citrate may also be prescribed to manage lactic acidosis.
Because anesthesia can potentially aggravate respiratory symptoms and bring on respiratory failure, careful consideration should be given to its use and close monitoring prior to, during, and after its use.
Progression and new symptoms should be monitored regularly (typically every 6-12 months). Evaluations with a neurologist, ophthalmologist, audiologist, and cardiologist are recommended.
Specific treatment is possible for the three nuclear gene-encoded Leigh-like syndromes (milder conditions with similar features). These include biotin-thiamine-responsive basal ganglia disease (BTBGD), biotinidase deficiency, and coenzyme Q10 deficiency caused by mutation of PDSS2.
What is the prognosis for Leigh's disease?
The prognosis for individuals with Leigh's disease is poor. Individuals who lack mitochondrial complex IV activity and those with pyruvate dehydrogenase deficiency tend to have the worst prognosis and die within a few years. Those with partial deficiencies have a better prognosis, and may live to be 6 or 7 years of age. Some have survived to their mid-teenage years.