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.
