Subacute necrotizing encephalopathy
Necrotizing encephalopathy infantile subacute of Leigh
Leigh's necrotizing encephalopathy
Leigh syndrome is a severe neurological disorder that usually becomes apparent in the first year of life. This condition is characterized by progressive loss of mental and movement abilities (psychomotor regression) and typically results in death within two to three years, usually due to respiratory failure. A small number of individuals do not develop symptoms until adulthood or have symptoms that worsen more slowly.
The first signs of Leigh syndrome seen in infancy are usually vomiting, diarrhea, and difficulty swallowing (dysphagia), which disrupts eating. These problems often result in an inability to grow and gain weight at the expected rate (failure to thrive). Severe muscle and movement problems are common in Leigh syndrome. Affected individuals may develop weak muscle tone (hypotonia), involuntary muscle contractions (dystonia), and problems with movement and balance (ataxia). Loss of sensation and weakness in the limbs (peripheral neuropathy), common in people withLeigh syndrome, may also make movement difficult.
Several other features may occur in people with Leigh syndrome. Many individuals with this condition develop weakness or paralysis of the muscles that move the eyes (ophthalmoparesis); rapid, involuntary eye movements (nystagmus); or degeneration of the nerves that carry information from the eyes to the brain (optic atrophy). Severe breathing problems are common, and these problems can worsen until they cause acute respiratory failure. Some affected individuals develop hypertrophic cardiomyopathy, which is a thickening of the heart muscle that forces the heart to work harder to pump blood. In addition, a substance called lactate can build up in the body, and excessive amounts are often found in the blood, urine, or the fluid that surrounds and protects the brain and spinal cord (cerebrospinal fluid) of people with Leigh syndrome.
The signs and symptoms of Leigh syndrome are caused in part by patches of damaged tissue (lesions) that develop in the brains of people with this condition. A medical procedure called magnetic resonance imaging (MRI) reveals characteristic lesions in certain regions of the brain. These regions include the basal ganglia, which help control movement; the cerebellum, which controls the ability to balance and coordinates movement; and the brainstem, which connects the brain to the spinal cord and controls functions such as swallowing and breathing. The brain lesions are often accompanied by loss of the myelin coating around nerves (demyelination), which reduces the ability of the nerves to activate muscles used for movement or relay sensory information from the rest of the body back to the brain.
There is also a form of Leigh disease (called X-linked Leigh disease) which is the result of mutations in a gene that produces another group of substances that are important for cell metabolism. This gene is only found on the X chromosome.
The symptoms of Leigh disease usually begin between the ages of 3 months and 2 years. Since the disease affects the central nervous system, symptoms may include:
- Ppoor sucking ability
- Difficulty holding up the head
- Losing motor skills the infant had such as grasping a rattle and shaking it
- Loss of appetite
- Continuous crying
As Leigh disease becomes worse over time, the symptoms may include:
- Generalized weakness
- Lack of muscle tone (hypotonia)
- Episodes of lactic acidosis (accumulation of lactic acid in the body and brain) that may impair breathing and kidney function
- Heart problem
The symptoms of Leigh syndrome vary greatly from person to person. Very rarely, affected people with near-normal neurologic findings have been reported. Most people with Leigh syndrome have central nervous system and peripheral nervous system abnormalities, without involvement of other body systems.
Central nervous system abnormalities may include:
- Developmental delay or regression
- Ophthalmoparesis (weakness in the muscles that control eye movement)
- Optic atrophy
- Retinitis pigmentosa
Peripheral nervous system abnormalities may include polyneuropathy and myopathy.
Although most people with Leigh syndrome only have neurological abnormalities, some people also have non-neurologic abnormalities. These may include:
- Distinct physical features
- Hormone abnormalities resulting in short stature or hypertrichosis
- Heart abnormalities (hypertrophic or dilated cardiomyopathy)
- Gastrointestinal symptoms such as diarrhea
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.
The inheritance of Leigh syndrome depends on where the responsible gene is located in each case. This is because it can be due to mutations in either mitochondrial DNA or nuclear DNA. A genetic disorder that causes Leigh disease can be inherited in three different ways.
- It may be inherited on the X (female) chromosome as a genetic deficiency of an enzyme called pyruvate dehydrogenase complex (PDH-Elx): In a few cases of Leigh syndrome due to mutations in nuclear DNA, inheritance is X-linked recessive. X-linked recessive conditions usually occur in males, who only have one X chromosome (and one Y chromosome). Females have two X chromosomes, so if they have a gene mutation on one of them, they still have a normal copy on their other X chromosome. For this reason, females are typically unaffected. While females can have an X-linked recessive condition, it is very rare.
If a mother is a carrier of an X-linked recessive condition and the father is not, the risk to children depends on each child's sex.
- Each son has a 50% chance to be unaffected, and a 50% chance to be affected
- Each daughter has a 50% chance to be unaffected, and a 50% chance to be an unaffected carrier
If a father has the condition and the mother is not a carrier, all sons will be unaffected, and all daughters will be unaffected carriers.
- It may be inherited as an autosomal recessive condition that affects the assembly of an enzyme called cytochrome-c-oxidase (COX): It is most commonly inherited in an autosomal recessive manner. This means that to be affected, a person must have a mutation in both copies of the responsible gene in each cell. Affected people inherit one mutated copy of the gene from each parent, who is referred to as a carrier. Carriers of an autosomal recessive condition typically do not have any signs or symptoms (they are unaffected). When 2 carriers of an autosomal recessive condition have children, each child has a:
- 25% chance to be affected
- 50% chance to be an unaffected carrier like each parent
- 25% chance to be unaffected and not a carrier
Autosomal recessive inheritance applies to most of the associated genes in nuclear gene-encoded Leigh syndrome.
- It may also be inherited as a mutation in the DNA in the cell mitochondria (also called maternal inheritance): In about 20% of cases, when Leigh syndrome is due to mutations in mitochondrial DNA (mitochondrial DNA-associated Leigh syndrome), it is inherited in a mitochondrial pattern. This is also called maternal inheritance. Only egg cells, but not sperm cells, pass mitochondria on to children. This means that children can inherit mtDNA mutations from their mother only. This type of Leigh syndrome can occur in every generation of a family, and can affect males and females. However, affected males do not pass the condition on to their children. The father of an affected child is not at risk of having the mtDNA mutation, but the mother of an affected child usually has the mutation and may or may not have symptoms. In some cases, an mtDNA mutation occurs for the first time in an affected person and is not inherited. This is called a de novo mutation.
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.
No data are available on the prevalence of Leigh syndrome. Prevention. The only prevention of Leigh disease lies in genetic counseling or prenatal diagnosis.
Leigh syndrome may be diagnosed by using the following criteria, defined by Rahman et al. in 1996:
- Progressive neurologic disease with motor and intellectual developmental delay
- Signs and symptoms of brainstem and/or basal ganglia disease
- Raised lactate concentration in blood and/or cerebrospinal fluid (CSF)
- The presence of one or more of the following:
Characteristic features on brain imaging (CT scan or MRI)
Typical nervous system tissue changes
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.
The prognosis for individuals with Leigh 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.
Treatment of Leigh disease usually includes vitamins such as thiamine (vitamin B1) and it is directed toward the specific symptoms present in each person.
Supportive care for Leigh syndrome includes treatment of acidosis, seizures, dystonia, and cardiomyopathy, and attention to nutritional status.
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.
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