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Severe progressive necrotizing encephalopathy
occurring between the age of 3 months and 2 years. Caused by a mitochondrial
disorder impeding oxidative phosphorylation. Symptoms include loss of
previously acquired motor skills, muscle weakness, hypotonia, lactic
acidosis associated with respiratory and kidney dysfunction.
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Cytochrome Oxidase Deficiency Disease; Infantile Subacute
Necrotizing Encephalopathy; Necrotizing Encephalopathy; Pyruvate
Decarboxylase Deficiency; Subacute Necrotizing Encephalomyelitis, X-Linked
Infantile Necrotizing Encephalopathy.
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Mutation in the oxidative phosphorylation system resulting
in necrotizing encephalopathy transmitted either as an autosomal trait or
via mitochondrial DNA (maternal transmission only).
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Unknown. Male-to-female ratio is 3:2.
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Genetic inheritance is variable: about half of
cases are autosomal recessive with multiple loci, a few are dominant or
X-linked, and the remainder are a result of mitochondrial DNA defects (and
thus maternally inherited only).
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When related to a mutation in the mitochondrial
DNA, a single base pair is changed from thymine to either cytosine or
guanidine in the gene coding for ATPase, an enzyme involved in the electron
transfer chain allowing oxidative phosphorylation (resulting in deficiency
of cytochrome C oxidase, which is the terminal enzyme of the mitochondrial
respiratory chain). Because of the vital nature of this process, ATPase is
only partially defective in Leigh syndrome, or several types of mitochondria
coexist, some with normal ATPase and some with the defective version. Brain
neurons are mainly affected, but liver and heart cells also may deteriorate.
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Diagnosis is usually made during the first or second
year of life with delayed psychomotor development or regression of already
acquired skills. Ophthalmoplegia and hypotonia are often associated. Further
neurologic signs include poor vision, nystagmus, tremor, ataxia, seizures,
positive Babinski sign, and absent tendon reflexes. Respiratory signs
include alternation of polypnea “sine materia” and bradypnea, poor
response to hypoxia or hypercarbia, and eventually respiratory failure.
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Leigh syndrome is a progressive necrotizing
encephalopathy, usually presenting with feeding and swallowing problems,
dysautonomia, weakness, ataxia, and convulsions. There are several foci of
necrosis in the brainstem, putamen, and globus pallidus. Respiratory
involvement is late in the evolution and is associated with poor prognosis.
Laboratory investigations include elevated lactate and pyruvate levels and
low glucose levels in blood and cerebrospinal fluid (CSF). Several enzymes have been involved in
Leigh syndrome: a decrease of pyruvate decarboxylase, inhibition of thiamine
pyrophosphate-ATP phosphoryl transferase, or blockade of pyruvate
dehydrogenase. Pyruvate dehydrogenase is itself a complex of six enzymes.
Other mitochondrial genetic defects can lead to the clinical picture of
Leigh syndrome. These enzymatic defects prevent entry of pyruvate in the
Krebs cycle.
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Assess blood lactate and glucose
levels. Evaluate breathing pattern. Define a strategy in case of respiratory
failure, especially with postoperative management. Check preoperative diet
and carbohydrate intake.
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Because the brainstem is often involved,
meticulous care should be devoted to temperature, airway, and control of
ventilation. Prevent hypocarbia because hypocarbia inhibits pyruvate
decarboxylase and further increases lactate levels. Prevent hypothermia ...