Leigh Syndrome

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.

Cytochrome Oxidase Deficiency Disease; Infantile Subacute Necrotizing Encephalopathy; Necrotizing Encephalopathy; Pyruvate Decarboxylase Deficiency; Subacute Necrotizing Encephalomyelitis, X-Linked Infantile Necrotizing Encephalopathy.

Mutation in the oxidative phosphorylation system resulting in necrotizing encephalopathy transmitted either as an autosomal trait or via mitochondrial DNA (maternal transmission only).

Unknown. Male-to-female ratio is 3:2.

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).

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.

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.

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.

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.

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 because hypermetabolism caused during rewarming can lead to severe metabolic acidosis and hypoglycemia. Maintain normal blood glucose levels at all times, with frequent measurement of glucose concentration. A stress-free anesthesia decreases metabolic response to surgery and lactate production. Maintain adequate preload and prevent tachycardia, which may lead to obstructive cardiomyopathy because of septal hypertrophy. Patients with Leigh syndrome have elevated endorphin levels in CSF and are highly sensitive to intravenous narcotics. These patients should be carefully observed postoperatively. Postoperative respiratory failure is common following general anesthesia or even sedation, especially in the presence of preoperative respiratory impairment; general anesthesia carries a significant risk of postoperative apnea or respiratory failure, and postoperative mechanical ventilation must be considered. Regional anesthetic techniques such as spinal anesthesia may minimize postoperative respiratory complications.

Avoid lactate-containing solutions (Ringer lactate). Thiopental, halothane, and possibly other volatile anesthetic agents may inhibit neoglucogenesis and worsen hypoglycemia. Isoflurane should be preferred to sevoflurane because of the central nervous system (CNS) excitatory effect of sevoflurane in patients susceptible to convulsions. Nitrous oxide and benzodiazepines seem safe. Because of the increased opiate sensitivity, these drugs should be used with caution; short-acting opiates are preferred. Because of the muscular involvement observed with Leigh syndrome patients, succinylcholine may be contraindicated. Short-acting agents such as mivacurium are better indicated. Short-acting agents, remifentanil and desflurane, offer the advantages of quick recovery with limited postoperative CNS and respiratory depression. The potential inhibition of mitochondrial function caused by propofol may preclude its use.

Creutzfeldt-Jakob Disease: Degenerative, invariably fatal brain disorder typically developing in patients older than 60 years; the variant transmitted from cattle contamination (“mad cow disease”) can affect young adults and even children.

Wilson Disease: Progressive multivisceral failure as a result of copper accumulation resulting from an inability to produce sufficient levels of ceruloplasmin. Gene map locus is 13q14.3.

Neuronal Ceroid Lipofuscinoses: Kufs Disease, also known as Juvenile Neuronal Ceroid Lipofuscinosis type IV, is characterized by an onset in late adolescence or early adulthood. The clinical symptoms include muscle weakness, ataxia, lack of muscle coordination, chorea, confusion, behavioral changes, and seizures. Batten Disease, also known as type III juvenile form of Neuronal Ceroid Lipofuscinosis, is characterized by an onset during childhood or early adolescence and most often presenting clinical features of rapid visual loss, deterioration of earlier psychomotor development, behavior changes, and severe seizure activities. Individuals affected with this condition often develop kyphoscoliosis. It is inherited as an autosomal recessive trait.

Tay-Sachs Disease (Gangliosidosis GM2 Type II): Caused by accumulation of GM2 gangliosides in the brain because of absence of the enzyme hexosaminidase A. The consequence of this metabolic disorder is progressive destruction of the central nervous system. Clinically, the symptoms begin at approximately age 4 months and may include mild muscle weakness, abnormal startle response, and muscle spasms. Between 6 and 10 months of age, feeding difficulties, severe muscle weakness, restlessness, and visual abnormalities (e.g., staring episodes, unusual eye movements, cherry red macular spots) are present. It is generally observed among children of Eastern European Jewish descent.

Sandhoff Disease (Gangliosidosis GM2 Type II): Rare lipid storage disorder resulting in progressive deterioration of the central nervous system because of deficiency in the enzyme hexosaminidase (β subunit). Sandhoff disease is known as a severe form of Tay-Sachs Disease and is not limited to any particular ethnic group. The clinical features include feeding problems, general muscle weakness and hypotonia, and an exaggerated startle reflex in response to sudden loud noises. Other symptoms may include red spots in the eyes, motor delays, mental deterioration, spasticity, heart murmurs, seizures, blindness, and splenomegaly.

Niemann-Pick Disease: Affects most frequently infants and children. Symptoms may include poor feeding habits, physical and mental impairment, hepatosplenomegaly, severe abdominal distension, and vomiting. Some children experience neurologic impairment, including loss of speech, inability to coordinate voluntary muscle movements, convulsions, and dementia.

Alpers Disease: Affects infants and children. It is a rare progressive neurologic disorder characterized by degeneration of the gray matter of the brain. The clinical features include psychomotor retardation, partial paralysis, growth delays, severe seizures, and myoclonus. Liver damage and blindness may develop. The symptoms may be intensified by stress (e.g., anesthesia and surgical stress) or other illnesses.