2/15/2019 Shadab Salehpour

Leigh disease Shadab Salehpour

Introduction Leigh's disease is an inherited early-onset progressive neurodegenerative/ neurometabolic disorder with a characteristic neuropathology consisting of focal, bilateral lesions in one or more areas of the central nervous system, including the brainstem, thalamus, basal ganglia, cerebellum, and spinal cord. The lesions are areas of demyelination, gliosis, necrosis, spongiosis, or capillary proliferation. 2/15/2019 Shadab Salehpour

Etiology Leigh's disease can be caused by mutations in mitochondrial DNA or by deficiencies of an enzyme called pyruvate dehydrogenase It may be a feature of a deficiency of any of the mitochondrial respiratory chain complexes: I, II, III deficiencies, complex IV deficiency (cytochrome c oxidase), or complex V deficiency. The most common underlying cause is a defect in oxidative phosphorylation. 2/15/2019 Shadab Salehpour

Genetics Nuclear DNA comprises most of the genome of an organism and in sexually reproducing organisms is inherited from both parents in contrast to mitochondrial DNA's maternal pattern of inheritance. Leigh syndrome caused by nuclear DNA mutations is inherited in an autosomal recessive pattern. 2/15/2019 Shadab Salehpour

This means that two copies of the mutated gene are required to cause the disease, so two unaffected parents, each of whom carries one mutant allele, can have an affected child if that child inherits the mutant allele from both parents. 2/15/2019 Shadab Salehpour

75 to 80 percent of Leigh syndrome is caused by mutations in nuclear DNA. Mutations affecting the function or assembly of the fourth complex involved in oxidative phosphorylation, cytochrome c oxidase (COX), cause most cases of Leigh's disease. 2/15/2019 Shadab Salehpour

Mutations in a gene called SURF1 are the most common cause of this subtype of Leigh syndrome. The protein that SURF1 codes for is terminated early and therefore cannot perform its function, shepherding the subunits of COX together into a functional protein complex. 2/15/2019 Shadab Salehpour

This results in a deficit of COX protein, reducing the amount of energy produced by mitochondria. Another nuclear DNA mutation that causes Leigh syndrome affects another protein complex in the mitochondria, pyruvate dehydrogenase, which is an enzyme in the glycolysis pathway. 2/15/2019 Shadab Salehpour

Leigh disease which is caused by deficiency of the pyruvate dehydrogenase complex (PDHC), most commonly involving a PDHC subunit which is encoded by an X-linked gene. The neurological features of Leigh disease caused by PDHC deficiency are indistinguishable from other forms. However, non-neurological features (other than lactic acidosis) are not seen in PDHC deficiency. 2/15/2019 Shadab Salehpour

Epidemiology Leigh disease occurs in at least 1 of 40,000 live births, though certain populations have much higher rates. In the Saguenay-Lac-Saint-Jean region of central Quebec, Leigh syndrome occurs at a rate of 1 in 2000 newborns. 2/15/2019 Shadab Salehpour

Clinical presentations Clinical symptoms depend on which areas of the central nervous system are involved. This progressive disorder begins in infants between the ages of three months and two years. Rarely, it occurs in teenagers and adults. 2/15/2019 Shadab Salehpour

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. 2/15/2019 Shadab Salehpour

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. In Leigh's disease, genetic mutations in mitochondrial DNA interfere with the energy sources that run cells in an area of the brain that plays a role in motor movements. 2/15/2019 Shadab Salehpour

The primary function of mitochondria is to convert the energy in glucose and fatty acids into a substance called adenosine triphosphate (ATP). The energy in ATP drives virtually all of a cell's metabolic functions. Genetic mutations in mitochondrial DNA, therefore, result in a chronic lack of energy in these cells, which in turn affects the central nervous system and causes progressive degeneration of motor functions. 2/15/2019 Shadab Salehpour

Management The most common treatment for Leigh's disease is thiamine (Vitamin B1). Oral sodium bicarbonate or sodium citrate (Shohl’s solution) may also be prescribed to manage lactic acidosis. 2/15/2019 Shadab Salehpour

Researchers are currently testing dichloroacetate to establish its effectiveness in treating lactic acidosis. In individuals who have the X-linked form of Leigh's disease, a high-fat, low-carbohydrate diet may be recommended. 2/15/2019 Shadab Salehpour

Prognosis 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. 2/15/2019 Shadab Salehpour

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