Leigh's syndrome is a progressive neurological disease caused by mitochondrial dysfunction leading to loss of oxidative phosphorylation, the process primarily responsible for the production of ATP in the body. Since ATP is the chief source of energy within all body cells, such disorders threaten the fundamental life processes.
In many cases Leigh syndrome is genetic and caused by variants in many genes. It is inherited from both parents or only from the mother, depending on whether the mutation is in the nuclear DNA or in the mitochondrial DNA. The condition is the most common disorder associated with oxidative phosphorylation in very young children.
Prognosis in Infantile Necrotizing Encephalomyelopathy
Since Leigh’s syndrome is characterized by focal symmetrical cystic lesions forming within the thalamus, brainstem, basal ganglia, cerebellum, and spinal cord, the prospect of permanent and progressive loss of neurologic function is most probable. This is especially true when the patient is an infant or a child. The disease typically begins between 3-12 months of age, and when this occurs, it could lead to death within a couple of years. The affected child is likely to develop motor and mental regression or retardation, hypotonia and weakness of muscles, visual defects, dystonia, and brainstem deficits, among others. In most cases, the disease is first seen around seven months, and is equally reported in both genders. Intrauterine onset is also known in a minority of cases.
Almost 60% of children need to be admitted in a hospital at least once, with one in four of them having three episodes of worsening and almost 40% requiring intensive medical care. These children are likely to develop infections, breathing difficulties, stroke-like symptoms, and insufficient nutritional intake or dehydration. After the onset of these symptoms, the condition becomes rapidly worse.
Death is usually due to respiratory problems, infections, or severe progression of the disease. Children who were affected at birth, who had evidence of solitary basal ganglia involvement, and who show presence of convulsions, have a higher risk of relapses and acute exacerbations.
Most of these factors, along with the need for intensive care, certain specific mutations, failure to thrive, and evidence of brainstem lesions, reduce the likelihood of prolonged survival. One study showed that only 20% of patients live up to the age of 20. Death is most likely to occur within 18 months to 2.4 years. Meanwhile, brainstem lesions are likely to cause respiratory difficulties requiring intensive care; hence, the association of these factors with rapidly progressing disease and early death.
Several mutations exist affecting a variety of mitochondrial pathways which may account for significant differences between the prognoses of various forms of the condition. An elevated lactate level in the cerebrospinal fluid is also a possible risk factor for poor prognosis as it denotes severe metabolic strains due to deficient oxidative phosphorylation.
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Delayed diagnosis is a common feature in mitochondrial diseases because of the wide variation in the genetic basis as well as the phenotypic expression of the different forms of these conditions. Therefore, more research is required to elucidate clinical and pathological markers of the disease, as well as predictors of its severity and prognosis.
- Goldstein, A. (n.d.). Mitochondrial Diseases. Retrieved from www.childneurologyfoundation.org/disorders/mitochondrial-diseases/.
- Leigh’s Disease. (2010). Retrieved from www.lhsc.on.ca/.../DiseaseDatabase.htm#Leigh.
- Leigh syndrome. Retrieved from https://rarediseases.info.nih.gov/diseases/6877/leigh-syndrome.
- Rahman et al (2015). Nuclear Gene-Encoded Leigh Syndrome Overview. In Adam et al. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK320989/.
- Sofou et al. (2014). A multicenter study on Leigh syndrome: disease course and predictors of survival. Orphanet Journal of Rare Diseases, 9,52. https://doi.org/10.1186/1750-1172-9-52.
- Thorburn, D.R., Rahman, J., & Rahman, S. (2003). Mitochondrial DNA-Associated Leigh Syndrome and NARP. In Adam et al. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK1173/.