Whole Exome Sequencing Useful to Diagnose Leigh Syndrome

Even if two individuals are affected by the same disease, such as Leigh syndrome, they may not have identical symptoms or causes of disease. For example, Leigh syndrome is associated with over 30 gene mutations, making it difficult to use single-gene identification as a cost-effective means of pinpointing Leigh syndrome. Instead, whole exome sequencing may significantly improve the detecting capacities of gene sequencing for Leigh syndrome in a less cost prohibitive manner.

“In general, genes involved in Leigh syndrome are often involved in aerobic energy production. Approximately, 70% to 90% of the cases of genetically defined Leigh syndrome are associated with nuclear genes,” Claudia Soler-Alfonso, MD, wrote in the article “Identification of HIBCH Gene Mutations Causing Autosomal Recessive Leigh Syndrome: A Gene Involved in Valine Metabolism,” which was published in the journal Pediatric Neurology. More often than not, mutations occur in genes that code for pyruvate dehydrogenase complex, respiratory complexes, or proteins involved in assembling respiratory complexes.

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However, in rare cases, mitochondrial encephalopathy is caused by genes related to protein catabolism. When patients who unknowingly have these mutations visit the doctor’s office for symptoms associated with Leigh syndrome, the patient can have their whole exome sequenced to find any anomalies.

Such was the case for a four-year-old girl who seemed to be healthy and normal until three months of age. Early in life, she showed developmental delay in physical capacity and spoken language. At about two years old, she demonstrated mild bilateral ptosis (eye drooping) among other symptoms and was placed on a special diet. Her new diet led to a complete turnaround in developmental milestones. This diet consisted of a standard maple syrup urine disease supplemented with leucine and isoleucine amino acids, L-carnitine, folate, and riboflavin. The key factor of the diet was valine restriction.

During one of her visits to the doctor’s office, the patient underwent DNA sequencing for a standard set of genes, but the results showed no anomalies. The team at University of Texas Health Science Center at Houston, led by Dr. Soler-Alfonso, sent samples to Baylor Medical Genetics Laboratories in Houston, Texas, and identified a novel heterozygous mutation in the HIBCH gene. Finding this mutation put the last piece of the puzzle together. HIBCH codes for an enzyme important to protecting cells from reaction products in the valine catabolism pathway. Only two other patients were previously identified to have an HIBCH mutation, and neither had Leigh syndrome.

This study brings to light the fact that there is still much to learn about Leigh syndrome and its diagnosis. “Thorough investigation to identify the genetic etiology for children with Leigh syndrome could lead to identification of treatable inborn errors of metabolism in this population,” wrote Dr. Soler Alfonso.