Researchers identify mechanism behind treatment for rare brain disorder

Findings may lead to improvements in therapy

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Riboflavin (vitamin B2) helps children overcome the devastating effects of a hereditary brain disorder by helping one protein fill in for a disabled protein, according to a study by researchers at the National Institutes of Health (NIH) and other institutions. The findings offer the prospect that researchers may be able to improve the treatment for infantile leukoencephalopathy, a rare brain disorder resulting in blindness, debilitation, and early death.

The study appears in Cell Metabolism and was conducted by Nunziata Maio, Ph.D, and Tracey Rouault, Ph.D., of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development and colleagues in Italy and the United Kingdom.


Infantile leukoencephalopathy is a hereditary disorder resulting in the loss of myelin, the insulating material that fosters the transmission of electrical signals within the cells of the brain. The disorder results from mutations ina gene called SDHAF1. The gene produces a protein in succinate dehydrogenase, an important  enzyme in the Krebs cycle, the sequence of chemical reactions that supplies energy to cells. Children who lack two functional copies of the gene have difficulty making myelin and often develop vision problems and loss of muscle coordination and control. The disease varies in severity. In untreated children, death may occur as early as 18 months, although some patients have survived through the teenage years.  In earlier work, the Italian coauthors of the current study found that treatment with riboflavin increases survival and alleviates some of the debilitating effects of having the mutation.

Results of Study

In the current study, the researchers deciphered the role the SDHAF1 protein plays in the function of succinate dehydrogenase.  The enzyme is embedded in the membrane of the cell’s mitochondria, where the Krebs cycle takes place. The researchers also uncovered the sequence of chemical events that take place during the riboflavin treatment and showed how the vitamin enables succinate dehydrogenase to continue its role in the Krebs cycle.


The study findings may lead to the development of more effective treatments for infantile leukoencephalopathy.  Such new treatments might consist of more-precise doses of the vitamin and a more appropriate frequency at which the doses are given. The findings also could lead to the development of new drugs that are more effective than riboflavin.

Next Steps

The researchers hope their findings lead to greater awareness among physicians treating young children who have myelination disorders with no apparent cause. Because of its rarity, researchers believe many cases of the disease may go unrecognized and untreated, so improving diagnoses of the condition is important.

“Some disorders only remain rare until people recognize what to start looking for,” said NICHD’s Dr. Rouault.

She added that genetic counselors advising couples whose families include a member with an undiagnosed myelination disorder might consider adding mutations in SDHAF1 to the other mutations they test for.


Maio N, Ghezzi, D, Verrigni D, Rizza, T, Bertini E, Martinellia D, Zeviani M, Singh A, Carrozzo R, and Rouault TA. Disease-causing SDHAF1 mutations impair transfer of Fe-S clusters to SDHB. Cell Metabolism (2014)

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