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Research explores genetic mutations behind nutritional deficiencies linked to the disorder

Preclinical research on a rare, newly discovered genetic disorder involving autism, intellectual disability, and epilepsy caused by an inborn error of metabolism suggests this condition—and perhaps other types of autism—can be prevented and treated.

Writing in the October issue of Science, Dr. Gaia Novarino of the University of California at San Diego (UCSD) and a multi-institutional team of researchers led by Joseph G. Gleeson, MD, of UCSD describe how they discovered a causative mutation in children with autism, intellectual disability, and epilepsy from two consanguineous Middle Eastern families.

The mutation occurs in the BCKDK gene, which halts a protein complex that metabolizes certain branched chain amino acids (BCAAs) [Novarino et al., 2012]. BCAAs help regulate metabolism of essential amino acids the human body cannot produce. They must be obtained through diet.

In mice that lacked the BCKDK gene, nutritional supplements containing the BCAAs alleviated neurological signs associated with the comparable diseases in humans, the authors write. The research reveals a new genetic disorder, says first author Gaia Novarino, PhD, an Assistant Scientist at UCSD. “I'm sure there are other cases like these out there. It's important that geneticists know about this condition,” Dr. Novarino explains.

The paper suggests dietary supplements may alleviate clinical manifestations of BCKDK mutations in human subjects, notes an accompanying editorial. Based on the research, the Emory Genetics Laboratory in Decatur, Georgia plans to add the BCKDK gene to its clinical next-generation sequencing panel test for autism spectrum disorders in 2013.

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Study Results

  1. Top of page
  2. Study Results
  3. Newborn Screening Possible
  4. Carnitine: Another Culprit?
  5. References

BCKDK interferes with the BCAAs that regulate metabolism of valine, leucine, and isoleucine, three of nine amino acids essential in human diets. The affected children had mutations in both copies of BCKDK and very low levels of BCAAs in their blood.

The researchers used the mice to test the idea that neurological signs could be treated by BCAA dietary supplements. The mice were healthy at birth, but as adults had neurological abnormalities including tremors, epileptic seizures, and hind limb clasping observed in other mouse models of autism spectrum disorders. After a week of feeding the mutant mice a BCAA-enriched diet, these symptoms stopped, suggesting that this phenotype is both inducible and reversible with BCAA supplementation, the researchers write.

The research team is now giving the human subjects BCAA supplements, Dr. Novarino told AJMG Sequence in an interview. Doing so has resulted in normal BCAA levels in their blood, and none has had a seizure since receiving supplements, she says. The research is ongoing and has not been published.

Newborn Screening Possible

  1. Top of page
  2. Study Results
  3. Newborn Screening Possible
  4. Carnitine: Another Culprit?
  5. References

Might newborn screening of BCAA levels detect more children who will suffer from the 3 disorders as they age? In the editorial accompanying the paper, Arthur L. Beaudet, MD, of Baylor College of Medicine in Houston, Texas, suggests this prospect is worth considering because more than 50 other inborn errors of metabolism are currently included in newborn screening panels (Beaudet et al., 2012).

Dr. Beaudet explains that low BCAA levels seen in study participants represent the reverse of the increased BCAA levels seen in maple syrup urine disease, which involves toxic buildup of BCAAs and their metabolites. Testing for this disease is included in most state newborn screening panels.

Newborn screening might entail measuring the plasma ratio of BCAAs to other amino acids, or the ratio of BCAAs to their respective keto acids that break them down, or sequence analysis, Dr. Beaudet writes. He also suggests universal carrier detection for autosomal recessive, or X-linked mutations, to alert carrier couples to their odds of having an autistic child. Testing before conception would allow couples to consider preimplantation diagnosis.

Newborn screening for low BCAAs in the blood is worth exploring, says Gerard Berry, MD, Director of the Metabolism Program at Boston Children's Hospital in Massachusetts. But Dr. Berry sees a possible problem. “The mother's and baby's diets will influence those levels, so it may be difficult to distinguish between a genetic disorder versus decreased levels due to diet alone,” Dr. Berry says, indicating that specificity and false positives may pose a challenge.

Dr. Beaudet also suggests testing children's cerebrospinal fluid for metabolite levels to reveal problematic BCAA levels and to identify other treatable, or preventable, forms of autism. Doing so would be useful from a research perspective, especially because children with autism and intellectual disability have poor outcomes, adds Roberto F. Tuchman, MD, Clinical Professor of Neurology and Psychiatry at Florida International University in Miami. Dr. Tuchman participates in the Network for Epilepsy and Autism Research (NEAR) consortium, as does Dr. Gleeson.

But convincing parents to allow spinal taps to be performed on their children and finding appropriate age- and sex-specific controls would be difficult, says Solomon L. Moshé, MD, Director of Pediatric Neurology and Clinical Neurophysiology at Yeshiva University's Albert Einstein School of Medicine in New York, and a collaborator in NEAR.

Carnitine: Another Culprit?

  1. Top of page
  2. Study Results
  3. Newborn Screening Possible
  4. Carnitine: Another Culprit?
  5. References

BCKDK deficiency isn't the first inborn error of metabolism linked with autism, Dr. Beaudet notes, suggesting that deficiency of carnitine, an amino acid derivative, deserves more attention. His own research concludes that deletion of part of the gene TMHLE, which plays a role in the synthesis of carnitine, may play a role in milder forms of autism because insufficient carnitine could hamper normal movement of fatty acids from cytoplasm into brain cells' mitochondria. Dr. Beaudet's study found major increases in some carnitine-related chemicals in children with autism. His research suggests dietary intake of carnitine from birth through the first few years of life might modify autism risk.

While the papers about BCKDK mutations and carnitine deficiency are interesting, Dr. Moshé cautions against becoming overenthusiastic about their role in autism. “Autism, epilepsy, and intellectual disability are very heterogeneous. There are many mechanisms involved,” he explains.

Dr. Moshé is more enthusiastic about recent studies aimed at mechanism-based therapies for tuberous sclerosis (TS), which is often detected in infancy and known to cause autism, epilepsy, intellectual disability, and brain tumors.

Recent research has identified the mTOR pathway, a protein that regulates cell growth and connections between neurons, as a therapeutic target in TS. That's because mutations that remove regulators of the mTOR pathway are associated with TS, and mTOR inhibitors have recently had promising results (Sahin et al., 2012).

The idea that a selective deficiency of certain nutrients in brain cells could have a genetic basis, cause autism, and be reversed, is an exciting concept that deserves more study, says Dr. Berry. Papers by Dr. Novarino, Dr. Beaudet, and Dr. Sahin all send a valuable message, says Dr. Tuchman. “If there's a child with autism, epilepsy, and intellectual disability, you should be persistent in pursuing the etiology,” he notes.

References

  1. Top of page
  2. Study Results
  3. Newborn Screening Possible
  4. Carnitine: Another Culprit?
  5. References
  • Beaudet Al, 2012. Preventable forms of autism? Science 338: 342343.
  • Celestino-Sopera PB, Violante S, Crawford EL, Luo R, Lionel AC, Delaby E, Cai G, Sadikovic B, Lee K, Lo C, Gao K, Person RE, Moss TJ, German JR, Huang N, Shinawia M, Treadwell-Deering D, Szatmari P, Roberts W, Fernandez B, Schroer RJ, Stevenson RE, Buxbaum JD, Betancur C, Scherer SW, Sanders SJ, Geschwind DH, Sutcliffe JS, Hurles ME, Wanders RJA, Shaw CA, Leal SM, Cook EH Jr, Goin-Kochel RP, Vaz FM, Beaudet AL. 2012. A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism. Proc Natl Acad Sci USA 109: 79747981.
  • Novarino G, El-Fishawy P, Kayserili H, Meguid NA, Scott EM, Schroth J, Silhavy JL, Kara M, Khalil RO, Ben-Omran T, Ercan-Sencicek AG, Hashish AF, Sanders SJ, Gupta AR, Hashem HS, Matern D, Gabriel S, Sweetman L, Rahimi Y, Harris RA, State MW, Gleeson JG. 2012. Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. Science 338: 394397.
  • Sahin M. 2012. Targeted treatment trials for tuberous sclerosis and autism: no longer a dream. Curr Opin Neurobiol 22: 895901.