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A Possibly Treatable Type of Autism

Summary and Comment |
October 1, 2012

A Possibly Treatable Type of Autism

  1. Barbara Geller, MD

Genetic mutations lead to altered branched chain amino acid pathways that might be normalized with dietary supplementation.

  1. Barbara Geller, MD

Investigators genotyped exome regions in three consanguineous families of patients who had autism, seizures (or electroencephalographic abnormality), and intellectual impairment.

Affected people had various mutations in the branched chain ketoacid dehydrogenase gene (BCKDH). This gene encodes a protein that catabolizes branched chain amino acids (BCAAs; leucine, isoleucine, and valine). Mice with this gene knocked out had low BCAA levels in plasma and in the brain and exhibited neurological impairments that are observed in other autism models — including seizures, tremors, and hind-limb grasping. The knockout mice also showed perturbations in BCAA transporters (which also transport major neurotransmitters) across the blood–brain barrier, as well as elevated brain levels of other amino acids, but how these perturbations are related to phenotypic manifestations is unknown.

Bckdh-knockout mice fed a diet enriched in BCAAs showed neurological improvements. Patients had lower plasma BCAA levels than relatives and population references; after dietary supplementation, levels increased significantly immediately afterward and showed a trend toward normalization in fasting tests. Phenotypic assessments are planned.

Comment

Clinical quandaries include whether to test for plasma levels of branched chain amino acids and whether to prescribe supplements to patients with low levels. Given the current paucity of therapeutic data, clinicians need to make these decisions on a case-by-case basis. Even if plasma BCAAs are normalized, patients might be beyond the critical periods for developing social and language skills. Recent research, however, on reopening these critical periods (Nature 2012; 487:24) may eventually be applicable for skills development in older autistic individuals with treatable mutations.

Citation(s):

Reader Comments (2)

Barbara Geller, MD

The reader correctly notes that mutations of many genes result in increased plasma levels. By contrast, the mutations of the BCKDH gene in this study affected pathways that led to a decrease in plasma levels of branched chain amino acids, as noted in the article:

"Mice deficient for Bckdk display increased basal activity of the BCKDH complex as well as reduced BCAAs in various tissues (11). We measured plasma BCAAs in our patients and found that each patient with a homozygous mutation showed notably lower levels of plasma BCAAs compared with their healthy relatives and reference ranges (Fig.2D and tables S3 to S5). Declines in BCAAs in affected patients with null mutations were more substantial compared to normal reference ranges than those in patients with missense variants (tables S3 to S5) (12)."

Competing interests: Summary author

R. B. Kerr

The summary stated "Affected people had various mutations in the branched chain ketoacid dehydrogenase gene (BCKDH). This gene encodes a protein that catabolizes branched chain amino acids (BCAAs; leucine, isoleucine, and valine). Mice with this gene knocked out had low BCAA levels in plasma and in the brain". It seems counter intuitive that knocking out a gene that produces a protein that catabolizes BCAA's would lead to low levels of the BCAA's. It seems like knocking out this gene would decrease the catabolism of BCAA's and hence increase their level. I would appreciate if someone might further expand on the biochemistry of this to clarify how decreasing the catabolism of BCAA's leads to their low level.

Competing interests: None declared

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