1. Home>
2. Specialties>
3. Psychiatry>
4. Summary and Comment

A Possibly Treatable Type of Autism

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

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.

— Barbara Geller, MD

Published in Journal Watch Psychiatry October 1, 2012

Citation(s):

Novarino G et al. Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. Science 2012 Sep 6; [e-pub ahead of print]. (http://dx.doi.org/10.1126/science.1224631)

Reader Remarks:

Review and add to remarks on this article

• Biochemisitry of BCAA
  R. B. Kerr, 4 Oct 2012 12:20 PM EST
  Specialty: Internal Medicine
  The summary stated "Affected people had various mutations in the branched chain ketoacid dehydrogenase gene (BCKDH). This gene encodes a... [more]
• A response from JW Psychiatry Associate Editor Barbara Geller
  Barbara Geller, MD, Professor Emerita of Psychiatry, Washington University in St. Louis, 4 Oct 2012 3:17 PM EST
  Specialty: Psychiatry
  The reader correctly notes that mutations of many genes result in increased plasma levels. By contrast, the mutations of the... [more]

Image Gallery