Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy – 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. Science. 2012 Oct 19;338(6105):394-7. [PMID: 22956686]

ASD is often complicated by co-occurring conditions such as epilepsy, which occurs in about 25% of individuals with ASD, as well as intellectual disability. Analyzing the DNA of individuals with these co-occurring conditions could identify gene mutations that may contribute to the cause of ASD in this subgroup of individuals. This study used a genetic approach called whole-genome sequencing to determine the complete DNA sequences of members of three families that had children with co-occurring ASD, epilepsy, and intellectual disability. Comparing the whole genome sequences of these individuals, researchers identified a mutation present in each of the families in a gene for branched chain ketoacid dehydrogenase kinase—or BCKDK—that regulates a protein that breaks down certain types of naturally-occurring amino acids, called branched chain amino acids (BCAAs), that must be obtained from food. Lower levels of these BCAAs were observed in the blood of patients with the BCKDK mutation. In order to more fully explore the effects of the BCKDK mutation, researchers modified the bckdk gene in mice to make it non-functional and reported that the adult mice developed a number of neurological abnormalities, including epileptic seizures. Examination of the brains of these mice revealed abnormal levels of several different amino acids normally found in the brain and abnormalities in the networks of transporter proteins that are needed to help amino acids pass from the blood into the brain. The researchers hypothesized that the decreased blood levels of BCAAs caused by the mutation in the bckdk gene may send a signal that transport of brain amino acids into the brain is not needed, resulting in decreased availability of transporter proteins and reduced entry of amino acids into the brain. The reduced level of brain amino acids could impact neurological development and normal electrical activity in the brain. Importantly, when the mice with impaired bckdk gene activity were fed diets with added BCAAs, their seizures and other neurological deficits subsided. Similar dietary supplementation for the families with the BCKDK mutation in this study resulted in normalized blood levels of BCAAs, suggesting that it may be possible in the future to treat individuals that have the BCKDK mutation and co-occurring ASD, intellectual disability, and epilepsy with dietary supplementation of branched chain amino acids.

Differences in white matter fiber tract development present from 6 to 24 months in infants with autism – Wolff JJ, Gu H, Gerig G, Elison JT, Styner M, Gouttard S, Botteron KN, Dager SR, Dawson G, Estes AM, Evans AC, Hazlett HC, Kostopoulos P, McKinstry RC, Paterson SJ, Schultz RT, Zwaigenbaum L, Piven J; IBIS Network. Am J Psychiatry. 2012 Jun;169(6):589-600. [PMID: 22362397]

Early symptoms of ASD are generally observed to emerge within the first 2 years of life after a period of relatively typical development. This study provides evidence that, despite outward appearances, these ASD symptoms are in fact preceded by atypical brain development. Researchers studied a group of 92 infants who had older siblings with ASD and were therefore considered at “high risk” for developing ASD. Using diffusion tensor imaging (DTI)—a brain imaging technique—the brain structure in these high-risk infants was evaluated at 6, 12, and 24 months of age, before the onset of ASD symptoms. This technique allowed researchers to examine and create three-dimensional maps revealing the structure of specific white matter pathways (tracts)—bundles of nerve fibers that connect various parts of the brain—that have been associated with ASD. Behavioral assessments were conducted at 24 months, and the brain imaging scans from infants who met the behavioral criteria for ASD were compared to those from infants who did not in order to assess differences in brain structure. Images from the 6, 12, and 24-month time points were assembled to create a changing, three-dimensional picture of how the white matter pathways developed over time in these infants, allowing comparison of the developmental trajectories of infants who later were diagnosed with ASD with those who were not diagnosed with ASD. Compared to infants who did not go on to develop ASD, those who did showed differences in the development of 12 out of the 15 white matter pathways studied. At 6 months, the white matter pathways in infants that went on to develop ASD were well ordered; often more so than those who did not develop ASD. However, the white matter pathways did not continue to develop in a structured manner and by 24 months of age were visibly less ordered than those in infants who did not develop ASD. The identification of altered white matter pathway development before of the onset of ASD symptoms points to a neurobiological basis of the behavioral symptoms. Furthermore, this study provides the earliest evidence of brain differences related to the later development of ASD symptoms, pinpointing a critical period of brain development. The identification of differences in brain structure during the first year of life may lead to the development of brain imaging-based biomarkers for early identification of children who will develop ASD, allowing for earlier treatment and intervention. 

Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function – Won H, Lee HR, Gee HY, Mah W, Kim JI, Lee J, Ha S, Chung C, Jung ES, Cho YS, Park SG, Lee JS, Lee K, Kim D, Bae YC, Kaang BK, Lee MG, Kim E. Nature. 2012 Jun 13;486(7402):261-5. [PMID: 22699620]

Researchers have identified a potentially treatable mechanism in the development of ASD that is caused by mutations within SHANK2—a gene that codes for specific structural proteins in neurons. To study the mechanisms underlying the development of ASD, scientists developed a mouse model whose genetics were manipulated to mimic mutations in SHANK2, found previously to be associated with ASD and intellectual disability in humans. The SHANK2 mouse model, carrying the same mutation as found in humans with SHANK2-associated ASD, demonstrates what are considered ASD-like behaviors in mice, which include reduced social interaction and communication, repetitive jumping, anxiety-like behaviors, and hyperactivity. Researchers found that neurons in these mice did not function properly and exhibited impairments in the functioning of the NMDA glutamate receptor (NMDAR), which plays an important role in learning and memory. When the SHANK2 mouse model was treated with D-cycloserine—a drug previously shown to reduce some ASD-like symptoms in mice—NMDAR function was restored, and social interactions in the mice improved. Even greater improvements were found when scientists administered CDPPB—a drug with antipsychotic and pro-cognitive effects—resulting in enhanced NMDAR function and learning in mice via activation of another glutamate receptor, mGluR5. Interestingly, while restoration of NMDAR function with D-cycloserine and CDPPB improved social interactions, other co-occurring behaviors, including jumping, anxiety-like behaviors, and hyperactivity were not altered.  These findings indicate that reduced NMDAR function may contribute to the development of ASD-like behaviors in a SHANK2 mouse model of ASD and that regulation of mGluR5 in particular may be a potential strategy to treat ASD.