Autism: Why the Silence?
Affecting 2-6 every 1000 children, predominantly boys, autism, now classified as autism spectrum disorder (ASD) to indicate the heterogeneity of its manifestations, has escaped (so far) most of the attempts at finding its structural and/or molecular basis. New findings presented at the Neuroscience conference shed some light in multiple directions: the genetic component, the occurrence of structural differences, changes in central neurotransmitters, and deficits in the response of autistic children to sound.
The finding that patients affected by ASD may have a smaller
cerebellum, a system important for language and attention-span control,
prompted an association with the results of a study in mice in which
deletion of the ENGRAILED 2 (En2) gene yielded a smaller cerebellum. In
addition, the human En2 gene maps to the region 7q36, linked in previous
studies to the occurrence of ASD. Analysis of 167 families from the Autism
Genetic Research Exchange[2,3] and then of 380 additional families showed
that 2 inheritable, intronic single nucleotide polymorphisms of En2
(rs1861972 and rs1861973) were found more frequently in autistic patients
than in their siblings. In contrast, 2 flanking, exonic single nucleotide
polymorphisms were not associated with ASD. From a functional
standpoint, En2 encodes a transcription factor that modulates expression of multiple, so far unknown genes. Further studies will identify how these downstream targets are affected by the presence of a polymorphic En2 gene and whether any of them has an ethiopathogenetic role in ASD, as proposed by the neurodevelopmental defect hypothesis.
Changes in neurotransmitter location and production have been
described by multiple groups in ASD, including a decrease in the
inhibitory neurotransmitter GABA in the hippocampus, of type 2A serotonin receptors in the cortex, and of acetylcholine in specific cortical areas. Such
changes are thought to alter the balance between excitatory and inhibitory signals in various, and perhaps critical, regions of the central nervous systems of ASD patients. In the study reported at the Meeting, the researchers confirmed a decrease in muscarinic type 2 acetylcholine receptors and further mapped it to the medial accessory olive, a structure connected to
the cerebellum, in tissues from 4 ASD patients. Conversely, binding of
3[H]AFDX-labeled muscarinic type 2 receptors was normal in other regions
of the dorsal accessory and principal olive.
Structural changes may also occur in the brains of patients with
ASD, namely, a narrower vertical organization. In recent studies, minicolumns
appeared more numerous, narrower, and closer to each other in the frontal
but not in the visual cortex of ASD patients vs controls.[6,7] Differences
were most prominent in the orbital region, with a reduction in column size
of approximately 23%. Although about 10% of ASD subjects are known to have unique abilities, especially in mathematics (“autistic savants”), it is
unclear at the moment whether such changes in neuronal organization yield
more or less efficient neural transmission and integration in ASD
In principle, smaller units packed in a tight area could ensure better
information processing, but this would hold true only if the smaller
minicolumns retain the same functional properties of their larger, non-ASD
Mapping of the behavioral, emotional, and social deficits seen in ASD patients is far from being accomplished. Preliminary studies, however, suggest that the language impairment seen in these children may be partly ascribed to a reduced brain response to external sounds, as shown by magnetoencephalography.
A flattened M100 response was detected in the auditory cortex of ASD children (ages 9-11 years) vs controls. This was associated with an inability to hear sounds with the same, wide dynamic range of non-ASD children — a deficit that, according to the investigators of the study, may explain the difficulties these children have in understanding and learning speech.