Autism and Genetic Disease

One point that I really want to emphasize is that there is a very heavy genetic determinant of Autism, and one way I can emphasize that is to just list for you a number of easily recognized Neurogenetic syndromes that are causative or have been associated with Autism. Most commonly, Fragile X. You know that this is the most common cause of mental retardation in institutionalized men and boys, and associated features are macrocephaly, large pinnae, testicular enlargement, hypotonia, joint hyperextensibility. Fragile X, for which I will show you some better illustrations, may account for somewhere between 3% and 4% of Autistic Spectrum Disorders. So it's not the case that most kids who have Autism have Fragile X, but it is the case that somewhere between 30% and 50% of kids who have Fragile X are on the Autism Spectrum. Neurocutaneous Syndromes can be causal, notably, Tuberous Sclerosis, which you know for the hypopigmented macules seen on the skin, associated kidney lesions, Central Nervous System hamartomas, seizures, mental retardation, and attentional disorders. PKU, Phenylketonuria, is present on the newborn screening and treatable by dietary therapy, and so it is a preventable cause of Autism. Angelman Syndrome is a known cause of Autism. It occurs when the maternally expressed UBE3A gene on Chromosome 15 is not -- it fails to be expressed. What's caused when the paternally derived -- Prader-Willi, exactly. Okay. So Angelman Syndrome, you know is Happy Puppet. There is characteristic EEG findings. There is hypotonia, there is spasticity, and in genetic testing, you need often to do Methylation studies to figure out which -- to verify that it is the maternally derived Chromosome 15 gene that's not expressed. Rett Syndrome I told you is one of the pervasive developmental disorders that is not typically included with the ASDs, because again, the gene is known. I will show you some illustrations. It affects primarily girls, although since the gene has been known, we now know that boys can be affected. It has acquired microcephaly, seizures, and a very characteristic hand wringing stereotype. Interestingly, the Autism of Rett Syndrome plateaus and improves even as the other symptoms, breathing abnormalities and seizures, get worse. Smith-Lemli-Opitz is a rare cause of Autism. It has syndactyly, which you know is fusion of the second and third toes, and hypotonia. The reason it's important is, I believe, it is autosomal recessive, and therefore if that is a known cause of Autism, genetic counseling is imperative. Then one other less commonly known, but probably quite important neurogenetic syndrome is PTEN. Phosphatase and tensin homolog is a tumor suppressor gene found on Chromosome 10. It is associated with cancers, with nonmalignant Harmatomas Syndromes, and with Macrocephaly, and it is advised that macrocephalic children with Autism symptoms be screened for PTEN even in the absence of tumors. So I just have a couple of illustrations of the Single Gene Disorders associated with Autism. Rett Syndrome, 1 in 10,000 girls. They look normal up until 6-18 months. They then stop showing normal head growth. They regress in motor skills. Kids who used to able to turn the pages of a book, stop being able to do so, and they begin these clapping or hand wringing, highly characteristic, if you ever see this, you will never forget it. You can see the posture of the hands in these affected girls. They have breathing abnormalities, seizures, sleep disorders, but the Autistic features may plateau or improve and again, there is a lot of attention being paid to MECP2 and its role in the expression of genes that alter the development of the nervous system. Fragile X, another Single Gene Disorder known to be associated with Autism. Most common genetic cause of Autism. 1 in 4,000 boys, 1 in 6,000 girls are affected. We know that it is caused by a CGG Repeat. Do you know why it came to be called Fragile X? Does anybody know that story? In a lab, I believe in Australia, an error was made in the media in which chromosomes were being grown and folate was left out, and it was noticed in studies that were screening, institutionalized, mentally retarded men and boys, that the X chromosome would break at one particular spot. For many years the way we genetically diagnosed Fragile X Syndrome was to grow the chromosomes in folate-deficient media, on a slide, drop the slide from a height of 10 cms and count the number of X chromosomes that were broken. Same Australian lab, once it replaced its media with media that contained folate was no longer able to replicate its results. But this did lead to the treatment. I do it, I don't know if it's effective of treating the Fragile X patients with high doses of folate. In any event, it was discovered many years later that we didn't have to drop chromosomes and count broken X chromosomes, we could actually -- we didn't have to grow chromosomes in folate-deficient media and count their broken Xs, we could actually analyze DNA for CGG Repeats. Again, 30% of affected boys are Autistic. if we expand the phenotype to include Autism Spectrum Disorders, Asperger's Syndrome etcetera, it's 50% or 60%. Carrier girls may also be autistic. These are just illustrations of some of the facial features, the elongated faces and the protuberant ears that you might see in boys with Fragile X Syndrome. Again, to drive home the PTEN story, kids with large head circumferences should be screened for PTEN mutations even in the absence of tumors. When I grew up and saw the Elephant Man I thought that he had neurofibromatosis. It has subsequently been established that he probably had Proteous Syndrome which itself is probably a PTEN mutation.