Schizophrenia and Autism: the Phelan-McDermid Syndrome

Many years ago I found myself reviewing the literature for childhood onset schizophrenia. I was planning on writing an article reporting the autopsy findings of three such cases that came to my attention. Fortunately I had a acquired a good number of tissue samples and had performed many stains on them. The microscopic exam offered me some clues as to the possible underlying mechanism which I thought was worth publishing. The reason for this particular study was the idea that the neuropathology of schizophrenia when manifested at younger ages would be more severe and easier to recognize than that in adults.

Twenty or thirty years ago the medical literature suggested that autism was a form of childhood schizophrenia. Indeed Kanner’s original designation of “autism” for his original cohort of patients was borrowed from Eugen Bleuler’s term describing how schizophrenic patients tended to withdraw from reality. This equiparation is presently recognized as erroneous and starting with the Diagnostic and Statistical Manual-III (DSMIII) schizophrenia and autism have been classified as different disorders. However, in clinical circles, the demarcation between childhood schizophrenia and autism remains cloudy.

Retrospective studies of patients with early onset schizophrenia reveal delays in language acquisition, visual-motor coordination and transient motor stereotypies all of which are symptoms characteristic of autism spectrum disorder (Asarnow et al., 1995; Alaghband-Rad et al., 1995). It is therefore unsurprising that a blog in the Psychiatric Times ( ) states that, “Although the disorders are distinct, they have shared clinical features. Social withdrawal, communication impairment, and poor eye contact seen in ASD are similar to the negative symptoms seen in youths with schizophrenia (Posey et al., 2004). When higher-functioning individuals with autism are stressed, they become highly anxious and at times may appear thought-disordered and paranoid, particularly when they are asked to shift set (such as being asked to change a topic of conversation or to stop an activity that they are engaged in and begin a new activity) (Berney, 2000). A subset of children (28%) in the ongoing NIMH study of childhood onset schizophrenia (COS) have been reported to have comorbid COS and ASD (Rapoport et al, 2009).” In addition to similarities in the clinical signs and symptoms mentioned above, genetic data suggests an overlap among risk genes associated with both conditions, including CNTNAP2, NRXN1, DISC1, and SHANK3. According to a database study in Israel and Sweden people with a schizophrenic sibling are 12 times more likely to have autism than those that do not have schizophrenia in the family.

In this particular blog I will be talking primarily about a syndrome caused by a loss of the terminal segment of long arm of chromosome 22. This loss is accompanied, in the majority of cases, with a deletion of the SHANK3 gene. Loss of the terminal segment of chromosome 22 or mutations of the SHANK3 gene provide for the signs and symptoms observed in the Phelan-McDermid syndrome (PMS). The larger the piece of chromosome missing, the more severe the manifestations. A study for the gene encoding the protein SHANK3 in 285 controls and 185 schizophrenia patients with unaffected parents indicated the presence of mutations in two families (one of them having three affected brothers). Since mutations for SHANK3 have already been described in autism, the study suggested to its authors a genetic link between these neurodevelopmental conditions (Gauthier et al., 2010).

Only 1000 or so cases have been diagnosed with PMS world-wide. Many of the manifestations of the Phelan-McDermid syndrome are common to both childhood schizophrenia and autism. Indeed, the Phelan-McDermid syndrome is characterized by a global developmental delay, mental retardation, delayed speech and poor muscle tone. Close to a third of patients suffer from seizures and approximately half of them have problems sleeping. They also exhibit maladaptive behaviors (e.g., biting, hair pulling) and tend to be impulsive. Some behaviors are described as autistic-like with tactile defensiveness, self stimulatory behaviors, avoidance of gaze, and social anxiety. Interestingly some patients appear to attain normal communication milestones, babbling and saying a few words, and then lose the same at 2-3 years of age.

I recently had the opportunity to visit the Greenwood Genetics Center where Dr. Phelan described the first set of patients that now bear her name as an eponym. I was struck by all of the research they had been able to perform and even by the large series of patients that they had gathered. Hopefully with the amount and quality of research that is presently being performed some useful finding(s) may provide a difference in the life of patients in the no so distant future.

A link to the Phelan McDermid association:

For information about clinical trials and potential interventions contact:

Katy Phelan, Ph.D., FACMG
Director, Cytogenetics
Molecular Pathology Laboratory Network
250 East Broadway
Maryville, TN 37804

Gail Stapleton, MS, C.G.C
Genetic Counselor
Greenwood Genetic Center/Greenville
2 Doctors Drive
Greenville, SC 29605

Randy Riddle
Chair, New Members Committee, 22q13 Deletion Support Group


Alaghband-Rad J, McKenna K, Gordon CT, et al. Childhood-onset schizophrenia: the severity of premorbid course. J Am Acad Child Adolesc Psychiatry. 1995;34:1273-1283.

Asarnow RF, Brown W, Strandburg R. Children with a schizophrenic disorder: neurobehavioral studies. Eur Arch Psychiatry Clin Neurosci. 1995;245:70-79.

Berney TP. Autism—an evolving concept. Br J Psychiatry. 2000;176:20-25.

Gauthier et al. De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia. Proc Natl Acad Sci U S A. 2010 Apr 27; 107(17): 7863–7868.

Posey DJ, Kem DL, Swiezy NB, et al. A pilot study of D-cycloserine in subjects with autistic disorder. Am J Psychiatry. 2004;161:2115-2117.

Rapoport J, Chavez A, Greenstein D, et al. Autism spectrum disorders and childhood-onset schizophrenia: clinical and biological contributions to a relation revisited. J Am Acad Child Adolesc Psychiatry. 2009;48:10-18.

3 responses to “Schizophrenia and Autism: the Phelan-McDermid Syndrome

  1. The NIH has published a gene book written by Katy Phelan the co-discoveror of the syndrome an excellent reference source:

    20% of autism is caused by the genetic syndromes with an identifiable genetic medical cause.The vast majority of cases are caused by a de novo gene mutation and are not inherited. They are caused by a reproductive error, a gene mutation in sperm or egg that is not present in either parent. I remain perplexed why the research community has little interest in the origins these reproductive cell mutations.

    Michael Rutter has asked important questions about the de novo mutations… ‘Where do they come from?”

    Secondly those affected by these mutations don’t reproduce (reduced fecundity). No person diagnosed with Phelan McDermid Syndrome has ever produced a child. Rutter again asked the important question, ‘Why have’nt the genetic syndromes become extinct?’

    My view is that environmental risk factors can be linked to the production of egg or sperm mutations that are preventable as in the case of the genetic syndrome 1p36 deletion syndrome and benzene exposure:


    • I think the same way and believe that an environmental exigency is at play. In my case I believe that prenatal ultrasound may provide a risk factor. As to why certain genes may be involved to confer risk, a study by my wife cited a commonality among them on the number and size of transposable elements. These elements make the gene have a higher capacity to mutate to any insult.

      Thank you for the reference. I was not aware that Katy had been a fellow at Greenwood when she described her series of patients. Everybody there spoke quite highly of Phelan “the researcher” and I though that she was part of the faculty.


    • Not to leave the ultrasound as a loose comment, US is being used as part of a project that promotes its use as a non-hormonal alternative to contraception in males. It is also used prenatally in many cases for the purpose of establishing sex (focusing its energy in the genitalia).


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