Mining for meaning

Hakonarson is a molecular geneticist who in this study has revealed his lack of knowledge concerning ‘autism’. He does however have a remarkable gift of hyper over-exaggerating the meaning of his research.

He claims to have replicated the existence of genetic variations (deletions and additions) in the region of chromosome 15Q11-13 and the mutations in the UBE3A gene associated with ‘Autism’.

The only problem is that these variations have been known for more than a decade and the association is not with autism but rather with Angelman Syndrome which is a genetic syndrome associated with severe mental retardation and seizures. Hakonarson never mentioned Angelman Syndrome in the paper. A small minority of children diagnosed with Angelman Syndrome have enough isolated secondary symptoms to qualify for an ASD diagnosis.

The National Angelman Syndrome Organization on its website even states that Angelman children are often misdiagnosed with cerebral palsy or autism:

http://www.angelman.org/stay-informed/

Hakonarson also claims to have replicated the 16P11.2 genetic variation reported earlier from the Boston Medical Hospital Group:

http://content.nejm.org/cgi/content/full/358/7/667

Not exactly replication since the primary source in both studies were datasets taken from the AGRE data. The Boston study did include a second cohort described as following:

“we observed the identical deletion in 5 of 512 children referred to Children’s Hospital Boston for developmental delay, mental retardation, or suspected autism spectrum disorder”.

Obviousy the second cohort was not a group of autistic children but rather a group that included a subset ’suspected’ of having autism.

Subsequently, a Dutch group found the same 16P11.2 in a group of mentally retarded patients without autism:

http://www.ncbi.nlm.nih.gov/pubmed/19306953?

How could a subset of multiple incidence families with a genetic condition associated with mental retardation and seizures have managed to be present in the AGRE dataset?

The AGRE data set excluded from participation only families with Fragile X syndrome. Further research also found a few families which included Down’s Syndrome members.

Are the Angelman cases and the 16P11.2 cases ‘autistic’ or are they a small subset of mentally retarded children who have enough isolated secondary symptoms to qualify for an ASD diagnosis.

We may never know. The AGRE tests did not include the Wechsler scales, the Gold Standard for measuring global IQ that is used to identify levels on mental retardation (pround, severe, moderate and mild).

Instead they relied on the Raven Matrices which tends to give higher IQ scores than the Wechsler Scales. This design flaw in the AGRE dataset means AGRE data cannot seperate the confounding variable of mental retardation from autistic type symptoms and cannot differentiate a genetic mental retardation syndrome from ‘autism’ however loosely it is defined.

Final thoughts on why the AGRE cohort may need to be abandoned. Hakonarnon has invoked neurologins as a susceptability family of genes for autism with data taken from multiple incident families (AGRE) in several studies. When the confounder of mental retardation is controlled by selecting a large sample of subjects meeting criteria for autism, but who are of normal or greater IQ (high functioning, Asperger, atypical) the candidate family of neuologin genes as a candidate autism susceptability gene(s) have not been replicated:

http://www.ncbi.nlm.nih.gov/pubmed/18189281?

While researchers agree that there is a problem of heterogeneity in genome scans, underrecognized, is the even greater problem of nonspecificity. None of the genes reported as candidate autism genes are specific to autism (yet), they have either not been replicated in other samples or have been found in a host of developmental problems (schizophrenia, mental retardation, seizures, developmental delay, ADHD) as well as unaffected family members.

Only by recruiting volunteer families with autistic members of normal or greater IQ can the confounder of mental retardation and nonspecificity be controlled if the purpose is to identify candidate genes specific to ‘autism’.

How genetic mental retardation syndromes (Down’s Syndrome, Angelman yndrome, 16P11.2 syndrome) may have found their way into the AGRE cohort and why there is the appearance of an autism epidemic has been explained by Leo Kanner in 1965. Noting an unexplained rise in the incidence of autism in the US and Europe during the late 1950’s and early 1960’s.

Kanner wrote:

“This sage advice was not heeded by many authors. While the majority of the Europeans were satisfied with a sharp delineation of infantile autism as an illness sui generis, there was a tendency in this country to view it as a developmental anomaly ascribed exclusively to maternal emotional determinants. Moreover, it became a habit to dilute the original concept of infantile autism by diagnosing it in many disparate conditions which show one or another isolated symptom found as a part feature of the overall syndrome. Almost overnight, the country seemed to be populated by a multitude of autistic children, and somehow this trend became noticeable overseas as well. Mentally defective children who displayed bizarre behavior were promptly labeled autistic and, in accordance with preconceived notions, both parents were urged to undergo protracted psychotherapy in addition to treatment directed toward the defective child’s own supposedly underlying emotional problem.

By 1953, van Krevelen rightly became impatient with the confused and confusing use of the term infantile autism as a slogan indiscriminately applied with cavalier abandonment of the criteria outlined rather succinctly and unmistakably from the beginning. He warned against the prevailing “abuse of the diagnosis of autism,” declaring that it “threatens to become a fashion.” A little slower to anger, I waited until 1957 before I made a similar plea for the acknowledgment of the specificity of the illness and for adherence to the established criteria”.

http://neurodiversity.com/library_kanner_1965.html

Kanner’s complaints are as relevant today as they were in 1965. The expansion of the concept of the definition of autism was introduced in 1994 when Kanner’s core defining feature ‘A pervasive lack of response to other people – autism (DSM-III 1980)’ was completly removed from all diagnostic schemes and replaced by the vague and subjective ‘Qualitative impairment in social interaction’ included in DSM-IV-TR (1994), ICD-10(1994) (and all the ‘Gold Standard’ diagnostic tools based on DSM-IV-TR and ICD-10 diagnostic criteria. The ever increasing prevelance rates of autisn can be traced directly to major changes in autism definition that took place in 1994. Pre 1994 rates were 2-4 per 10,000, post 1994 prevelance rates have climbed to 60-70 per 10,000

Kanner’s explanation for an unexpected rise in the incidence of autism 40 years is as spot on as the current concepts of autism and Kanner has explained why the AGRE cohort may not be a representative sample of the children he described in 1943.

Science writers need to approach their work with at least a small degree of healthy skepticism about what autism is, how it is defined and question interpretations of results of these gene studies, especially where the samples are of questionable reliability, such as the AGRE cohort..