Autism Spectrum Disorder (ASD)

Dr. Philip Grossi
Saturday, 08 December 2012

Autism spectrum disorders are a genetically heterogeneous array of syndromes which have as their core impairment social interactions, abnormal development of the social brain.  These syndromes have received increasing attention because of what appears to be an increasing incidence and high impact on families from an emotional as well as financial standpoint. All treatments including somatic ones have been ineffective in addressing the core pathology but have been somewhat effective in dealing with specific symptoms clusters.

The genetic underpinning has thus far been elusive but with newer technologies such as DNA microarrays (DNA chip) and exome sequencing ( a strategy to sequence the coding portions of the genome) that allow for detection of CNV (copy number variation in DNA which presents as an abnormal number of gene copies or portions of genes) and point mutations suggests that progress is likely at hand.  Point mutations have been discovered supporting the statistical conclusion that increased paternal age is a risk factor.

In the October 2012 issue of Science, Novarino use exome sequencing  in related families to discover an inborn metabolic error associated with epilepsy, autism, and intellectual disability. Their results suggest that the more serious autistic presentations offer the best chance to find a causative mutation. There is an overlap in the genetics of these severe autistic disorders and severe intellectual disability presentations.

Additional observations suggest that the same genotype can lead to a number of phenotypes (presentations) including autism, intellectual disability, schizophrenia, bipolar disorder, and epilepsy. There is a large number of genetic combinations present in any single patient which implies variability of genetic expression in those individuals who do not meet criteria for any disorder.

Novvarino identified a point mutation for the gene BCKDK which results in increased degradation of branched chained amino acids. This defect in mice can largely be reversed by feeding branched chained amino acids. This suggests that newborn screening for this error, which has not yet been developed, could lead to a straightforward treatment. It's only a hope now but should it be proven effective, it would be a very big development.

Caution: Bath Salts

Dr. Philip Grossi
Tuesday, 06 November 2012

Drug abuse is constantly changing and presents evolving therapeutic challenges to psychiatrists and other treating providers. In about the last eighteen months especially, "bath salts" or "plant food", have burst on the scene aided by the electronic marketplace, the internet, and the rapid movement of information. They are named for their white crystalline-pellet appearance and are the latest abusable substances. They are synthetic derivatives of cathinone, a naturally occuring psychostimulant found in the khat plant.  Natives of East Africa and the Arabian peninsula (mostly unmarried men in their 20s) have chewed the leaves of this plant for centuries to experience stimulation and relaxation.The most prevalent active ingredients are mephedrone, methylone, and methylenedioxypyrovalerone. They have amphetamine-like properties and will increase alertness, increase musical sensations, heighten libido and sexuality, euphoria, and relaxation. These are caused by the rapid release and reuptake blockade of dopamine, serotonin, and norepinephrine. The drug can be ingested, injected, smoked, or inhaled and they produce their effect in less than one hour.

Bath salt intoxication is a medical and psychiatric emergency. Auditory and visual hallucinations, delusions, paranoid thinking, agitation, and disorientation are common psychiatric symptoms.  Physical symptoms can include hypertension, hyperthermia, diaphoresis, tremors, hypereflexia, clonus, ocular clonus, flushed skin, and muscle breakdown which can cause kidney damage. The physical signs sound like serotonin toxicity as described in the blog, MAOI and Drugs.That fits the data as mephedrone can cause a tenfold increase in serotonin level. The psychotic signs are likely related to a sudden rise in dopamine and the neurovegetative signs are serotonin and norepinephrine related.

In short, bath salts are extraordinarily dangerous and could even be fatal. Do not use under any circumstances.


Dr. Philip Grossi
Tuesday, 06 November 2012

In the September 2012 issue of the American Journal of Psychiatry Karen Ersche, PhD, et al. published an article entitled "Cognitive Dysfunction and Anxious-Impulsive Personality Traits Are Endophenotypes for Drug Dependence". Most readers are probably not familiar with the term endophenotype. The authors are saying that the behavior, addiction, is related to an underlying phenotype, anxious-impulsive personality traits, which in turn have a genetic connection. Another common example is colonic polyps which if left alone for long periods tend to become cancerous.

This article assumes that addiction disorders depend on antecedent behavior or features or traits which may be inherited. So, substance abuse which is highly prevalent in anxiety, affective, and impulse control disorders may be a manifestation of an underlying neural dysregulation of motivation, arousal, impulsivity, reward sensitivity or impaired executive function.

In the Ersche study, 45 of the 50 stimulant dependent probands were using during the study thus avoiding any confounds arising from withdrawal. The authors were then measuring the characteristics likely to indicate genetic risk for the condition. They measured environmental, behavioral, cognitive, and social factors and focused on similar features shared by drug dependent subjects and their unaffected siblings that were not shared by healthy comparitors.

The important findings include the following. Stimulant dependence is strongly related to impulsivity and especially impaired response inhibition. The results also showed greater impulsive and anxious personality traits in probands.  They also demonstrated a strong positive correlation between impulsivity and anxiety which may be related to dysregulation of arousal. A type of impulsivity associated with negative or stressful emotion results in responses which may contribute to suicidal behavior which is a risk in substance use disorders.

The investigators also examined the impact of early environmental stressors and chaotic family life. They found that stressful events and stimulants interact to produce a reinforcing pattern leading to increased stimulant usage. This may be the mechanism that leads from sporadic usage to addictive use and further suggests that susceptibility to substance use disorder may lie in susceptibility to the behavioral sensitization.  Conversely, it suggests that siblings may be resistant if they do not have this susceptibility even though they share the same environment.

A cautionary note should be sounded, however. The subjects of this study do not possess the genome they were born with but one that has been modified epigenetically by stress and stimulant usage in the probands. The differences between the probands and their siblings could either be accounted for by inheritance or epigenetic consequences of stimulant usage. Interestingly, this study does not address the issue of resilience which was the topic of the prior blog.