Proopiomelanocortin (POMC) disregulation and response to opiate blockers

Abstract

Autism is a collection of disorders or subtypes with distinctive or prominent phenotypes and genotypes. The study of adults with autism offers a unique opportunity to examine its phenotypic diversity. Recent evidence has identified disturbances in specific neurochemical systems that are associated with primary autistic symptoms. Establishing biological markers, such as specific neurochemical disturbances, not only confers greater precision in phenotyping individuals but also provides the basis for rational intervention. Our initial studies in adult individuals exhibiting self-injurious behavior (SIB) generated evidence that the proopiomelanocortin (POMC) system, specifically the endogenous opioid system, may be disregulated in subgroups of autistic patients. These findings, corroborated in at least 15 other laboratories, indicated that treatment with an opiate blocker, naltrexone (NTX), reduced SIB in 30-70% of individuals observed. However, the effects of NTX on SIB were not simple. We and others have found that concentration of plasma POMC fragments, specifically opioid fragments, contributed to the symptoms of autism and to the response to treatment. Uncoupling of the release of POMC products predicted the efficacy of NTX treatment on the expression of SIB. Uncoupling of POMC fragments among autistic and SIB patients suggested a basic, underlying defect, perhaps in the POMC gene. The findings of a maternal influence on the C-terminal BE fragment among individuals with autism (Leboyer et al. [1999] Soc Biol Psychiatry 45:158-163) and our preliminary findings, reported here, of a mutation in the opioid region of the POMC gene in an autistic individual, were consistent with the prospect that a subgroup of patients will be identified who share a POMC genetic defect.1999 Wiley-Liss, Inc.

Temporal patterns of self-injurious behavior correlate with stress hormone levels in the developmentally disabled

“…Indeed, numerous studies from many laboratories have shown that the functioning, relations, and processing of the POMC system are uncoupled or perturbed in subgroups of self-injuring individuals, resulting in different ratios of βE and ACTH, particularly under conditions of stress (Leboyer et al, 1994(Leboyer et al, , 1999Gillberg, 1995;Cazzullo et al, 1999;Sandman et al, 1990aSandman et al, , 1990bSandman et al, , 1995Sandman et al, , 1997Sandman et al, , 1999Sandman et al, , 2000aSandman et al, , 2002Sandman et al, , 2003.…”

Multidisciplinary Assessment and Treatment of Self-Injurious Behavior in Autism Spectrum Disorder and Intellectual Disability: Integration of Psychological and Biological Theory and Approach

“…A possible mechanism relating SIB to opioids is the finding of a dysregulated POMC or opioid system in an estimated 30-70 % of individuals with SIB (Sandman et al 1999). The precursor POMC is considered to be a stressrelated molecule and its products, BE and ACTH, are part of the hypothalamic-pituitary-adrenal axis.…”

Self‐injurious behavior: Gene–brain–behavior relationships

“…Behavioral intervention techniques, which can be used for assessing [Iwata et al, 1982] and intervening with most forms of SIB, burgeoned in the 1980s. In the 1990s the interaction of these trends to study gene-environment interactions [Sackett, 1999], environmental effects on neurotransmitter functions [Tessel et al, 1995], and their combination [Thompson et al, 1995;Sandman et al, 1999] have predominated. The next decade holds new promise for developing a more comprehensive and theoretically driven approach to the study of this devastating disorder, its intervention, and ultimately its prevention.…”

“…These findings suggested that a comprehensive examination of the POMC molecule and the genes that control its expression may be a productive strategy to better understand a biological pathway relevant to SIB. Sandman et al [1999] have initiated such studies and have preliminary evidence of a mutation in the opioid region of the POMC gene.…”