Pathophysiology of Autism with Diagnostic Tests - Research Paper Example

Pathophysiology of Autism with diagnostic tests. Autism is a neurodevelopmental disorder characterized by severe and sustained impairment in social interaction, deviance in communication, and patterns of behavior and interest that are restricted, stereotyped, or both. However, the precise mechanisms underlying the pathophysiology of this disorder remain to be determined (Genichi Sugihara). The term “autistic syndrome” is intended to describe a pattern of similar behaviors produced by a variety of different insults. The need to understand the causes of autism and the underlying patho-physiology has become more acute since the number of diagnosed cases has risen markedly in recent years (White). Autism is a life-long developmental disorder affecting as many as 1 in 500 children. The causes for this profound disorder are largely unknown (White). The pathophysiology of autism is classified into two: etiology and brain mechanisms (State of the Science in Autism: Report to the National Institutes of Health). Several pathophysiological conditions are responsible to cause autism, and one of them is Hepatocyte growth factor (HGF). HGF is a polypeptide growth factor which acts by binding to the MET tyrosine kinase receptor. HGF influences the growth, motility and morphogenesis of various epithelial and endothelial cells and functions as a trophic factor for organ regeneration. Accumulating evidence suggest that HGF and its receptor MET play a role in neuronal cell development. First, HGF and its receptor MET are widely expressed in the developing and mature mouse brain, with expression beginning as early as embryonic day 12 (E12) and E13, respectively Second, HGF promotes the migration of cortical interneurons from the ventral to the dorsal telencephalon in rodents,and HGF-MET signaling systems are implicated in regulating the proliferation and differentiation of cerebellar granule cells. Furthermore, HGF plays a role in regulating the morphology of cortical pyramidal dendrites in the early postnatal period, and endogenous levels of HGF are necessary for the normal development of these neurons. Taken together, these findings Sugihara et al., 2007 suggested that HGF may be a candidate for mediating interneuron development in vivo. In this study, these researchers studied whether serum HGF levels in subjects with high-functioning autism are altered as compared with age-matched healthy controls. Furthermore, they also examined the relationship between serum HGF levels and clinical symptoms in subjects with autism. The findings suggested that disruption of the HGF-MET signaling systems results in complex alterations in GABAergic interneuron development in the forebrain. Taken together, it is likely that decreased HGF levels may be implicated in the high rates of seizure disorder in autism although further studies on the role of HGF-MET signaling systems on the high rate of seizure in autism are required for investigation of its pathological roles in autism (Genichi Sugihara). Intestinal pathophysiology-Recent research has uncovered pathology in the gastrointestinal tract of autistic children. In a study published in 1998, 12 children diagnosed with autism (all of the regressive pattern) and exhibiting a variety of GI ailments, including abdominal pain, diarrhea, and bloating, were examined extensively. The GI symptoms had developed coincident with the onset of autistic behavior, according to the parents. Lymph nodules are encapsulated bodies lying within the submucosa of the intestinal wall. Lymph nodules contain lymphocytes and neutrophils. The fluid absorbed from the intestinal lumen by the action of the absorptive epithelial cells is filtered through the lymph nodes. Here, antibodies are formed. Of the 12 children, eight also displayed abnormalities in the mucosa, the connective tissue, and muscularis mucosae. Mucosal abnormalities included granularity, loss of vascular pattern, and patchy erythema (nonspecific colitis). The findings were supported by histological examinations of mucosal biopsies. Cerebral magnetic resonance imaging (MRI) and electroencephalography (EEG) revealed no neurological abnormalities in the children. Low activity of intestinal carbohydrate digestive enzymes was observed in 21 children, whereas 27 exhibited increased exocrine secretion of pancreatic- biliary fluid after intravenous administration of the GI hormone secretin. The pathological conditions is autism shows a clear connection from the esophagus to the colon arises form the severity of symptoms expressed in autism (White). Role of nitric oxide and adrenomedullin in autism. Studies indicate that nitric oxide (NO) may have a pathophysiological role in autism. Adrenomedullin (AM), a recently discovered 52-amino acid peptide hormone, induces vasorelaxation by activating adenylate cyclase and also by stimulating NO release. AM immune reactivity is present in the brain consistent with a role as a neurotransmitter. It has been stated that NO and AM do function in the regulation of many neurodevelopmental processes. Zoroglu et al., 2003 hypothesized that NO and AM activities have been affected in autistic patients and aimed to examine these molecules. Twenty-six autistic patients and 22 healthy control subjects were included in this study. AM and total nitrite (a metabolite of NO) levels were measured in plasma. The mean values of plasma total nitrite and AM levels in the autistic group were significantly higher than control values, respectively. There was no correlation between total nitrite and AM levels. Further research is continued to study the role of NO and adrenomedullin in autism (Zoroğlu SS). Role of Amygdala: Autism is a neurodevelopmental disorder that is defined behaviorally by severe deficiencies in reciprocal social interaction, verbal and nonverbal communication, and restricted interests. The amygdala is involved in the regulation of social behaviors and may be an important site of pathology for the social dysfunction seen in autism. Researchers performed a magnetic resonance imaging study to better define the neuropathology of autistic spectrum disorders. The findings were based on the amygdala and the hippocampal formation. Borders of the amygdala, hippocampus, and cerebrum were defined, and their volumes were measured in male children (7.5-18.5 years of age) in four diagnostic groups: autism with mental retardation, autism without mental retardation, Asperger syndrome, and age-matched typically developing controls. Although there were no differences between groups in terms of total cerebral volume, children with autism (7.5-12.5 years of age) had larger right and left amygdala volumes than control children. There were no differences in amygdala volume between the adolescent groups (12.75-18.5 years of age). Interestingly, the amygdala in typically developing children increases substantially in volume from 7.5 to 18.5 years of age. Thus, the amygdala in children with autism is initially larger, but does not undergo the age-related increase observed in typically developing children. Children with autism, with and without mental retardation, also had a larger right hippocampal volume than typically developing controls, even after controlling for total cerebral volume. Children with autism but without mental retardation also had a larger left hippocampal volume relative to controls. These cross-sectional findings indicate an abnormal program of early amygdala development in autism and an abnormal pattern of hippocampal development that persists through adolescence. The cause of amygdala and hippocampal abnormalities in autism is currently unknown (Schumann CM). Table : 1 Table of pervasive developmental disorders/autism spectrum disorders (Patricia Manning-Courtney) Autism Asperger syndrome Rett syndrome Childhood disintegrative disorder (CDD) Pervasive developmental disorder– not otherwise specified (PDD-NOS) Delayed and disordered Similar to Autism Almost always girls Clinically significant regression Features of one of the other autism communication Atypical social interaction except language skills relatively intact Regression in skills between 6 and 18 mo in skills (language, social skills, bowel, bladder control, play motor skills) before age 10 y spectrum disorders but insufficient for a diagnosis of autism specifically Restricted range of interest interests Onset before 3 years of Usually not congnitively delayed Repetitive hand movements age Environmental and genetic factors Recently higher rates of autism diagnosis suggest involvement of environmental factors in causing this developmental disorder, in concert with genetic risk factors. Autistic children exhibit evidence of oxidative stress and impaired methylation, which may reflect effects of toxic exposure on sulfur metabolism. The metabolic relationship between oxidative stress and methylation, with particular emphasis on adaptive responses that limit activity of cobalamin and folate-dependent methionine synthase is studied. Methionine synthase activity is required for dopamine-stimulated phospholipid methylation, a unique membrane-delimited signaling process mediated by the D4 dopamine receptor that promotes neuronal synchronization and attention, and synchrony is impaired in autism. Genetic polymorphisms adversely affecting sulfur metabolism, methylation, detoxification, dopamine signaling and the formation of neuronal networks occur more frequently in autistic subjects. On the basis of these observations, a "redox/methylation hypothesis of autism" is described, in which oxidative stress, initiated by environment factors in genetically vulnerable individuals, leads to impaired methylation and neurological deficits secondary to reductions in the capacity for synchronizing neural networks (Deth R). Diagnosis of Autism Autistic phenotype is a behavioral syndrome described by the Diagnostic and Statistical Manual of Mental Disorders , DSM-IV based on the presence of at least 6 of 12 symptoms related to impairment in social interaction, verbal and nonverbal communication deficits, restricted interests, and repetitive behaviors, which are present by the age of 3 years. The following criteria relates to autism is stated by the American Psychiatric Association, from Diagnostic and Statistical Manual of Mental Disorders, DSM IV. (A) qualitative impairment in social interaction, as manifested by at least two of the following: 1. marked impairments in the use of multiple nonverbal behaviors such as eye-to-eye gaze, facial expression, body posture, and gestures to regulate social interaction 2. failure to develop peer relationships appropriate to developmental level 3. a lack of spontaneous seeking to share enjoyment, interests, or achievements with other people, (e.g., by a lack of showing, bringing, or pointing out objects of interest to other people) 4. lack of social or emotional reciprocity ( note: in the description, it gives the following as examples: not actively participating in simple social play or games, preferring solitary activities, or involving others in activities only as tools or "mechanical" aids ) (B) qualitative impairments in communication as manifested by at least one of the following: 1. delay in, or total lack of, the development of spoken language (not accompanied by an attempt to compensate through alternative modes of communication such as gesture or mime) 2. in individuals with adequate speech, marked impairment in the ability to initiate or sustain a conversation with others 3. stereotyped and repetitive use of language or idiosyncratic language 4. lack of varied, spontaneous make-believe play or social imitative play appropriate to developmental level (C) restricted repetitive and stereotyped patterns of behavior, interests and activities, as manifested by at least two of the following: 1. encompassing preoccupation with one or more stereotyped and restricted patterns of interest that is abnormal either in intensity or focus 2. apparently inflexible adherence to specific, nonfunctional routines or rituals 3. stereotyped and repetitive motor mannerisms (e.g hand or finger flapping or twisting, or complex whole-body movements) 4. persistent preoccupation with parts of objects. (II) Delays or abnormal functioning in at least one of the following areas, with onset prior to age 3 years: (A) social interaction (B) language as used in social communication (C) symbolic or imaginative play (III) The disturbance is not better accounted for by Retts Disorder or Childhood Disintegrative Disorder (Dignostic and Statistical Manual of Mental Disorders; 4th ed). Summary Our understanding of autism has changed dramatically in the past 10 to 15 years. Autism Spectrum Disorders are fairly common, and early and intensive treatment may significantly affect long-term outcome. Primary care providers are encouraged to be familiar with early presenting features and with the absolute indications for further evaluation. Therapies including speech-language, occupational, early intervention, or preschool programming can be initiated, even before a diagnosis. Medications may be indicated to target specific behavioral features. Although a specific cause remains unknown, Autism Spectrum Disorders are now recognized as neurologically based, and current and future research will no doubt help identify specific causes and beneficial treatments. (Patricia Manning-Courtney) Sources: Deth R, Muratore C, Benzecry J, Power-Charnitsky VA, Waly M. "How environmental and genetic factors combine to cause autism: A redox/methylation hypothesis." Neurotoxicology. (2007). Dignostic and Statistical Manual of Mental Disorders; 4th ed. Washington DC: American Psychitric Association, 1994. Genichi Sugihara, Kenji Hashimoto , Yasuhide Iwata , Kazuhiko Nakamura,. "Decreased serum levels of hepatocyte growth factor." Progress in Neuro-Psychopharmacology & Biological Psychiatry (2007): 412-415. Patricia Manning-Courtney, Jennifer Brown,Cynthia A. Molloy, Judy Reinhold, Donna Murray, Rena Sorensen-Burnworth, Teri Messerschmidt, and Bridget Kent. "Diagnosis and Treatment of Autism Spectrum Disorders." Curr Probl Pediatr Adolesc Health Care 2003 (2003): 280-304. http://dx.doi.org/10.1016/S1538-5442(03)00108-1 Schumann CM, Hamstra J, Goodlin-Jones BL, Lotspeich LJ, Kwon H, Buonocore MH, Lammers CR, Reiss AL, Amaral DG. "The amygdala is enlarged in children but not adolescents with autism; the hippocampus is enlarged at all ages." J Neurosc (2004): 6392-401. < http://www.jneurosci.org/cgi/content/full/24/28/6392> "State of the Science in Autism: Report to the National Institutes of Health." Journal of Autism and Developmental Disorders. (1996): 121-154. White, John F. "Intestinal Pathophysiology in Autism." Exp Biol Med (2003): 639-649.< http://www.ebmonline.org/cgi/content/full/228/6/639> Zoroğlu SS, Yürekli M, Meram I, Söğüt S, Tutkun H, Yetkin O, Sivasli E, Savaş HA, Yanik M, Herken H, Akyol O. "Pathophysiological role of nitric oxide and adrenomedullin in autism." Cell Biochem Funct (2003): 55-60. DOI: 10.1002/cbf.989   Annotated Bibiographies Genichi Sugihara, Kenji Hashimoto , Yasuhide Iwata , Kazuhiko Nakamura,. "Decreased serum levels of hepatocyte growth factor." Progress in Neuro-Psychopharmacology & Biological Psychiatry (2007): 412-415. http://dx.doi.org/10.1016/j.pnpbp.2006.10.010 The Researchers at the Department of phychiatry and Neurology in Japan studied the mechanisms underlying the pathophysiology of autism, which is currently unknown. Given the role of hepatocyte growth factor (HGF) in brain development, the researchers hypothesized that HGF plays a role in the pathophysiology of autism. They further studied whether serum HGF levels are altered in subjects with high-functioning autism. Using ELISA, they measured serum levels of HGF in 17 male adults with high-functioning autism and age-matched 18 male healthy subjects. The researchers concluded that reduced HGF levels may play a role in the pathophysiology of high-functioning autism. White, John F. "Intestinal Pathophysiology in Autism." Exp Biol Med (2003): 639-649.< http://www.ebmonline.org/cgi/content/full/228/6/639> In his minireview, John F. White of Department of Physiology, Emory University, Atlanta, Georgia discussed the controversial subject of pathophysiology of autism i.e., the Intestinal Pathophysiology. Recent research has uncovered pathology in the gastrointestinal tract of autistic children. The pathology, reported to extend from the esophagus to the colon, is described in this review along with other studies pointing to a connection between diet and the severity of symptoms expressed in autism. Collectively, the reports represent a potentially important new advance in our understanding of autism and related developmental disorders. However, the author points that there is very considerable controversy surrounding the published findings, as well as many of the related issues dealt with in this review. For this reason, there is a great deal that needs to be done. He suggests that it is essential that others examine the GI tract of symptomatic autistic children to substantiate the earlier findings of Wakefield and of Horvath and their respective coworkers. Patricia Manning-Courtney, Jennifer Brown,Cynthia A. Molloy, Judy Reinhold, Donna Murray, Rena Sorensen-Burnworth, Teri Messerschmidt, and Bridget Kent. "Diagnosis and Treatment of Autism Spectrum Disorders." Curr Probl Pediatr Adolesc Health Care 2003 (2003): 280-304. http://dx.doi.org/10.1016/S1538-5442(03)00108-1 Patricia Manning-Courtney and her co-workers at Cincinnati Medical Hospital, USA discusses the Diagnosis and Treatment of Autism Spectrum Disorders. The history suggests that ASD appears to be much more common than was once thought. The introduction is followed by the diagnosis, follow-up, treatment, and current research for this frequently occurring developmental disorder. ASD is a complex genetic disease with multiple loci contributing to the phenotype. Genetic dissection has been difficult because of the marked heterogeneity of the phenotype and the probable gene-gene and gene environment interactions, but recent technological advances in the areas of genetic analysis show promise for rapid progress in the future. Read More