Go to:

Abstract

Autism spectrum disorder (ASD) is a syndrome that affects normal brain development and is characterized by impaired social interaction as well as verbal and non-verbal communication and by repetitive, stereotypic behavior. ASD is a complex disorder arising from a combination of multiple genetic and environmental factors that are independent from racial, ethnic and socioeconomical status. The high heritability of ASD suggests a strong genetic basis for the disorder. Furthermore, a mounting body of evidence implies a role of various ion channel gene defects (channelopathies) in the pathogenesis of autism. Indeed, recent genome-wide association, and whole exome- and whole-genome resequencing studies linked polymorphisms and rare variants in calcium, sodium and potassium channels and their subunits with susceptibility to ASD, much as they do with bipolar disorder, schizophrenia and other neuropsychiatric disorders. Moreover, animal models with these genetic variations recapitulate endophenotypes considered to be correlates of autistic behavior seen in patients. An ion flux across the membrane regulates a variety of cell functions, from generation of action potentials to gene expression and cell morphology, thus it is not surprising that channelopathies have profound effects on brain functions. In the present work, we summarize existing evidence for the role of ion channel gene defects in the pathogenesis of autism with a focus on calcium signaling and its downstream effects.

Keywords: 

Channelopathy pathogenesis in autism spectrum disorders

Abstract

Channelopathy pathogenesis in autism spectrum disorders

Autism spectrum disorder (ASD) is a syndrome that affects normal brain development and is characterized by impaired social interaction as well as verbal and non-verbal communication and by repetitive, stereotypic behavior. ASD is a complex disorder arising from a combination of multiple genetic and environmental factors that are independent from racial, ethnic and socioeconomical status. The high heritability of ASD suggests a strong genetic basis for the disorder. Furthermore, a mounting body of evidence implies a role of various ion channel gene defects (channelopathies) in the pathogenesis of autism. Indeed, recent genome-wide association, and whole exome- and whole-genome resequencing studies linked polymorphisms and rare variants in calcium, sodium and potassium channels and their subunits with susceptibility to ASD, much as they do with bipolar disorder, schizophrenia and other neuropsychiatric disorders. Moreover, animal models with these genetic variations recapitulate endophenotypes considered to be correlates of autistic behavior seen in patients. An ion flux across the membrane regulates a variety of cell functions, from generation of action potentials to gene expression and cell morphology, thus it is not surprising that channelopathies have profound effects on brain functions. In the present work, we summarize existing evidence for the role of ion channel gene defects in the pathogenesis of autism with a focus on calcium signaling and its downstream effects.

Keywords: calcium, mTOR, Fragile X syndrome, tuberous sclerosis, Rett syndrome, Prader-Willi syndrome, Angelman syndromeGalina Schmunk^1,2 and J. Jay Gargus^1,2,3,*

Author information ► Article notes ► Copyright and License information ►

Article here

Autism PLUS other abnormalities? Think mitochondrial: Mitochondrial disease in autism spectrum disorder patients.

Autism PLUS other physical or neurologic abnormalities? Think mitochondrial disease.

Excess fatiguability was the most common symptom in this cohort of children with autism AND mitochondrial disease.

60% had other neurodevelopmental abnormalities. 

64% had gastrointestinal problems.

As the authors write:

"Although all patients' initial diagnosis was idiopathic autism, careful clinical and biochemical assessment identified clinical findings that differentiated them from children with idiopathic autism. 

These and prior data suggest a disturbance of mitochondrial energy production as an underlying pathophysiological mechanism in a subset of individuals with autism."

Sadly, there are many children who have autism and have NEVER seen a specialist.

JR

What were the features?

Twenty-one patients had histories of major non-neurological medical problems, most commonly of the gastrointestinal system, with gastroesophageal reflux affecting nine and constipation affecting eight subjects. 

Seven patients had structural or functional cardiovascular abnormalities. 

In addition, 17 patients had excessive fatigability or exercise intolerance and several children had abnormal physical exam findings including six with facial dysmorphism, four with microcephaly, four with macrocephaly, and five with growth retardation.

PLoS One. 2008;3(11):e3815. doi: 10.1371/journal.pone.0003815. Epub 2008 Nov 26.

Mitochondrial disease in autism spectrum disorder patients: a cohort analysis.

Weissman JR, Kelley RI, Bauman ML, Cohen BH, Murray KF, Mitchell RL, Kern RL, Natowicz MR.

Source

Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, Ohio, United States of America.

Abstract

BACKGROUND:

Previous reports indicate an association between autism spectrum disorders (ASD) and disorders of mitochondrial oxidative phosphorylation. One study suggested that children with both diagnoses are clinically indistinguishable from children with idiopathic autism. There are, however, no detailed analyses of the clinical and laboratory findings in a large cohort of these children. Therefore, we undertook a comprehensive review of patients with ASD and a mitochondrial disorder.

METHODOLOGY/PRINCIPAL FINDINGS:

We reviewed medical records of 25 patients with a primary diagnosis of ASD by DSM-IV-TR criteria, later determined to have enzyme- or mutation-defined mitochondrial electron transport chain (ETC) dysfunction. 

Twenty-four of 25 patients had one or more major clinical abnormalities uncommon in idiopathic autism. 

Twenty-one patients had histories of significant non-neurological medical problems. 

Nineteen patients exhibited constitutional symptoms, especially excessive fatigability. 

Fifteen patients had abnormal neurological findings. Unusual developmental phenotypes included marked delay in early gross motor milestones (32%) and unusual patterns of regression (40%).

 Levels of blood lactate, plasma alanine, and serum ALT and/or AST were increased at least once in 76%, 36%, and 52% of patients, respectively. 

The most common ETC disorders were deficiencies of complex I (64%) and complex III (20%). Two patients had rare mtDNA mutations of likely pathogenicity.

CONCLUSIONS/SIGNIFICANCE:

Although all patients' initial diagnosis was idiopathic autism, careful clinical and biochemical assessment identified clinical findings that differentiated them from children with idiopathic autism. These and prior data suggest a disturbance of mitochondrial energy production as an underlying pathophysiological mechanism in a subset of individuals with autism.

PMID:

 

19043581

 

[PubMed - indexed for MEDLINE] 

PMCID:

 

PMC2584230

 

Full article here