Mitochondrial dysfunction in autism spectrum disorders: a population-based study

Abstract

A minority of cases of autism has been associated with several different organic conditions, including bioenergetic metabolism deficiency. In a population-based study, we screened associated medical conditions in a group of 120 children with autism (current age range 11y 5mo to 14y 4mo, mean age 12y 11mo [SD 9.6mo], male:female ratio 2.9:1). Children were diagnosed using Diagnostic and Statistical Manual of Mental Disorders criteria, the Autism Diagnostic Interview--Revised, and the Childhood Autism Rating Scale; 76% were diagnosed with typical autism and 24% with atypical autism. Cognitive functional level was assessed with the Griffiths scale and the Wechsler Intelligence Scale for Children and was in the normal range in 17%. Epilepsy was present in 19 patients. Plasma lactate levels were measured in 69 patients, and in 14 we found hyperlactacidemia. Five of 11 patients studied were classified with definite mitochondrial respiratory chain disorder, suggesting that this might be one of the most common disorders associated with autism (5 of 69; 7.2%) and warranting further investigation.

Brief Report: High Frequency of Biochemical Markers for Mitochondrial Dysfunction in Autism: No Association with the Mitochondrial Aspartate/Glutamate Carrier SLC25A12 Gene

“…Because hyperlactacidemia and increased lactate/pyruvate ratio may be due to one of several inherited metabolic defects of gluconeogenesis, pyruvate oxidation, the Krebs cycle or the respiratory chain, it is possible that multiple genes influence the observed changes in lactate and pyruvate levels, and that genetic heterogeneity underlies mitochondrial dysfunction associated with autism. Supporting this hypothesis is the fact that, even in the limited number of patients with confirmed mitochondrial disease in our study, we find deficiencies in more than one respiratory chain complexes (Oliveira et al, 2005). The findings also do not corroborate the recently described association of autism with the SLC25A12 gene (Ramoz et al, 2004).…”

“…Mitochondrial functional studies confirmed the diagnosis of mitochondrial disease in 5 of these patients (7.2%), a surprisingly high frequency in autism. While the mitochondrial and nuclear genomes exert a dual genetic control on the biogenesis and maintenance of mitochondrial function, in our patients mtDNA mutations were not detected, suggesting the involvement of nuclear genes encoding proteins involved in mitochondrial function (Oliveira et al, 2005).…”

“…A number of cases of mitochondrial respiratory chain (MRC) disorders have been described associated with autism, including a child with autism and documented MRC complex IV deficiency by Lászlo, Horvath, Eck, and Fekete (1994), an autistic boy and his sister with Leigh syndrome with MRC complex IV defect and a mitochondrial DNA (mtDNA) G8363A mutation (Graf et al, 2000), two autistic children with 15q inverted duplication, mitochondrial hyperproliferation and respiratory complex III defect (Filipek et al, 2003) and five patients with autism and mtDNA mutations or mtDNA deletion (Pons et al, 2004). In a previous population-based study of autistic children in Portugal (Oliveira et al, 2005), we have found hyperlactacidemia, a biochemical marker of mitochondrial dysfunction, in 20.3% of 69 tested patients. Mitochondrial functional studies confirmed the diagnosis of mitochondrial disease in 5 of these patients (7.2%), a surprisingly high frequency in autism.…”

“…Patients were diagnosed as previously described (Oliveira et al, 2005) and only idiopathic subjects and patients with mitochondrial disease were included in the study. Controls were healthy adult blood donors.…”

“…Measurement of muscle respiratory chain complex activities in isolated deltoid muscle mitochondria and mtDNA study were performed as previously described (Oliveira et al, 2005). The clinical/laboratorial classification of these patients was according to the revision by Bernier et al (2002) of current diagnostic criteria in adults for application to paediatric age.…”