Mitochondrial dysfunction in autistic patients with 15q inverted duplication

Abstract

Two autistic children with a chromosome 15q11‐q13 inverted duplication are presented. Both had uneventful perinatal courses, normal electroencephalogram and magnetic resonance imaging scans, moderate motor delay, lethargy, severe hypotonia, and modest lactic acidosis. Both had muscle mitochondrial enzyme assays that showed a pronounced mitochondrial hyperproliferation and a partial respiratory chain block most parsimoniously placed at the level of complex III, suggesting candidate gene loci for autism within the critical region may affect pathways influencing mitochondrial function. Ann Neurol 2003;53:801–804

Evidence of Mitochondrial Dysfunction in Autism and Implications for Treatment

“…In several studies of individuals presenting with autism, but without classical mitochondrial disease, increased ammonia has also been described; this led some authors to conclude that MtD was present [40,63,64] . Typically, these ammonia levels are not nearly as elevated as those that have been observed in some conditions that can cause autism, such as urea cycle disorders [66] .…”

“…However, many of these laboratory abnormalities have also been described in autistic individuals with MtD and without any other evidence of classical mitochondrial disease. For example, elevated blood lactate levels consistent with MtD have been described in numerous autistic individuals [29,40,[61][62][63][64][65] , sometimes affecting as many as 43% of children with autism studied when compared to neurotypical children [17] . In one study, ASD children with an elevated blood lactate level underwent deltoid muscle biopsy and approximately 35% (5 out of 14) were found to have classical mitochondrial disease [22] .…”

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

“…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.…”

A comparative study of the oxidative stress indices of children with autism and healthy children

“…22 Investigations into causes of elevated oxidants have pointed to mitochondrial dysfunction in autistic patients. 7,23 The role of mitochondria in the electron transport system (ETS) makes them the major source of oxidants and primary targets of free radicals (FRs). 24 Free radicals are highly toxic to neurons and they are generated significantly in the human brain, which is extremely sensitive to oxidative stress.…”