Disturbed Energy Metabolism May Be a Factor in Some Autism Spectrum Disorders

Jacquelyn K. Beals, PhD

October 28, 2009

October 28, 2009 (Honolulu, Hawaii) — A new study provides evidence of abnormal energy metabolism as an underlying mechanism in some individuals with autism spectrum disorders (ASDs). The report, presented here at the American Society of Human Genetics 59th Annual Meeting, evaluated the prevalence of ASD in a large population with suspected mitochondrial disease, summarized the mitochondrial and nuclear defects, and found "evidence that there is disturbed energy metabolism as an underlying pathological mechanism in a specific subset of patients within the spectrum of ASD."

ASDs are defined by deficits in social interaction, impaired perception and communication skills, and repetitive behavior. Impairments are usually identified before a child is 3 years old, and often coexist with abnormal cognitive functioning, learning, attention, and sensory processing. Diagnosis is typically reached through clinical observation of development.

Autism is now considered 1 of several ASDs, which also include pervasive developmental disorder not otherwise specified and Asperger's syndrome. Currently, biological and genetic markers for early identification are largely lacking. A February 2007 Centers for Disease Control and Prevention report estimated the prevalence of ASDs in the United States to be approximately 6.7 children out of 1000, or 0.67%.

Mitochondrial respiratory chain disease (MRCD) is a complex dual-genome disease. Presenter Lee-Jun C. Wong, PhD, from the Department of Molecular and Human Genetics at Baylor College of Medicine in Houston, Texas, noted in her talk that more than 200 genes are targeted to mitochondria, so defects in nuclear and/or mitochondrial genomes can affect mitochondrial function. Disorders can be autosomal recessive or dominant, sex-linked, or maternally inherited. Thus, both MRCD and ASDs are genetically heterogeneous disorders.

"Mitochondria are the only organelles that contain their own DNA. So, in order to be a dual [genome disease], you have to have DNA in the mitochondria involved," Dr. Wong told Medscape Pathology. She explained that a primary defect can be in the mitochondrial genome, but mitochondria are unable to function alone with just the mitochondrial genome. Nuclear genes are also required, so there will always be interaction.

The current study reviewed the records of more than 4000 individuals evaluated by the Mitochondrial Diagnostic Laboratory at Baylor College of Medicine and the Pediatric Genetics Clinic at Texas Children's Hospital in Houston. Among more than 4000 individuals suspected of having mitochondrial dysfunction, 282 showed autistic features (ASD). The male/female ratio was close to 1 in those without ASD, but was 1.74 among individuals with ASD. The researchers also found more males than females with suspected MRCD and definite ASD.

Of the 282 individuals with ASD, 14 (10 males and 4 females) met the modified Walker diagnostic criteria for mitochondrial disease. These individuals tested negative on chromosome microarray analysis, fragile X syndrome, Angelman syndrome, and Rett syndrome, among other tests. Neurological characteristics accompanying their ASD included ataxia, dystonia, seizure disorder, and developmental delay. All 14 demonstrated molecular or biochemical problems.

Electron transport chain abnormalities were detected in 8 of the 14 individuals (4 had a common mitochondrial mutation); in addition, 2 females with ataxia and other problems had mutations of the nuclear gene POLG, which functions in the replication of human mitochondrial DNA. Additional nuclear gene mutations among the 14 ASD individuals affected SCO2, TWINKLE, SUCLA2, and other genes involved in mitochondrial DNA depletion. One patient with a homozygous SCO2 mutation also showed COX deficiency; 2 had primary LHON mutations.

"Mitochondria are making energy, but brain function requires a lot of energy," Dr. Wong said. So we think that if you have mitochondrial dysfunction, you probably also have a brain [that does] not function very well. And that's what causes the ASD."

However, the diagnosis of ASD is "so nonspecific that you can almost apply it to anyone," observed session comoderator Jerry Vockley, MD, PhD, professor of pediatrics at the University of Pittsburgh School of Medicine, professor of human genetics at the Graduate School of Public Health, and chief of medical genetics at the Children's Hospital of Pittsburgh of UPMC in Pennsylvania, in an interview with Medscape Pathology.

"If you've got all these other symptoms and autism spectrum disorder, should you follow-up and look for respiratory chain deficiency? Absolutely!" said Dr. Vockley. "But if you have nothing but autism spectrum disease, mild — even severe — neurointellectual deficits, and no other somatic findings, no neuromuscular findings, no lactic acidosis, nothing on metabolite analysis, is it worth looking for mitochondrial dysfunction? . . . There are no data right now that suggest that it's worth doing."

Dr. Vockley feels that a basic neurometabolic screen is reasonable in children with autism, as well as various blood and urine tests, and perhaps even a skin biopsy for enzyme testing.

"But if you don't have anything on either symptom or metabolite analysis that points to the mitochondria, the next step is very invasive — it's muscle biopsy. I don't think that we have the data yet to say . . . that's a reasonable thing to do," he said.

"The problem is that both disorders are becoming quite frequently diagnosed. If you look at the fringes of both, the atypical presentations for either, both are frequent enough that eventually they're goIng to intersect," noted Dr. Vockley. "The question is: Do they intersect functionally? And we're not there yet."

Dr. Wong and Dr. Vockley have disclosed no relevant financial relationships.

American Society of Human Genetics (ASHG) 59th Annual Meeting: Abstract 62. Presented October 22, 2009.

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