Autism spectrum disorders (ASD) have long been known to have a strong genetic basis. Until recently, the tendency for ASD to run in families was thought to be due solely to the passage of nuclear genes from parent to child. Now scientists are beginning to investigate whether mitochondrial genes could also play a role. What are nuclear genes and mitochondrial genes, and how could mitochondrial gene mutations cause ASD?
The human body is made of trillions of cells. Each cell contains a nucleus, which can be thought of as the “control center” of the cell and is home to billions of DNA base pairs that make up the nuclear genome (usually referred to simply as the human genome). Yet, the nucleus is not the only place in the cell that has DNA. DNA is also found in a cell’s mitochondria. Mitochondria can be thought of as the energy factory or power generator of the cell, whose main function is to take in nutrients, break them down, and generate energy. A typical cell has thousands of mitochondria that serve as the energy supply for all of the body’s activities. The density of mitochondria varies from tissue to tissue depending on its energy requirement. Cells of the central and peripheral nervous system, from the neurons of the brain down to the myocytes of skeletal muscle, have very large energy requirements, and, therefore, are particularly sensitive to problems with mitochondrial function. Mitochondrial genes regulate many aspects of mitochondrial function. In 1988 scientists first discovered that mutations, or errors in the sequence, of the mitochondrial genome could cause disease. Since then over 200 point mutations in the mitochondrial genome have been associated with disease, and the vast majority of these diseases cause problems with the function of the nervous system.
How are Mitochondrial Disorders and Autism Spectrum Disorders Related?
Autistic symptoms have long been known to be one of the possible features of mitochondrial disease. Difficulties with social interaction, communication and repetitive, stereotyped behaviors are clearly present in a subset of children who have been diagnosed with a mitochondrial disorder. In addition, autistic symptoms can be the earliest symptoms to occur in a child with a mitochondrial disorder. Currently, routine diagnostic testing in children with ASD does not include testing for mitochondrial disorders. The percentage of cases of ASD that could be secondary to mitochondrial disorders is still unknown. One population-based study, done in Portugal, has examined the rate of mitochondrial disorders in children with ASD. This study found that approximately 7% of cases of ASD were due to mitochondrial disorders, a rate higher than any other known genetic etiology. While this estimate is based on just one study, the findings clearly demonstrate the need for further research into the role that mitochondrial disorders may play in causing ASD.
What Other Symptoms Can be Caused by a Mitochondrial Disorder?
Because mitochondria are everywhere in the body, any organ could potentially be affected, including the heart, liver, gastro-intestinal tract, or kidneys. The most common symptoms, however, are those related to problems with the function of the nervous system. These include seizures, cognitive disability, weakness, difficulty seeing or hearing, and movement disorders. Some of the more subtle symptoms that may go unrecognized include exercise intolerance and short stature. An individual with a mitochondrial disorder may show just one of these symptoms or numerous symptoms depending on a variety of factors, including the number and distribution of abnormal mitochondria throughout the body. One notable feature of many mitochondrial disorders is the worsening of symptoms in the setting of a physical stressor, such as an infection, other illness, or physical exertion. In these conditions, the body requires greater amounts of energy. This increased energy requirement may be difficult for the body to handle if its mitochondria are not functioning at an optimal level, and this can lead to a worsening of symptoms.
How are Mitochondrial Disorders Passed from Parent to Child?
When the egg and sperm combine at the time of fertilization, both contribute nuclear DNA, however, all mitochondrial DNA comes from the egg. Therefore, a child’s mitochondrial DNA comes entirely from the mother, and only mothers can pass a mitochondrial disease to their children. Both males and females can be affected by mitochondrial disorders, but only females can pass the disorder on to their children. A mother who passes the mitochondrial gene mutation to her child may not be aware that she has a mitochondrial disorder. Her symptoms may be extremely mild and remain undetected throughout her life span. In many cases, a mitochondrial disorder in the mother is diagnosed only after her child has been diagnosed.
How Common are Mitochondrial Disorders?
Although mitochondrial disorders were once believed to be rare (prevalence estimated at 1 in 5,000 individuals), they are now thought to be much more common. One population-based study screened healthy newborn infants for the ten most common disease-causing mitochondrial DNA mutations and found that 1 in 200 infants had one of these mutations. Mitochondrial disorders are likely to be under-diagnosed because of the wide range of symptoms and because symptoms may be very mild. Mitochondrial disorders were once believed to be rare diseases that were always accompanied by severe symptoms in multiple systems. These disorders are now known to be far more common and to produce a wide range of symptoms of variable severity, including isolated neurological symptoms as well as subtle symptoms in other systems (both of which are characteristic of ASD).
How are Mitochondrial Disorders Diagnosed?
A common initial screening test for mitochondrial disorders is to measure the level of lactate in the blood. This is a routine test that can be performed easily in any clinical lab, but if the blood is collected or stored improperly the lactate level may be falsely elevated. Another difficulty with this test is that blood lactate might be normal in an individual who has a mitochondrial disorder; thus, a normal reading does not rule out the presence of a mitochondrial disorder. A more definitive and also more invasive test is a tissue biopsy, which is generally done by taking a small piece of tissue from one of the larger muscles of the body, such as the quadriceps muscle. The tissue specimen can then be tested for a variety of histological, biochemical, or genetic markers that would indicate a mitochondrial disorder. Imaging of the brain using magnetic resonance spectroscopy can also aid in diagnosis. This type of brain imaging can show whether certain brain regions have elevated levels of lactate. More recently, detailed genetic testing for specific mitochondrial gene mutations has become available. Technology is also being developed to enable testing of the entire mitochondrial genome for disease-causing mutations, but this is not yet available on a routine basis. Because mitochondrial disorders can be diagnosed in a variety of ways, and because for some individuals test results may appear normal even when a mitochondrial disorder is present, accurate diagnosis requires ongoing monitoring and evaluation by a skilled physician, usually a neurologist or geneticist, who has expertise in mitochondrial disorders.
How are Mitochondrial Disorders Treated?
A variety of treatments are available for mitochondrial disorders. The appropriate treatment depends largely on the specific features of an individual’s disorder, such as the specific genetic and biochemical disturbance and the degree and type of symptoms. Treatment often includes a “cocktail” of cofactors and metabolites that are believed to support mitochondrial function. These include Coenzyme Q10, L-carnitine, thiamine, riboflavin, folic acid, copper, creatine, and vitamins E and C. In some individuals, treatment might include procedures to remove noxious metabolites. For individuals with seizures, movement disorders, cognitive or psychiatric symptoms, or problems with the function of the heart or other organs, many highly effective therapies are available to address their symptoms. In all cases, early diagnosis and appropriate management by a skilled physician are crucial to enabling the best possible outcomes.
Dr. Suzanne Goh is a graduate of Harvard College and Harvard Medical School. She studied at Oxford University as a Rhodes Scholar. She completed her residency in Pediatric Neurology at University of California San Francisco. Her research interests include autism, mental retardation, neuro-imaging, and genetics. She is currently a Post Doctoral Clinical Fellow in Clinical Psychiatry at Columbia University’s Department of Child Psychiatry, and a recent recipient of the Gray Matters at Columbia Fellowship.
For more information about Autism Spectrum Disorders or to learn about opportunities to participate in research at Columbia University’s Autism Research Program, please email AutismResearch@childpsych.columbia.edu or call (212) 543-6705. Research includes The Simons Simplex Collection–a genetics-based study focusing on families with only one incidence of Autism in the family. Other studies include an MRI study, A Study on Sleep Disorders, and a study on Relationships.
In addition, the Developmental Neuropsychiatry Program at Columbia University is a unique clinic for Autism and Related Disorders, offering clinical evaluations and individualized treatments for pre-school aged children through adults from our caring and professional award-winning staff. For more information please call 212-342-1600.