Mitochondrial and Channelopathy Disorders and Dysfunction in Autism Spectrum Disorders: Genotypic and Phenotypic Correlations

Short Title

The Center for Neurobiological and Neurodevelopmental Health II, CNNH II

Project Description

Autism Spectrum Disorders (ASDs) are complex neurobiological disorders of early brain development defined and characterized by qualitative impairment in social interaction and communication, as well as restricted, repetitive and stereotypic patterns of behavior, interests and activities. However, the diagnosis of an ASD is not dependent on its biological cause. Like any medical disorder, it is important to understand what causes ASDs, and what are the clinical symptoms and signs of the biological mechanism that lead to the developmental and behavioral manifestations of ASDs. Since early brain development and function is highly dependent upon how brain cells produce energy and electrical impulses, abnormalities in these processes can lead to impaired brain development and ASDs, or can cause associated problems of ASDs, such as epilepsy, gastrointestinal problems, behavioral issues, intellectual and cognitive impairment, psychiatric disorders, sleep difficulties, and more. A major source of cellular energy is found in the machinery of the cell called “mitochondria”. Additionally, cellular activation (excitation) and inhibition is dependent upon the flow of elements ("ions") such as calcium, sodium and potassium through gated “channels”. Thus, abnormalities in the function of mitochondria or electrolyte channels can lead to impairment of brain development, reduced brain function, and abnormalities in the function of other high-energy organ systems, such as heart, muscle, liver and the gastrointestinal system. Problems with mitochondrial or ion channel function can also affect immune function or contribute to inflammation.

It is estimated that up to 80% of individuals with ASDs have abnormalities in the function of mitochondria (“mitochondrial disorders” or “mitochondrial dysfunction”) and/or ion channels (“channelopathies”). Additionally, many mitochondrial disorders and channelopathies are treatable or actionable. The clinical manifestations of mitochondrial disorders/dysfunction or channelopathies can be identified or detected by changes in laboratory tests, abnormalities on brain testing (neuropsychological testing, electrical brain function), behavioral abnormalities (analytical behavioral analyses, or ABA). The risk or susceptibility for having a genetic predisposition for mitochondrial disorders or channelopathies can be determined with advanced and painless techniques in genetic testing called "Next Generation DNA Sequencing". The result is “genotype-phenotype” correlations (i.e. the underlying gene abnormalities and how they are expressed in terms of clinical manifestations) that will result in descriptions of new diseases causing ASDs, avoid expensive and otherwise unnecessary diagnostic testing, know ahead of time what therapies will not be of use, and simultaneously help to decide and choose effective therapies. Our study will enroll individuals with moderate to severe ASDs associated with intellectual disabilities and/or epilepsy. Subjects will undergo extensive clinical testing to include dense-array electroencephalography (dEEG, or “brain wave” testing), neuropsychological testing (including intellectual and cognitive functioning), functional behavior assessment (ABA), measurements of sleep, and other clinical assessments. All testing and assessments are non-invasive. Additionally, a saliva or blood sample will be obtained and undergo advanced Next Generation DNA Sequencing of almost 2,000 genes known to be vital in mitochondrial and ion channel functioning, and a laboratory assessment of mitochondrial output ("enzymology"). Abnormalities known as gene variations or mutations will be identified, and then compared to results of clinical testing.

This will result in descriptions of new biological diseases and disorders causing ASDs or the complications of ASDs. Results of this study will assist clinicians and physicians in prescribing treatments specifically targeted to the “genotype-phenotype” profile, leading to “personalized medical care”. Results of our study will assist other researchers in untangling the mysteries of the causes of ASDs, and transform the approach to clinical management of individuals with ASDs by focusing on identifying biological mechanisms of disease that can be targeted with specific therapies and treatments, rather than approaches that attempt only to suppress external behavioral symptoms.

Selection Criteria

Subjects must be between 6 and 30 years of age (inclusive) and have the diagnosis of moderate to severe autism spectrum disorder with co-morbid intellectual disability and/or epilepsy
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Team Members

Mark Mintz
Principal Investigator

Laura Szklarski
Project Coordinator
(856) 346-0005

Pnina Mintz

Contact Info
(856) 346-0005
2050 Voorhees Town Center
Voorhees, NJ 08043