Mitochondrial Dysfunction in Autism Spectrum Disorder

Objective: The main objective of this proposal is to develop a minimally-invasive biological
assay that can be widely used to identify variations in mitochondrial function and
dysfunction in children with autism spectrum disorder (ASD). This assay will allow the
investigators to determine the true range of mitochondrial function and dysfunction across a
population of children with ASD. The relationship between mitochondrial function and
dysfunction in ASD, redox metabolism and core ASD symptomology will also be investigated. To
understand the true variation in mitochondrial function and its relationship to cognitive
development and autism symptoms, participants will be evaluated at two time points to
understand the within subject variation of mitochondrial measurements.

Specific Aims: 1) To develop a minimally-invasive assay that can accurately identify children
with ASD/MD from the general ASD population. 2) To establish whether there is simply an
ASD/MD subgroup or whether mitochondrial dysfunction occurs on a spectrum from mild to severe
in ASD. 3) To determine the relationship between mitochondrial function and redox metabolism
in children with ASD. 4) To evaluate the effect of mitochondrial dysfunction and glutathione
redox status on language and social development and ASD symptoms.

Study Design: Using the Seahorse Analyzer, investigators will develop profiles of
mitochondrial function for individuals with ASD and known MD (ASD/MD) and individuals with
ASD known not to have MD (ASD/NoMD). These two groups will serve as the two ends of the
spectrum of mitochondrial function in children with ASD and will be compared to profiles from
TD children. Investigators will then examine the profiles of mitochondrial function in a
general population of individuals with ASD to determine how these individuals fall into this
spectrum defined by the ASD/MD and ASD/NoMD groups, as well as DD and no ASD/MD. Glutathione
redox metabolism will be measured in all participants. The relationship between mitochondrial
function, redox metabolism and core ASD symptoms will be studied in the ASD groups with
particular attention to whether ASD symptoms, language ability and adaptive behavior are
directly related to mitochondrial function or indirectly related to mitochondrial function
through its effect on redox metabolism.

Study Population: Investigators will recruit several groups of children for this study: 50
children with ASD who have MD (ASD/MD); 50 children with ASD who do not have MD (ASD/NoMD);
50 no ASD/MD; 50 no ASD/no MD but DD; 100 TD controls; and a general population of 150
children with ASD.

Children with ASD with and without MD will be identified in the autism multispecialty clinic
(AMC), as well as the ATN and other medical clinics that evaluate children with ASD in
outpatient clinics in Arkansas. When a child is identified, the study coordinator will
contact the parents and describe the study. If the parents are interested, the coordinator
will screen by asking inclusion/exclusion criteria questions. If the child qualifies, the
coordinator will schedule the visit and mail consent forms to the parents for their review.
During the visit they will undergo a blood draw for metabolic testing. The child will then be
sent to breakfast since the blood tests require collection prior to breakfast. After
breakfast the participant will undergo further language and behavioral assessment while the
parent will be interviewed for the Vineland and other questionnaires. The parents will be
provided questionnaires for the teacher to fill out and mail in an addressed, postage paid
envelope.

For the TD participants, these children will be recruited in several ways including using
social media through Arkansas Children's Hospital, flyers posted in the community (i.e.
primary pediatric clinics), as well as referrals from pediatricians. When a child is
identified, the study coordinator will contact the parents and describe the study. If the
parents are interested, the coordinator will screen by asking inclusion/exclusion criteria
questions. If the child qualifies, the coordinator will schedule the visit and mail consent
forms to the parents for their review. During the visit they will undergo a blood draw for
metabolic testing.

Inclusion Criteria:

Inclusion Criteria for ASD children

1. Autism Spectrum Disorder (As defined by a gold standard measure for ASD diagnosis: the
Autism Diagnostic Observation Schedule, Autism Diagnostic Interview, and/or the
minimum Arkansas state requirement for autism classification, as defined by a
consensus diagnosis of ASD by a medical doctor, speech pathologist, and
psychologist.). In an event where sufficient diagnostic information is lacking, and
the PI believes that the clients meet all other inclusion criteria and a prospective
diagnosis of an ASD is clinically warranted, and a formal diagnosis is scheduled to
occur within a reasonable time frame from the date of study entry, then the client may
be considered as potentially eligible.

2. 0 years through 17 years 11 months of age

Inclusion Criteria for TD children

1. 0 years to 17 years 11 months of age

Exclusion Criteria:

- Discussed on a case by case basis