Treatment of Social and Language Deficits With Leucovorin for Young Children With Autism

Evaluate the change in social communication symptoms

Aberrant Behavior Checklist-2, Social Withdrawal Subscale. The ABC is a 58-item parent-reported measure with ratings in the following domains: irritability, social withdrawal, stereotypic behavior, hyperactivity, and inappropriate speech. Each item is rated from 0 (Not a Problem) to 3 (Severe Problem). The raw score will be reported. The total raw score is the sum of the domain raw scores. A higher raw score in any of the domains indicates more severe problems in that domain; a higher total raw score indicates more severity of stereotypical autism symptoms overall.

Evaluate the safety and tolerability of L-leucovorin calcium in young children with ASD

Modified Dosage Record and Treatment Emergent Symptoms: treating clinician will perform a review of medical and behavioral history at each visit to assess incidence of treatment-emergent adverse events. The treating clinician will use the scale to record presence and intensity of adverse effects. Intensity is rated on a scale of 0 (Not present) to 3 (Severe). The treating clinician will also judge the adverse effects' relatedness to treatment. Relatedness is rated on a scale of 1 (None) to 4 (Defined). The treating clinician will denote action taken. Action taken is rated on a scale of 0 (None) to 5 (Discontinue Treatment). No total score is calculated. However, higher ratings on any individual item indicate greater severity of adverse effects.

Evaluate adverse effect symptoms in young children with ASD

Routine complete blood counts will be collected to determine whether treatment-emergent basic blood chemistry is altered. Presence of any changes during the course of study enrollment will be evaluated by the treating physician and determined clinically significant or not clinically significant. If determined by the treating physician, a change will be considered an adverse event.

Evaluate the biologic safety of L-leucovorin calcium in young children with ASD

Routine comprehensive blood panels will be collected to determine whether treatment-emergent basic blood chemistry is altered. Presence of any changes during the course of study enrollment will be evaluated by the treating physician and determined clinically significant or not clinically significant. If determined by the treating physician, a change will be considered an adverse event.

Evaluate the safety of L-leucovorin calcium in young children with ASD on antiepileptic drugs

For children using antiepileptic drugs, the level of that drug will be measured. If determined by the treating physician, a change will be considered an adverse event.

Demonstrate changes in neuronal activation and connectivity associated with treatment response using non-invasive neuroimaging methods

Using magnetoencephalography at Phoenix Children's Hospital and functional near-infrared spectroscopy and the State University of New York, the investigators will assess whether the following pathways are altered by leucovorin calcium treatment: M100 auditory evoked gamma-band power, connectivity, and coherence. Both the magnetoencephalography and functional near-infrared spectroscopy will be able to capture these same values. Treatment-emergent change in these values will indicate that a change has occurred in the neural pathway.

Evaluate the effect of L-leucovorin on cellular regulatory pathways known to be implicated in social communication

Evaluate changes in the following cellular regulatory pathways known to be implicated in social communication: peripheral blood mononuclear cell, plasma, DNA, red blood cells, and oxidative stress rates. Treatment-emergent change in these biomarkers will indicate that a change has occurred at the cellular level.

Test if biomarkers (single nucleotide polymorphisms) predict clinical response to L-leucovorin

Saliva will be collected to determine presence of the following single nucleotide polymorphisms: MTR, MTHFR6, DHFR, GCH1, MTHFR12, RFC, FOLH, COMT. Presence or absence of these genetic polymorphisms will be analyzed to assess correlation with response to L-leucovorin treatment.