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Disclosures

• Advisory Board to Invitae (genetic information company) Differential Diagnosis of ASD • Hold shares/warrants in Chemocentryx, Retrotope, Jacaranda (a Neurologist’s perspective) Biosciences

Elliott Sherr MD PhD Departments of Neurology, Pediatrics Institute of Human Genetics UCSF

Outline (and goals for presentation) The Null Hypothesis • What is autism? •Autism doesn’t exist • What causes autism? • Genetics • Environmental • What looks like autism? • How do we investigate? • How and when can we treat?

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The mirror image hypothesis Functional Model

Clinical Manifestations of Autism •Autism is a singular biological entity Standardized Clinical Measurements

Autism “biomarkers” Imaging, EEG etc

G x E Interactions

Primary Causes of Autism Genetics, Environment

When to think: will the diagnosis impact care? Approximate Breakdown of ASD Causes (or when is this not just idiopathic non-progressive ASD/GDD?) • The Null Hypothesis: ALWAYS!!

• A range of clinical features give added weight to this • Regression (or late onset) , Encephalopathy Monogenic/Idiopathic (10%) • Seizures, other neurologic manifestations, such as movement disorders, Syndromic (10%) spasticity, weakness, hemiparesis Idiopathic Polygenic (50%) • Exam findings : Dysmorphic features, macro or microcephaly, Other (E, GxE) (30%) organomegaly, skin findings, etc • Involvement of other functional systems : e.g. horseshoe kidney, cardiac malformation • Positive Family History

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The work up for ASD/GDD Any of the aforementioned red flags increases the need for this type of evaluation Imaging Findings that are actionable

Referral to a neurologist for Findings on brain imaging further evaluation

Broad based "first pass" If these evaluations are all includes brain MRI, EEG, negative, would consider Refer to a clinical geneticist microarray, Fragile X and whole exome and “Exome Clinic” biochemical evaluation sequencing

IF biochemical testing is revealing, may need Referral to a metabolic additional testing, eg specialist mitochondrial genome testing X-Linked Adrenoleukodystophy Focal Cortical Dysplasia Left Hemisphere Stroke

Rare but Treatable Causes (examples) Whole Exome Sequencing

• Phenylketonuria (PKU) • Tested for in newborn screens throughout the U.S. and most of developed world • 50+ conditions screened for in the U.S., 12 in Germany and 2 in the U.K. gDNA • Presentation: ASD/ID, Irritability, Seizures, hypopigmentation • Easily treated with dietary restriction of phenylalanine • Should ALWAYS consider in child born outside of the US • Arginase deficiency • Presents with progressive but slow loss of function • Analogous to ASD regression • Also notable for progressive spasticity • Partially treatable by early diet intervention • Creatine Deficiency Syndromes • Pyridoxine Dependent Epilepsy (along with regression and ASD features) • NMDA receptor encephalopathy

Johnsen J M et al. Blood 2013;122:3268-3275

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De Novo Mutations in Developmental Genetic Findings that are actionable Disorders • KNOWN SYNDROME

Potential off-label intervention Genetic Findings that are actionable (beginnings of “precision medicine”) • Novel Syndrome

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Parents form support/research groups Genetic Findings that are actionable

• Incidental, but essential findings

Monogenic (or genetic locus) ASD Causes Study of Monogenic Causes Leads to Advances: Example:16p11.2 del/dup (some common examples ) • Syndromic • Fragile X • 45% of FXS Males have ASD; 15% of FXS Females have ASD • 80% of FXS Males have ID • Rett Syndrome • >40% of Rett syndrome patients have ASD • >90% of Rett syndrome patients have ID • Tuberous Sclerosis • 40% approximately exceeded ASD threshold cut off • >many had more social deficits and less repetitive behviors • Non-syndromic single /genetic loci causes • Copy number variants • 16p11.2, 15q11-q13, 22q11.21, • Single gene • ANK2, ARID1B, CHD2, CHD8, DYRK1A, GRIN2B, SCN2A

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Del and Dup: Clinical Similarity, Imaging Differences Mechanisms—integrating poly and mono genetic

CNTL DEL DUP

Novel Treatments Future Directions

• Ongoing trials • Genetics and other platforms to develop “early diagnosis” leading to • Transcranial Direct Current early behavioral interventions • Neurofeedback • Whole genome sequencing at birth/during pregnancy • Neuropeptides (administered intranasally) • Cell free DNA of developing fetus • Oxytocin • • Vasopressin Therapies targeted to help correct biochemical deficiencies • Enzyme replacement for storage disorders • Advances in gene therapy, “genome editing--CRISPR” approaches to • New techniques that aim to cross the blood-brain barrier correct mutations for many • Placement of reservoirs for intrathecal access • Gene therapy in early stages • Trials that did not meet with success • R-baclofen • Questions: [email protected] ; 415-514-9306. • mGLuR agonists

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