Treatable Intellectual Disability Endeavor (TIDE)

Tier 1: Nontargeted Metabolic Screening to Identify 54 (60%) Treatable IEM

• Blood Plasma amino acids Plasma total homocysteine Acylcarnitine profile Copper, ceruloplasmin Urine Organic acids Purines and pyrimidines Creatine metabolites Oligosaccharides Glycosaminoglycans Amino acids (when indicated)

Tier 2: Current Practice Adhering to International Guidelines* (1 or more of:)

• 1) Audiology 2) Ophthalmology 3) Cytogenetic testing (array CGH) 4) Thyroid studies 5) Complete blood count (CBC) 6) Lead 7) Metabolic testing 8) Brain MRI and 1H spectroscopy (where available) 9) Fragile X 10) Targeted gene sequencing/ molecular panel

Tier 3: Targeted Workup to Identify 35 (40%) Treatable IEM Requiring Specific Testing

• 1) Specific biochemical/gene test 2) Whole blood manganese 3) Plasma cholestanol 4) Plasma 7-dehydroxycholesterol: cholesterol ratio 5) Plasma pipecolic acid and urine α- amino adipic semialdehyde(AASA) 6) Plasma very-long-chain fatty acids 7) Plasma vitamin B12 and folate 8) Serum and CSF lactate to pyruvate ratio 9) Enzyme activities (leukocytes): arylsulfatase A, biotinidase, glucocerebrosidase, fatty aldehyde dehydrogenase 10) Urine deoxypyridinoline 11) CSF amino acids 12) CSF neurotransmitters 13) CSF-to-plasma glucose ratio 14) CoQ measurement: fibroblasts 15) Molecular analysis: CA5A, NPC1, NPC2, SC4MOL, SLC18A2, SLC19A3, SLC30A10, SLC52A2, SLC52A3, PDHA1, DLAT, PDHX, SPR, TH genes