Table 1 A and B Definitions and search terms

A. Definitions used in literature review

Global developmental delay (DD): applied to age < 5 years; significant delay (= performance two standard deviations or more below the mean on age-appropriate, standardised norm-referenced testing) in two or more developmental domains including gross/fine motor skills, speech/language, cognition, social/personal, activities of daily living [53]

Intellectual disability (ID): applied to age ≥ 5 years and manifesting before age 18 years, historically referred to as ‘mental retardation’; intellectual functioning level (IQ) less than 70 to 75 and significant limitations in two or more adaptive skills [54, 55]

Inherited Metabolic Disorder (IMD): impairment of specific enzymes or biochemical pathways that is intrinsic to the pathomechanism. The presence of an abnormal metabolite is no longer a prerequisite [6]. This term excludes endocrine disorders such as hypothyroidism

Causal of ID/DD: sufficient evidence in literature from bench and/or clinical research to make a pathophysiological relationship between IMD and ID/DD highly likely

Treatable ID: if a particular therapeutic modality is capable of preventing or improving ID/DD phenotype, or halting/slowing neurocognitive decline (with acceptable adverse effects) in the IMD, i.e., positively influencing the ‘outcome measures’

Treatment strategies:

Nutritional therapy, vitamin & trace element, enzyme replacement therapy, hematopoietic stem cell transplant, solid organ transplantation, pharmacological therapy, gene-based therapy, other (e.g., hemodialysis)

Outcome measure/effect: A = improves psychomotor/cognitive development/IQ, B = improves behavioural/psychiatric disturbance(s), C = prevents acute metabolic decompensation, D = prevents, halts, or slows clinical deterioration, E = improves neurological manifestations (incl. neuro-imaging), F = improves seizure/epilepsy control, G = improves systemic manifestations

Levels of evidence: Level of evidence: Level 1a = systematic review of RCT's, 1b = individual RCT, 1c = ‘All or None’ [= (prolongation of) survival with therapy]; Level 2a = systematic review of cohort studies, 2b = individual cohort study, 2c = ‘Outcomes Research’ [focused on end results of therapy for chronic conditions, including functioning and quality of life]; Level 3 = systematic review of case– control studies; Level 4 = individual case–control study or case-series/report; Level 5 = expert opinion without critical appraisal; based on physiology, bench research or first principles. If only one patient was reported, we assigned level ‘4–5′ as a way to nuance the treatment effects

B. Terms used for search strategy in PubMed [56]

Developmental delay/intellectual disability: mental retardation, learning disorder(s), developmental disability/ disabilities, learning disability/disabilities, intellectual disability/disabilities, developmental delay, intelligence/classification, mentally disabled (persons), childhood/juvenile Alzheimer's, childhood/juvenile dementia, neurodegenerative disease

Inherited Metabolic Disorder: metabolic disease(s), inborn error(s) of metabolism, metabolic disorder(s), metabolic condition(s), inherited metabolic disease(s), inherited metabolic disorder(s), biochemical disease(s)

Treatment: treatment, management, therapy, cure, trial, (dietary) supplement, (dietary) restriction, diet, substrate inhibition, small molecule substrate reduction, enzyme replacement, vitamin(s), co-factor(s), bone marrow transplant, hematopoietic stem cell transplant, umbilical cord blood transplant(− ation), gene therapy