Treatable inborn errors of metabolism causing intellectual disability: a systematic literature review

Mol Genet Metab. 2012 Mar;105(3):368-81. doi: 10.1016/j.ymgme.2011.11.191. Epub 2011 Nov 30.


Background: Intellectual disability ('developmental delay' at age<5 years) affects 2.5% of population worldwide. Recommendations to investigate genetic causes of intellectual disability are based on frequencies of single conditions and on the yield of diagnostic methods, rather than availability of causal therapy. Inborn errors of metabolism constitute a subgroup of rare genetic conditions for which an increasing number of treatments has become available. To identify all currently treatable inborn errors of metabolism presenting with predominantly intellectual disability, we performed a systematic literature review.

Methods: We applied Cochrane Collaboration guidelines in formulation of PICO and definitions, and searched in Pubmed (1960-2011) and relevant (online) textbooks to identify 'all inborn errors of metabolism presenting with intellectual disability as major feature'. We assessed levels of evidence of treatments and characterised the effect of treatments on IQ/development and related outcomes.

Results: We identified a total of 81 'treatable inborn errors of metabolism' presenting with intellectual disability as a major feature, including disorders of amino acids (n=12), cholesterol and bile acid (n=2), creatine (n=3), fatty aldehydes (n=1); glucose homeostasis and transport (n=2); hyperhomocysteinemia (n=7); lysosomes (n=12), metals (n=3), mitochondria (n=2), neurotransmission (n=7); organic acids (n=19), peroxisomes (n=1), pyrimidines (n=2), urea cycle (n=7), and vitamins/co-factors (n=8). 62% (n=50) of all disorders are identified by metabolic screening tests in blood (plasma amino acids, homocysteine) and urine (creatine metabolites, glycosaminoglycans, oligosaccharides, organic acids, pyrimidines). For the remaining disorders (n=31) a 'single test per single disease' approach including primary molecular analysis is required. Therapeutic modalities include: sick-day management, diet, co-factor/vitamin supplements, substrate inhibition, stemcell transplant, gene therapy. Therapeutic effects include improvement and/or stabilisation of psychomotor/cognitive development, behaviour/psychiatric disturbances, seizures, neurologic and systemic manifestations. The levels of available evidence for the various treatments range from Level 1b,c (n=5); Level 2a,b,c (n=14); Level 4 (n=45), Level 4-5 (n=27). In clinical practice more than 60% of treatments with evidence level 4-5 is internationally accepted as 'standard of care'.

Conclusion: This literature review generated the evidence to prioritise treatability in the diagnostic evaluation of intellectual disability. Our results were translated into digital information tools for the clinician (, which are part of a diagnostic protocol, currently implemented for evaluation of effectiveness in our institution. Treatments for these disorders are relatively accessible, affordable and with acceptable side-effects. Evidence for the majority of the therapies is limited however; international collaborations, patient registries, and novel trial methodologies are key in turning the tide for rare diseases such as these.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Cost-Benefit Analysis
  • Humans
  • Intellectual Disability / drug therapy
  • Intellectual Disability / genetics*
  • Metabolism, Inborn Errors / diagnosis*
  • Metabolism, Inborn Errors / drug therapy*
  • Metabolism, Inborn Errors / prevention & control
  • Molecular Diagnostic Techniques