Treatable Inborn Errors of Metabolism Causing Intellectual Disability: A Review and Diagnostic Approach

Abstract

Intellectual disability (ID) is a devastating condition, affecting between 2% and 3% of children and adults globally. Early recognition of underlying conditions associated with ID that are amenable to treatment can dramatically improve health outcomes and decrease burdens to patients, families and society. However, current recommendations to investigate genetic causes of ID are based on frequencies of single conditions and diagnostic yields, rather than availability of causal therapy. Inborn errors of metabolism (IEM) constitute a subgroup of rare genetic conditions for which an increasing number of treatments has become available. Our systematic literature review identified 81 IEMs which present with ID as a prominent feature and are amenable to causal therapy. Therapeutic modalities were also identified and prioritised. The evidence created by our research has been translated into a two‐tiered diagnostic protocol currently implemented in our institution, the BC Children's Hospital. The first tier of this protocol includes easily available biochemical group tests, with the potential to identify 65% of the currently known treatable IDs. This first tier can be applied by community paediatricians and specialists in all patients presenting with global developmental delay/ID without referral to a specialised centre. The second tier includes specific tests, which should be ordered based on the differential diagnosis, established by physicians experienced with rare treatable IDs. A digital tool (an App www.treatable‐id.org) supports the protocol, and serves as information portal for all users, ranging from students to specialists.

Key Concepts:

  • Inborn errors of metabolisms (IEMs) constitute a subgroup of rare genetic conditions for which an increasing number of treatments has become available.

  • Early recognition of IEMs allows for timely initiation of treatment to prevent or minimise brain damage.

  • Early recognition and treatment of IEMs is crucial for improving health outcomes and reducing disease burden for affected individuals, their families and societies.

  • A total of 81 treatable IEM presenting with intellectual disability as a major feature were identified in the systematic review.

  • Sixty‐two percent of IDs can be reliably detected through a panel of readily available metabolic screening tests on blood and urine. The remainder of treatable IDs is diagnosed via disease‐specific tests.

  • A protocol indicating metabolic group tests capturing 65% of treatable IDs enables community‐based paediatricians and other specialists to perform the first tier diagnostic work‐up of treatable Ids.

  • Normal newborn screening results in a patient with ID of unknown origin should not reassure the clinician that treatable metabolic disorders have been ruled out, as the patient might not have been screened for a particular disease or at all.

  • Therapeutic modalities are accessible and most with acceptable side effects.

  • The development of the treatable ID App capitalises on new digital and social media to raise awareness for rare treatable diseases and increase the likelihood of early diagnosis in children with ID of unknown origin.

Keywords: inborn errors of metabolism; global development delay; intellectual disability; guanidinoacetate methyltransferase; intellectual disability treatment, knowledge translation, TIDE App, digital tool, information portal, App

Figure 1. Bar graph depicting the yield of ‘metabolic screening tests’.
Figure 2.

TIDE diagnostic protocol implemented in BC Children's Hospital since 2011.

Figure 3.

TIDE App home page (freely downloadable via the Apple App Store), including access to the Treatable ID App (via ‘diagnostic tool’ button).

Figure 4.

Example of a ‘Disease Page’ on the Treatable ID App.

close

References

Banka S, Blom HJ, Walter J et al. (2011) Identification and characterization of an inborn error of metabolism caused by dihydrofolate reductase deficiency. American Journal of Human Genetics 88: 216–225.

Cartier N and Aubourg P (2010) Hematopoietic stemcell transplantation and hematopoietic stem cell gene therapy in X‐linked adrenoleukodystrophy. Brain Pathology 20: 857–862.

Curry CJ, Stevenson RE, Aughton D et al. (1997) Evaluation of mental retardation: recommendations of a Consensus Conference: American College of Medical Genetics. American College of Medical Genetics 72: 468–477.

Engbers HM, Berger R, van Hasselt P et al. (2008) Yield of additional metabolic studies in neurodevelopmental disorders. Annals of Neurology 64: 212–217.

Fernandes J, Saudubray JM, van den Berghe G and Walter JH (2006) Inborn Metabolic Diseases: Diagnosis and Treatment, 4th edn. Berlin: Springer.

Garcia‐Cazorla A, Wolf NI, Serrano M et al. (2009) Mental retardation and inborn errors of metabolism. Journal of Inherited Metabolic Disease 32: 597–608.

He M, Kratz LE, Michel JJ et al. (2011) Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay. Journal of Clinical Investigation 121: 976–984.

Jansen DE, Krol B, Groothoff JW and Post D (2004) People with intellectual disability and their health problems: a review of comparative studies. Journal of Intellectual Disability Research 48: 93–102.

Kahler SG and Fahey MC (2003) Metabolic disorders and mental retardation. American Journal of Medical Genetics Part C Seminars in Medical Genetics 117C: 31–41.

Kállay K, Liptai Z, Benyó G et al. (2012) Successful unrelated umbilical cord blood transplantation in Lesch–Nyhan syndrome. Metabolic Brain Disease 27: 193–196.

van Karnebeek CD, Hartmann H, Jaggumantri S et al. (2012) Lysine restricted diet for pyridoxine‐dependent epilepsy: first evidence and future trials. Molecular Genetics and Metabolism 107: 335–344.

van Karnebeek CD, Shevell M, Zschocke J, Moeschler JB and Stockler S (2014b) The metabolic evaluation of the child with an intellectual developmental disorder: diagnostic algorithm for identification of treatable causes and new digital resource. Molecular Genetics Metabolis. doi: 10.1016/j.ymgme.2014.01.011. [Epub ahead of print].

van Karnebeek CD, Sly WS, Ross CJ et al. (2014a) Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood. American Journal of Human Genetics. doi: 10.1016/j.ajhg.2014.01.006. [Epub ahead of print].

van Karnebeek CDM, Jansweijer MCE, Leenders AGE et al. (2005) Diagnostic investigations in individuals with mental retardation: a systematic literature review. European Journal of Human Genetics 13: 6–25.

van Karnebeek CDM, Scheper FY, Abeling NG et al. (2005) Etiology of mental retardation in children referred to a tertiary care center: a prospective study. American Journal on Mental Retardation 110: 253–267.

van Karnebeek CDM and Stockler S (2012) Treatable inborn errors of metabolism causing intellectual disability: a systematic literature review. Molecular Genetics and Metabolism 105: 3368–3381.

Kayser MA (2008) Inherited metabolic diseases in neurodevelopmental and neurobehavioral disorders. Seminars in Pediatric Neurology 15: 127–131.

Leen G, Klepper J, Verbeek MM et al. (2010) Glucose transporter‐1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder. Brain 133: 655–670.

Luckasson R and Reeve A (2001) Naming, defining, and classifying in mental retardation. Mental Retardation 39: 47–52.

Meerding WJ, Bonneux L, Polder JJ et al. (1998) Demographic and epidemiological determinants of healthcare costs in Netherlands: cost of illness study. British Medical Journal 317: 111–117.

Moeschler J (2008) Genetic evaluation of intellectual disabilities. Seminars in Pediatric Neurology 15: 2–9.

Moeschler J and Shevell M (2006) Clinic genetic evaluation of the child with mental retardation or developmental delay. Pediatrics 117: 2304–2316.

Oeseburg B, Jansen DEMC, Groothoff JW et al. (2010) Emotional and behavioural problems in adolescents with intellectual disability with and without chronic diseases. Journal of Intellectual Disability Research 54: 81–99.

Papavasiliou AS, Bazigou H, Paraskevoulakos E and Kotsalis C (2000) Neurometabolic testing in developmental delay. Journal of Child Neurology 15: 620–622.

Prasad VK and Kurtzberg J (2010) Transplant outcomes in mucopolysaccharidoses. Seminars in Hematology 47: 59–69.

Scriver C, Beaudet A, Sly W et al. (2000) The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw Hill.

Shevell M (2008) Global developmental delay and mental retardation or intellectual disability: conceptualization, evaluation, and etiology. Pediatric Clinics of North America 55: 1071–1084.

Shevell M (2010) Present conceptualization of early childhood neurodevelopmental disabilities. Journal of Child Neurology 25: 120–126.

Shevell M, Ashwal S, Donley D et al. (2003) Practice parameter: evaluation of the child with global developmental delay. Neurology 60: 367–380.

van Spronsen FJ and Enns GM (2010) Future treatment strategies in phenylketonuria. Molecular Genetics and Metabolism 99: S90–S95.

Valle D, Beaudet AL, Vogelstein B et al. (2011) Online Metabolic and Molecular Bases of Inherited Disease. McGraw‐Hill Medical. Available at: http://ommbid.mhmedical.com/ommbid-index.aspx (accessed 01 Sept 2012).

Further Reading

van Karnebeek CD, Houben RF, Lafek M, Giannasi W and Stockler S (2012) The treatable intellectual disability APP www.treatable‐id.org: A digital tool to enhance diagnosis & care for rare diseases. Orphanet Journal of Rare Diseases 7: 47 http://www.ojrd.com/content/7/1/47.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
van Karnebeek, Clara DM, and Stockler, Sylvia(Mar 2014) Treatable Inborn Errors of Metabolism Causing Intellectual Disability: A Review and Diagnostic Approach. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024466]