Scholarly article on topic 'Treatable inborn errors of metabolism causing intellectual disability: A systematic literature review'

Treatable inborn errors of metabolism causing intellectual disability: A systematic literature review Academic research paper on "Clinical medicine"

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Molecular Genetics and Metabolism
OECD Field of science
{"Inborn errors of metabolism" / "Intellectual disability" / "Developmental delay" / Therapy / Evidence / "Systematic review"}

Abstract of research paper on Clinical medicine, author of scientific article — Clara D.M. van Karnebeek, Sylvia Stockler

Abstract Background Intellectual disability (‘developmental delay’ at age<5years) 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.

Academic research paper on topic "Treatable inborn errors of metabolism causing intellectual disability: A systematic literature review"


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

Clara D.M. van Karnebeek a'*, Sylvia Stockler

a Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, Room K3-201, 4480 Oak Street, Vancouver B.C. V6H 3V4, Vancouver, Canada b Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, Room K3-204, 4480 Oak Street, Vancouver B.C. V6H 3V4, Vancouver, Canada


Article history:

Received 18 October 2011

Received in revised form 17 November 2011

Accepted 17 November 2011

Available online 30 November 2011


Inborn errors of metabolism Intellectual disability Developmental delay Therapy Evidence

Systematic review


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 (www., 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.

© 2011 Elsevier Inc. All rights reserved.


1. Introduction ..........................................................................................................................369

2. Methods and results....................................................................................................................369

2.1. Identification and characterisation of treatable IEMs causing ID ....................................................................369

2.1.1. Literature search........................................................................................................369

Abbreviations: DD, global developmental delay; ID(s), intellectual disability (-ies); IEM(s), inborn errors of metabolism(s); MPS, Mucopolysaccharidosis. * Correspondence to: C.D.M. van Karnebeek and S. Stockler, BC Children's Hospital, Room K3-204,4480 Oak Street, Vancouver B.C. V6H 3V4 Canada. Fax: +1 604 875 2349. E-mail addresses: (C.D.M. van Karnebeek), (S. Stockler).

1096-7192/$ - see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2011.11.191

2.1.2. Definition of outcomes..................................................................................................369

2.1.3. Inclusion/exclusion criteria..............................................................................................370

2.1.4. Treatable IDs............................................................................................................371

2.1.5. Clinical features..........................................................................................................371

2.1.6. Diagnostic tests..........................................................................................................371

2.2. Identification and characterisation of treatment modalities..........................................................................371

2.2.1. Literature search........................................................................................................371

2.2.2. Levels of evidence........................................................................................................371

2.2.3. Effect(s) of treatments on outcome measures..............................................................................371

2.2.4. Treatments and clinical practice..........................................................................................371

2.2.5. References and information sources......................................................................................373

3. Discussion..............................................................................................................................373

Role of funding source......................................................................................................................378


Appendix A. Suplementary data............................................................................................................378


1. Introduction

Intellectual disability (ID) is a life-long and debilitating condition with deficits in cognitive functioning (IQ< 70) and adaptive skills [1,2]. ID is often associated with behavioural problems (autism, hyperactivity, aggressivity and self-injurious behaviour), epilepsy and other neurological disabilities, all resulting in psychological, social and economic burdens [3,4]. In children <5years of age with deficits in two or more developmental domains (e.g. fine/gross motor skills, speech, interaction, etc.), the term global developmental delay (DD) is applied [5]. Here we will use the term ID collectively for both ID and DD. ID is frequent, affecting 2-3% of children and adults worldwide. ID is the disease category with one of the largest health care costs [6]. The etiology of ID is diverse, including infectious, traumatic and toxic causes. Genetic etiologies constitute the most frequent cause and are demonstrable in more than 50% of individuals with ID [7], ranging from numeric and structural chromosomal abnormalities and submicroscopic Copy Number Variants to methylation abnormalities, and to single gene defects [8].

Current guidelines aimed at structuring the evaluation of genetic causes of ID, are based on frequencies of single conditions and yield of diagnostic methods and procedures [9]. Therefore, karyotyping and array-comparative genomic hybridisation, which yield a causal diagnosis in 20% of cases, is standard practice as part of the first-line investigation [10]. Unfortunately these high diagnostic yields do not translate into therapeutic benefit, as at the present time causal therapy is not available for most conditions identified by these investigations. One category of genetic conditions is amenable to treatment however: inborn errors of metabolism (IEMs). This group of single gene disorders is not systematically screened for [11], despite increasing opportunities to causally treat and profoundly improve prognosis.

The yield of routine metabolic investigations of ID/DD patients varies from 0.8 to 2.5% [7,9,12], but detailed metabolic reassessment yielded a previously unknown causative IEM in up to 14% of cases [13,14]. Based on these studies, concerns have been raised that treatable diagnoses may be missed if we weigh too heavily on current practice parameters [15]. In addition, during the past decades the number of IEM which has become amenable to causal therapy has constantly increased. Although technologies for better recognition have been introduced into clinical practice, this has not translated into practice guidelines for diagnostic evaluation children with ID such as those of the American College of Medical Genetics (1997) [16], the American Academy of Pediatrics (2006) [17], and the American Academy of Neurology (2003) [18]. To strengthen our level of understanding in an evidence-based manner, we performed a systematic literature

review to: 1) investigate the number of treatable IEM presenting with ID; and 2) to characterise types of treatments and evidence for effect. In stark contrast to the general notion that only few IEMs are treatable, we identified as many as 81 IEMs with ID as a major clinical feature.

2. Methods and results

For the design of this systematic review we followed Cochrane Collaboration methodology (http :// as closely as possible. All steps were performed by two independent reviewers (CvK and SS) with regular consensus meetings. The main goal of our review was to identify all treatable IEMs presenting with ID as a major feature. We characterised the clinical and diagnostic recognition patterns as well as treatment modalities pertinent to the identified IEMs, and made an attempt to assess the level of available evidence and effect of the various treatments on clinical outcome measures.

2.1. identification and characterisation of treatable IEMs causing ID

2.1.1. Literature search

Definitions of terms relevant for the search strategy and key words for terms indicating developmental delay/intellectual disability, inborn error of metabolism, and treatment are shown in Table 1A and B.

We searched Pubmed (; 1960-August 2011) using a combination of the keywords identified. We also reviewed all chapters of the textbook 'Metabolic and Molecular Bases of Inherited Disease' [19] as well as the online version www. [20], with special attention to reports on treatment of IEMs presenting with ID.

2.1.2. Definition of outcomes

The ideal outcome of therapy for an IEM is improvement of IQand related developmental scores. As improvement of co-morbid features such as epilepsy, neurologic, behavioural or psychiatric problems is often a prerequisite for improved cognitive outcomes these were included as 'secondary outcomes'. An example of such developmental improvement is seen in patients with GLUT-1 deficiency in whom the ketogenic diet is successful in controlling medicine refractory epilepsy [21]. Beneficial changes in neuro-imaging and neurologic deficits were also designated secondary outcomes, as for some disorders this is the most objective parameter of improvement, e.g. stemcell transplant in X-linked Adrenoleukodystophy [22]. Improvements in biochemical markers of disease indicating metabolic control were

Table 1

Definitions and search terms.

A. Definitions used in systematic 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 of developmental domains including gross/fine motor skills, speech/language, cognition, social/personal, activities of daily living [2].

Inteliectuai 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 [1,5].

Inborn error of metabolism (IEM): genetic disease involving a disorder of metabolism with confirmation based on the internationally accepted diagnostic test(s) for that IEM (gene mutations, enzyme deficiency, or specific biochemical marker). This term excludes endocrine disorders such as hypothyroidism and hyperinsulinism.

Causal ofID/DD: sufficient evidence in literature from bench and/or clinical research to make a pathophysiological relationship between IEM 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 IEM, ie positively influencing the 'outcome measures'.

Therapeutic modaiities: dietary restriction/supplement, co-factor/-enzyme, vitamin, substrate inhibition, (small molecule) substrate reduction, enzyme replacement, bone marrow and hematopoietic stem cell transplant, gene therapy.

Outcome measure/effect: primary = IQ, developmental testing score/performance, survival; secondary = epilepsy, behaviour, psychiatric, neurological deficit (e.g. movement disorder), neuro-imaging, systemic symptoms influencing developmental/cognitive performance (e.g. ichtyosis, liver disease).

Levels 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' [focussed 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.

Standard of care: a formal treatment process a physician will follow for a patient with a specific illness, which experts generally accept as 'best clinical practice'.

Individual patient basis: decision to start specific treatment depends on patient characteristics (ie disease stage), physician's opinion, availability of treatment, potential side-effects.

B. Terms used for search strategy in Pubmed (

Developmental delay/inteliectual 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].

Inborn error of metabolism: 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, 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.

also designated secondary outcomes, but only if these correlated closely with neurodevelopmental outcome; e.g. Kuvan therapy which in addition to dietary phenylalanine restriction can further improve blood phenylalanine levels, thereby prevent brain damage) [23]. Finally, as some therapies make the difference between life and death (e.g. haematopoietic stemcell transplant for Hurler syndrome) [24], 'survival' which obviously allows for development was also included as an outcome measure.

2.1.3. Inclusion/exclusion criteria

In general, we considered only IEMs for which a) a causal relationship with ID is likely; b) articles which have been published in English language and peer-reviewed journals, reporting one or more of the defined treatment outcomes in human(s).

We included conditions irrespective of whether they are captured in Newborn Screening panels.

We included IEMs presenting with severe co-morbid features such as epilepsy (e.g. Pyridoxine Dependent Epilepsy due to ALDH7A1 deficiency) and or congenital malformations (Smith-Lemli-Opitz Syndrome), because despite early presentation, the aetiology may remain unclear until later in life thus presenting as unclarified complex ID.

IEMs for which treatment has only recently become available and/or reported to be effective, were included if the case report(s) provided a solid and detailed description of outcome: this applied in the following instances: cPMP (Cyclic Pyranopterin Monophosphate/Precursor Z) treatment resulted in seizure contol and improved psychomotor development and head growth in an infant with Molybdenum Co-factor Deficiency [25]; Creatine, glycine, and arginine therapy improved epilepsy and behaviour in a female with creatine transporter deficiency [29]; Arginine therapy has proven effective in preventing metabolic stroke and thus slowing neurodegeneration both clinically and on neuro-imaging in patients with MELAS syndrome (13513G>A mutations) [26].

In case of contradictory literature reports on presence versus absence of therapeutic effect in an IEM, the quality and level of evidence were weighed in combination with the pathophysiologic rationale and/or target of therapy. Effects of cholesterol supplements and statins in Smith-Lemli-Opitz patients are contradictory in the literature, but included because of the qualitative strength of the study designs (including outcome measures) and reporting of the positive reports and the rationale behind the treatment itself. [27,28]. This is true also for creatine, arginine and glycine supplements in Creatine Transporter Deficiency. Mercimek-Mahmutoglu et al. (2010) [29] reported positive effects on behaviour and seizure control for single female patient, whilst Valayannapoulos et al. [30] identified improvements in muscular symptoms but not in cognitive or psychiatric manifestations.

We excluded IEMs for which ID is not a consitent finding and/or for which treatment has not or inconsistently proven effect on intellectual or related outcomes:

• In Galactosemia treatment with a galactose free diet prevents life-threatening liver failure, but despite good diet control a majority of patients develops speech delay, low IQ scores and ataxia [31];

• In Prolidase deficiency oral Ascorbate and Manganese (co-factor of prolidase), consistently improves skin ulcers but neurological outcomes are only infrequently affected [32];

• In Hartnup disease and Tyrosinemia type 3, ID is not a consistent part of the clinical picture [33,34] and treatment has only been shown to be effective for skin lesions.

• Farber disease (a lysosomal storage disorder) causes somatic problems due to the granulomatous inflammation; but for mild cases - the only form amenable to treatment with haematopoietic stem cell transpla-nation - ID is not part of the clinical picture [35].

• In histidinemia, which was previously considered a treatable ID, natural history studies of cases identified through newborn screening suggested that there is likely no causal relationship between the biochemical trait and ID [36].

Finally we excluded IEMs for which reports of therapeutic effect are only available in conference abstract form. For example, Vockley et al. [37] presented two patients with SC4MOL deficiency (OMIM#607545), a defect in cholesterologenesis, with positive response to statins and cholesterol/bile acid supplements, at the American Medical Genetics 2010 meeting but the case has not been published yet. Another example is the presentation at the 'Society for the Study of Inborn Errors of Metabolism' Annual Symposium 2011 by Cario et al. [38] of Dihydrofolate Reductase Deficiency (OMIM#613839); folinic acid reportedly improves the features of this complex hematological and neurological disease accompanied by cerebral folate deficiency. Also, case reports of treatable IDs referred to only as 'unpublished data' in an article were excluded from this review; e.g. S-adenosylmethionine supplementation in

PRPS1 spectrum diseases (phosphoribosylpyrophosphate synthetase) by de Brouwer et al. [39].

2.1.4. Treatable IDs

The literature search in Pubmed (1960-2011) yielded 2945 articles. Based on the defined inclusion/exclusion criteria we identified 71 treatable IDs. The search in the textbook 'Metabolic and Molecular Bases of Inherited Disease' [19] and its online version www.ommbid. org [20] yielded another 10 treatable ID. All 81 treatable IDs including MIM number, biochemical deficiency and corresponding gene(s), are listed in Table 2. In this table IEMs are grouped according to the biochemical phenotype as presented in standard textbooks, and alphabetically. This type of classification has proven valuable for didactic purposes and systematic comprehension of IEMs.

2.1.5. Clinical features

The main clinical recognition patterns of each of the 81 treatable IEM with ID as a predominant feature, are shown in Supplements I and II in the online version of this journal. These supplementary tables lists the main clinical presentation of each disease, i.e. the most characteristic, specific and consistent signs and symptoms.

We subdivided the clinical features in neurological and non-neurological:

Neurologic features include ataxia, behavioural disturbance, dementia, dystonia, encephalopathic crisis, epilepsy, hearing loss, hypotonia/myopathy, neuro-imaging abnormalities (basal ganglia, cerebellum, cerebrum, cysts/dysgenesis, white matter, mixed), neuropathy, ocular movement abnormality, psychiatric disturbance, sensorineural hearing loss, spasticity, stroke, vision loss. All IEM except one (Tyrosinemia type II) are associated with at least one additional prominent neurologic feature, of which the most frequent are epilepsy and various types and degrees of movement disorders (e.g. spasticity, dyskinesia, ataxia etc.). However, many of these conditions can present with ID as sole feature for a considerable time prior to manifestation of the full phenotype. Examples include disorders of creatine sythesis and transport, female OTC deficiency, unrecognised PKU, and mild Homocystinuria. The non-neurologic features affect the following anatomic/organ systems: bones and joints, dermatology, endocrinology, eye, facial dys-morphism, growth and stature, heart, gastrointestinal, haematology, immunology, kidney, liver, odour. For 55 out of the 81 (69%) treatable IEM, a non-neurologic feature is a prominent part of the phenotype.

We emphasise that that absence or presence of specific signs and/ or symptoms not fitting our list does not rule out the specific disorder in a patient. Also, these lists are subject to change as new diagnostic techniques provide novel insights into the spectrum of phenotypic presentation and natural history of metabolic diseases. For the most recent and updated version of these lists, please visit our website www.treatable-id-org.

2.1.6. Diagnostic tests

To facilitate a practical guide for biochemical and genetic diagnosis, we assessed which tests are necessary to diagnose each of the conditions. Accordingly we grouped the diseases into IEMs diagnosed via 'metabolic screening tests' versus IEMs diagnosed via 'single test per single disease' approach. As screening tests we defined those tests in blood and urine, which are readily available in biochemical laboratories in most developed countries, and with a yield of at least 2 IEMs per test. Fig. 1 depicts the type and the yield of the specific metabolic screening tests, demonstrating that urine organic acid profiling is a powerful screening test with the potential to identify 22 IEMs.

Overall, these screening tests reliably provide clues for diagnosis for 62% (50/81) of all treatable IDs. For the remaining 31 treatable

IDs (38%), a specific 'one test per one disease' approach is required. The respective conditions and the nature of the most specific diagnostic tests are shown in Table 3. Treatable IDs, for which biochemical markers are difficult to interpret, and/or conventional diagnostic approach requires an invasive procedure or poorly accessible test (ie only performed in a very few centres worldwide) are shown in Table 4. Primary gene analysis is likely the most effective diagnostic approach for the 20 genes underlying these conditions.

2.2. Identification and characterisation of treatment modalities

2.2.1. Literature search

To ensure comprehensiveness of treatment modalities, we identified all relevant references reporting outcome/effect for each of the selected treatments and IEMs. We searched Pubmed (1960-2011) combining as keywords all known names for each IEM as well as gene and enzyme with the relevant therapeutic modalities. For all IEMs the pages on 'therapy' of each relevant chapter in the textbook 'Metabolic and Molecular Bases of Inherited Disease' [19] as well as the online version www. [20] were searched as well the textbook 'Inborn Metabolic Diseases: Diagnosis and Treatment [40]. The Cochrane Database of Systematic Reviews ( and Cochrane Central Register of Controlled Trials ( ovidguide/cctrdb.htm) were searched using as keywords the names for each IEM.

A total of 91 causal therapies were identified, each with a proven effect on primary and/or secondary outcomes as previously defined. For 10 IEMs two distinct treatments are available. An overview of all therapies for each IEM is provided in Table 5, along with corresponding level(s) of evidence, therapeutic effect(s), current use in clinical practice.

2.2.2. Levels of evidence

We assessed the quality of evidence for the beneficial effect of each therapeutic modality, on primary and/or secondary outcome(s) measure for each corresponding IEM by adopting the 'Oxford Centre for Evidence Based Medicine Levels of Evidence 2009' approach in 'best available' fashion to the relevant peer-reviewed literature (http:// Detailed critical appraisal of each literature report for the outcome of causal treatments in the 81 IEMs was outside of the scope of the study; instead we screened the studies for general quality of study design (incl. outcome measures) and reporting. As the level of evidence of treatment may vary per literature report, the highest available level was awarded based on those studies with qualitatively strong study design and reporting. In summary, for 21% of causal therapies, the level of evidence is high (1 or 2), whilst for the remainder (almost 80%) the evidence ranks at levels 4 to 5.

2.2.3. Effect(s) of treatments on outcome measures

We defined and coded outcome measures as follows: treatment improves psychomotor/cognitive development/IQ(A); treatment improves behaviour (B); treatment prevents acute metabolic decompensation (C); treatment prevents, halts, or slows deterioration (D); treatment improves neurological manifestations (E); treatment improves seizure/epilepsy control (F); treatment improves systemic manifestations (G). Outcome measures of the various treatments are shown in Table 5. Most therapies sorted a positive effect on multiple outcomes, varying from 1 to 5. Interestingly improvement of cognitive/psychomotor development, ie the primary outcome, is only achieved for 20% of IEM whilst for the majority of treatable IDs the secondary outcomes are positively influenced by therapy.

2.2.4. Treatments and clinical practice

For rare diseases, the level of evidence is usually not decisive in treatment protocols; therefore we also defined the clinical significance according to the current clinical practice in treating these IEMs, by specifying

Overview of all 81 treatable IDs.

In this table, the IEMs are grouped according to the biochemical phenotype as presented in standard textbooks, and alphabetically. Of note, primary CoQ deficiency was considered as one single IEM even though more though 6 genes have been described; this is true as well for MELAS and Pyruvate Dehydrogenase Complex deficiency.

Biochemical category Disease name OMIM# Biochemical deficiency Gene(s)

Amino acids HHH syndrome (hyperornithinemia, 238970 Ornithine translocase SLC25A15 (AR)



l.o. Non-ketotic hyperglycinemia 605899 Aminomethyltransferase/glycine decarboxylase/ AMT/GLDC/GCSH (AR)

glycine cleavage system H protein

Phenylketonuria 261600 Phenylalanine hydroxylase PAH (AR)

PHGDH deficiency (Serine deficiency) 601815 Phosphoglycerate dehydrogenase PHGDH (AR)

PSAT deficiency (Serine deficiency) 610992 Phosphoserine aminotransferase PSAT1 (AR)

PSPH deficiency (Serine deficiency) 614023 Phosphoserine phosphatase PSPH (AR)

Tyrosinemia type II 276600 Cytosolic tyrosine aminotransferase TAT (AR)

Cholesterol & bile Cerebrotendinous xanthomatosis 213700 Sterol-27-hydroxylase CYP27A1 (AR)

acids Smith-Lemli-Opitz Syndrome 270400 7-Dehydroxycholesterol reductase DHCR7 (AR)

Creatine AGAT deficiency 612718 Arginine: glycine amidinotransferase GATM (AR)

Creatine transporter Defect 300352 Creatine transporter SLC6A8 (X-linked)

GAMT deficiency 612736 Guanidino-acetate-N-methyltransferase GAMT(AR)

Fatty aldehydes Sjogren-Larsson syndrome 270200 Fatty aldehyde dehydrogenase ALDH3A2 (AR)

Glucose transport & GLUT1 deficiency syndrome 606777 Glucose transporter blood-brain barrier SLC2A1 (AR)

regulation Hyperinsulinism hyperammonemia 606762 Glutamate dehydrogenase superactivity GLUD1 (AR)


Hyperhomocysteinemia Cobalamin C deficiency 277400 Methylmalonyl-CoA mutase and homocysteine : MMACHC (AR)

methyltetrahydrofolate methyltransferase

Cobalamin D deficiency 277410 C2ORF25 protein MMADHC (AR)

Cobalamin E deficiency 236270 Methionine synthase reductase MTRR (AR)

Cobalamin F deficiency 277380 Lysosomal cobalamin exporter LMBRD1 (AR)

Cobalamin G deficiency 250940 5-Methyltetrahydrofolate-homocysteine MTR (AR)


Homocystinuria 236200 Cystathatione ß-synthase CBS (AR)

l.o. MTHFR deficiency 236250 Methylenetetrahydrofolate reductase deficiency MTHFR (AR)

Lysosomes a-Mannosidosis 248500 a-Mannosidase MAN2B1 (AR)

Aspartylglucosaminuria 208400 Aspartylglucosaminidase AGA (AR)

Gaucher disease type III 231000 ß-Glucosidase GBA (AR)

Hunter syndrome (MPS II) 309900 Iduronate-2-sulfatase IDS (X-linked)

Hurler syndrome (MPS I) 607014 a-L-iduronidase IDUA (AR)

l.o. Metachromatic leukodystrophy 250100 Arylsulfatase A ARSA (AR)

Niemann-Pick disease type C 257220 Intracellular transport cholesterol & sphingosines NPC1 NPC2 (AR)

Sanfilippo syndrome A (MPS Ilia) 252900 Heparan-N-sulfatase SGSH (AR)

Sanfilippo syndrome B (MPS IlIb) 252920 N-acetyl-glucosaminidase NAGLU (AR)

Sanfilippo syndrome C (MPS IIIc) 252930 Acetyl-CoA glucosamine-N-acetyl transferase HGSNAT(AR)

Sanfilippo syndrome D (MPS IIId) 252940 N-acetyl-glucosamine-6-Sulfatase GNS (AR)

Sly syndrome (MPS VII) 253220 ß-glucuronidase GUSB (AR)

Metals Aceruloplasminemia 604290 Ceruloplasmin (iron homeostasis) CP (AR)

Menkes disease/Occipital horn 304150 Copper transport protein (efflux from cell) ATP7A (AR)


Wilson disease 277900 Copper transport protein (liver to bile) ATP7B (AR)

Mitochondria Co enzyme Q10 deficiency 607426 Coenzyme Q2 or mitochondrial parahydroxybenzoate- COQ2, APTX, PDSS1,

polyprenyltransferase; aprataxin; prenyl diphosphate PDSS2, CABC1, COQ9

synthase subunit 1; prenyl diphosphate synthase (most AR)

subunit 2; coenzyme Q8; coenzyme Q9

MELAS 540000 Mitochondrial energy deficiency MTTL1, MTTQ MTTH,




PDH complex deficiency OMIM# according to each Pyruvate dehydrogenase complex (E1a, E2, E3) PDHA1 (X-linked),

enzyme subunit deficiency: DLAT (AR), PDHX (AR)

312170; 245348; 245349

Neurotransmission DHPR deficiency (biopterin deficiency) 261630 Dihydropteridine reductase QDPR (AR)

GTPCH1 deficiency (biopterin 233910 GTP cyclohydrolase GCH1 (AR)


PCD deficiency (biopterin deficiency) 264070 Pterin-4a-carbinolamine dehydratase PCBD1 (AR)

PTPS deficiency (biopterin deficiency) 261640 6-Pyruvoyltetrahydropterin synthase PTS (AR)

SPR deficiency (biopterin deficiency) 612716 Sepiapterin reductase SPR (AR)

SSADH deficiency 271980 Succinic semialdehyde dehydrogenase ALDH5A1 (AR)

Tyrosine Hydroxylase Deficiency 605407 Tyrosine Hydroxylase TH (AR)

Organic acids 3-Methylcrotonyl glycinuria GENE OMIM# 210200; 3-Methylcrotonyl CoA carboxylase (3-MCC) MCC1/MCC2 (AR)


3-Methylglutaconic aciduria type I 250950 3-Methylglutaconyl-CoA hydratase AUH (AR)

3-Ketothiolase deficiency 203750 Mitochondrial acetoacetyl-CoA thiolase ACAT1 (AR)

Cobalamin A deficiency 251100 MMAA protein MMAA (AR)

Cobalamin B deficiency 251110 Cob(I)alamin adenosyltransferase MMAB (AR)

Ethylmalonic encephalopathy 602473 Mitochondrial sulfur dioxygenase ETHE1 (AR)

l.o. Glutaric acidemia I 231670 Glutaryl-CoA dehydrogenase GCDH (AR)

Glutaric acidemia II 231680 Multiple acyl-CoA dehydrogenase ETFA, ETFB, ETFDH (AR)

Table 2 (continued)

Biochemical category Disease name OMIM# Biochemical deficiency Gene(s)

HMG-CoA lyase deficiency 246450 3-Hydroxy-3-methylglutaryl-CoA lyase HMGCL (AR)

l.o. Isovaleric acidemia 243500 Isovaleryl-CoA dehydrogenase IVD (AR)

Maple syrup urine disease (variant) 248600 Branched-chain 2-ketoacid complex BCKDHA/BCKDHB/ DBT

l.o. Methylmalonic acidemia 251000 Methylmalonyl-CoA mutase (AR) (AR) MUT(AR)

MHBD deficiency 300438 2-Methyl-3-hydroxybutyryl-CoA dehydrogenase HSD17B10

(X-linked recessive)

mHMG-CoA synthase deficiency 605911 Mitochondrial 3-hydroxy-3-Methylglutaryl-CoA HMGCS2 (AR)


l.o. Propionic acidemia 606054 Propionyl-CoA carboxylase PCCA/PCCB (AR)

SCOT deficiency 245050 Succinyl-CoA 3-oxoacid CoA transferase OXCT1 (AR)

Peroxisomes X-linked adrenoleukodystrophy 300100 Peroxisomal transport membrane protein ALDP ABCD1 (X-linked)

Pyrimidines Pyrimidine 5-nucleotidase GENE OMIM # 606224 Pyrimidine-5-nucleotidase Superactivity NT5C3 (AR)


Urea cycle l.o. Argininemia 207800 Arginase ARG1 (AR)

l.o. Argininosuccinic aciduria 207900 Argininosuccinate lyase ASL (AR)

l.o. Citrullinemia 215700 Argininosuccinate Synthetase ASS1 (AR)

Citrullinemia type II 605814 Citrin (aspartate-glutamate carrier) SLC25A13

l.o. CPS deficiency 237300 Carbamoyl phosphate synthetase CPS1 (AR)

l.o. NAGS deficiency 237310 N-acetylglutamate synthetase NAGS (AR)

l.o. OTC Deficiency 311250 Ornithine transcarbamoylase OTC (X-linked)

Vitamins/co-factors Biotinidase deficiency 253260 Biotinidase BTD (AR)

Biotin responsive basal ganglia 607483 Biotin transport SLC19A3(AR)


Cerebral folate receptor-a deficiency 613068 a.o. Cerebral folate transporter FOLR1 (AR)

Congenital intrinsic factor deficiency 261000 Intrinsic factor deficiency GIF (AR)

Holocarboxylase synthetase 253270 Holocarboxylase synthetase HLCS (AR)


Imerslund Grasbeck syndrome 261100 IF-Cbl receptor defects (cubulin/amnionless) CUBN &AMN (AR)

Molybdenum co-factor deficiency 252150 Sulfite oxidase & xanthine dehydrogenase & MOCS1 , MOCS2, (AR)

type A aldehyde oxidase

Pyridoxine dependent epilepsy 266100 Pyridoxine phosphate oxidase ALDH7A1 (AR),

Thiamine responsive 606152 Thiamine transport SLC19A3 (AR)


l.o. = late-onset form.

Mode of inheritance: for each gene is denoted as AD = autosomal dominant, AR = autosomal recessive, Mt = mitochondrial; X-linked = X-linked. OMIM#: denotes the Online Mendelian Inheritance in Man ( number for the specific disease (versus gene), unless otherwise indicated.

whether administration of a specific therapy is considered 'Standard of Care' or rather decided on an 'Individual (Patient) Basis'. We defined 'Standard of Care' as a formal treatment process a physician will follow for a patient with a specific illness, which experts generally accept as 'best clinical practice'. The majority for all treatments (n = 63/69%) are considered Standard of Care. For the remaining 31%, the decision to initiate treatment is made on an 'individual (Patient) Basis', i.e. a combination of patient characteristics (disease stage: e.g. Loes Score for X-linked Adre-noleukodystrophy), physician's opinion, availability of treatment, potential side-effects.

For all 91 therapies, Table 6 provides a numeric overview of distribution amongst the various levels of evidence levels, and for each level separately the distinction between types of clinical practice. Not suprisingly, all treatments for these rare metabolic diseases with high evidence levels - ranking at 1 or 2 (n = 19/ 21%) - are internationally accepted as Standard of Care except for the stemcell transplant for X-linked Adrenoleukodystrophy. However, for therapies with low levels of evidence (4-5: case series/reports or expert opinion) which constitute the bulk of 91 treatments, this also true. More than 60% (45/72) is accepted as 'best clinical practice', despite solid evidence for therapeutic effect.

2.2.5. References and information sources

Given the limited space available in printed journals, it was not possible to generate a detailed list of references for each treatable IEM. We aimed to provide relevant overview articles for each addressing general aspects of the disease as well as treatment specifics. For a comprehensive information on each of the treatable IDs, we kindly refer the reader to the 'disease pages' on our website and to the

textbooks 'Inborn Metabolic Diseases: Diagnosis and Treatment' [40] and 'Metabolic and Molecular Bases of Inherited Disease' [19].

3. Discussion

This systematic review is the first evidence-based approach to demonstrate the significance of inborn errors of metabolism (lEMs) in the diagnostic work up of intellectual disability/developmental delay. Whilst current recommendations for the diagnostic work up of ID prioritise frequency of conditions and yield of diagnostic tests, our approach prioritises treatability over frequency and strategises metabolic/biochemical evaluation in a two-tiered fashion.

Several reviews have been published about metabolic causes of intellectual disability, mostly reflecting expert opinions and individual expertise in the field of IEM [41-43]. The need for multiple tests to exclude a few rare to ultra-rare conditions, and the limited availabilities of laboratories offering comprehensive diagnostic testing, explains why outside highly specialised centres, metabolic work up of patients with lD is tedious, cost consuming and still remains incomplete in many cases. Because of all these limitations, the diagnostic yield of metabolic testing has been reportedly low in patients presenting with ID. Our approach focusses on treatable IEM, because even rare, treatability clearly justifies extensive work-up of otherwise unrecognised conditions.

In this review we identified 81 lEMs with ID as major clinical feature. Arguably, the incidence of the individual 81 conditions is low, ranging from 1:10,000 to less than 1:200,000 [53]. Their recognition is of importance however, because treatability overweights the rare nature of these conditions [15]. Collectively their incidence in the ID

Summary of all treataNe IEM (n-=50/62%) which can be detected by 'Metabolic Screening Tests', each of which is affordable and accessible with the potential to identify at Jeast 2 IEM (and up to 22), Each bar represents the yield of the specific screening test, and lists the number and types of treatable IEM it can identify.

Urine Tests

Urine Organic Acids (n=22)

Urine Glycosamlnoglycans (n=7) Urine Creatine Metabolites (n=3) Urine oligosaccharides (n=2)

Urine Purines & Pyrimldines (n=2)

Blood Tests

Plasma Ammo-Acids (n=13J Plasma Total Homocysteine (n=9)

^ ß-Ketothiolase Deficiency ► Glutaric Acidemia type II ► MHBD Deficiency

t Cobalamin A Deficiency ► HMG-CoA Lyase Deficiency ► mHMG-CoA Synthase Deficiency

► Cobalamin В Deficiency ► Holocarboxylase Synthetase Deficiency » l.o. Proprionic Acidemia (&ACP)

► Cobalamin С Deficiency (& tHcy) ► Homocystinuria ► SCOT Deficiency

► Cobalamin D deficiency (& tHcy) ► 1.0. Isovaleric Acidemia (&ACP) ► SSADH deficiency

> Cobalamin F deficiency (& tHcy) ► 3-Methylcrotonyl Glycinurta (&ACP) > Tyrosinemia type II (&PAA)

► Ethyimalonlc Encephalopathy (SACP) ► 3-Methylglutaconlc Aciduria

► Glutaric Acidemia type 1 к 1.0. Methylmalonic Acidemia (&ACP)

. Hunter syndrome (MPS II) » Santilippo syndrome (type a, b. cr dj > Huiler Syndrome (MPS I) к Sty syndrome IMPS VI)

>AGAT deficiency »Creabne ' GAMT deficiency Transporter Detect

> «-Mannosidflsis » Aspartylglucosaminuria

> Pyrimidine 5'nucteotidase soperactliity . Molybdenum Cofactor Type A deficiency

► Lo. Argininosucclnic Aciduria ► HHH syndrome > 1.0. OTC Deficiency

► Lo. Citrullinemla > Maple Syrup Urine Disease > Phenylketonuria

► Lo. Citrullinemia туре II (Variant) > PDH Complex Deficiency

► Lo. CPS Deficiency ► l.o. MTHFR Deficiency (Шсу) ► Tyrosinemia type II (&U0A)

► Lo. Argininemia > l,o, NAGS Deficiency

> Homocysfinuria (ША)

I i.e. MTHFR Deficiency (SPAA)

> Cobalamin С Deficiency |£ UDA) * Cobalamin D Deficiency (& UOA)

► Cobalamin E Deficiency

> Cobalamin F Deficiency (& UDA) . Cobalamin G Deficiency

Legend Abbreviations: plasma amino adds (PAA). Total homocysteine (tHcy), plasma acylcamltineprofile (ACP). uhne organic acids (UOA).

E^hejmicopslysacchaadoses, enzyme activity should measured as a next step: Hurler flduronidasej; Hunter syndrome (lduronate-2-sulphatasel; Sanfilippo syndrome (Ilia = Heparan-N-sultatase, Mb = N-acetyl-glucosaminidase, lllc = Acetyl CoA glucosamine N-acetyl transferase. Hid = N-Acetyl-glucosamlne-6-sulfatase); Sty syndrorm= ^-Glucuronidase)

Fig. 1. Bar graph depicting the yield of'Metabolic Screening Tests'.

population may be much higher than currently estimated, as shown by a study performed in the Sylvia Tôth centre in the Netherlands [13]. Through a multidisciplinary approach and expertise in lEMs, the diagnostic yield in individuals with ID exceeded 10%, standing in sharp contrast to frequently quoted yields of 0.5%.

The majority of conditions identified in this systematic review presents with more multiple co-morbidities including epilepsy, neurologic symptoms and signs, and behavioural and psychiatric disturbances. Systemic manifestations occur in 69% of conditions. However, the clinical spectrum of treatable lD is variable and the absence of co-morbidites does not exclude the presence of a treatable ID. Rather the clinical picture is determined by the state of disease progression and by particular disease variants. For example, progressive neurologic decline is characteristic of advanced stages of X-linked Adrenoleukodys-trophy. However, signs of lD and subtle loss of cognitive functions with behavioural disturbances are often the first manifestations. Recognition of the diagnosis at this early disease stage opens a unique window of opportunity for causal treatment with stem cell transplantation, which at a later stage is not effective any more. Thus whilst clinical co-morbidities are traditionally considered characteristic of metabolic causes of lD, the absence of such co-morbidities does not exclude them. This is true also for neurodegeneration, as many of the lEMs on our list present with stable lD', i.e. without a history of regression or plateauing.

' Late-onset' or atypical variants of conditions typically presenting as acute metabolic decompensation in the neonatal period deserve special attention. Whilst patients with acute metabolic crisis are diagnosed before they are assessed for developmental delay/intellectual disability, the clinical presentation of the late onset forms of these conditions is unspecific and of chronic nature. For example, OTC deficiency typically manifests with severe neonatal hyperammonemia with extremely poor outcomes in affected males, whereas females

with late-onset variants with OTC deficiency often present with ID and/or behavioural problems as only manifestation(s) [44]. Timely recognition of the underlying metabolic defect allowing appropriate treatment to control blood ammonia levels, not only helps to prevent acute hyperammonic crises at a later stage of life, but also improves cognitive functions and behaviour.

We found that a considerable proportion of treatable IDs (62%) can be reliably detected through a panel of metabolic screening tests on blood (total homocysteine, plasma aminoacids) and urine (organic acids, purines and pyrimidines, creatine and guanidinoacetate, glycos-aminoglycans, oligosaccharides). In general these tests are offered by most biochemical genetics laboratories around the world at afforable prices and with considerable yield per test. Careful interpretation of results - in particular for mild and atypical disease variants - seems to be crucial in this respect. Foremost interpretation of results below the normal range is challenging. For example, a subtle decrease of both plasma and CSF serine levels was initially not considered significant in a 2-year old girl with developmental delay and seizures sufficiently controlled with antiepileptic mono-therapy; however, thorough diagnostic work-up revealed two potentially disease-causing mutations on the PGDH gene along with decreased serine synthesis in cultivated skin fibroblasts. Diagnosis of a serine biosynthesis defect in this patient not only extends the phenotypic spectrum of the disease, but more importantly provides the opportunity to start serine supplements with the aim of improving neurologic status and development as well as prevention of any future deterioration (personal communication CvKand SS). A systematic approach including screening of all patients with ID under standardised pre-analytical conditions and with careful analysis of apparently unspecific results will show the true diagnostic value of these metabolic screening tests, in particular in the recognition of mild and atypical variants of treatable amino-acidopathies and organic acidurias.

All IEMs (n = 31/38%) requiring a 'specific test' for diagnosis.

The IEMs are listed per biochemical category, and for each the specific biochemical/genetic diagnostic test. Abbreviations include: CSF = cerebrospinal fluid, l.o. = late-onset form, PAA = plasma amino acids, Phe = phenylalanine.

Biochemical category


Specific diagnostic test

Amino acids

Cholesterol/bile acids

Fatty aldehydes

Glucose transport & regulation





Peroxisomal Vitamins/co-factors

l.o. Non-ketotic hyperglycinemia

PHGDH deficiency (serine deficiency)

PSAT deficiency (serine deficiency)

PSPH deficiency (serine deficiency)

Cerebrotendinous Xanthomatosis

Smith-Lemli-Opitz Syndrome

Sjogren-Larsson syndrome

GLUT1 deficiency syndrome

Hyperinsulinism hyperammonemia syndrome

Gaucher disease type III

l.o. Metachromatic leukodystrophy

Niemann-Pick disease type C


Menkes disease-occipital horn syndrome

Wilson disease

Co enzyme Q10 deficiency

PDH complex deficiency

DHPR deficiency (biopterin deficiency) GTPCH deficiency (biopterin deficiency) PCD deficiency (biopterin deficiency) PTPS deficiency (biopterin deficiency) SPR deficiency

Tyrosine hydroxylase deficiency X-linked Adrenoleukodystrophy Biotinidase deficiency Biotin responsive basal ganglia disease Cerebral folate receptor deficiency Congenital intrinsic factor deficiency Imerslund Grasbeck syndrome Pyridoxine dependent epilepsy Thiamine-responsive encephalopathy

CSF amino acids (& PAA) CSF amino acids (& PAA) CSF amino acids (& PAA) CSF amino acids (& PAA) Plasma cholestanol

Plasma 7-dehydrocholesterol:cholesterol ratio Fatty aldehyde dehydrogenase enzyme activity CSF glucose:plasma glucose ratio GDH gene analysis (& ammonia, glucose, insulin) Glucocerebrosidase enzyme activity (lymphocytes) Arylsulfatase-A enzyme activity

Filipin staining test (fibroblasts) & NPC1/NPC2 gene analyses

Serum ceruloplasmin, copper, iron, ferritin

Serum copper & ceruloplasmin; urine deoxypyridinoline

Serum copper & ceruloplasmin, urine copper

Coenzyme Q10 (fibroblasts) & gene(s) analysis (see Table 2)

Mitochondrial DNA mutation testing (see Table 2)

Blood & CSF lactate:pyruvate ratio

(enzyme activity, gene(s) analysis)

CSF neurotransmitters & biopterin loading test

CSF neurotransmitters & biopterin loading test

CSF neurotransmitters & biopterin loading test

CSF neurotransmitters & biopterin loading test

CSF neurotransmitters & biopterin/Phe loading test

CSF neurotransmitters & TH gene analysis

Plasma Very Long Chain Fatty Acids

Biotinidase enzyme activity

SLC19A3 gene analysis

CSF tetrahydrofolate

Plasma Vit B12, folate

Plasma Vit B12, folate

Urine a-aminoadipic semialdehyde & plasma pipecolic acid SLC19A3 gene analysis

The clinical signs and symptoms may be clue to diagnosis for those conditions, which are not detectable by any of the aforementioned screening tests. In this review we indentified 31 conditions which require a 'single test per single disease' approach. As many of these tests are invasive (e.g. requiring skin biopsies), and expensive (because laborious and offered only by a few laboratories worldwide), a careful clinical differential diagnosis is mandatory for a time- and cost-effective diagnostic evaluation.

Primary gene analysis is a way to enhance the diagnostic yield in conditions with unspecific clinical and biochemical presentation. For example, low urinary excretion of guanidinoacetate is characteristic of AGAT deficiency, a treatable disorder of creatine synthesis, but the

detection of low levels continues to pose an analytical challenge, as currently available methods mainly detect extreme elevations of accumulating metabolites. The current diagnostic approach to Niemann-Pick Disease Type C requires demonstration of free cholesterol via filipin staining in cultivated skin fibroblasts. This test is invasive, time- and cost-consuming, available only in a limited number of labs worldwide and not always sensitive. In the future, high-throughput sequencing technologies will likely lower the diagnostic threshold for such disorders, through facilitation of analysis of multiple genes in one sample for afforfable prices. Advances in sequencing coverage, bio-informatics and insight into the significance of detected mutations is prerequisite.

IEMs (n = 13) for which molecular analysis might serve as the primary 'specific test'.

Direct molecular or gene(s) analysis was deemed the most appropriate diagnostic approach for an IEM if: the biochemical marker is unavailable or unreliable and/or the test requires an invasive procedure and/or the test is difficult to access. This table lists a total of 13 such IEMs with 30 encoding genes.


AGAT deficiency

Biotin responsive basal ganglia disease

Cerebral glucose transporter deficiency

Co enzyme Q10 deficiency

l.o. CPS deficiency

Creatine transporter deficiency

Hyperinsulinism-hyperammonia syndrome

l.o. NAGS deficiency Niemann-Pick disease type C Serine biosynthesis defects Sjögren-Larssen disease Thiamine-responsive encephalopathy







Overview of all causal therapies (n = 91).

This Table provides an overview of the specific therapy/-ies available for each IEM with relevant level(s) of evidence, therapeutic effect(s) on primary and/or secondary outcomes and use in clinical practice. For 10 IEMs, two therapies are available; these are listed separately (in brackets).

Disease name Therapeutic modality ( — ies) Level of Clinical practice Treatment Literature

evidence effect references

Aceruloplasminemia Iron chelation 4 Standard of care D,E [45-47]

(X-linked)adrenoleukodystrophy Stemcell transplantation (Gene therapy) 1c (5) Individual basis D,E (D,E) [48-50]

(Individual basis)

AGAT deficiency Creatine supplements 4 Standard of care A,D [51-53]

a-Mannosidosis Haematopoietic stem cell transplantation 4-5 Individual basis D [54]

l.o. Argininemia Dietary protein restriction, arginine supplement, sodium 2b (4) Standard of care B,C,D,E,F,G [55-61]

benzoate, phenylbutyrate (Liver transplantation) (Individual basis) (C)

l.o. Argininosuccinic aciduria Dietary protein restriction, arginine supplement, sodium 2b (4) Standard of care B,C,D,E,F,G [55-58,60,61]

benzoate, phenylbutyrate (liver transplantation) (individual basis) (C)

Aspartylglucosaminuria Haematopoietic stem cell transplantation 4-5 Individual basis D [62]

ß-Ketothiolase deficiency Avoid fasting, sickday management, protein restriction 5 Standard of care C [63-65]

Biotin responsive basal ganglia Biotin supplement 4 Standard of care A,E [66]


Biotinidase deficiency Biotin supplement 2c Standard of care A,E,G [67]

Cerebral folate receptor-a Folinic acid 4 Standard of care A,D,E,F [68,69]


Cerebrotendinous xanthomatosis Chenodesoxycholic acid, HMG reductase inhibitor 4 Standard of care B,D,E,G [70-72]

l.o. Citrullinemia Dietary protein restriction, arginine supplement, sodium 2b (4) Standard of care B,C,D,E,F,G [55-57,60,61]

benzoate, phenylbutyrate (Liver transplantation) (Individual basis) (C)

Citrullinemia type II Dietary protein restriction, arginine supplement, sodium 2b (4) Standard of care B,C,D,E,F,G [50-52,73,55,56]

benzoate, phenylbutyrate (Liver transplantation) (Individual basis) (C)

Co enzyme Q10 deficiency CoQ supplements 4 Standard of care E,F [74,75]

Cobalamin A deficiency Hydroxycobalamin, protein restriction 4 Standard of care C,G [76-79]

Cobalamin B deficiency Hydroxycobalamin, protein restriction 4 Standard of care C,G [76-79]

Cobalamin C deficiency Hydroxycobalamin 4 Standard of care C,D,G [76-79]

Cobalamin D deficiency Hydroxy-/cyanocobalamin 4 Standard of care C,D,G [76-79]

Cobalamin E deficiency Hydroxy-/methylcobalamin, betaine 4 Standard of care C,D,G [76-79]

Cobalamin F deficiency Hydroxycobalamin 4 Standard of care C,D,G [76-79]

Cobalamin G deficiency Hydroxy-/methylcobalamin, betaine 4 Standard of care C,D,G [76,78,79]

Congenital intrinsic factor deficiency Hydroxycobalamin 4 Standard of care A,E,G [80]

l.o. CPS deficiency Dietary protein restriction, arginine supplement, sodium 2b & 4 Standard of care B,C,D,E,F,G [55-57,60,61]

benzoate, phenylbutyrate (Liver transplantation) (Individual basis) (C)

Creatine transporter defect Creatine, glycine, arginine supplements 4-5 Individual basis F [29]

DHPR deficiency BH4,diet, amine replacement, folinic acid 4 Standard of care A,E [52]

Ethylmalonic encephalopathy N-acetylcysteine, oral metronidazol 4 Standard of care E,G [81]

GAMT deficiency Arginine restriction, creatine & ornithine supplements 4 Standard of care B,D,E,F [48,52,82,83]

Gaucher disease type III Haematopoietic stem cell transplantation 4-5 Individual basis D,G [84,85]

GLUT1 deficiency syndrome Ketogenic diet 4 Standard of Care F [19,86]

l.o. Glutaric acidemia I Lysine restriction, carnitine supplements 2c Standard of care C,D,E,G [87,88]

Glutaric acidemia II Carnitine, riboflavin, p-hydroxybutyrate supplements; 5 Standard of care C,G [89,90]

sick day management

GTPCH1 deficiency BH4, amine replacement 4 Standard of care A,E [91]

HHH syndrome Dietary protein restriction, ornithine supplement, sodium 4 Standard of care B,C,D,E,F,G [92]

benzoate, phenylacetate

HMG-CoA lyase deficiency Protein restriction, avoid fasting, sick day management, 5 Standard of care C [58-60,93]

Holocarboxylase synthetase Biotin supplement 4 Standard of care A,E,G [94,95]


Homocystinuria Methionine restriction, +/-pyridoxine, +/-betaine 2c Standard of care C,D,G [96,76]

Hunter syndrome (MPS II) Haematopoietic stem cell transplantation 4-5 Individual basis D,G [24,85,97]

Hurler syndrome (MPS I) Haematopoietic stem cell transplantation 1c Standard of care D,G [24,85,97]

Hyperammonemia- Diazoxide 4-5 Standard of care D [98,99]

Hyperinsulinism syndrome

Imerslund Gräsbeck syndrome Hydroxycobalamin 4 Standard of Care A,E,G [100]

l.o. Isovaleric acidemia Dietary protein restriction, carnitine supplements, 2c Standard of care C,G [101-104,93]

avoid fasting, sick day management

l.o. NAGS deficiency Dietary protein restriction, arginine supplement, sodium 2b & 4 Standard of care B,C,D,E,F,G [55-

benzoate, phenylbutyrate (Liver transplantation) (Individual basis) (C) 57,105,60,61]

l.o. Non-ketotic Glycine restriction; +/-sodium benzoate, NMDA 4-5 Standard of Care B,D,E,F [106]

hyperglycinemia receptor antagonists, other neuromodulating agents

Maple syrup urine disease (variant) Dietary restriction branched amino-acids, avoid fasting, 4&4 Standard of care B,C,D (AC) [107-110]

(Liver transplantation) (Individual basis)

MELAS Arginine supplements 4-5 Standard of Care C,D,E,F [26]

Menkes disease occipital horn Copper histidine 4 Individual basis D [111-113]


l.o. Metachromatic Haematopoietic stem cell transplantation 4-5 Individual basis D [114,85]


3-Methylcrotonyl glycinuria Dietary protein restriction; carnitine, glycine, biotin 5 Standard of care C [115,116]

supplements; avoid fasting; sick day management

3-Methylglutaconic aciduria Carnitine Supplements, Avoid Fasting, Sick Day Management 5 Standard of care C [117]

type I l.o. Methylmalonic acidemia Dietary protein restriction, carnitine supplements, avoid 2c Standard of care C,G [101-104,93]

fasting, sick day management

C.D.M. van Karnebeek, S. Stockler / Molecular Genetics and Metabolism 105 (2012) 368-381 377

Table 5 (continued)

Disease name Therapeutic modality (— ies) Level of Clinical practice Treatment Literature

evidence effect references

MHBD deficiency Avoid fasting, sick day management, isoleucine restricted diet 5 Standard of care C [63-65,93]

mHMG-CoA synthase Avoid fasting,sick day management, +/-dietary 5 Standard of care C [63-65,93]

deficiency precursor restriction

Molybdenum co-factor Precursor Z/cPMP 4 Individual basis A,F [25]

deficiency type A

l.o. MTHFR deficiency Betaine supplements, +/-folate, carnitine, 4 Standard of care C,D,G [76,79]

methionine supplements

Niemann-Pick disease type C Miglustat 1b Standard of care D,E [118-121]

l.o. OTC deficiency Dietary protein restriction, citrulline supplements, 2b & 4 Standard of care B,C,D,E,F,G [55-57,60,61]

Sodium benzoate/phenylbutyrate (Liver transplantation) (Individual basis) (C)

PCD deficiency BH4 4 Standard of care A,E [91]

PDH complex deficiency Ketogenic diet & thiamine 4 Individual basis D,E,F [122]

Phenylketonuria Dietary phenylalanine restriction +/-amino-acid 2a (4) Standard of care B, D, E [123,23,124,143]

supplements (BH(4) supplement) (Individual basis) (C)

PHGDH deficiency L-serine & +/-glycine supplements 4 Standard of care D,F [125,126]

PSAT deficiency L-serine & +/-glycine supplements 4 Standard of care D,F [125,126]

l.o. Propionic acidemia Dietary protein restriction, carnitine supplements, 2c Standard of care C,G [101-104,93]

avoid fasting, sick day management

PSPH deficiency L-serine & +/-glycine supplements 4 Standard of care D,F [125,126]

PTPS deficiency BH4, diet, amine replacement 4 Standard of care A,E [91]

Pyridoxine dependent epilepsy Pyridoxine 4 Standard of care A,F [127,128]

Pyrimidine 5-nucleotidase Uridine supplements 1b Standard of care A,B,F,G [129]


Sanfilippo syndrome A (MPS IIIa) Haematopoietic stem cell transplantation 4-5 Individual basis D [24,85,97]

Sanfilippo syndrome B (MPS IIIb) Haematopoietic stem cell transplantation 4-5 Individual basis D [24,85,97]

Sanfilippo syndrome C (MPS IIIc) Haematopoietic Stemcell Transplantation 4-5 Individual Basis D [24,85,97]

Sanfilippo syndrome D (MPS IIId) Haematopoietic stem cell transplantation 4-5 Individual basis D [24,85,97]

SCOT deficiency Avoid fasting, protein restriction, sick day management 5 Standard of care C [65]

Sjogren-Larsson syndrome Diet: low fat, medium chain & essential fatty acid 5 Individual basis D,G [130,131]

supplements & Zileuton

Sly syndrome (MPS VII) Haematopoietic stem cell transplantation 4-5 Individual basis D [24,85,97]

Smith-Lemli-Opitz syndrome Cholesterol & simvastatin 4-5 Individual basis B,D [27,132,133]

SPR deficiency Amine replacement 4 Standard of care A,E [134]

SSADH deficiency Vigabatrin 4 Individual basis B,F [135]

Thiamine-responsive Thiamin supplement 4-5 Standard of care E [136,137]


Tyrosine hydroxylase deficiency L-dopa substitution 4 Standard of care A,E [138]

Tyrosinemia type II Dietary phenylalanine & tyrosine restriction 4-5 Standard of care D,G [34,139,140]

Wilson disease Zinc & tetrathiomolybdate 1b Standard of care E,G [113,141,142]

Individual basis: the decision to initiate a specific treatment depends on a careful evaluation of the specific patient characteristics, physician's opinion, availability of treatment, and potential side-effects.

Levels of evidence (source: Level 1a = systematic review of randomized controlled trials (RCT), 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' (focussed 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 4-5 = single case report; Level 5 = expert opinion without critical appraisal.

Sick day management: intervention(s) to guarantee sufficient fluid and caloric intake to maintain anabolic state, plus continuation/modification of disease specific therapy Standard of care: initiation of the specific treatment upon diagnostic confirmation is generally accepted by experts world-wide as 'best clinical practice'.

Therapeutic effect(s): 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.

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, because the patient might not have been screened for a particular disease or at all. A "universal" newborn screening, does not exist, as panels still vary from mere 3 to more than 30. In a global society, children may have been born in countries without any newborn screening at all. Even for those IEMs included in most newborn screening programs such as classic organic acidurias and urea cycle defects, 'late-onset' forms consituting treatable IDs can be missed as newborn screening may not be sensitive and specific enough to safely detect such disease-variants.

Treatments include diets (e.g. modified in protein intake); sick day management ensuring sufficient calorie intake during illnesses; supplementation of vitamins, co-factors or nutritional supplements; pharmacological substrate inhibition; organ/stem cell transplantation; and gene therapy. Except for gene therapy and organ/stem cell transplantation, these treatments are relatively safe, non-invasive and affordable. The only expensive treatment included in this review is

substrate inhibition therapy for Niemann-Pick Disease Type C. Compliance is an important factor determining the treatment outcomes. This is particularly true for dietary treatments with unphysiological and culturally incompatible composition of the nutritional intake.

Although most treatments have long been established and many are considered 'standard of care', the evidence level for their effect is low. Only one-fifth of the treatments identified in our review has evidence level 1b, c and 2a, b, c whereas the majority of treatments (n = 72) ranks at evidence level of 4 or lower. Paradoxically, 62% of evidence level 4 and 5 treatments are initiated as 'standard of care' by clinicians. This highlights the fact that, due to the rare nature of single conditions, most treatments have only been evaluated on a case for case basis. Thus the low evidence level of treatments for IEM and ID may be due rather to methodological shortcomings than effect-size per se.

To enable instant use of the results of this literature review in clinical practice, we have developed digital tools by designing an interactive website with downloadable 'App' using

Levels of evidence & clinical practice for all 91 therapies.

Level of evidence Definition No. of therapies Standard of care (% of therapies Individual basis (% of therapies

(% of total therapies; n = 91) with specific evidence level) with specific evidence level)

1a Systematic review of RCTs 0 (0%) 0 (0%) 0 (0%)

1b Individual RCT 3(3%) 3 (100%) 0 (0%)

1c 'All or None' 2 (2%) 1 (50%) 1 (50%)

2a Systematic review of cohort studies 1 (1%) 1(100%) 0 (0%)

2b Individual cohort study 7 (8%) 7(100%) 0 (0%)

2c 'Outcomes research' 6 (7%) 6(100%) 0 (0%)

3 Systematic review of case-control studies 0 (0%) 0 (0%) 0 (0%)

4 Case-control study & case series 45 (50%) 32 (71%) 13 (29%)

4-5 Single case report(s) 17(19%) 5 (29%) 12 (71%)

5 Expert opinion 10 (11%) 8 (80%) 2 (20%)

All (1-5) 91 (100%) 63 (69%) 28 (31%)

RapidWeaver software for most types of handheld devices (e.g. BlackBerry, iPad). These digital tools comprise modes to review all treatable IDs according to biochemical defects and categories, diagnostic tests, clinical features, treatment modalities with levels of evidence and effect. In addition, for each of the 81 IEMs a 'Disease Page' has been designed as information portal with links to relevant pages/ chapters on online resources (Gene Reviews, Orphanet, OMIM, patient organisations, clinical trials, Pubmed, online 'Metabolic and Molecular Bases of Inherited Disease' etc.). The target audience includes clinicians and scientists active in the diagnostic evaluation of ID (pediatricians, neurologists, biochemical/clinical geneticists, metabolic specialists). Our aim is to enhance awareness and diagnostic recognition of treatable forms of ID. Input from experts around the world is welcomed and will be incorporated in the site. Finally the site will be updated every 3 months according to the continuously expanding list of treatable IDs, treatments, literature evidence, etc.

Finally, based on our literature review we have designed an evidence-based protocol for the diagnostic evaluation of genetic causes of ID in children with the premise to consider treatable IEMs at the outset. In the first tier, metabolic screening tests in blood and urine will be performed in all patients, followed by clinical algorithms facilitated by our digital tools for those treatable IDs which require a specific test in the 2nd tier. These metabolic layers will be superimposed and interposed to existing standard genetic and (pediatric) neurologic parameters [17,18]. As part of a funded study on treatable ID, we will implement this protocol in our tertiary care hospital and evaluate the (cost-)effectiveness, efficiency, diagnostic yields and patient and physician satisfaction as prerequisite to expand it to other centres, with the ultimate aim to adopt active identification of treatable IDs as best care practice to improve health outcomes.

Role of funding source

'Stichting Metakids', Utrecht, The Netherlands (website www.

B.C. Children's Hospital Foundation (1st 'Collaborative Area of Innovation'), Vancouver, Canada

Rare Diseases Foundation, Vancouver, Canada


We gratefully acknowledge the following individuals for their significant contributions: Mr. Arnold G. Leenders (clinical librarian, Academic Medical Centre, Amsterdam, The Netherlands) for his expert design and implementation of literature search strategies in Pubmed and other online resources; Mr. Roderick Houben (health and IT consultant at www. for the design and creation of our digital tools (; Mrs. Mirafe Lafek (MD-research coordinator in our division of at B.C. Children's Hospital) for retrieval and organisation of data and journal articles; Mrs. Marlee McGuire (student medical

anthropology) and Mrs. Ruth Giesbrecht (secretary in our division at B.C. Children's Hospital) for her administrative support.

Appendix A. Suplementary data

Supplementary data to this article can be found online at doi:10. 1016/j.ymgme.2011.11.191.


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