Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 https://doi.org/10.1186/s13023-021-01727-2

REVIEW Open Access Treatable inherited metabolic disorders causing intellectual disability: 2021 review and digital app Eva M. M. Hoytema van Konijnenburg1†, Saskia B. Wortmann2,3,4†, Marina J. Koelewijn2, Laura A. Tseng1,4, Roderick Houben6, Sylvia Stöckler‑Ipsiroglu5, Carlos R. Ferreira7 and Clara D. M. van Karnebeek1,2,4,8*

Abstract Background: The Treatable ID App was created in 2012 as digital tool to improve early recognition and intervention for treatable inherited metabolic disorders (IMDs) presenting with global developmental delay and intellectual disabil‑ ity (collectively ‘treatable IDs’). Our aim is to update the 2012 review on treatable IDs and App to capture the advances made in the identifcation of new IMDs along with increased pathophysiological insights catalyzing therapeutic development and implementation. Methods: Two independent reviewers queried PubMed, OMIM and Orphanet databases to reassess all previously included disorders and therapies and to identify all reports on Treatable IDs published between 2012 and 2021. These were included if listed in the International Classifcation of IMDs (ICIMD) and presenting with ID as a major feature, and if published evidence for a therapeutic intervention improving ID primary and/or secondary outcomes is avail‑ able. Data on clinical symptoms, diagnostic testing, treatment strategies, efects on outcomes, and evidence levels were extracted and evaluated by the reviewers and external experts. The generated knowledge was translated into a diagnostic algorithm and updated version of the App with novel features. Results: Our review identifed 116 treatable IDs (139 genes), of which 44 newly identifed, belonging to 17 ICIMD categories. The most frequent therapeutic interventions were nutritional, pharmacological and vitamin and trace ele‑ ment supplementation. Evidence level varied from 1 to 3 (trials, cohort studies, case–control studies) for 19% and 4–5 (case-report, expert opinion) for 81% of treatments. Reported efects included improvement of clinical deterioration in 62%, neurological manifestations in 47% and development in 37%. Conclusion: The number of treatable IDs identifed by our literature review increased by more than one-third in eight years. Although there has been much attention to gene-based and enzyme replacement therapy, the major‑ ity of efective treatments are nutritional, which are relatively afordable, widely available and (often) surprisingly efective. We present a diagnostic algorithm (adjustable to local resources and expertise) and the updated App to facilitate a swift and accurate workup, prioritizing treatable IDs. Our digital tool is freely available as Native and Web App (www.treatable-id.org) with several novel features. Our Treatable ID endeavor contributes to the Treatabolome

*Correspondence: [email protected] †Eva M. M. Hoytema van Konijnenburg and Saskia B. Wortmann have contributed equally to this work 1 Department of Pediatrics, Amsterdam UMC, Amsterdam, The Netherlands Full list of author information is available at the end of the article

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and International Rare Diseases Research Consortium goals, enabling clinicians to deliver rapid evidence-based inter‑ ventions to our rare disease patients. Keywords: Inborn error of metabolism, Metabolic disorders, Management, Therapy, Epilepsy, Intellectual developmental disorders, Diet, Pharmacological, Nutraceutical, Diagnostic, Outcomes, Evidence

Background Table 1 A and B Defnitions and search terms

Te past decade has seen revolutionary changes in the A. Defnitions used in literature review diagnosis and discovery of inherited metabolic disor- Global developmental delay (DD): applied to age < 5 years; signifcant ders (IMDs), as well as development of new treatments delay ( performance two standard deviations or more below the = [1]. Trials with small patient numbers remain challeng- mean on age-appropriate, standardised norm-referenced testing) in two or more developmental domains including gross/fne motor skills, ing, but new methods for trial design, e.g., using natural speech/language, cognition, social/personal, activities of daily living history data as controls and crossover n-of-1 designs, [53] have advanced our ability to determine whether treat- Intellectual disability (ID): applied to age 5 years and manifesting before age 18 years, historically referred to as ‘mental≥ retardation’; intellectual ments are efective or not [2]. What have these advances functioning level (IQ) less than 70 to 75 and signifcant limitations in meant over the past decade for the treatment options of two or more adaptive skills [54, 55] global developmental delay (DD according to the defni- Inherited Metabolic Disorder (IMD): impairment of specifc enzymes or biochemical pathways that is intrinsic to the pathomechanism. The tion in Table 1A) and intellectual disability (ID), which presence of an abnormal metabolite is no longer a prerequisite [6]. This is characterized by limitations starting before the age of term excludes endocrine disorders such as hypothyroidism 18 years in both intellectual functioning (IQ less than Causal of ID/DD: sufcient evidence in literature from bench and/or clini‑ cal research to make a pathophysiological relationship between IMD 70) and adaptive behavior. Our systematic literature and ID/DD highly likely review changed paradigms for this previously consid- Treatable ID: if a particular therapeutic modality is capable of preventing ered untreatable condition afecting 1–3% of the world’s or improving ID/DD phenotype, or halting/slowing neurocognitive decline (with acceptable adverse efects) in the IMD, i.e., positively population with substantial comorbidity, high lifetime infuencing the ‘outcome measures’ costs, and emotional burden by identifying 81 treatable Treatment strategies: IDs in 2012, which increased to 89 in 2014 [3, 4]. With Nutritional therapy, vitamin & trace element, enzyme replacement therapy, hematopoietic stem cell transplant, solid organ transplan‑ our review, we aimed to increase awareness and avoid tation, pharmacological therapy, gene-based therapy, other (e.g., the diagnostic and treatment delays so often sufered by hemodialysis) rare diseases patients, with 25% of patients waiting 5 to Outcome measure/efect: A improves psychomotor/cognitive develop‑ ment/IQ, B improves behavioural/psychiatric= disturbance(s), C pre‑ 30 years for a diagnosis alone [5]. Now once again we vents acute= metabolic decompensation, D prevents, halts, or slows= address this medical gap and present an updated list of clinical deterioration, E improves neurological= manifestations (incl. = all Treatable IDs, which we defne as IMDs which present neuro-imaging), F improves seizure/epilepsy control, G improves systemic manifestations= = with global developmental delay (DD) or ID yet are ame- Levels of evidence: Level of evidence: Level 1a systematic review nable to interventions targeting pathophysiology (e.g., of RCT’s, 1b individual RCT, 1c ‘All or None’= [ (prolongation of) = = = nutraceutical, pharmacological, surgical, etc.) if initiated survival with therapy]; Level 2a systematic review of cohort studies, 2b individual cohort study, 2c= ‘Outcomes Research’ [focused on in a timely fashion. end= results of therapy for chronic= conditions, including functioning Tere are several developments that should be con- and quality of life]; Level 3 systematic review of case– control studies; = sidered to place the current overview of Treatable IDs in Level 4 individual case–control study or case-series/report; Level 5 expert= opinion without critical appraisal; based on physiology, perspective. First, the new all-inclusive defnition of an bench= research or frst principles. If only one patient was reported, we IMD, proposed in 2015 by Morava et al. [6] and recently assigned level ‘4–5′ as a way to nuance the treatment efects endorsed by the international metabolic community in B. Terms used for search strategy in PubMed [56] the International Classifcation of Inherited Metabolic Developmental delay/intellectual disability: mental retardation, learning Disorders (ICIMD): ‘Any condition in which the impair- disorder(s), developmental disability/ disabilities, learning disability/ disabilities, intellectual disability/disabilities, developmental delay, intel‑ ment of a biochemical pathway is intrinsic to the patho- ligence/classifcation, mentally disabled (persons), childhood/juvenile physiology of the disease, regardless of whether there are Alzheimer’s, childhood/juvenile dementia, neurodegenerative disease abnormalities in currently available biochemical labo- Inherited Metabolic Disorder: metabolic disease(s), inborn error(s) of metabolism, metabolic disorder(s), metabolic condition(s), inherited ratory tests’(http://​www.​icimd.​org) [7]. Te number of metabolic disease(s), inherited metabolic disorder(s), biochemical IMDs now exceeds 1400 [8]. Second, the practice change disease(s) our diagnostic algorithm has inspired, with international Treatment: treatment, management, therapy, cure, trial, (dietary) sup‑ plement, (dietary) restriction, diet, substrate inhibition, small molecule professional societies now prioritizing IMDs in the diag- substrate reduction, enzyme replacement, vitamin(s), co-factor(s), bone nostic evaluation of patients with ID in whom the cause marrow transplant, hematopoietic stem cell transplant, umbilical cord blood transplant( ation), gene therapy is not evident after a thorough clinical exam [9–11] Te − Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 Page 3 of 35

digital tool ‘Treatable ID’ has certainly given this innova- comprising rare disease treatments at gene and variant tion a boost [12] as its digital accessibility proved useful levels was recently outlined [20]. Here, we contribute to both for educational as well as practical purposes (e.g., this goal by presenting an updated state-of the-art over- Continuum Child Neurology [13]), especially in remote view of all treatable IDs along with a new version of the areas where metabolic expertise might not be available digital App freely accessible to professionals as well as onsite. Te Treatable ID App was created in 2012, and is patients, and suggest an updated diagnostic algorithm. freely accessible as a Web App via http://​www.​treat​able-​ id.​org and since 2016 as a Native App via the App Store/ Material and methods Google Play. Te App is designed for a target audience of Our main goals were: (1) to identify all IMDs presenting various specialists evaluating children presenting with ID, with DD and/or ID (collectively termed ID in this paper) both clinicians and laboratory scientists from student to as a major feature, which are amenable to treatment tar- expert level [12]. Te Treatable ID App has a steady audi- geting pathophysiology, supported by evidence in the lit- ence. Over the past 8 years there have been over 75,000 erature reported up to January 2021, and (2) to translate diferent users for the web App and over 10,000 down- this information into an updated version of the Treatable loads of the native App. Te Treatable ID App is also part ID digital App, as well as (3) a diagnostic algorithm to of the Treatable Intellectual Disability Endeavor (TIDE) facilitate early detection of treatable IMD in patients pre- diagnostic protocol [14]. In the second tier of the TIDE senting with unexplained ID. algorithm, the Treatable ID App is incorporated to opti- mize selection of targeted metabolic workup [14]. Also, Literature review numerous clinical and commercial labs have requested For our literature review, we used a critical rather than access to the Treatable ID gene lists for their quick turna- a formal systematic literature review approach to answer round phenotype-driven (virtual) gene panels. Tird, as the above stated question. We followed the Treatabolome shown in a retrospective study by Sayson et al., using approach as much as possible [20]. Te systematic lit- the Treatable ID algorithm can reduce costs and diag- erature review in 2012 and its update in 2014 were used nostic delay for treatable IMDs underlying ID [15]. Te as a basis. Tree independent reviewers (EH, CvK, SW) same was shown in a prospective way, in our TIDE study searched and critically appraised the literature, charac- which implemented the Treatable ID algorithm in 498 terized the clinical and diagnostic recognition patterns unexplained ID patients referred to a tertiary care centre as well as treatment modalities pertinent to the identi- (biochemical and clinical genetics as well as neurology fed IMDs, and assessed the level of available evidence departments) as add-on to clinical practice parameters and efect of the various treatments on clinical outcome at the time (2015). Indeed, this manuscript currently measures. Te reviewers engaged in regular consensus under review illustrates the presence of IMDs (6%) in this meetings, and fnal decisions on any disagreements were group of patients, even those without a classical multi- reached by a majority vote of the reviewers plus an exter- organ or degenerative phenotype (van Karnebeek et al. nal expert (CRF). submitted) [16]. Te fourth development is the remark- ably large number of clinical trials with great promise, Identifcation of treatable IMDs causing ID even pioneering gene-based therapy targeting the central Literature search nervous system, few of which however have made it to Defnitions of terms relevant for the search strategy the real-world of reimbursed clinical care, and as such and keywords for terms DD, ID, IMD, and treatment are not included here. Finally, despite the advances, the are shown in Table 1A and B. We searched PubMed, inequality in access to exome sequencing (ES) and other restricted to English language and publication in peer- -omics technologies remains. Indeed, access determines reviewed journals (http://​www.​ncbi.​nlm.​nih.​gov/​pub- the diagnostic approach; while for some countries and med; 1960–January 2021) in a two-step approach. First, regions, metabolic testing is still the frst tier, for others the 89 IMDs included in the 2012 and 2014 database were the exome-frst approach has become standard of care reassessed under consideration of the additional litera- [17]. Tus, algorithms must be tailored to local possi- ture published; second, new treatable IDs were identifed bilities and expertise. Speed and accuracy are warranted and reviewed. Additionally, the reference lists of identi- as ‘time is brain’, i.e., early identifcation and interven- fed articles, Orphanet [21] and Online Mendelian Inher- tion before irreversible damage is done [18]. Increas- itance in Man (OMIM) [22] were queried with the same ingly, therapy is center stage; even in the interpretation of search terms, and experts in the feld were approached to genomic variants, response to therapy has been endorsed identify new treatable IDs. To ensure comprehensiveness as a valuable criterion to determine pathogenicity [19]. of treatment modalities, we identifed all relevant refer- Te ultimate goal of creating a Treatabolome database ences reporting outcome/efect for each of the selected Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 Page 4 of 35

treatments and IMDs. We searched bibliographies of and treatment efect (see Table 1A). Names and groups of included articles as well as PubMed (1960–January 2021) disorders were based on the most recent ICIMD [7]. Dis- combining as keywords all known names for each IMD orders caused by pathogenic variants in multiple genes (including gene and enzyme) with the relevant therapeu- were reported as separate entries if there were meaning- tic modalities (Table 1B). ful diferences in phenotype or treatment. For practical and user-friendliness purposes, if there were no mean- Outcomes and levels of evidence ingful diferences, genes were grouped or ‘lumped’ and Te ideal outcome of therapy for a treatable ID is the considered as one IMD. improvement of IQ and related developmental scores. As improvement of co-morbid features such as epilepsy, Compliance to the FAIR guidelines for scientifc data neurologic, behavioral or psychiatric problems is often a management and stewardship prerequisite for improved cognitive outcomes, these were We adhered as much as possible to the FAIR-compliant included as ‘secondary outcomes’. Levels of evidence were (fndable, accessible, interoperable, reusable) template defned and applied according to Table 1A. that will ultimately enable the building of a ‘Treatabo- lome’ database [20, 23]. We complied with the recom- Efect(s) of treatments on outcome measures mendations for a broad and inclusive literature search Efect(s) of treatment outcomes were defned as shown and the main elements of data extraction and data syn- in Table 1A. We included treatments if they had a direct thesis. Te main deviation from the FAIR-compliant efect on ID (improvement or stabilization), or if there template in our review is that, due to the multitude of was a reasonable expectation that ID would be improved included IMDs, we did not perform a formal system- by signifcant improvement of other symptoms—such atic review for each IMD. Furthermore, there are a few as seizures or severe movement disorders—thus making specifc deviations from the template: we used OMIM development possible. Supportive treatments and treat- gene/locus instead of phenotype OMIM numbers as we ments with improvement only of systemic symptoms that considered this approach more precise for the current were not reasonably related to ID were not included. If review, and we did not specify all (contra)indications a treatment was not efective for all reported patients, and marketing authorizations for each treatment due to we defned that at least a third of the patients needed to of the multitude of included IMDs; this was outside the show improvement to ensure inclusion of potential ben- scope of this review. efcial treatments. All decisions on inclusion and exclu- sion of IMDs and treatments were mutually agreed upon Diagnostic tests and algorithm during a fnal consensus meeting. In the previous review, We used our literature review results to update our diag- a classifcation about standard of care versus individual nosed algorithm proposed in 2014. During the past years, basis was assigned to each treatment; given the growing ES has become accepted as frst line tier testing in many attention to personalized medicine in IMD, we do not countries around the world. However, metabolic screen- feel this distinction appropriate for our current review. ing is still applied given the specifcity and sensitivity of tests, the short turnaround times and relative aford- Inclusion/exclusion criteria ability and availability [24]. Metabolic profles can also We included IMDs where ID was a major clinical feature serve as functional readout, and “deep metabolic phe- (present in more than 50% of reported patients) and for notyping” can help in the interpretation of genetic data. which evidence supported amenability to the defned Terefore, we included both strategies in our algorithm treatments with a positive efect on outcomes in at least to facilitate a practical guide for biochemical and genetic/ one-third of patients. genomic diagnosis. We frst assessed which tests are nec- essary to identify each of the conditions. Accordingly, we Data extraction grouped the IMDs into those diagnosed via ‘metabolic For all IMDs meeting the criteria of a Treatable ID, the screening tests’ (1st Tier) versus IMDs diagnosed via ‘sin- following information was captured: gle test per single disease’ (2nd Tier) approach. First tier Name of disease; gene and inheritance pattern; name screening tests were defned as tests in blood and urine of biochemical defciency; group of disorder; screening which are readily available in biochemical laboratories and specifc tests; neurological and non-neurological in most developed countries. Metabolic tests in the 2nd symptoms (only characteristic, specifc and consistent tier group evaluate Treatable IDs for which biochemical symptoms were noted, see http://​www.​treat​able-​ID.​org); markers are difcult to interpret, and/or conventional treatment strategies (see Table 1A for categorization); diagnostic approach requires an invasive procedure or specifc therapies; level of evidence for each treatment poorly accessible test (i.e., only performed in few centres Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 Page 5 of 35

worldwide). Furthermore, we analyzed which IMDs myopathy, encephalopathy, lactic acidosis and stroke- have no (reliable) biomarker profle and require primary like episodes (MTTL1/MTTQ/MTTH/MTTK/MTTC/ molecular or (targeted) ES analysis. Tis approach with MTTS1/MTND1/MTND5/MTND6/MTTS2). diferent strategies and tiers was then translated into a We further ‘split’ two previously grouped (‘lumped’) step-wise algorithm. disorders into fve separate disease entities: 1) Coen- zyme Q5 methyltransferase defciency, 2) Coenzyme Treatable ID App design and development Q8A (ADCK3) defciency, 3) Methylmalonic aciduria and Te Treatable ID App was created in 2012 and later homocystinuria, cblD type, 4) Homocystinuria, cblDv1 updated based on the 2012 and 2014 literature reviews [3, type, 5) Methylmalonic aciduria, cblDv2 type. Tis led to 4]. In 2021, the Treatable ID App has been updated and a fnal list of 72 treatable IDs that were already included improved extensively both in content and design. Te in the 2014 database. Our literature search for “new” content is updated based on our 2021 literature search treatable IDs identifed 44 disorders, combining to a total with updated and increased links to useful resources for number of 116 treatable IDs included in this 2021 update each IMD. Te design has been adapted to 2021 stand- and shown in Table 2 (new disorders are marked with an ards with a quick and solid interface. Both the Web App *). and the Native App use the same database which is an improvement over the previous version. As a result, new Classifcation information can be added easily and this will ensure Included treatable IDs belonged to the following 17 the content is always up to date. Te database is built in ICIMD categories: vitamin and cofactor metabolism 29 Oracle. (25%), amino acid metabolism 28 (24%), complex mol- Te Web App can be used in all major browsers and the ecule degradation 10 (9%), neurotransmitters 9 (8%), Native app can be downloaded from the App Store and nucleobase, nucleotide and nucleic acid metabolism 7 Google Play. Te creation of the Treatable ID App is sup- (6%), disorders of glycosylation 6 (5%), energy substrate ported and funded by the ‘Metakids Foundation’ in Te metabolism 5 (4%), trace elements and metals 5 (4%), Netherlands [25]. fatty acid, carnitine, and ketone body metabolism 5 (4%), lipid metabolism 3 (3%), mitochondrial cofactor biosyn- Results thesis 2 (2%), other disorders of mitochondrial function Literature review 2 (2%), carbohydrate metabolism 1 (1%), peptide and Treatable IDs amine metabolism 1 (1%), endocrine metabolic disorders Our frst systematic review identifed 81 treatable IDs [3] 1 (1%), mtDNA-related disorders 1 (1%), and nuclear- and was updated with another 8 disorders in 2014 [4]. encoded disorders of oxidative phosphorylation 1 (1%). From these 89 disorders, our current literature search led to exclusion of 20 treatable IDs, because of insufcient Types of treatment and levels of evidence evidence for efect of treatment on established outcome Te diferent types of treatment as defned in Table 1A measures (n = 10), ID no longer considered a major clini- are shown per disorder in Table 3. Nutritional therapy cal feature (n = 8), metabolic defect not causative of ID was the most frequently used treatment strategy (32%), (n = 1) and duplicate disorder (n = 1). Te disorders are followed by pharmacological therapy 22%, vitamin and listed in Additional File 1: Table 1. trace element substitution 22%, solid organ transplanta- Of the 69 remaining treatable IDs we grouped the fol- tion 8%, hematopoietic stem cell transplant 4%, enzyme lowing IMDs according to the method described: (1) replacement therapy 3%, gene-based therapy 2% and Glycine encephalopathy due to aminomethyltransferase other therapy 7% (multiple treatments per disease entity (AMT) or glycine decarboxylase (GLDC) defciency; (2) were possible). Electron transfer favoprotein subunit alpha (ETFA)/sub- Te level of evidence for each treatment as defned unit beta (ETFB)/dehydrogenase defciency (ETFDH); 3) in Table 1A is shown in Table 3. Most often, case series Branched-chain ketoacid dehydrogenase E1 alpha (BCK- or case reports with an evidence level of 4 (60%), 4–5 DHA)/beta (BCKDHB)/E2 (DBT) defciency; (4) Propi- (12%) and 5 (8%) were reported; higher evidence levels onic acidemia due to propionyl-CoA carboxylase subunit accounted for a minority (level 1 for 4%, level 2 for 14%, alpha (PCCA​)/beta (PCCB) defciency; (5) Niemann-Pick level 3 for 0.5%) (Table 3). disease type C1 (NPC1)/C2 (NPC2); (6) Pyruvate dehy- drogenase E1 alpha (PDHA1)/beta (PDHB)/E2 (DLAT)/ E3 (DLD)/E3BP (PDHX) defciency; (7) ATP-sensitive Efect(s) of treatments on outcome measures potassium channel regulatory/pore-forming subu- Treatment prevented, halted, or slowed clinical dete- nit superactivity (ABCC8/KCNJ11); (8) Mitochondrial rioration in 62%, improved neurological manifestations Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 Page 6 of 35 ‑ eine glycan profling glycan glycan profling glycan glycan profling glycan Plasma acylcarnitinesPlasma acids Urine organic Urine organic acids Urine organic acylcarnitinesPlasma Molecular testing Plasma amino acids Plasma Plasma total homocyst total Plasma Plasma amino acids Plasma Plasma amino acids Plasma ammonia Plasma Plasma amino acids Plasma ammonia Plasma Plasma amino acids Plasma ammonia Plasma Molecular testing Molecular testing Molecular testing Serum- transferrin/N Serum- transferrin/N Serum- transferrin/N Diagnostic test Diagnostic 2639 23,474 1373 4548 10,165 445 435 383 84,720 93,183 – 5373 55,343 7355 HPO# 608,801 608,451 608,307 156,570 603,859 603,470 608,310 608,313 614,730 610,273 311,770 601,785 605,881 314,375 OMIM gene/locus# 25 51,188 147 2170 247,582 247,525 23 90 247,262 83,639 – 79,318 99,843 356,961 Orphanet# GCDH (AR) ETHE1 (AR) CPS1 (AR) MTR (AR) MTR SLC25A13 (AR) SLC25A13 ASS1 (AR) ASS1 ASL (AR) ASL ARG1 (AR) PIGO (AR) PIGM (AR) PIGA (X-linked) PMM2 (AR) SLC35C1-CDG (AR) SLC35C1-CDG SLC35A2 (X-linked) SLC35A2 Gene(s) ‑ CDG* CDG* CoA dehydro CoA CDG* CDG* CDG* CDG* - - genase defciency glutaric (synonym: aciduria type 1) dioxygenase defciencydioxygenase ‑ ethyl (synonym: malonic encephalopa ‑ thy) synthetase 1 defciency defciency (synonym: homocystinuria - megaloblastic anemia, cblG type) synthetase defciency citrullinemia (synonym: type 1) defciency (synonym: argininemia) (synonym: Glutaryl - Mitochondrial sulfur Carbamoyl phosphate phosphate Carbamoyl Methionine synthase Citrin defciency Argininosuccinate Argininosuccinate Argininosuccinate lyase Argininosuccinate Arginase defciencyArginase PIGO PIGM PIGA - - PMM2 - SLC35C1 - SLC35A2 Name of disorder Overview tests and diagnostic of 116 treatableIDs metabolism metabolism metabolism metabolism metabolism metabolism metabolism metabolism glycosylation glycosylation glycosylation glycosylation glycosylation glycosylation Disorders of amino acid Disorders Disorders of amino acid Disorders Disorders of amino acid Disorders Disorders of amino acid Disorders Disorders of amino acid Disorders Disorders of amino acid Disorders Disorders of amino acid Disorders Disorders of amino acid Disorders 2 Table Congenital disorders of disorders Congenital Congenital disorders of disorders Congenital Congenital disorders of disorders Congenital Congenital disorders of disorders Congenital Congenital disorders of disorders Congenital Congenital disorders of disorders Congenital Group of disorder Group Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 Page 7 of 35 ‑ eine Plasma amino acids Plasma Plasma amino acids Plasma acids Urine organic Plasma acylcarnitinesPlasma acids Urine organic Blood lactate ammonia Plasma Plasma amino acids Plasma Plasma amino acids Plasma CSF amino acids Plasma amino acids Plasma ammonia Plasma Plasma acylcarnitinesPlasma acids Urine organic Urine organic acids Urine organic homocyst total Plasma Plasma amino acids Plasma ammonia Plasma Diagnostic test Diagnostic ‑ DHB), 1629 (DBT) 5053 5009 4594 593 (BCKDHA), 594 (BCK 275 (AMT), 2731 (GLDC) 162,417 3712 875 10,116 HPO# 248,611 (BCKDHB), 248,610 (DBT) (GLDC) 612,349 300,461 609,058 608,348 (BCKDHA), 238,310 (AMT), 238,300 608,300 607,036 613,381 603,861 OMIM gene/locus# 268,184 79,254 664 289,916, 79,312 268,145, 268,162, 407 927 33 394 415 Orphanet# / GLDC (AR) PAH (AR) PAH OTC (X-linked) OTC MMUT (AR) BCKDHB/ DBT (AR) BCKDHA / BCKDHB/ DBT AMT NAGS (AR) NAGS IVD (AR) CBS (AR) SLC25A15 (AR) SLC25A15 Gene(s) ‑ ‑ ‑ chain ketoacid ‑ dehy CoA lase defciency (syno phenylketonuria) nym: ase defciency - methylmalonyl due to mutase defciencyCoA dehydrogenase E1 dehydrogenase alpha (BCKDHA)/beta (BCKDHB)/E2 (DBT) defciency (synonym: maple syrup urine disease type 1a (BCK DHA)/2 (DBT);‑ Dihy transacylasedrolipoyl defciency (DBT)) ‑ aminomethyl due to (AMT)transferase or decarboxylaseglycine (GLDC) defciency nonketotic (synonym: hyperglycinemia) thase defciency drogenase defciencydrogenase isovaleric (synonym: acidemia) synthase defciency classic (synonym: homocystinuria) transporter defciency ‑ hyperornith (synonym: inemia - hyperammone mia - homocitrullinuria syndrome) ‑ hydroxy Phenylalanine Ornithine‑ transcarbamyl Methylmalonic aciduriaMethylmalonic Branched - Glycine encephalopathy encephalopathy Glycine N - acetylglutamate syn ‑ Isovaleryl - Cystathionine beta - Cystathionine Mitochondrial ornithine Name of disorder (continued) metabolism metabolism metabolism metabolism metabolism metabolism metabolism metabolism metabolism Disorders of amino acid Disorders Disorders of amino acid Disorders Disorders of amino acid Disorders Disorders of amino acid Disorders Disorders of amino acid Disorders Disorders of amino acid Disorders Disorders of amino acid Disorders Disorders of amino acid Disorders Disorders of amino acid Disorders 2 Table of disorder Group Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 Page 8 of 35 ‑ glucose ratio) eine CSF other (CSF:blood CSF other (CSF:blood Plasma amino acids Plasma CSF amino acids Plasma amino acids Plasma homocyst total Plasma Urine organic acids Urine organic Molecular testing Urine organic acids Urine organic Molecular testing Plasma amino acids Plasma ammonia Plasma blood lactate molecular testing Plasma amino acids Plasma Plasma amino acids Plasma acids Urine organic Plasma amino acids Plasma CSF amino acids Plasma acylcarnitinesPlasma acids Urine organic Blood lactate ammonia Plasma Plasma amino acids Plasma CSF amino acids Plasma amino acids Plasma CSF amino acids Diagnostic test Diagnostic (PCCB) 6513 2752 191 1892 26,275 763 10,295 6898 5723 5095 (PCAA), 5096 29,968 26,227 HPO# (PCCB) 138,140 610,015 613,752 616,277 250,620 114,761 614,901 613,018 172,480 232,000 (PCCA), 232,050 232,000 (PCCA), 610,936 606,879 OMIM gene/locus# 71,277 71,278 88,618 255,241 88,639 401,948 308,410 28,378 79,350 35 284,417 79,351 Orphanet# PCCB (AR) / PCCB SLC2A1 (AD) SLC2A1 GLUL (AR) GLUL AHCY (AR) ECHS1 (AR) HIBCH (AR) CA5A (AR) BCKDK (AR) TAT (AR) TAT PSPH (AR) ​ PCCA PSAT1 (AR) PSAT1 PHGDH (AR) Gene(s) ‑ ‑ CoA CoA CoA CoA - CoA car CoA CoA CoA - Hanhart chain ketoacid defciency* hydrolase defciency* hydrolase - chain enoyl 1 defciency*hydratase hydrolase defciency hydrolase beta - (synonym: hydroxyisobutyryl - deacylase defciency)* defciency dehydrogenase kinase dehydrogenase defciency* ferase defciencyferase (syno type tyrosinemia nyms: 2; Richner syndrome) phatase defciency - propionyl to boxylase subunit alpha (PCCB) (PCCA)/beta defciency aminotransferase aminotransferase defciency dehydrogenase def ‑ dehydrogenase ciency GLUT1 defciency GLUT1 Glutamine synthetase S - adenosylhomocysteine Mitochondrial short 3 - hydroxyisobutyryl - Carbonic anhydrase VA Carbonic VA anhydrase Branched - Tyrosine aminotrans ‑ Tyrosine Phosphoserine phos ‑ Phosphoserine Propionic acidemia due Propionic Phosphoserine Phosphoserine phosphoglycerate 3 - phosphoglycerate Name of disorder (continued) drate metabolism drate metabolism metabolism metabolism metabolism metabolism metabolism metabolism metabolism metabolism metabolism metabolism ‑ of carbohy Disorders Disorders of amino acid Disorders Disorders of amino acid Disorders Disorders of amino acid Disorders 2 Table Disorders of amino acid Disorders Disorders of amino acid Disorders Disorders of amino acid Disorders Disorders of amino acid Disorders Disorders of amino acid Disorders Disorders of amino acid Disorders Disorders of amino acid Disorders Disorders of amino acid Disorders Group of disorder Group Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 Page 9 of 35 ‑ (lactate:pyruvate ratio) (lactate:pyruvate ratio) lactate:pyruvate noacetate noacetate guanidinoacetate cans** tidyl - peptidase 1) cans** fatase A) cans** cans** CSF other other (blood Urine creatine & guanidi ‑ Urine creatine Urine creatine & guanidi ‑ Urine creatine (Plasma/) urine creatine & urine creatine (Plasma/) Molecular testing ‑ Urine glycosaminogly Enzymatic (Tripep testing ‑ Urine glycosaminogly - )sterols (oxy Plasma Enzymatic (Arylsul testing ‑ ‑ Urine glycosaminogly ‑ Urine glycosaminogly Urine oligosaccharides** Urine oligosaccharides** Diagnostic test Diagnostic (PDHB), 1737 (DLAT), 1738 (DLD), 8050 (PDHX) (NPC2) 5160 (PDHA1), 5162 2593 6535 2628 256,471 2517 1200 2990 4864 (NPC1), 10,577 410 3425 3423 175 4125 HPO# 179,060 (PDHB), 608,770 (DLAT), 238,331 (DLD), 608,769 (PDHX) (NPC2) 300,502 (PDHA1), 601,240 300,036 602,360 611,124 230,000 607,998 611,499 607,623 (NPC1), 601,015 607,574 252,800 300,823 613,228 609,458 OMIM gene/locus# (PDHB), 79,244 (DLAT), 2394 (DLD), 255,182 (PDHX) 309,271 79,243 (PDHA1), 255,138 382 52,503 35,704 228,366 349 228,349 584 646 309,256, 309,263, 93,473 217,085 93 309,282, 309,288 Orphanet# / DLD PDHX / PDHB DLAT(X-linked) (AR) PDHA1 GAMT (AR) SLC6A8 (X-linked) SLC6A8 GATM (AR) GATM MFSD8 (AR) FUCA1 (AR) TPP1 (AR) GUSB (AR) GUSB NPC1 / NPC2 (AR) ARSA (AR) IDUA (AR) IDUA IDS (X-linked) AGA (AR) AGA MAN2B1 (AR) Gene(s) glucuronidase glucuronidase E1 alpha (PDHA1)/beta (PDHB)/E2 (DLAT)/E3 (DLD)/E3BP (PDHX) defciency yltransferase defciencyyltransferase defciency notransferase (AGAT) (AGAT) notransferase defciency ciency* defciency (synonym: CLN2 disease)* defciency (synonym: Sly syndrome) type C1 (NPC1)/C2 (NPC2) ciency defciency (synonyms: Hurler syndrome Scheie syn ‑ [severe]; [attenuated]) drome defciency (synonym: syndrome) Hunter defciency defciency Pyruvate dehydrogenase dehydrogenase Pyruvate Guanidinoacetate meth ‑ Guanidinoacetate Creatine transporterCreatine Arginine:glycine amidi ‑ Arginine:glycine CLN7 disease* Alpha - fucosidase def ‑ - peptidase 1 Tripeptidyl Beta - Pick disease Niemann - Pick Arylsulfatase A def ‑ iduronidase Alpha - iduronidase Iduronate sulfatase Iduronate Aspartylglucosaminidase Alpha - mannosidase Name of disorder ‑ ‑ ‑ ‑ (continued) strate metabolism strate strate metabolism strate strate metabolism strate strate metabolism strate molecule degradation molecule degradation molecule degradation molecule degradation molecule degradation molecule degradation molecule degradation molecule degradation molecule degradation molecule degradation Disorders of energy sub of energy Disorders Disorders of energy sub of energy Disorders Disorders of energy sub of energy Disorders Disorders of energy sub of energy Disorders Disorders of complex Disorders Disorders of complex Disorders Disorders of complex Disorders Disorders of complex Disorders Disorders of complex Disorders Disorders of complex Disorders Disorders of complex Disorders Disorders of complex Disorders Disorders of complex Disorders Disorders of complex Disorders 2 Table of disorder Group Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 Page 10 of 35 cholestanol) fatty acids Molecular testing Molecular testing*** - )sterols (oxy Plasma Other (plasma Plasma veryPlasma long chain Plasma acylcarnitinesPlasma Urine organic acids Urine organic Urine organic acids Urine organic Plasma acylcarnitinesPlasma acids Urine organic Urine organic acids Urine organic Plasma amino acids Plasma acids Urine organic Diagnostic test Diagnostic 2110 (ETFDH) 56,997 84,274 1717 1593 215 55,217 3158 3115 2108 (ETFA), 2109 (ETFB), 2108 (ETFA), 38 54,704 HPO# (ETFB), 231,675 (ETFDH) 606,980 616,359 602,858 606,530 300,371 300,777 600,234 613,898 608,053 (ETFA), 130,410 608,053 (ETFA), 607,809 605,993 OMIM gene/locus# 139,485 818 909 139,396, 139,396 35,701 20 26,791 134 79,246 Orphanet# COQ8A (AR) COQ8A COQ5 (AR) COQ5 DHCR7 (AR) CYP27A1 (AR) CYP27A1 ABCD1 (X-linked) TMLHE (X-linked) HMGCS2 (AR) HMGCL (AR) / ETFB ETFDH (AR) ETFA ACAT1 (AR) ACAT1 PDP1 (AR) Gene(s) ‑ ‑ ‑ CoA CoA CoA lyase CoA CoA thiolase CoA CoA dehydroge CoA dehydrocholesterol dehydrocholesterol defciency transferase defciencytransferase reductase defciency defciency (synonym: cerebrotendinous xanthomatosis) ystrophy hydroxylase def ‑ hydroxylase ciency* 3 - methylglutaryl - synthase defciency glutaryl - defciency favoprotein subunit favoprotein alpha (ETFA)/subunit beta (ETFB)/dehydro genase defciency (ETFDH) (synonym: glutaric acidemia type 2A/2B/2C; multiple acyl - nase defciency type 2A/2B/2C) cetyl - defciency nase phosphatase defciency* - linked‑ adrenoleukod Coenzyme Q8A (ADCK3) Coenzyme‑ Q5 methyl 7 - hydroxylase 27 - hydroxylase Sterol X trimethyllysine Epsilon - N trimethyllysine - Mitochondrial 3 - hydroxy ‑ - 3 methyl 3 - hydroxy Electron transfer transfer Electron Mitochondrial‑ acetoa Pyruvate dehydroge Pyruvate Name of disorder ‑ ‑ ‑ (continued) chondrial cofactor biosynthesis chondrial cofactor biosynthesis metabolism metabolism metabolism carnitine, and ketonecarnitine, body metabolism carnitine, and ketonecarnitine, body metabolism carnitine, and ketonecarnitine, body metabolism carnitine, and ketonecarnitine, body metabolism carnitine, and ketonecarnitine, body metabolism strate metabolism strate Disorders of mito Disorders Disorders of mito Disorders Disorders of lipid Disorders 2 Table Disorders of lipid Disorders Disorders of lipid Disorders Disorders of fatty acid, of fatty acid, Disorders Disorders of fatty acid, of fatty acid, Disorders Disorders of fatty acid, of fatty acid, Disorders Disorders of fatty acid, of fatty acid, Disorders Disorders of fatty acid, of fatty acid, Disorders Disorders of energy sub of energy Disorders Group of disorder Group Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 Page 11 of 35 ‑ sialotransferrins, manga ‑ sialotransferrins, CSF lactate) nese, eine dines Other (serum zinc, Copper & ceruloplasmin Copper copper & Ceruloplasmin Copper & ceruloplasmin Copper Plasma total homocyst total Plasma Molecular testing Urine purines & pyrimi ‑ Molecular testing Molecular testing Molecular testing Molecular testing Molecular testing Diagnostic test Diagnostic 64,116 540 538 1356 4780 790 5631 4141 6301 10,056 51,520 3376 HPO# 608,732 606,882 300,011 117,700 600,492 114,010 311,850 156,560 607,529 609,690 151,350 600,709 OMIM gene/locus# 440,427 468,699 905 565 48,818 448,010 1187 397,735, 401,835, 88,616 178,506 370,088 541,423 Orphanet# SLC39A8 (AR) SLC39A8 ATP7B (AR) ATP7B ATP7A (AR) ATP7A CP (AR) NFE2L2 (AD) CAD (AR) PRPS1 (X-linked) MARS1 (AR) SARS1 (AR) FARSB (AR) FARSB LARS1 (AR) IARS1 (AR) Gene(s) ‑ ‑ - transporting - transporting ATPase subunit beta ATPase defciency (synonym: disease) Wilson ATPase subunit alpha ATPase defciency (synonyms: Menkes disease occipital horn [severe]; [milder]) syndrome defciency nym: immunodef ‑ nym: developmental ciency, and hypohomo delay, cysteinemia)* defciency* osphate synthetase osphate defciency* thetase 1 defciency* defciency* thetase subunit beta defciency* 1 defciency* thetase 1 defciency* SLC39A8 defciency* SLC39A8 Copper Copper Hereditary ceruloplasmin NRF2 superactivity (syno CAD trifunctional protein ‑ Phosphoribosylpyroph - tRNA syn ‑ Methionyl Seryl - tRNA synthetase 1 - tRNA syn ‑ Phenylalanyl Leucyl - tRNA synthetase Isoleucyl - tRNA syn ‑ Name of disorder ‑ ‑ ‑ ‑ (continued) ments and metals ments and metals ments and metals ments and metals amine metabolism nucleotide and nucleic acid metabolism nucleotide and nucleic acid metabolism nucleotide and nucleic acid metabolism nucleotide and nucleic acid metabolism nucleotide and nucleic acid metabolism nucleotide and nucleic acid metabolism nucleotide and nucleic acid metabolism Disorders of trace ele Disorders Disorders of trace ele Disorders Disorders of trace ele Disorders Disorders of trace ele Disorders Disorders of peptide and Disorders Disorders of nucleobase, of nucleobase, Disorders Disorders of nucleobase, of nucleobase, Disorders Disorders of nucleobase, of nucleobase, Disorders Disorders of nucleobase, of nucleobase, Disorders Disorders of nucleobase, of nucleobase, Disorders Disorders of nucleobase, of nucleobase, Disorders Disorders of nucleobase, of nucleobase, Disorders 2 Table of disorder Group Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 Page 12 of 35 ‑ ‑ ‑ ‑ ‑ ‑ eine eine eine eine eine eine drofolate) nidase) Urine organic acids Urine organic homocyst total Plasma Urine organic acids Urine organic homocyst total Plasma Plasma total homocyst total Plasma Urine organic acids Urine organic Plasma total homocyst total Plasma urine organic acids urine organic homocyst total Plasma Urine organic acids Urine organic homocyst total Plasma Urine organic acids Urine organic Urine organic acids Urine organic ‑ CSF other (methyltetrahy Enzymatic (Bioti ‑ testing Molecular testing Copper & ceruloplasmin Copper Molecular testing Diagnostic test Diagnostic 5826 55,788 4552 27,249 27,249 27,249 25,974 326,625 166,785 2348 686 80,704 1174 HPO# 603,214 612,625 603,568 611,935 611,935 611,935 609,831 607,568 607,481 136,430 609,019 606,152 609,313 OMIM gene/locus# 369,955 79,284 2169 308,442 308,380 79,283 79,282 79,311 79,310 217,382 79,241 65,284, 199,348 171,851 Orphanet# ABCD4 (AR) LMBRD1 (AR) MTRR (AR) MTRR MMADHC (AR) MMADHC (AR) MMADHC (AR) MMACHC (AR) MMACHC MMAB (AR) MMAA (AR) MMAA FOLR1 (AR) BTD (AR) BTD SLC19A3 (AR) SLC19A3 AP1S1 (AR) Gene(s) ‑ - and homocystinuria, cblJ type* and homocystinuria, cblF type reductase defciency homocyst(synonym: inuria - megaloblastic anemia, cblE type) cblDv2 type type and homocystinuria, cblD type and homocystinuria, cblC type cblB type cblA type defciency (synonym: neurodegeneration folate cerebral due to transport defciency) defciency (synonym: biotin - thiamine basal responsive ganglia disease) Methylmalonic aciduriaMethylmalonic Methylmalonic aciduriaMethylmalonic Methionine synthase Methylmalonic aciduria,Methylmalonic Homocystinuria, cblDv1 Methylmalonic aciduriaMethylmalonic Methylmalonic aciduriaMethylmalonic Methylmalonic aciduria,Methylmalonic Methylmalonic aciduria,Methylmalonic Folate receptor alpha receptor Folate Biotinidase defciency Thiamine transporterThiamine 2 MEDNIK syndrome Name of disorder ‑ (continued) cofactor metabolism cofactor metabolism cofactor metabolism cofactor metabolism cofactor metabolism cofactor metabolism cofactor metabolism cofactor metabolism cofactor metabolism cofactor metabolism cofactor metabolism cofactor metabolism ments and metals Disorders of vitamin and Disorders Disorders of vitamin and Disorders Disorders of vitamin and Disorders Disorders of vitamin and Disorders Disorders of vitamin and Disorders Disorders of vitamin and Disorders 2 Table Disorders of vitamin and Disorders Disorders of vitamin and Disorders Disorders of vitamin and Disorders Disorders of vitamin and Disorders Disorders of vitamin and Disorders Disorders of vitamin and Disorders Disorders of trace ele Disorders Group of disorder Group Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 Page 13 of 35 ‑ ‑ ‑ ‑ folate) folate & neopterin) folate test) alpha - aminoadipic semi ‑ aldehyde) test) eine dines (serum uric acid) eine, test) molecular testing CSF neurotransmitters CSF other (tetrahydro CSF neurotransmitters CSF other (tetrahydro CSF neurotransmitters Other (biopterin loading Other (plasma P6C, urine CSF neurotransmitters Other (biopterin loading Plasma amino acids Plasma homocyst total Plasma Urine purines & pyrimi ‑ Urine- sulfocyst sulftes/S Urine organic acids Urine organic CSF neurotransmitters CSF neurotransmitters Other (biopterin loading Diagnostic test Diagnostic 8884 1719 10,588 6697 501 5805 4524 4337 3141 2643 5860 HPO# 604,024 126,060 604,197 182,125 107,323 612,719 607,093 603,707 609,018 600,225 612,676 OMIM gene/locus# – 319,651 - 70,594 3006 13 395 308,386 79,242 2102 226 Orphanet# SLC5A6 (AR) SLC5A6 DHFR (AR) MTHFS (AR) MTHFS SPR (AR) ALDH7A1 (AR) PTS (AR) MTHFR (AR) MTHFR MOCS1 (AR) HLCS (AR) HLCS GCH1 (AR) QDPR (AR) Gene(s) ‑ - ‑ dependent mul ‑ tivitamin transporter defciency* defciency drofolate synthetase drofolate defciency (synonym: 5 - formyltetrahydro cycloligase folate defciency)* defciency ‑ dehy semialdehyde defciencydrogenase pyridoxine (synonym: dependent epilepsy) dropterin synthase dropterin defciency drofolate reductase reductase drofolate defciency monophosphate syn ‑ monophosphate thase defciency (syno molybdenum nym: cofactor defciency type A) thetase defciency GTP cyclohydrolase 1 GTP cyclohydrolase defciency tase defciency Sodium - Dihydrofolate reductase reductase Dihydrofolate ‑ 5,10 - methenyltetrahy Sepiapterin reductase Alpha - aminoadipic ‑ - tetrahy 6 - pyruvoyl ‑ 5,10 - methylenetetrahy Cyclic pyranopterin pyranopterin Cyclic Holocarboxylase syn ‑ Autosomal recessive recessive Autosomal ‑ reduc Dihydropteridine Name of disorder (continued) cofactor metabolism cofactor metabolism cofactor metabolism cofactor metabolism cofactor metabolism cofactor metabolism cofactor metabolism cofactor metabolism cofactor metabolism cofactor metabolism cofactor metabolism Disorders of vitamin and Disorders Disorders of vitamin and Disorders Disorders of vitamin and Disorders Disorders of vitamin and Disorders Disorders of vitamin and Disorders Disorders of vitamin and Disorders Disorders of vitamin and Disorders Disorders of vitamin and Disorders Disorders of vitamin and Disorders Disorders of vitamin and Disorders Disorders of vitamin and Disorders 2 Table of disorder Group Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 Page 14 of 35 ‑ lactate eine CSF neurotransmitters Urine organic acids Urine organic Molecular blood testing Molecular testing Serum/RBC folate CSF other (folate) CSF neurotransmitters Urine organic acids Urine organic homocyst total Plasma Molecular testing Molecular testing Blood lactate CSF neurotransmitters acids Urine organic Blood lactate CSF amino acids CSF other (vitamins) Molecular testing Diagnostic test Diagnostic - - TQ), TQ), - ND6), - CO1), 4513 CO1), TS1), 4578 TS1), - - - ND1), 4536 CO2), 4514 (MT CO2), - ND4), 4540 (MT - (MT ND5), 4541 (MT 4512 (MT (MT CO3), 4572 (MT CO3), 4574 (MT (MT - TW) 7054 7915 4535 (MT 6833 113,235 6948 60,386 128,240 27,010 55,163 HPO# CO3), CO3), CO2), CO2), CO1), CO1), TQ), TQ), TH), TL1), TF), TS1), TS2), TW) ------ND4), - ND5), - ND6), - - ND1), 590,030 (MT 590,040 (MT 590,050 (MT 590,070 (MT 590,080 (MT 590,085 (MT 590,095 (MT 516,050 (MT 516,040 (MT 516,003 (MT 516,005 (MT 516,006 (MT 516,030 (MT 191,290 610,045 516,000 (MT 600,509 229,050 275,350 606,521 608,862 614,458 603,287 OMIM gene/locus# 101,150 22 550 79,134 90,045 859 217,396 555,407 293,955 79,096 Orphanet# / MT- / MT-TF/ MT-TL1 MT-CO3/ / MT-CO3/ / MT-CPO2 MT-TW (Mt) / MT-TW / MT-TH TS1 / MT-TS2 ND6 / MT-CO1 MT-TQ TH (AR) ALDH5A1 (AR) / MT- / MT-ND5 / MT-ND4 MT-ND1 / AR) KCNJ11 (AD) (AD ABCC8 SLC46A1 (AR) SLC46A1 TCN2 (AR) TCN2 SLC25A19 (AR) SLC25A19 NAXE (AR) NAXE TPK1 (AR) PNPO (AR) Gene(s) ‑ - like coupled folate coupled folate forming subunit - forming sensitive potassium - sensitive defciency dehydrogenase def ‑ dehydrogenase ciency encephalopathy, lactic encephalopathy, acidosis and stroke episodes (MTTL1/ MTTQ/MTTH/MTTK/ MTTC/MTTS1/MTND1/ MTND5/MTND6/ MTTS2) channel regulatory/ pore superactivity* transporter defciency hereditary(synonym: malabsorption)* folate ciency* pyrophosphate trans ‑ pyrophosphate porter defciency* defciency* kinase defciency* phate oxidase def ‑ oxidase phate ciency* Tyrosine hydroxylase hydroxylase Tyrosine Succinic semialdehyde Succinic semialdehyde Mitochondrial myopathy, Mitochondrial myopathy, ATP - Proton Transcobalamin II def ‑ Transcobalamin Mitochondrial thiamine NAD(P)HX epimerase Thiamine pyrophospho Thiamine Pyridoxamine 5 ′ - phos ‑ Pyridoxamine Name of disorder (continued) disorders disorders disorders cofactor metabolism cofactor metabolism cofactor metabolism cofactor metabolism cofactor metabolism cofactor metabolism Neurotransmitter Neurotransmitter Neurotransmitter Neurotransmitter 2 Table related disorders mtDNA - related Endocrine metabolic Disorders of vitamin and Disorders Disorders of vitamin and Disorders Disorders of vitamin and Disorders Disorders of vitamin and Disorders Disorders of vitamin and Disorders Disorders of vitamin and Disorders Group of disorder Group Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 Page 15 of 35 = Human Phenotype . HPO Plasma amino acids Plasma ammonia Plasma Blood lactate Molecular testing other (muscle OXPHOS) Plasma amino acids Plasma CSF neurotransmitters Molecular testing Molecular testing Molecular testing Molecular testing CSF neurotransmitters CSF neurotransmitters Diagnostic test Diagnostic ® new treatable ID (not included in new treatable = cerebrospinal fuid. * fuid. cerebrospinal 2806 8604 28,976 56,521 2906 2904 2903 2902 1644 6571 HPO# Online Mendelian Inheritance in Man = mitochondrial. = mitochondrial. CSF = 138,150 612,949 611,126 617,384 602,717 138,252 138,253 138,249 107,930 193,001 OMIM gene/locus# - 353,217 99,901 508,523 442,835 - 289,266 - 35,708 352,649 Orphanet# autosomal recessive; X-linked (dominant); Mt (dominant); X-linked recessive; autosomal = consider white blood cells or muscle tissue CoQ10 analysis or muscle tissue CoQ10 blood cells white consider = autosomal dominant; AR dominant; autosomal = GOT2 (AR) GOT2 SLC25A12 (AR) SLC25A12 ACAD9 (AR) ACAD9 DNAJC12 (AR) GRIN2D (AD) GRIN2B (AD) GRIN2A (AD) GRIN1 (AD) DDC (AR) SLC18A2 (AR) SLC18A2 Gene(s) - - amino acid also identifed by targeted enzyme *** targeted by testing. also identifed aminotransferase aminotransferase defciency* glutamate carrierglutamate 1 defciencyisoform aralar def ‑ (synonym: ciency)* receptor NMDA type NMDA receptor subunit 2D superac ‑ tivity* receptor NMDA type NMDA receptor ‑ subunit 2B dysregula tion* receptor NMDA type NMDA receptor ‑ subunit 2A dysregula tion* receptor NMDA type NMDA receptor ‑ subunit 1 dysregula tion* decarboxylase def ‑ ciency* transporter 2 def ‑ ciency = Mitochondrial aspartate Mitochondrial aspartate ACAD9 defciency*ACAD9 DNAJC12 defciency* Ionotropic glutamate glutamate Ionotropic Ionotropic glutamate glutamate Ionotropic Ionotropic glutamate glutamate Ionotropic Ionotropic glutamate glutamate Ionotropic Aromatic L Aromatic Vesicular monoamine Vesicular Name of disorder ‑ ‑ (continued) encoded - chondrial function chondrial function disorders of oxidative of oxidative disorders phosphorylation disorders disorders disorders disorders disorders disorders disorders previous database/review). ** database/review). previous Other of mito disorders Other of mito disorders Nuclear Neurotransmitter Neurotransmitter Neurotransmitter Neurotransmitter Neurotransmitter Neurotransmitter Neurotransmitter Neurotransmitter Neurotransmitter Neurotransmitter Neurotransmitter Neurotransmitter Neurotransmitter Neurotransmitter 2 Table of disorder Group OMIM classifcation. on Inherited (ICIMD) Metabolic Disorders Conference International based on the most recent were of disorders Names and groups Ontology. Mode of inheritance for each gene is denoted as AD each gene is denoted Mode for of inheritance Ontology. Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 Page 16 of 35

(incl. neuro-imaging) in 47%, systemic manifestations in and solid interface. It is possible to search based on signs 44% and psychomotor/cognitive development/IQ in 37%; and symptoms for IMDs, the appropriate diagnostic tests it prevented acute metabolic decompensation in 30%, and gene lists and panel designs, available treatments and improved seizure/epilepsy control in 22% and improved evidence. Figure 2 illustrates the Treatable ID App fea- behavioural/psychiatric disturbance(s) in 21%. tures on mobile devices. Te App is available via the App Store, Google Play and online (http://​www.​treat​able-​id.​ org) freely downloadable for all interested users includ- Diagnostic algorithm ing but not limited to general practitioners, medical and Te diagnostic algorithm in Fig. 1 is proposed for the biochemical geneticists, neurologists, developmental and evaluation of a patient of any age presenting with DD or pediatricians, internists, metabolic diseases specialists, as ID in whom the cause is not apparent. It is based on the well as laboratory specialists and patients and families. following results: ­1st Tier or ‘basic’ metabolic screening (in blood: lactate, plasma ammonia, serum transferrin/N- Discussion glycan profling, serum/red blood cell folate, serum cop- Targeted therapies for treatable IDs: strengthening per and ceruloplasmin, plasma amino acids, plasma the Treatabolome total homocysteine, plasma (or dried bloodspot) acyl- Our systematic review from 2012 was the frst to pri- carnitines, very long chain fatty acids; in urine: organic oritize the treatability in the diagnostic evaluation of acids, creatine, guanidinoacetate, glycosaminoglycans patients with DD and ID in whom the cause was not and oligosaccharides) is available at most if not all diag- evident after a thorough clinical exam. As increasing nostic metabolic laboratories and can identify 69 (59%) numbers of patients are diagnosed through exome and of the 116 treatable IDs. Of course, further biochemical genome sequencing in clinical practice or within research and genetic confrmation is warranted, but for the sake projects, it becomes ever more crucial to enable fagging of prompt initiation of treatment, these frst-tier results of potentially treatable cases at a gene or variant level. yield sufcient diagnostic information. However, this knowledge was (and still is) largely avail- Importantly, for 23 of 116 IMDs (20%) no specifc bio- able only in ‘human-readable’ scientifc publications or marker is currently available and thus molecular testing in expert practice, and our website and app were the frst (targeted or via exome) is required (Fig. 1). to capture this knowledge in a computer-accessible form Lumbar puncture for cerebrospinal fuid (CSF) neu- that would allow automatic recognition and fagging in rotransmitter and amino-acid analysis is indicated in analysis and decision-support systems. Te implementa- patients with neonatal or infantile seizures of unknown tion of these web resources in national guidelines as well aetiology, dystonia or other movement disorders, pro- as treatment programs has successfully changed the clini- gressive intellectual neurological deterioration (85 IMDs, cal practice and inspired several reviews on other genetic 41% amenable to treatment [26]), severe psychiatric or diseases (e.g., neuromuscular disease [28], epilepsy [17] behavioral phenotypes, and/or clinical fndings sugges- or movement disorders [29]). Te fnal goal is a ‘treatabo- tive of dopamine defciency (hypersalivation, tempera- lome’ database accessible for all health care providers as ture dysregulation, oculogyric crises, or hypokinesia). well as patients. An abnormal profle has important diagnostic as well as therapeutic implications, such as neurotransmitter Diagnostics advances supplementation, e.g., in GTCPH defciency, or even in additional non-classic IMDs, e.g., in a PAK3 defciency Te feld of IMDs is a moving target with 44 newly- patient with severe automutilation and low CSF homo- defned IMDs included in our recent update, and still vanillic acid (HVA) [27]. the IMDs are the largest group of monogenic condi- tions underlying ID amenable to treatment. Te wide Treatable ID App implementation of NGS techniques has led to the iden- First, based on our 2021 literature search, the content tifcation of new IMDs and the better understanding of has been updated in the Treatable ID App, including the underlying pathophysiology has led to a substantial updated summaries, symptoms, diagnostic tests, treat- change in the defnition of IMDs (‘Any condition in which ments with levels of evidence and efects for each IMD. the impairment of a biochemical pathway is intrinsic to A disorder page has been designed of each IMD with the pathophysiology of the disease, regardless of whether links to Orphanet, OMIM, Human Phenotype Ontology there are abnormalities in currently available biochemi- (HPO), GeneReviews, GeneCards, IMDbase, Vademe- cal laboratory tests’). Tese changes led to an increas- cum Metabolicum and WikiPathways. Second, based on ing number of individuals being diagnosed with IMDs user feedback, the design has been updated with a quick for which no metabolic marker is available (e.g., CAD Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 Page 17 of 35 [ 70 , 71 ] [ 70 , 71 ] [ 68 , 69 ] [ 68 , 69 ] [ 67 ] [ 66 ] [ 66 ] [ 65 ] [ 63 , 64 ] [ 63 , 64 ] [ 62 ] [ 62 ] [ 62 ] [ 61 ] [ 61 ] [ 60 ] [ 59 ] [ 58 ] [ 57 ] ReferenceS D D, E A, D, G A, D, D, G D, E, G D, A, D, E, F A, D, A, D, E, F A, D, A, E G B D, E A, E, F A, B, E, F, G E, F, A, B, C, D, G C, D, C, D, G C, D, E D, E, F D, A, E, G C Efect of treatment 1c 4 to 5 4 to 2b 1c 4 4 4 4 4 1b 4 4 4 4 4 5 4 4 5 Level of evidence Level ‑ ‑ - factor ± ± reduced diet - reduced ± + carbidopa, 5 - Hydroxy ‑ tion tion hematopoietic stem cell transplan ‑ stem hematopoietic tation tryptophan, dihydro sapropterin chloride (synthetic BH4) co therapy balamin sick day management sick day dopa - - Serine, glycine Velmanase alfa Velmanase Hematopoietic stem cell transplanta ‑ stem Hematopoietic Intrathecal iduronidase Hematopoietic stem cell transplanta ‑ stem Hematopoietic (Umbilical cord/bone marrow) marrow) (Umbilical cord/bone Lysine restriction, arginine Lysine Pyridoxine Ribofavin Cholesterol Simvastatin Phenylalanine Folinic acid Folinic L Carnitine, methionine Carnitine, folate Betaine, methyltetrahydrofolate, methylco 5 - methyltetrahydrofolate, L Valine restriction Valine Protein defned diet, avoid fasting, fasting, defned diet, avoid Protein Treatment Enzyme therapy replacement Stem cell therapy Stem Enzyme therapy replacement Stem cell therapy Stem Stem cell therapy Stem Nutritional therapy Vitamin & trace element Vitamin Vitamin & trace element Vitamin Nutritional therapy Pharmacological therapy Pharmacological Nutritional therapy Vitamin & trace element Vitamin Pharmacological therapy Pharmacological Nutritional therapy Vitamin & trace element Vitamin Vitamin & trace element Vitamin Nutritional therapy Nutritional therapy Nutritional therapy Treatment strategy Treatment ‑ CoA CoA dependent - CoA hydrolase hydrolase CoA CoA deacylaseCoA Overview of all causal therapies dehydrocholesterol reductase dehydrocholesterol nyms: Hurler syndrome [severe]; [severe]; Hurler syndrome nyms: [attenuated]) Scheie syndrome epilepsy) dehydrogenase defciency dehydrogenase pyridoxine (synonym: defciency defciency reductase defciency synthetase defciency (synonym: cycloli ‑ 5 - formyltetrahydrofolate gase defciency) defciency defciency beta - (synonym: hydroxyisobutyryl - defciency) lyase defciency Alpha - mannosidase defciency iduronidase defciencyAlpha - iduronidase (syno Alpha - fucosidase defciency aminoadipic semialdehyde Alpha - aminoadipic semialdehyde ACAD9 defciencyACAD9 7 - tetrahydropterin synthase - tetrahydropterin 6 - pyruvoyl methylenetetrahydrofolate 5,10 - methylenetetrahydrofolate methenyltetrahydrofolate 5,10 - methenyltetrahydrofolate phosphoglycerate dehydrogenase dehydrogenase 3 - phosphoglycerate 3 - hydroxyisobutyryl - - 3 methylglutaryl - 3 - hydroxy 3 Table Name of disorder Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 Page 18 of 35 [ 79 , 80 ] [ 78 ] [ 76 , 77 ] [ 76 , 77 ] [ 74 , 75 ] [ 74 , 75 ] [ 74 , 75 ] [ 72 ] [ 72 ] [ 72 ] [ 72 ] [ 72 ] [ 72 ] [ 72 ] [ 72 ] [ 73 ] [ 72 ] [ 72 ] [ 72 ] [ 72 ] ReferenceS persists A, B, E, G A, B, D A, E D E, G E, G A, B, E A, B, B, C, D, E, G C, D, B, B, C, D, E C, D, B, D A, B, D, E D, A, B, B, C, D, E, G C, D, B, B, C, D, E C, D, B, D A, B, D, E, systemic phenotype E, systemic D, A, B, A, D, E A, D, B, C, D, E, G C, D, B, B, C, D, E C, D, B, D A, B, D, E D, A, B, Efect of treatment 4 4 to 5 4 to 2c 4 to 5 4 to 4 4 4 2b, efect on growth 4 on growth efect 2b, 2b 4 4 2b, efect on growth 4 on growth efect 2b, 2b 4 4 4 2b, efect on growth 4 on growth efect 2b, 2b 4 4 Level of evidence Level ± + carbidopa (depending 200 (stem cell - based gene - 200 (stem dopa - tion therapy) tion ine oxidase (MAO) inhibitors, inhibitors, (MAO) ine oxidase L on mutation) citrulline phenylbutyrate, sodium benzoate phenylbutyrate, citrulline phenylbutyrate, sodium benzoate phenylbutyrate, citrulline phenylbutyrate, sodium benzoate phenylbutyrate, Sulfonylurea Hematopoietic stem cell transplanta ‑ stem Hematopoietic OTL Hematopoietic stem cell transplanta ‑ stem Hematopoietic Dopamine agonist, monoam ‑ Pyridoxine, folinic acid folinic Pyridoxine, Gene therapy Protein defned diet, arginine or defned diet, arginine Protein Sodium phenylbutyrate, glycerol glycerol Sodium phenylbutyrate, Hemodialysis, peritoneal dialysis Hemodialysis, Liver transplantation Liver Protein defned diet, arginine or defned diet, arginine Protein Sodium phenylbutyrate, glycerol glycerol Sodium phenylbutyrate, Hemodialysis, peritoneal dialysis Hemodialysis, Liver transplantation Liver Creatine Protein defned diet, arginine or defned diet, arginine Protein Sodium phenylbutyrate, glycerol glycerol Sodium phenylbutyrate, Hemodialysis, peritoneal dialysis Hemodialysis, Liver transplantation Liver Treatment - based therapy - based therapy Pharmacological therapy Pharmacological Stem cell therapy Stem Gene Stem cell therapy Stem Pharmacological therapy Pharmacological Vitamin & trace element Vitamin Gene Nutritional therapy Pharmacological therapy Pharmacological Other Solid organ transplant Solid organ Nutritional therapy Pharmacological therapy Pharmacological Other Solid organ transplant Solid organ Nutritional therapy Nutritional therapy Pharmacological therapy Pharmacological Other Solid organ transplant Solid organ Treatment strategy Treatment forming subunit - forming - amino acid decarboxy ‑ (continued) sensitive potassium channel - sensitive regulatory/pore superactivity lase defciency defciency citrullinemia (synonym: type 1) (AGAT) defciency(AGAT) argininemia) ATP Aspartylglucosaminidase defciency Arylsulfatase A defciency Aromatic L Aromatic Argininosuccinate synthetase Argininosuccinate Argininosuccinate lyase defciency Argininosuccinate Arginine:glycine amidinotransferase amidinotransferase Arginine:glycine Arginase defciency Arginase (synonym: 3 Table Name of disorder Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 Page 19 of 35 [ 36 ] [ 87 ] [ 87 ] [ 87 ] [ 86 ] [ 86 ] [ 72 ] [ 72 ] [ 72 ] [ 72 ] [ 30 ] [ 85 ] [ 83 , 84 ] [ 83 , 84 ] [ 83 , 84 ] [ 83 , 84 ] [ 82 ] [ 81 ] [ 62 ] [ 62 ] [ 62 ] ReferenceS F B, C, D, E, F, G E, F, C, D, B, D C C, D C, D B, C, D, E, G C, D, B, B, C, D, E, D for carglumic acid carglumic E, D for C, D, B, D A, B, D, E D, A, B, A, F A, B, G A, B, A, C, D, G A, C, D, C, D, G C, D, D C, D, G C, D, A, E, G A, G D, G D, E A, E, F A, B, E, F, G E, F, A, B, Efect of treatment 4 to 5 4 to 4 4 4 4 4 2b, efect on growth 4 on growth efect 2b, 2b, 4 to 5 for carglumic acid carglumic 5 for 4 to 2b, 4 4 4 5 4 4 4 4 2c 4 4 4 4 4, 4 to 5 for 5 - Hydroxytryptophan 5 for 4, 4 to Level of evidence Level ‑ ‑ ‑ ‑ - factor ± carbo ‑ (carglu glutamate - glutamate (carglumic (carglumic glutamate reduced diet - reduced - chain triglycerides ± chain amino acid sup ± + carbidopa, 5 - Hydroxy ‑ - L carbamyl - L carbamyl hydrate diet, avoid fasting, avoid avoid fasting, diet, avoid hydrate lactose restriction, glucose iv, medium - acid) citrulline phenylbutyrate, sodium benzoate, sodium benzoate, phenylbutyrate, N - mic acid) plementation acids, isoleucine, valine, avoid fast avoid valine, isoleucine, acids, management sick day ing, tion tryptophan, dihydro sapropterin chloride (synthetic BH4) co therapy dopa - (Intrathecal) milasen - - fat/low High - protein/high Hemodialysis, peritoneal dialysis Hemodialysis, Liver Transplantation Liver Sick day management Sick day N - Protein defned diet, arginine or defned diet, arginine Protein Sodium phenylbutyrate, glycerol glycerol Sodium phenylbutyrate, Hemodialysis, peritoneal dialysis Hemodialysis, Liver transplantation Liver Uridine Branched - Restriction of branched chain amino Thiamine Hemodialysis, peritoneal dialysis Hemodialysis, Liver transplantation Liver Biotin Vestronidase Hematopoietic stem cell transplanta ‑ stem Hematopoietic Phenylalanine Folinic acid Folinic L Treatment Gene based therapy Nutritional therapy Other Solid organ transplant Solid organ Nutritional therapy Pharmacological therapy Pharmacological Nutritional therapy Pharmacological therapy Pharmacological Other Solid organ transplant Solid organ Pharmacological therapy Pharmacological Nutritional therapy Nutritional therapy Vitamin & trace element Vitamin Other Solid organ transplant Solid organ Vitamin & trace element Vitamin Enzyme therapy replacement Stem cell therapy Stem Nutritional therapy Vitamin & trace element Vitamin Pharmacological therapy Pharmacological Treatment strategy Treatment ‑ ‑ ‑ (continued) chain ketoacid dehydro chain ketoacid dehydro glucuronidase defciencyglucuronidase (syno defciency genase kinase defciency genase E1 alpha (BCKDHA)/beta (BCKDHB)/E2 (DBT) defciency maple syrup urine (synonym: disease type 1a (BCKDHA)/2 (DBT); transacylase def ‑ Dihydrolipoyl ciency (DBT)) nym: Sly syndrome) nym: drolase 1 defciencydrolase CLN7 disease Citrin defciency Carbonic anhydrase VA defciency VA Carbonic anhydrase Carbamoyl phosphate synthetase 1 phosphate Carbamoyl CAD trifunctional defciency protein Branched - Branched - Biotinidase defciency Beta - Autosomal recessive GTP cyclohy ‑ recessive Autosomal 3 Table Name of disorder Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 Page 20 of 35 [ 100 ] [ 99 ] [ 98 ] [ 98 ] [ 98 ] [ 97 ] [ 62 ] [ 62 ] [ 62 ] [ 96 ] [ 95 ] [ 95 ] [ 94 ] [ 93 ] [ 91 , 92 ] [ 91 , 92 ] [ 90 ] [ 89 ] [ 88 ] ReferenceS A, D, E, F A, D, A, B, C A, B, C, D C, D E, G A, D, E A, D, D, E A, E, F A, B, E, F, G E, F, A, B, F, G C, D, G C, D, D, E, G D, A, F A, F A, E, G A, E, G D E A, B, E A, B, Efect of treatment 4 4 to 5 4 to 5 5 2c 4 4 4 4 4 2c 2c 2b 4 4 4, 1b for tetrathiomolybdate 4, 1b for 4 4 to 5 4 to 4 to 5 4 to Level of evidence Level ‑ ‑ - factor ± reduced diet - reduced + carbidopa ± , ± + carbidopa, 5 - Hydroxy ‑ dopa - 5 - hydroxytryptophan tryptophan, dihydro sapropterin chloride (synthetic BH4) co therapy restriction date dopa - Folinic acid Folinic Carnitine Carnitine Ribofavin Beta - hydroxybutyrate BH4, L Phenylalanine Folinic acid Folinic L Folic acid Folic Protein defned diet, methionine Protein Pyridoxine, betaine Pyridoxine, Cyclic pyranopterin monophosphate pyranopterin Cyclic Creatine, glycine, arginine glycine, Creatine, Zinc Copper chelators, tetrathiomolyb chelators, Copper Copper histidine Copper CoQ10 CoQ10 Treatment Vitamin & trace element Vitamin Nutritional therapy Nutritional therapy Vitamin & trace element Vitamin Nutritional therapy Pharmacological therapy Pharmacological Nutritional therapy Vitamin & trace element Vitamin Pharmacological therapy Pharmacological Vitamin & trace element Vitamin Nutritional therapy Vitamin & trace element Vitamin Pharmacological therapy Pharmacological Nutritional therapy Vitamin & trace element Vitamin Pharmacological therapy Pharmacological Pharmacological therapy Pharmacological Vitamin & trace element Vitamin Vitamin & trace element Vitamin Treatment strategy Treatment CoA CoA (continued) transporting ATPase subunit - transporting ATPase transporting ATPase subunit - transporting ATPase (synonym: neurodegeneration neurodegeneration (synonym: transport folate cerebral due to defciency) lase defciency alpha (ETFA)/subunit beta (ETFB)/ alpha (ETFA)/subunit defciency (ETFDH)dehydrogenase glutaric acidemia type(synonym: 2A/2B/2C; multiple acyl - defciency typedehydrogenase 2A/2B/2C) ciency defciency classic (synonym: homocystinuria) synthase defciency (synonym: molybdenum cofactor defciency type A) beta defciency (synonym: Wilson Wilson beta defciency (synonym: disease) alpha defciency Men ‑ (synonyms: occipital hornkes disease [severe]; [milder]) syndrome defciency Folate receptor alpha defciency receptor Folate ‑ hydroxy Epsilon - N trimethyllysine Electron transfer favoprotein subunit favoprotein transfer Electron DNAJC12 defciency Dihydropteridine reductase def ‑ Dihydropteridine Dihydrofolate reductase defciency reductase Dihydrofolate Cystathionine beta - synthase Cystathionine Cyclic pyranopterin monophosphate monophosphate pyranopterin Cyclic Creatine transporterCreatine defciency Copper Copper Coenzyme defciency Q8A (ADCK3) Coenzyme Q5 methyltransferase 3 Table Name of disorder Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 Page 21 of 35 [ 117 ] [ 114 , 115 ] [ 116 ] [ 116 ] [ 114 , 115 ] [ 111 , 113 ] [ 112 ] [ 110 , 111 ] [ 109 ] [ 108 ] [ 61 ] [ 107 ] [ 106 ] [ 105 ] [ 104 ] [ 44 ] [ 103 ] [ 101 ] [ 102 ] ReferenceS A, B, G A, B, A, E, G C, G C, G A, E, G A, F A F A, F D, E, G D, C, D, G C, D, D D, E B, D, E, F D, B, B, D, E, F D, B, C, D, E, G C, D, A, E F A, E Efect of treatment 4 to 5 4 to 4 to 5 4 to 2c 4 4 to 5 4 to 4 4 to 5 4 to 4 4 to 5 4 to 4 4 4 4 4 4 2c 4 to 5 4 to 4 2b Level of evidence Level ± of - function muta ‑ glutamate (carglumic (carglumic glutamate - - L carbamyl fasting, sick day management sick day fasting, acid) tion tions) tion ornithine ylamine receptor antagonists ylamine receptor tion, carnitine leucine, natural protein fortifcation natural protein - leucine, isoleucine, natural protein fortifca ‑ natural protein - isoleucine, serine (for loss - - serine (for Zinc acetate L Protein defned diet, carnitine, avoid avoid defned diet, carnitine, Protein N - L Memantine, IVIG Memantine, L Memantine, IVIG Memantine, Memantine Hematopoietic stem cell transplanta ‑ stem Hematopoietic Hydroxycobalamin, betaine Hydroxycobalamin, Biotin Iron chelation Arginine restriction, creatine and restriction, creatine Arginine ‑ N - nitrosodimeth Sodium benzoate, ‑ defned diet, lysine restric Protein Glutamine Ketogenic diet Triheptanoin Treatment Vitamin & trace element Vitamin Nutritional therapy Nutritional therapy Pharmacological therapy Pharmacological Nutritional therapy Pharmacological therapy Pharmacological Nutritional therapy Pharmacological therapy Pharmacological Pharmacological therapy Pharmacological Stem cell therapy Stem Vitamin & trace element Vitamin Vitamin & trace element Vitamin Other Nutritional therapy Pharmacological therapy Pharmacological Nutritional therapy Nutritional therapy Nutritional therapy Pharmacological therapy Pharmacological Treatment strategy Treatment ‑ (continued) CoA dehydrogenase dehydrogenase CoA CoA dehydrogenase def ‑ dehydrogenase CoA defciency isovaleric (synonym: acidemia) ciency NMDA type subunit 2D superac ‑ NMDA tivity ‑ type subunit 2B dysregula NMDA tion ‑ type subunit 2A dysregula NMDA tion ‑ type subunit 1 dysregula NMDA tion nym: Hunter syndrome) Hunter nym: ciency defciency aminomethyltransferase (AMT)aminomethyltransferase decarboxylaseor glycine (GLDC) defciency nonketotic (synonym: hyperglycinemia) ciency glutaric aciduria (synonym: type 1) MEDNIK syndrome Leucyl - tRNA synthetase 1 defciency Isovaleryl - Isoleucyl - tRNA synthetase 1 def ‑ Ionotropic glutamate receptor receptor glutamate Ionotropic Ionotropic glutamate receptor receptor glutamate Ionotropic Ionotropic glutamate receptor receptor glutamate Ionotropic Ionotropic glutamate receptor receptor glutamate Ionotropic Iduronate sulfatase defciencyIduronate (syno Homocystinuria, cblDv1 type Holocarboxylase synthetase def ‑ Hereditary ceruloplasmin defciency Guanidinoacetate methyltransferase methyltransferase Guanidinoacetate Glycine encephalopathy due to due to encephalopathy Glycine Glutaryl - Glutamine synthetase defciency GLUT1 defciency GLUT1 3 Table Name of disorder Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 Page 22 of 35 [ 120 ] [ 120 ] [ 120 ] [ 120 ] [ 120 ] [ 120 ] [ 120 ] [ 120 ] [ 120 ] [ 120 ] [ 120 ] [ 120 ] [ 120 ] [ 120 ] [ 119 ] [ 61 ] [ 61 ] [ 61 ] [ 61 ] [ 61 ] [ 118 ] [ 61 ] [ 61 ] ReferenceS C, D, G C, D, C, D, G C, D, D D C, D, G C, D, C, D, G C, D, C, D, G C, D, D D C, D, G C, D, C, D, G C, D, C, D, G C, D, D C, D, G C, D, D, G D, G A, D, G A, D, A, D, G A, D, C, D, G C, D, C, D, G C, D, A, G C, D, G C, D, C, D, G C, D, Efect of treatment 4 4 4 4 4 4 4 4 4 4 2c 4 4 4 4 to 5, 5 for betaine 5, 5 for 4 to 4 5 4 to 5, 5 for betaine 5, 5 for 4 to 5 4 5 4, 5 for betaine 4, 5 for 4, 5 for betaine 4, 5 for Level of evidence Level ± ± ± ± glutamate (carglumic (carglumic glutamate glutamate (carglumic (carglumic glutamate glutamate (carglumic (carglumic glutamate - - - ± ± - L carbamyl - L carbamyl - L carbamyl fasting, sick day management sick day fasting, acid), sodium benzoate, antibiotics acid), sodium benzoate, transplantation fasting, sick day management sick day fasting, acid), sodium benzoate, antibiotics acid), sodium benzoate, transplantation fasting, sick day management sick day fasting, acid), sodium benzoate, antibiotics acid), sodium benzoate, Protein defned diet, carnitine, avoid avoid defned diet, carnitine, Protein Hydroxycobalamin N - Hemodialysis, peritoneal dialysis Hemodialysis, Liver transplantation and/or kidneyLiver Protein defned diet, carnitine, avoid avoid defned diet, carnitine, Protein Hydroxycobalamin N - Hemodialysis, peritoneal dialysis Hemodialysis, Liver transplantation and/or kidneyLiver Protein defned diet, carnitine, avoid avoid defned diet, carnitine, Protein N - Hemodialysis, peritoneal dialysis Hemodialysis, Liver and/or kidneyLiver transplantation Hydroxycobalamin, betaine Hydroxycobalamin, Hydroxycobalamin, betaine Hydroxycobalamin, Carnitine Hydroxycobalamin, betaine Hydroxycobalamin, Carnitine Hydroxycobalamin, betaine Hydroxycobalamin, Methionine, increase protein intake protein increase Methionine, Hydroxycobalamin, betaine Hydroxycobalamin, Hydroxycobalamin, betaine Hydroxycobalamin, Treatment Nutritional therapy Vitamin & trace element Vitamin Pharmacological therapy Pharmacological Other Solid organ transplant Solid organ Nutritional therapy Vitamin & trace element Vitamin Pharmacological therapy Pharmacological Other Solid organ transplant Solid organ Nutritional therapy Pharmacological therapy Pharmacological Other Solid organ transplant Solid organ Vitamin & trace element Vitamin Vitamin & trace element Vitamin Nutritional therapy Vitamin & trace element Vitamin Nutritional therapy Vitamin & trace element Vitamin Nutritional therapy Vitamin & trace element Vitamin Vitamin & trace element Vitamin Treatment strategy Treatment ‑ ‑ ‑ ‑ CoA mutase defciencyCoA (continued) - ylmalonyl cystinuria, cblJ type cystinuria, cblF type cystinuria, cblD type cystinuria, cblC type defciency ciency homocystinuria (synonym: - megaloblastic anemia, cblE type) (synonym: homocystinuria(synonym: - mega ‑ loblastic anemia, cblG type) Methylmalonic aciduria,Methylmalonic cblB type Methylmalonic aciduria,Methylmalonic cblA type Methylmalonic aciduria meth ‑ Methylmalonic due to Methylmalonic aciduriaMethylmalonic and homo Methylmalonic aciduriaMethylmalonic and homo Methylmalonic aciduriaMethylmalonic and homo Methylmalonic aciduriaMethylmalonic and homo - tRNA synthetase 1 Methionyl Methionine def ‑ synthase reductase Methionine synthase defciency 3 Table Name of disorder Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 Page 23 of 35 [ 127 ] [ 127 ] [ 72 ] [ 72 ] [ 72 ] [ 72 ] [ 58 ] [ 125 , 126 ] [ 124 ] [ 123 ] [ 123 ] [ 122 ] [ 121 ] [ 120 ] [ 120 ] [ 120 ] [ 120 ] [ 120 ] ReferenceS persists E, G A B, C, D, E, G C, D, B, B, C, D, E C, D, B, D A, B, D, E, systemic phenotype E, systemic D, A, B, A, E, G C, D, E, F C, D, A, E, F A A, F C C C, D, G C, D, C, D, G C, D, D D C, D, G C, D, Efect of treatment 4 4 2b, efect on growth 4 on growth efect 2b, 2b 4 4 to 5 4 to 4 4 to 5, 2b for Taurine 5, 2b for 4 to 4 4 4 5 5 4 4 4 4 4 Level of evidence Level ± glutamate (carglumic (carglumic glutamate - - L carbamyl citrulline phenylbutyrate, sodium benzoate phenylbutyrate, protein restriction, isoleucine protein restriction dietary restriction precursor fasting, sick day management sick day fasting, acid), sodium benzoate, antibiotics acid), sodium benzoate, transplantation - serine N - acetylcysteine, antibiotics Liver transplantation Liver Protein defned diet, arginine or defned diet, arginine Protein Sodium phenylbutyrate, glycerol glycerol Sodium phenylbutyrate, Hemodialysis, peritoneal dialysis Hemodialysis, Liver transplantation Liver Valine restriction Valine Arginine, citrulline, taurine citrulline, Arginine, Ketogenic diet L Pyridoxine Avoid fasting, sick day management, sick day fasting, Avoid Avoid Fasting, sick day management, sick day Fasting, Avoid Protein defned diet, carnitine, avoid avoid defned diet, carnitine, Protein Hydroxycobalamin N - Hemodialysis, peritoneal dialysis Hemodialysis, Liver transplantation and/or kidneyLiver Treatment Pharmacological therapy Pharmacological Solid organ transplant Solid organ Nutritional therapy Pharmacological therapy Pharmacological Other Solid organ transplant Solid organ Nutritional therapy Nutritional therapy Nutritional therapy Nutritional therapy Vitamin & trace element Vitamin Nutritional therapy Nutritional therapy Nutritional therapy Vitamin & trace element Vitamin Pharmacological therapy Pharmacological Other Solid organ transplant Solid organ Treatment strategy Treatment - ‑ CoA CoA - TH/ TS2/ - - ND4/ - CoA CoA glutamate glutamate - CO1/MT - TQ/MT - - chain enoyl TS1/MT - - - ND1/MT - ND6/MT TF/MT - CO3/ MT CO3/ - (continued) CoA synthase defciencyCoA TL1/MT - ND5/MT - defciency (synonym: ethylmalonic defciency ethylmalonic (synonym: encephalopathy) ‑ defciency hyperornith (synonym: - homoc ‑ inemia - hyperammonemia itrullinuria syndrome) hydratase 1 defciencyhydratase MT - TW) lopathy, lactic acidosis and stroke lopathy, like episodes (MT MT CPO2/MT MT nym: aralar defciency)nym: carrier 1 defciency isoform (syno ferase defciencyferase thiolase defciency glutaryl - Mitochondrial short Mitochondrial sulfur dioxygenase Mitochondrial ornithine transporter Mitochondrial myopathy, encepha ‑ Mitochondrial myopathy, Mitochondrial aspartate Mitochondrial aspartate aminotrans ‑ Mitochondrial acetoacetyl - ‑ - 3 methyl Mitochondrial 3 - hydroxy Methylmalonic aciduria,Methylmalonic cblDv2 type 3 Table Name of disorder Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 Page 24 of 35 [ 134 ] [ 59 ] [ 59 ] [ 133 ] [ 115 ] [ 43 ] [ 43 ] [ 43 ] [ 72 ] [ 72 ] [ 72 ] [ 72 ] [ 132 ] [ 132 ] [ 130 , 131 ] [ 129 ] [ 72 ] [ 72 ] [ 72 ] [ 72 ] [ 128 ] ReferenceS A, F D, E, F D, D, E, F D, D, G A, G B, D, E D, B, B, D, E D, B, B, D, E D, B, B, C, D, E, G C, D, B, B, C, D, E C, D, B, D A, B, D, E D, A, B, A A D, E A, G B, C, D, E, G C, D, B, B, C, D, E, D for carglumic acid carglumic E, D for C, D, B, D A, B, D, E D, A, B, C, D Efect of treatment cyclodextrin 4 4 4 4 4 to 5 4 to 2a, GMP 4 1b 1b 2b, efect on growth 4 on growth efect 2b, 2b 4 4 4 to 5 4 to 4 to 5 4 to - β 2 - hydroxypropyl 2b for 1b, 4 to 5 4 to 2b, efect on growth 4 on growth efect 2b, 2b, 4 for carglumic acid carglumic 4 for 2b, 4 4 4 Level of evidence Level - cyclodextrin ‑ (carglu glutamate - factor therapy - - amino acid suppletion/ - L carbamyl free L free large (GMP), Glycomacropeptide neutral amino acid (LNAA), fatty acids thetic BH4) co citrulline phenylbutyrate, sodium benzoate phenylbutyrate, - β 2 - hydroxypropyl citrulline phenylbutyrate, sodium benzoate, sodium benzoate, phenylbutyrate, N - mic acid) - Serine, glycine - Serine, glycine - phenylalanine Ketogenic diet L L S - adenosylmethionine L Protein defned diet, phenylalanine Protein Sapropterin dihydrochloride (syn ‑ dihydrochloride Sapropterin Pegvaliase Protein defned diet, arginine or defned diet, arginine Protein Sodium phenylbutyrate, glycerol glycerol Sodium phenylbutyrate, Hemodialysis, peritoneal dialysis Hemodialysis, Liver transplantation Liver Ascorbic acid Luteolin Miglustat, intrathecal Niacin, CoQ10 Protein defned diet, arginine or defned diet, arginine Protein Sodium phenylbutyrate, glycerol glycerol Sodium phenylbutyrate, Hemodialysis, peritoneal dialysis Hemodialysis, Liver transplantation Liver Thiamine Treatment Nutritional therapy Nutritional therapy Nutritional therapy Pharmacological therapy Pharmacological Nutritional therapy Nutritional therapy Pharmacological therapy Pharmacological Enzyme therapy replacement Nutritional therapy Pharmacological therapy Pharmacological Other Solid organ transplant Solid organ Vitamin & trace element Vitamin Pharmacological therapy Pharmacological Pharmacological therapy Pharmacological Vitamin & trace element Vitamin Nutritional therapy Pharmacological therapy Pharmacological Other Solid organ transplant Solid organ Vitamin & trace element Vitamin Treatment strategy Treatment (continued) CDG ciency defciency synthetase defciency nit beta defciency (synonym: phenylketonuria) (synonym: ciency immunodefciency, developmental developmental immunodefciency, and hypohomocysteinemia) delay, (NPC1)/C2 (NPC2) ciency phate transporterphate defciency PIGA - Phosphoserine phosphatase def ‑ Phosphoserine Phosphoserine aminotransferase aminotransferase Phosphoserine Phosphoribosylpyrophosphate Phosphoribosylpyrophosphate - tRNA synthetase subu ‑ Phenylalanyl Phenylalanine hydroxylase defciency hydroxylase Phenylalanine Ornithine def ‑ transcarbamylase NRF2 superactivity (synonym: Pick disease typeNiemann C1 - Pick NAD(P)HX epimerase defciency N - acetylglutamate synthase def ‑ Mitochondrial‑ thiamine pyrophos 3 Table Name of disorder Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 Page 25 of 35 [ 146 ] [ 145 ] [ 144 ] [ 143 ] [ 134 ] [ 134 ] [ 142 ] [ 114 , 115 ] [ 62 ] [ 62 ] [ 141 ] [ 141 ] [ 140 ] [ 138 , 139 ] [ 138 , 139 ] [ 137 ] [ 136 ] [ 120 ] [ 120 ] [ 120 ] [ 120 ] [ 135 ] [ 134 ] [ 134 ] ReferenceS D B, F B, D, E, G D, B, A, D, G A, D, F A, G E, F, G E, F, A, B, G A, B, A, B, E, F, G E, F, A, B, A, E, F A, E, G A, E, G A, D, E A, D, A, D, E, F A, D, D, E, F D, D, E, F D, A, E, F, G A, E, F, C, D, G C, D, C, D, G C, D, D C, D, G C, D, E, G F A, F Efect of treatment genes 4 4 3a 4 4 4 4 4 to 5 4 to 4 5 4 4 to 5 4 to 4 4 for PDHA1 and PDHX, 5 for other PDHA1 and PDHX, 5 for 4 for 4 for some mutations 4 for 4 4 2c 4 4 4 1b 4 to 5 4 to 4 Level of evidence Level ‑ ± glutamate (carglumic (carglumic glutamate - ± + carbidopa, 5 - Hydroxytryp )folinic acid - )folinic - L carbamyl acid tophan phosphatidylcholine fasting, sick day management sick day fasting, acid), sodium benzoate, antibiotics acid), sodium benzoate, dopa - serine - Thiamine Vigabatrin Chenodeoxycholic Acid Chenodeoxycholic lipoic acid, pantothenic pantothenic Biotin, alpha - lipoic acid, Galactose, manganese, uridine Galactose, manganese, Fucose Galactose L L Folinic acid Folinic Methionine restriction, creatinine, Methionine restriction, creatinine, Liver transplantation Liver Ketogenic diet, thiamine Ketogenic diet Thiamine Pyridoxal phosphate Pyridoxal (Levo Protein defned diet, carnitine, avoid avoid defned diet, carnitine, Protein N - Hemodialysis, peritoneal dialysis Hemodialysis, Liver and/or kidneyLiver transplantation Acetazolamide Pyridoxine Sodium phenylbutyrate Treatment Vitamin & trace element Vitamin Pharmacological therapy Pharmacological Pharmacological therapy Pharmacological Vitamin & trace element Vitamin Nutritional therapy Nutritional therapy Nutritional therapy Nutritional therapy Pharmacological therapy Pharmacological Vitamin & trace element Vitamin Nutritional therapy Solid organ transplant Solid organ Nutritional therapy Nutritional therapy Vitamin & trace element Vitamin Vitamin & trace element Vitamin Vitamin & trace element Vitamin Nutritional therapy Pharmacological therapy Pharmacological Other Solid organ transplant Solid organ Pharmacological therapy Pharmacological Vitamin & trace element Vitamin Pharmacological therapy Pharmacological Treatment strategy Treatment ‑ (continued) CDG CDG dependent multivitamin coupled folate transporter coupled folate CDG CDG CDG - - defciency nase defciency (synonym: cerebrotendinous cerebrotendinous (synonym: xanthomatosis) transporter defciency defciency phatase defciency (PDHA1)/beta (PDHB)/E2 (DLAT)/ E3 (DLD)/E3BP (PDHX) defciency defciency defciency hereditary (synonym: malabsorption) folate CoA carboxylaseCoA subunit alpha defciency (PCCB) (PCCA)/beta Thiamine pyrophosphokinaseThiamine Succinic semialdehyde dehydroge Succinic semialdehyde hydroxylase defciency 27 - hydroxylase Sterol Sodium - SLC39A8 defciency SLC39A8 - SLC35C1 - SLC35A2 Seryl - tRNA synthetase 1 defciency Sepiapterin reductase defciency adenosylhomocysteine hydrolase S - adenosylhomocysteine hydrolase Pyruvate dehydrogenase phos ‑ dehydrogenase Pyruvate Pyruvate dehydrogenase E1 alpha dehydrogenase Pyruvate phosphate oxidase oxidase 5 ′ - phosphate Pyridoxamine - Proton - propionyl acidemia due to Propionic - PMM2 PIGO PIGM 3 Table Name of disorder Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 Page 26 of 35 [ 153 ] [ 154 ] [ 152 ] [ 151 ] [ 150 ] [ 149 ] [ 148 ] [ 147 ] ReferenceS individual cohort study, individual cohort study, = individual case–control study or = prevents, halts, or slows clinical or slows halts, prevents, = D, E D, E A, E A, E D, G D D, E, G D, D Efect of treatment systematic review of cohort 2b review studies, systematic = systematic review of case– control studies; Level 4 of case– studies; Level review systematic control prevents acute metabolic decompensation, D metabolic decompensation, acute prevents = = improves systemic manifestations systemic improves 5 1c 4 4 4 G, 5 for D 4 G, 5 for 2b 4 2c for thiamine, 4 for biotin 4 for thiamine, 2c for Level of evidence Level = (prolongation of)(prolongation 2a survival Level with therapy]; + carbidopa improves seizure/epilepsy control, G control, seizure/epilepsy improves ‘All or None’ [ = or None’ ‘All = tion and tyrosine restrictionand tyrosine dopa = improves behavioural/psychiatric disturbance(s), C disturbance(s), behavioural/psychiatric improves - Gene therapy Hematopoietic stem cell transplanta ‑ stem Hematopoietic Pramipexol (dopamine agonist) (dopamine Pramipexol L Protein defned diet, phenylalanine defned diet, phenylalanine Protein Cerliponase alfa Cyanocobalamin, hydroxycobalamin Cyanocobalamin, Thiamine, biotin Thiamine, Treatment = individual RCT, 1c individual RCT, = - based therapy Gene Stem cell therapy Stem Pharmacological therapy Pharmacological Pharmacological therapy Pharmacological Nutritional therapy Enzyme therapy replacement Vitamin & trace element Vitamin Vitamin & trace element Vitamin Treatment strategy Treatment ‑ - respon systematic review of RCT’s, 1b of RCT’s, review systematic as a way to nuance the treatment the treatment nuance to 5 ′ as a way ‘4 to level assigned we reported, If was or frst principles. only one patient bench research expert based on physiology, opinion without critical appraisal; = = improves psychomotor/cognitive development/IQ, B development/IQ, psychomotor/cognitive improves = improves neurological manifestations (incl. neuro-imaging), F neuro-imaging), (incl. manifestations neurological improves = (continued) - Hanhart syndrome) ‘Outcomes Research’ [focused on end results of therapy for chronic conditions, including functioning and quality of life]; Level 3 including functioning Level and quality conditions, of life]; chronic for of therapy on end results [focused Research’ ‘Outcomes = defciency (synonyms: tyrosinemia type tyrosinemia (synonyms: 2; Richner (synonym: CLN2 disease) (synonym: (synonym: biotin - thiamine (synonym: basal ganglia disease) sive - linked adrenoleukodystrophy X Vesicular monoamine transporter 2 Vesicular Tyrosine hydroxylase defciency hydroxylase Tyrosine Tyrosine aminotransferase defciency aminotransferase Tyrosine - peptidase 1 defciency Tripeptidyl Transcobalamin II defciency Transcobalamin deterioration, E deterioration, Thiamine transporterThiamine 2 defciency case-series/report; 5 Level efects A Efect of treatment: 2c 3 Table Name of disorder 1a Level of evidence: Level Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 Page 27 of 35

Fig. 1 Diagnostic algorithm for treatable IDs. 1st Tier consists of non-targeted metabolic screening tests that are readily available in most developed countries. 2nd Tier consists of targeted metabolic tests, often more invasive and/or less available. Some IMDs are identifed by multiple (screening) tests in the 1st and 2nd Tier. Genetic testing (targeted molecular analysis as well as exome sequencing) can be performed in parallel. (ID Intellectual disability; IMD Inherited Metabolic Disorder) = = defciency [30]), in turn leading to prioritization of exome access to accurate genetic counseling, supportive care sequencing (panels) in the diagnostic algorithm. How- and reimbursement. ever, these techniques are not always available or have Te exact order of diagnostic tests still depends on local signifcantly longer turnaround times than conventional resources and expertise and needs critical appraisal and metabolic screening in body fuids. Conversely, about personalization of the subsequent treatment itself. Te 50% of all individuals undergoing genetic testing for ID diagnostic algorithm as shown in Fig. 1 is our recommen- remain without a diagnosis, which still makes metabolic dation, based on the yield of metabolic tests combined in screening an important part of the diagnostic workup. the tiers, as well as availability at most if not all metabolic Tis is further underlined by a recent study on genomic laboratories. Te algorithm can be adapted according to newborn screening, showing that ES identifes only 9 the clinician’s insights and laboratory specialist’s exper- out of 10 IMDs picked up reliably by tandem mass spec- tise, as well as the patient’s clinical phenotype (red fags) trometry. Tus picking up all patients eligible for early along with local laboratory resources. intervention urges a combined approach [31] Te 1st and Increasingly, metabolomics or next generation metabo- 2nd tier metabolic tests will also identify IDs not amena- lomic screening (NGMS) will replace the individual bio- ble to targeted therapy. Of course, any type of diagnosis chemical tests and assays, similar to ES replacing single is benefcial as it provides closure, end to a diagnostic gene tests or panels [32]. Already today, most genetic odyssey, information to patients and families, as well as laboratories solely work with ES and use virtual panels or virtual single gene analysis when these tests are required. Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 Page 28 of 35

Fig. 2 The updated Treatable ID App, an interactive digital tool for the clinician to a search for IMDs according to genes, signs and symptoms, diagnostic tests, and treatments, and b fnd information on specifc IMDs along with links to other digital resources. (IMD Inherited Metabolic = Disorder) Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 Page 29 of 35

Hence, in most clinical situations, it seems reasonable to individuals, while not meeting the “evidence-based” def- initiate metabolic screening and genetic testing in par- nition for group as a whole. allel. Te metabolic screening results can validate the As our literature review shows, new disorders have functional impact of genetic variants identifed by ES been added to this list at a high pace, with 44 new disor- (eg N-acetyl-mannosamine for NANS-CDG [33]), thus ders added since 2014. Representative examples include providing a functional read-out. In ES negative patients, CAD trifunctional protein defciency in which oral sup- metabolic aberrations can help to guide the genetic inves- plementation of uridine (monophosphate) has shown to tigations to scrutinize genes in specifc pathways and vice dramatically improve epilepsy and enable psychomotor versa, the genetic results can direct the NGMS interpre- development [30, 37]; or memantine repurposing for the tation and/or require additional specifc metabolic test- treatment of Ionotropic glutamate receptor NMDA type ing (e.g., enzyme assays). In life-threatening situations subunit 2A (GRIN2A) dysregulation. For other IMDs, or Progressive Intellectual and Neurologic Deterioration even with treatment, patients still have very severe symp- (PIND), quick turn-around is indicated for both meta- toms, with improvement of IQ seldom reported, but bolic/NGMS screening (within hours) and ‘accelerated’/ often with improvement of communication skills and ‘Turbo’ genome sequencing whenever available. behavior. Also, improvement of seizure frequency and intensity can be achieved. While data are scarce to prove Treatment advances the assumption that early treatment will lead to better In parallel, rare disease and (tailored) genetic therapies outcomes, this still seems logical and should prompt the are gaining mainstream attention with the Food and earliest possible diagnosis. Drug Administration (FDA) approval of the antisense oligonucleotide (Nusinersen) as well as the gene therapy Prioritizing treatable IMDs in the ID workup (onasemnogene abeparvovec) for Spinal muscular atro- Te systematic review of 2012 and its update in 2014 phy (SMA) [34, 35] and the frst personalized antisense were the frst evidence-based approach to demonstrate oligonucleotide (Milasen) for CLN7-related neurodegen- the signifcance of IMDs in the diagnostic work up of eration [36]. ID/DD. Whilst most recommendations for the diagnos- Our data show that although there has been much tic workup of DD/ID prioritize frequency of conditions attention given to gene-based and enzyme replacement and yield of diagnostic tests, our approach prioritized therapy, the majority of currently available, efective treatability over frequency and strategizes metabolic/bio- treatment strategies are nutritional, via dietary inter- chemical evaluation in a two-tiered fashion. Te utility ventions and supplementation of vitamins and trace of this approach was recently shown in the 7-year TIDE- elements. Tese are relatively cheap, widely available, BC study, where we used the two-tiered TIDE diagnos- non-invasive and can be surprisingly efective. tic algorithm for treatable IMD detection superimposed Outcomes of disease and efect of treatment vary onto current guidelines for the evaluation of unex- widely, depending on the IMD and therapy in question as plained ID. A total of 498 patients (63% male) patients well as the severity of the phenotype, the disease course were enrolled; etiologic diagnoses were established in and phase, the patient’s age and co-morbidity as well as 260 patients (52%), including treatable IMDs in 5%, a yet unknown factors. For some IMDs, timely and contin- third of whom presented with nonspecifc symptoms not ued treatment ensures patients live (almost) normal lives, primarily suggestive of an IMD. Another 15 individuals with Phenylketonuria (PKU) being the most prominent were diagnosed with a non-treatable IEM [16]. Tis study example. PKU is not only a superb example for a treat- represents the frst comprehensive metabolic evaluation able ID managed with a ‘classical’ nutritional interven- of a large cohort of patients with ID that is broadly repre- tion to restrict the toxic substrate, but also how further sentative of the population seen in a tertiary centre with research can broaden the therapeutic opportunities (e.g., a biochemical and genetic focus, and therefore possible tetrahydrobiopterin, Pegvaliase) and how the genotype bias towards IMD. Te 29 treatable IMD cases identi- can help in treatment planning. fed and the high overall etiologic diagnosis rate demon- We decided to exclude certain disorders where ID is strate the clinical utility of overlaying the TIDE protocol no longer considered one of the main clinical features onto current guidelines [16]. Te results emphasize the (e.g., Succinyl-CoA:3-oxoacid-CoA transferase (SCOT) importance of testing for treatable IEMs in all patients defciency, Ribofavin transporter defciency (RTD)), or with unexplained ID, as earlier diagnosis provides the where treatment was shown to be inefective in larger opportunity to mitigate or possibly prevent irreversible studies (e.g., Sanflippo syndrome A-D). However, with brain damage. Even IMDs for which the typical pheno- the increasing focus on personalized treatment we realize type comprises complex neurologic abnormalities, PIND that some therapies will show positive efects in selected or multi-organ disease rather than isolated or stable ID, Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 Page 30 of 35

the earliest or presenting symptom is often developmen- literature is low. Guidelines, following methodologies tal delay only (e.g. mucopolysaccharidoses) and thus established by Scottish Intercollegiate Guideline Network applying the proposed algorithm and App broadly will (SIGN) [41] and Grading of Recommendations, Assess- enhance early pick-up and treatment of IMDs. ment, Development and Evaluations (GRADE) [42] based on rigorous evidence rating and transparent grading of Treatable ID App recommendations have become an important tool for Te updated Treatable ID App is designed to serve as an the standardization of clinical management of IMDs. up-to-date, easily accessible and freely available digital Tese are, however, only available for 13 of the > 1400 tool for all clinicians and laboratory specialists evaluating known IMDs (e.g., for PKU [43], Glutaric aciduria I [44] children presenting with ID. Given the challenge of keep- or Cobalamin defciencies [45]). Tis is refected by our ing up with clinical and scientifc developments, possibly literature review identifying most often non-analytic case even more so for rare disorders, this app is meant to facil- series or case reports with an evidence level of 4 (60%), itate this process and translate the vast knowledgebase 4–5 (12%) and 5 (8%). into a handy resource for early diagnosis and timely treat- Because of the nature of rare disorders itself and ment. Searching based on signs and symptoms to gen- the current trend to simultaneously develop (or better erate a diferential diagnosis and overviews of tests and explore) diferent treatment modalities for single IMDs, treatments is a new feature. Also, a gene list for targeted alternative clinical trial designs with the ability to evalu- exome analysis can be generated. Te App is kept suc- ate treatments in small populations within a short time cinct in order to facilitate quick and easy use. Links are are needed more than ever [46]. provided to more extensive databases, such as IEMbase With the emergence of drug repurposing for person- [8], that provide more details on diagnostics and symp- alized therapies, N-of-1 trials will be increasingly used toms. Tis way, clinicians can easily access more infor- for proof of principle studies in single patients. Such mation as needed. Obviously, the Treatable ID App will trial designs will address clinical heterogeneity [47], and need to be updated regularly to refect advances in the incorporate personally meaningful outcomes refecting feld. Te current implementation is designed to facilitate patients’ preferences and real world daily experience of this updating process, every 12 months. the rare disease. In cases where clinical trials cannot be performed, registries with well-defned clinical endpoints Limitations and improvements can elevate the evidence created by registry-based tri- Treatobolome database als. Adopting common data elements with standardized Te development of the ‘treatabolome’ database poses ontologies [48] as well as the agreement on core outcome many challenges, especially with regard to curation, and sets, [49] is now considered a prerequisite for compara- will require expert input from both the clinical domain bility of data collected across the medical systems caring and the computational and data stewardship domain. for rare diseases patients.

Multi‑omics to improve metabolic and genetic (newborn) Access of patients to new technologies and treatments screening Our Treatable ID App and algorithm aligns with the Another ongoing challenge is the improvement of meta- vision of the International Rare Diseases Research Con- bolic screening towards comprehensive tests (next gen- sortium to enable all people living with a rare disease to eration metabolic screening, combining metabolomics, receive an accurate diagnosis and personalized care plan. glycomics and lipidomics, etc.) [32]. Tis is in line with However access to therapy is still a considerable hurdle in the needs to improve and extend genetic screening meth- many parts of the world. European Reference Networks ods by adding mitochondrial DNA analysis from exome and designated centres of expertise address this medical data, genome sequencing and RNA sequencing to the gap. To ‘leave no one behind’, we encourage timely refer ‘frst tier’ genetic toolbox [38] [39] [40]. Te implemen- all diagnosed patients (at least once) to a such centre to tation of genetic screening into newborn screening pro- enable access to therapeutic interventions as well as par- grams together with metabolic screening is one of the ticipation in clinical trials and other research studies. ongoing challenges. Expertise in compounding drugs and magistral prepara- tions is essential for equitable access, as well as a voice Standardizing therapies and creating higher evidence levels in health policy on reimbursement of and access to Our literature search revealed several shortcomings (for (orphan) drug and nutritional therapy reimbursement a general review on this topic, the evidence creation in [50] [51] [52]. IMD, see Stockler-Ipsiroglu et al. [2]) that need to be addressed in the future. Te evidence of the investigated Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 Page 31 of 35

Conclusions and the initial version of the App, critical assessment of data, and edited the current version of the manuscript. CF contributed to the literature review, Treatable IMDs are a moving target. Te broad imple- performed data extraction and critical assessment, participated in consensus mentation of next-generation genomic and metabo- meetings and revised the manuscript. CvK designed study, supervised the lomic testing in daily clinical practice has accelerated the literature review, critical assessment and data extraction, participated in con‑ sensus meetings, translated and prepared data for the App, drafted and edited diagnostics for many individuals with ID. In parallel, the the manuscript. All authors approved the fnal version of the manuscript. increasing knowledge about the genetic basis of disease, insights into pathophysiology, and advances in therapeu- Funding CvK is supported by a salary award from ‘Stichting Metakids’ in The Nether‑ tic and targeting strategies catalyze the Treatabolome as lands. SW is supported by ERAPERMED2019-310—Personalized Mitochondrial a whole; this is true as well for IMDs causing ID. At the Medicine (PerMiM) and FWF Jubiläumsfondprojekt Nr. 18023. same time, methods for evidence generation with small Availability of data and materials patient numbers as well as more extensive and longer- All data generated and analyzed during this study are included in this term follow-up studies will reveal that some therapeutic published article, the supplementary information fles and the Treatable ID interventions initially deemed efective do not alter pri- app (www. Treatable-id.org). The literature search and data are available upon request. mary or secondary outcomes. Tese exciting develop- ments require continuous updates of the Treatable ID Ethics approval and consent to participate App, the Treatabolome database, as well as other digital Not applicable. resources. In parallel, diagnostic protocols—whether Consent for publication metabolic or genomic—should also be adjusted to pri- Not applicable. oritize treatable conditions in the diagnostic workup of Competing interests suspected IMDs and ensure the earliest possible inter- The authors declare that they have no competing interests. vention. We encourage clinicians to use our App to facili- tate diagnosis and intervention for treatable IDs, and Author details 1 Department of Pediatrics, Amsterdam UMC, Amsterdam, The Netherlands. welcome all feedback including treatable IDs we may 2 Department of Pediatrics, Radboud Center for Mitochondrial Medicine, have missed. Radboud University Medical Center, Nijmegen, The Netherlands. 3 University Children’s Hospital, Paracelsus Medical University, Salzburg, Austria. 4 On Behalf of United for Metabolic Diseases, Amsterdam, The Netherlands. 5 Division Abbreviations of Biochemical Diseases, Department of Pediatrics, BC Children’s Hospital, Van‑ 6 ES: Exome sequencing; DD: Global developmental delay; IMD: Inherited couver, BC V6H 3V4, Canada. Health2Media, Amsterdam, The Netherlands. 7 metabolic disorder; ICIMD: International classifcation of inherited metabolic National Human Genome Research Institute, National Institutes of Health, 8 disorders; ID: Intellectual disability; CSF: Cerebrospinal fuid; HVA: Homovanillic Bethesda, MD, USA. Department of Pediatrics ‑ Metabolic Diseases, Amalia acid; NGS: Next generation sequencing; NGMS: Next generation metabolomic Children’s Hospital, Geert Grooteplein 10, Radboud University Medical Center, screening; PIND: Progressive intellectual and neurologic deterioration; SMA: 6525 GA Nijmegen, The Netherlands. Spinal muscular atrophy; PKU: Phenylketonuria; COS: Core outcome measure set. Received: 23 December 2020 Accepted: 3 February 2021

Supplementary Information The online version contains supplementary material available at https://​doi.​ org/​10.​1186/​s13023-​021-​01727-2. References 1. van Karnebeek CDM, Wortmann SB, Tarailo-Graovac M, Langeveld M, Ferreira CR, van de Kamp JM, et al. The role of the clinician in the multi- Additional File 1. Inherited metabolic disorders (IMDs) included in our omics era: are you ready? J Inherit Metab Dis. 2018;41:571–82. 2012 (PMID 22212131) and 2014 (PMID 24518794) reviews and currently 2. Stockler‐Ipsiroglu S, Potter BK, Yuskiv N, Tingley K, Patterson M, excluded. Karnebeek C. Developments in evidence creation for treatments of inborn errors of metabolism. J Inherit Metab Dis. 2020;jimd.12315. 3. van Karnebeek CDM, Stockler S. Treatable inborn errors of metabo‑ Acknowledgments lism causing intellectual disability: A systematic literature review. The authors are grateful to the patients and families for daily teaching and 2012;105:368–81. inspiration, to the clinical and scientifc colleagues for all their eforts to 4. van Karnebeek CDM, Shevell M, Zschocke J, Moeschler JB, Stockler S. advance diagnosis and treatment of IMDs and fnally to Mr Jef Joa (Vancou‑ The metabolic evaluation of the child with an intellectual developmen‑ ver) for his technical contribution to the App. tal disorder: diagnostic algorithm for identifcation of treatable causes and new digital resource. Mol Genet Metab. 2014;111:428–38. Authors’ contributions 5. International joint recommendations to address specifc needs of EHvK performed the literature review, critical assessment and data extrac‑ undiagnosed rare disease patients. SWAN UK (the support group run by tion, participated in consensus meetings, drafted and edited the manuscript. Genetic Alliance UK), the Wilhelm Foundation, EURORDIS (Rare Diseases SW performed the literature review, critical assessment and data extraction, Europe), Rare Voices Australia (RVA), the Canadian Organization for Rare participated in consensus meetings, drafted and edited the manuscript. MK Disorders (CORD), the Advocacy Service for Rare and Intractable Dis‑ contributed to the literature review and critical assessment, performed data eases’ stakeholders in Japan (ASrid) and the National Organization for extraction, participated in consensus meetings and edited the manuscript. Rare Disorders (NORD). http://​downl​oad2.​euror​dis.​org.​s3.​amazo​naws.​ LT contributed to the literature review and critical assessment, and revised com/​docum​ents/​pdf/​Undia​gnosed-​Inter​natio​nal-​Joint-​Recom​menda​ the manuscript. RH contributed to review data translation and Treatable ID tions.​pdf. Accessed 23 Dec 2020. App design with feature updates, and contributed to the App sections of the manuscript. SS performed the initial systematic review on treatable IDs Hoytema van Konijnenburg et al. Orphanet J Rare Dis (2021) 16:170 Page 32 of 35

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