Treatable inherited metabolic disorders causing intellectual disability: 2021 review and digital app

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 disability (collectively ‘treatable IDs’). Our aim is to update the 2012 review on treatable IDs and App to capture the advances made in the identification 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 Classification 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 available. Data on clinical symptoms, diagnostic testing, treatment strategies, effects 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 identified 116 treatable IDs (139 genes), of which 44 newly identified, belonging to 17 ICIMD categories. The most frequent therapeutic interventions were nutritional, pharmacological and vitamin and trace element 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 effects included improvement of clinical deterioration in 62%, neurological manifestations in 47% and development in 37%. Conclusion The number of treatable IDs identified 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 majority of effective treatments are nutritional, which are relatively affordable, widely available and (often) surprisingly effective. 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 and International Rare Diseases Research Consortium goals, enabling clinicians to deliver rapid evidence-based interventions to our rare disease patients.

Diagnosing pediatric mitochondrial disease: lessons from 2,000 exomes

“…The copyright holder for this preprint this version posted June 25, 2021. ; https://doi.org/10.1101/2021.06.21.21259171 doi: medRxiv preprint In our cohort, disease-modifying treatments, such as a ketogenic diet in PDHA1 defects, are reported based on case reports for 29 of the identified MD gene defects, across 177 patients in our study (Bick et al, 2020, Hoytema van Konijnenburg et al, 2021, Distelmaier et al, 2017, as exemplified in our earlier publications , Repp et al, 2018, Distelmaier et al, 2013, Haack et al, 2012. In addition, 43 of the identified disease genes in the MDphenocopies across 61 patients, have reported treatments.…”

“…Amongst the MD gene hits were 29 defects identified in 177 patients where defect-specific vitamin supplementation, replenishment of a critical cofactor, dietary modification, or idebenone therapy offers the potential for targeted disease-modifying treatment (Fig. 2d) (Table S5) (Bick et al, 2020, Hoytema van Konijnenburg et al, 2021, Distelmaier et al, 2017. The most frequent MD-phenocopy gene hits were MORC2, MECP2, and POLR3A, each with ≥6 cases.…”

Adult GAMT deficiency: A literature review and report of two siblings

“…GAMT deficiency is one of 85 IEMs described in Warmerdam et al as presenting with progressive intellectual and neurological deterioration (PIND) [ 30 ]. At the same time therapeutic intervention is possible, and it is included in the 2021 updated Treatable Intellectual Disability review and app [ 31 ]. For a progressive disorder such as this one, where early diagnosis and timely therapeutic intervention is crucial in preventing serious neurological decline, misinterpretation of early presenting signs may result in delayed diagnosis with negative outcomes.…”

Urine Organic Acids as Metabolic Indicators for Global Developmental Delay/Intellectual Disability in Chinese Children

“…Several organic acids were in the same pathway, whereas others were involved in multiple pathways. To date, the metabolites that have been explored as possible GDD/ID biomarkers include: methylmalonic acid, propionic acid, methyl citrate, propionyl carnitine, propionyl glycine ( Horster and Hoffmann, 2004 ; Wongkittichote et al, 2017 ), glutaric acid, 3-hydroxyglutaric acid ( van Karnebeek and Stockler, 2012 ; Hoytema van Konijnenburg et al, 2021 ), 4-hydroxybutyric acid, γ-aminobutyric acid ( Li et al, 2015 ), 3-hydroxyisobutyric acid ( van Karnebeek and Stockler, 2012 ), 2-hydroxyglutaric acid ( Kranendijk et al, 2012 ). The exact pathogenesis of the accumulation of these metabolites leading to GDD/ID is still unclear.…”