Rare Disease Report

Researchers Review Neurometabolic Disorder Guidelines

DECEMBER 31, 2015
Rebekah Harrison
Inherited neurometabolic disorders (INMDs) represent 700 of the 7000 known rare diseases. Unfortunately, only a handful of those 700 diseases have guidelines to help clinicians. And given the rarity of the conditions and the limited information available, it is not certain if those guidelines are reliable.   
The guidelines have never been systemically evaluated. Until now.
The European project "Inherited NeuroMetabolic Disease Information Network" (InNerMeD-I-Network) was launched with the aim of creating a network of information related to diagnosis and treatment of Inherited neurometabolic disorders. The goal of the project project was to determine the number and the methodological quality of existing guidelines and recommendations for INMDs.
For these guidelines, INMDs were classified into 10 different categories including:
  • Disorders of amino acids and organic acids
  • Purine, pyrimidine and neurotrasmitter metabolism diseases
  • Disorders of carbohydrate metabolism
  • Disorders of lipid metabolism
  • Disorders of vitamin and non protein cofactor metabolism and transport
  • Disorders of porphyrin and hem metabolism
  • Disorders of mineral absorption and transport
  • Disorders of energy metabolism
  • Disorders of lysosomal and lysosomal-related organelles
  • Peroxisomal diseases
In their evaluation, researchers reviewed 55 guidelines  that met their criteria and used the Appraisal of Guidelines, Research, and Evaluation II (AGREEII) instrument, to assess their usefulness.
The AGREE II instrument assessed the transparency of the selected guidelines and recommendations based on 23 key items that address 6 quality domains: scope and purpose, stakeholder involvement, rigor of development, clarity of presentation, applicability and editorial independence..
Of the  55 guidelines, 11% were about groups of disorders, whereas the majority encompassed only one disorder. Lysosomal disorders, and in particular Fabry, Gaucher disease and mucopolysaccharidoses where the most studied.
The overall methodological quality of the recommendation was acceptable and increased over time, with 25 % of the identified guidelines strongly recommended by the appraisers, 64% recommended, and only 11% not recommended.
The level of recommendation of the guidelines and recommendations was determined by the number of items scoring ≥50%. The AGREE II analysis revealed that 25% of the identified guidelines were strongly recommended (SR), 64% recommended (R), and 11% not recommended. (See Figure A below) Figure B shows overall quality assessment (OQA) of guidelines and recommendations, most reaching over 50%. Correlation between OQA and year of publication, shows steady linear regression (figure C). The grade of recommendation (GR) of guidelines and recommendations (scores from 1 = not recommended to 3 = recommended without modifications) show that most would guidelines would be recommended with little modifications. (See Figure D). All the documents had at least one item scoring ≥50%. 

The authors focused on 2 lysosomal storage disorders; Gaucher disease and Fabry disease. For Gaucher disease, authors did not find an increase in the scores referring to all 6 domains. However, a statistically significant increase in the overall quality assessment (OQA) was observed over time. (See Figure B below). For Fabry disease, no improvement was observed in none of the appraised domains nor over time (Figures C and D).

Legend: Guidelines and recommendations for Gaucher disease and Fabry disease were scored on a 7-point scale for the 23 items belonging to domain 1–6. Numbers indicate the scores obtained in each domain by the guidelines and recommendations grouped by year of publication from 2000 to 2015. 

Positive News About Current Guidelines

Regardless, this is still great news for physicians and INMD patients. AGREE II scores indicate that the overall quality of the guidelines and recommendations for selected INMDs is acceptable and increasing over time. In addition, in all the appraised guidelines and recommendations, the authors sufficiently describe the overall objectives, the covered health questions and the population whom they are directed.
The expert appraisers agreed that for most of the documents, the recommendations were specific, unambiguous and easily identified, and the different options for diagnosis or management were clearly presented. The availability of identifiable information facilitates the task of the health professionals when choosing the proper guidance.

Room For Improvement

In the original search for the guidelines, only 23% (of a total of 251 documents) met the inclusion criteria for guidelines. Furthermore, the authors noted there was widespread misuse of the term "guideline" that was utilized for systematic reviews, algorithms or letters.
Another concern is that investigators observed that many of the guidelines and recommendations for Pompe disease, Gaucher disease, Fabry disease and MPSs were partially or totally funded by pharmaceutical companies, which may be particularly interested in the distribution of recommendations that promote the use of their own treatments.
Another issue is that the investigators observed was that the majority of the guidelines and recommendations were published without an external review prior to submission for publication.
Also, 73% of the guidelines and recommendations did not provide a procedure for updating and some disorders were covered by only 1 document published years ago.
In addition, most of the analyzed documents did not consider the economical impact of actually applying the recommendations listed in the guidelines.
Finally, none of the appraised guidelines and recommendations evaluated the risks versus benefits related to different social, economic or geographic realities.


Cassis L, Cortes-Saladelafont E, Molero-Luis M et al. Review and evaluation of the methodological quality of the existing guidelines and recommendations for inherited neurometabolic disorders. Orphanet Journal of Rare Diseases 2015, 10:164  doi:10.1186/s13023-015-0376-9

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