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  • Review Article
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Metabolic masqueraders of paediatric and adult rheumatic diseases

Nature Reviews Rheumatology volume 22, pages 239–255 (2026) Cite this article

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Abstract

Inborn errors of metabolism comprise a clinically diverse group of conditions that arise from the decreased activity of an enzyme or metabolite transporter and subsequent blockade in a metabolic pathway. These disorders are typically considered in the differential diagnosis of critically ill neonates or young children presenting with hypoglycaemia, metabolic acidosis or hyperammonaemia. However, beyond these classic presentations, a broader group of inborn errors of metabolism can manifest more subtly, with progressive articular and multi-systemic involvement that mimics or overlaps with typical features of rheumatological disease. Consequently, these conditions might be misdiagnosed for years as rheumatological diseases, including juvenile idiopathic arthritis, systemic sclerosis, idiopathic inflammatory myopathies and systemic lupus erythematosus. Moreover, these disorders provide unique opportunities to understand the complex interplay between metabolism and immune function. With the growing availability of disease-modifying therapies for inborn errors of metabolism, rheumatologists must be able to recognize these disorders, particularly in patients with atypical features or treatment-refractory disease.

Key points

  • Metabolic ‘mimickers’ of rheumatological disease provide unique opportunities to understand the complex interplay between metabolism and immune function.

  • Chronic activation of the innate immune system in lysosomal storage disorders results from the accumulation of lysosomal substrates and leads to joint manifestations mimicking arthritis.

  • Metabolic myopathies, which have overlapping features with immune-mediated inflammatory myopathies, include disorders that impact glycogen metabolism, fatty acid oxidation and mitochondrial respiration.

  • Inborn errors of metabolism with systemic symptoms highlight diverse mechanisms — including defects of amino acid transport, oligosaccharide processing and lipid and cholesterol metabolism — by which metabolic alterations drive immune dysregulation.

  • Genetic testing should be considered in the evaluation of atypical or treatment-refractory juvenile idiopathic arthritis and other early-onset and/or atypical rheumatological presentations given the overlap between metabolic ‘mimickers’ and rheumatological disorders.

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Fig. 1: Clinical features of Farber disease in a paediatric patient.
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Fig. 2: Typical radiographic findings of dysostosis multiplex.
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Fig. 3: Knee arthrosis in a paediatric patient with α-mannosidosis.
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Acknowledgements

L.C.B. is supported by a Burroughs Wellcome Fund Career Award for Medical Scientists.

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  1. These authors contributed equally: Tiphanie P. Vogel, Lindsay C. Burrage.

Authors and Affiliations

  1. Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA

    Steven H. Lang, Cher Sha, Chelsi M. Rose, V. Reid Sutton & Lindsay C. Burrage

  2. Texas Children’s Hospital, Houston, TX, USA

    Steven H. Lang, Chelsi M. Rose, V. Reid Sutton & Tiphanie P. Vogel

  3. Division of Rheumatology, Department of Paediatrics, Baylor College of Medicine and William T. Shearer Center for Human Immunobiology, Houston, TX, USA

    Tiphanie P. Vogel & Lindsay C. Burrage

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Contributions

S.H.L., C.M.R. and C.S. researched data for the article. T.P.V., S.H.L., V.R.S. and L.C.B. contributed substantially to discussion of the content. S.H.L., C.M.R. and C.S. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Lang, S.H., Sha, C., Rose, C.M. et al. Metabolic masqueraders of paediatric and adult rheumatic diseases. Nat Rev Rheumatol 22, 239–255 (2026). https://doi.org/10.1038/s41584-026-01352-y

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