J Inherit Metab Dis. 2022 Apr 11.
M Schwantje,
M S Ebberink,
M Doolaard,
J P N Ruiter,
S A Fuchs,
N Darin,
C Hedberg-Oldfors,
L Régal,
L Donker Kaat,
H H Huidekoper,
S Olpin,
D Cole,
S J Moat,
G Visser,
S Ferdinandusse.
Mitochondrial trifunctional protein (MTP) is involved in long-chain fatty acid β-oxidation (lcFAO). Deficiency of one or more of the enzyme activities as catalyzed by MTP causes generalized MTP deficiency (MTPD), long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), or long-chain ketoacyl-CoA thiolase deficiency (LCKATD). When genetic variants result in thermo-sensitive enzymes, increased body temperature (e.g. fever) can reduce enzyme activity and be a risk factor for clinical decompensation. This is the first description of five patients with a thermo-sensitive MTP deficiency. Clinical and genetic information was obtained from clinical files. Measurement of LCHAD and LCKAT activities, lcFAO-flux studies and palmitate loading tests were performed in skin fibroblasts cultured at 37°C and 40°C. In all patients (four MTPD, one LCKATD), disease manifested during childhood (manifestation age: 2-10 years) with myopathic symptoms triggered by fever or exercise. In four patients, signs of retinopathy or neuropathy were present. Plasma long-chain acylcarnitines were normal or slightly increased. HADHB variants were identified (at age: 6-18 years) by whole exome sequencing or gene panel analyses. At 37°C, LCHAD and LCKAT activities were mildly impaired and lcFAO-fluxes were normal. Remarkably, enzyme activities and lcFAO-fluxes were markedly diminished at 40°C. Preventive (dietary) measures improved symptoms for most. All patients with thermo-sensitive MTP deficiency had a long diagnostic trajectory and both genetic and enzymatic testing were required for diagnosis. The frequent absence of characteristic acylcarnitine abnormalities poses a risk for a diagnostic delay. Given the positive treatment effects, upfront genetic screening may be beneficial to enhance early recognition. Positive treatment effects emphasize the need for early recognition of thermo-sensitive MTP deficiency, but the frequent absence of characteristic acylcarnitine abnormalities poses a risk for a diagnostic delay and shows the importance of both genetic and enzymatic testing for a proper diagnosis. M.S., S.F., S.A.F. and G.V. were involved in acquisition of data, interpretation of data and drafting of the manuscript. S.F., M.D., M.E. and J.R. were involved in the biochemical analysis for all patients. N.D., C.H.O, L.R., L.K.D., H.H.H., S.O., D.C. and S.J.M. were involved in diagnostics and long-term care of patients. All authors were involved in the interpretation of data and reviewing and editing the manuscript. M.S. and S.F. take responsibility for the collection of data, the interpretation and publication. All authors have given final approval of the version to be published. Marit Schwantje, Merel Ebberink, Mirjam Doolaard, Jos Ruiter, Sabine Fuchs, Niklas Darin Carola Hedberg-Oldfors, Luc Régal, Laura Donker Kaat, Hidde Huidekoper, Simon Olpin, Duncan Cole, Stuart Moat, Gepke Visser and Sacha Ferdinandusse declare to have no potential conflicts of interests. None of the authors have accepted reimbursements, fees, funds, or salaries from an organization that may in any way gain or lose financially from the results reported in this manuscript. None of the authors have any competing interests regarding relevant financial activities outside the submitted work, intellectual property or any other relationships. This research was funded by Metakids and PNO zorg. The content of the article has not been influenced by the sponsor. Ethical approval was not required for this study, as the paper does not report on primary research but on a retrospective chart study. All data were collected as part of routine diagnostics and treatment. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent for publication was obtained from all patients and/or their guardians. This work was generated within the "United for Metabolic Diseases (UMD)" and the "European Reference Network for Hereditary Metabolic Disorders (MetaBERN)". The authors are grateful for their efforts to improve care for patients with (genetic) metabolic diseases. We thank Conny Dekker and Heleen te Brinke for their technical assistance on the immunoblot analysis.
Keywords: Long-chain fatty acid oxidation disorders; long-chain ketoacyl-CoA thiolase deficiency; mitochondrial trifunctional protein complex; mitochondrial trifunctional protein deficiency; myopathy; thermo-sensitivity