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Thermo‐sensitive mitochondrial trifunctional protein deficiency presenting with episodic myopathy

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‐Co...

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Published in:Journal of inherited metabolic disease 2022-07, Vol.45 (4), p.819-831
Main Authors: Schwantje, Marit, Ebberink, Merel S., Doolaard, Mirjam, Ruiter, Jos P. N., Fuchs, Sabine A., Darin, Niklas, Hedberg‐Oldfors, Carola, Régal, Luc, Donker Kaat, Laura, Huidekoper, Hidde H., Olpin, Simon, Cole, Duncan, Moat, Stuart J., Visser, Gepke, Ferdinandusse, Sacha
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cited_by cdi_FETCH-LOGICAL-c4313-343be82e42df5985c9af904e5eafd925196b8eb72ea7202edd7adbbb6d12b683
cites cdi_FETCH-LOGICAL-c4313-343be82e42df5985c9af904e5eafd925196b8eb72ea7202edd7adbbb6d12b683
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container_title Journal of inherited metabolic disease
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creator Schwantje, Marit
Ebberink, Merel S.
Doolaard, Mirjam
Ruiter, Jos P. N.
Fuchs, Sabine A.
Darin, Niklas
Hedberg‐Oldfors, Carola
Régal, Luc
Donker Kaat, Laura
Huidekoper, Hidde H.
Olpin, Simon
Cole, Duncan
Moat, Stuart J.
Visser, Gepke
Ferdinandusse, Sacha
description 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. In conclusion, 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.
doi_str_mv 10.1002/jimd.12503
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N. ; Fuchs, Sabine A. ; Darin, Niklas ; Hedberg‐Oldfors, Carola ; Régal, Luc ; Donker Kaat, Laura ; Huidekoper, Hidde H. ; Olpin, Simon ; Cole, Duncan ; Moat, Stuart J. ; Visser, Gepke ; Ferdinandusse, Sacha</creator><creatorcontrib>Schwantje, Marit ; Ebberink, Merel S. ; Doolaard, Mirjam ; Ruiter, Jos P. N. ; Fuchs, Sabine A. ; Darin, Niklas ; Hedberg‐Oldfors, Carola ; Régal, Luc ; Donker Kaat, Laura ; Huidekoper, Hidde H. ; Olpin, Simon ; Cole, Duncan ; Moat, Stuart J. ; Visser, Gepke ; Ferdinandusse, Sacha</creatorcontrib><description>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. In conclusion, 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. 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N.</creatorcontrib><creatorcontrib>Fuchs, Sabine A.</creatorcontrib><creatorcontrib>Darin, Niklas</creatorcontrib><creatorcontrib>Hedberg‐Oldfors, Carola</creatorcontrib><creatorcontrib>Régal, Luc</creatorcontrib><creatorcontrib>Donker Kaat, Laura</creatorcontrib><creatorcontrib>Huidekoper, Hidde H.</creatorcontrib><creatorcontrib>Olpin, Simon</creatorcontrib><creatorcontrib>Cole, Duncan</creatorcontrib><creatorcontrib>Moat, Stuart J.</creatorcontrib><creatorcontrib>Visser, Gepke</creatorcontrib><creatorcontrib>Ferdinandusse, Sacha</creatorcontrib><title>Thermo‐sensitive mitochondrial trifunctional protein deficiency presenting with episodic myopathy</title><title>Journal of inherited metabolic disease</title><addtitle>J Inherit Metab Dis</addtitle><description>Mitochondrial trifunctional protein (MTP) is involved in long‐chain fatty acid β‐oxidation (lcFAO). 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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. In conclusion, 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. 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subjects Abetalipoproteinemia
beta-oxidation
Body temperature
Children
defects
dehydrogenase
disorders
Endocrinology & Metabolism
Enzymatic activity
enzyme
Enzymes
fatty-acid oxidation
Fever
Fibroblasts
Genetic diversity
Genetic screening
Genetics & Heredity
long-chain fatty acid oxidation disorders
long-chain ketoacyl-CoA
long‐chain ketoacyl‐CoA thiolase deficiency
Medicine
mitochondrial trifunctional protein complex
mitochondrial trifunctional protein deficiency
mutations
Myopathy
Neurologi
Neurology
Neuropathy
Palmitic acid
pathophysiology
Patients
Pediatrics
Pediatrik
Protein deficiency
Research & Experimental
Retinopathy
Risk factors
thermo-sensitivity
Thiolase
thiolase deficiency
title Thermo‐sensitive mitochondrial trifunctional protein deficiency presenting with episodic myopathy
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