Abstract
FBXL4 deficiency is a recently described disorder of mitochondrial maintenance associated with a loss of mitochondrial DNA in cells. To date, the genetic diagnosis of FBXL4 deficiency has been established in 28 individuals. This paper retrospectively reviews proxy-reported clinical and biochemical findings and evaluates brain imaging, morphological and genetic data in 21 of those patients. Neonatal/early-onset severe lactic acidosis, muscular hypotonia, feeding problems and failure to thrive is the characteristic pattern at first presentation. Facial dysmorphic features are present in 67 % of cases. Seven children died (mean age 37 months); 11 children were alive (mean age at follow-up 46 months), three children were lost to follow-up. All survivors developed severe psychomotor retardation. Brain imaging was non-specific in neonates but a later-onset, rapidly progressive brain atrophy was noted. Elevated blood lactate and metabolic acidosis were observed in all individuals; creatine kinase was elevated in 45 % of measurements. Diagnostic workup in patient tissues and cells revealed a severe combined respiratory chain defect with a general decrease of enzymes associated with mitochondrial energy metabolism and a relative depletion of mitochondrial DNA content. Mutations were detected throughout the FBXL4 gene albeit with no clear delineation of a genotype-phenotype correlation. Treatment with “mitochondrial medications” did not prove effective. In conclusion, a clinical pattern of early-onset encephalopathy, persistent lactic acidosis, profound muscular hypotonia and typical facial dysmorphism should prompt initiation of molecular genetic analysis of FBXL4. Establishment of the diagnosis permits genetic counselling, prevents patients undergoing unhelpful diagnostic procedures and allows for accurate prognosis.
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Acknowledgments
We gratefully acknowledge the contribution of Georg F. Hoffmann, Franz A. Zimmermann and Richard J. Rodenburg. We thank C. Terrile for technical support.
This project was supported by grants from the BMBF funded German Network for Mitochondrial Disorders (mitoNET #01GM1113C) and by the E-Rare project GENOMIT (01GM1207) and GENOMIT FWF I 920-B13 to WS and 01GM1207 to HP.
RWT and RM are supported by The Wellcome Trust Centre for Mitochondrial Research (906919 Z/11/Z), the Lily Foundation and the UK NHS Highly Specialised Commissioners which funds the “Rare Mitochondrial Disorders of Adults and Children” Diagnostic Service in Newcastle upon Tyne (http://www.mitoresearch.org.uk/).
D.E.-F. acknowledges support from the Graduate Academy of the University of Heidelberg, the Young Investigator Award Program at Ruprecht-Karls-University Heidelberg Faculty of Medicine, the Daimler and Benz Foundation (Daimler und Benz Stiftung, Ladenburg, Germany) and the Reinhard-Frank Foundation (Reinhard-Frank-Stiftung, Hamburg, Germany).
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All procedures followed were in accordance with the ethical standards of the responsible local committees on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained by the reporting physicians from their patients for being included in the study.
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Communicated by: Eva Morava
Martina Huemer, Daniela Karall, Wolfgang Sperl, Holger Prokisch and Robert McFarland contributed equally to this work.
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Huemer, M., Karall, D., Schossig, A. et al. Clinical, morphological, biochemical, imaging and outcome parameters in 21 individuals with mitochondrial maintenance defect related to FBXL4 mutations. J Inherit Metab Dis 38, 905–914 (2015). https://doi.org/10.1007/s10545-015-9836-6
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DOI: https://doi.org/10.1007/s10545-015-9836-6