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Thymidine kinase 2 and alanyl-tRNA synthetase 2 deficiencies cause lethal mitochondrial cardiomyopathy: case reports and review of the literature

Published online by Cambridge University Press:  14 November 2016

Stella Mazurova ,
Martin Magner ,
Vendula Kucerova-Vidrova ,
Alzbeta Vondrackova ,
Viktor Stranecky ,
Anna Pristoupilova ,
Josef Zamecnik ,
Hana Hansikova ,
Jiri Zeman  and
Marketa Tesarova
...Show all authors
Stella Mazurova
Affiliation:
Department of Paediatrics and Adolescent Medicine, First Medical Faculty, Charles University in Prague and General University Hospital in Prague, Czech Republic
Martin Magner
Affiliation:
Department of Paediatrics and Adolescent Medicine, First Medical Faculty, Charles University in Prague and General University Hospital in Prague, Czech Republic
Vendula Kucerova-Vidrova
Affiliation:
Department of Paediatrics and Adolescent Medicine, First Medical Faculty, Charles University in Prague and General University Hospital in Prague, Czech Republic
Alzbeta Vondrackova
Affiliation:
Department of Paediatrics and Adolescent Medicine, First Medical Faculty, Charles University in Prague and General University Hospital in Prague, Czech Republic
Viktor Stranecky
Affiliation:
Institute of Inherited Metabolic Disorders, First Medical Faculty, Charles University in Prague and General University Hospital in Prague, Czech Republic
Anna Pristoupilova
Affiliation:
Institute of Inherited Metabolic Disorders, First Medical Faculty, Charles University in Prague and General University Hospital in Prague, Czech Republic
Josef Zamecnik
Affiliation:
Department of Pathology and Molecular Medicine, Charles University in Prague, Second Medical Faculty and University Hospital Motol in Prague, Prague, Czech Republic
Hana Hansikova
Affiliation:
Department of Paediatrics and Adolescent Medicine, First Medical Faculty, Charles University in Prague and General University Hospital in Prague, Czech Republic
Jiri Zeman
Affiliation:
Department of Paediatrics and Adolescent Medicine, First Medical Faculty, Charles University in Prague and General University Hospital in Prague, Czech Republic
Marketa Tesarova
Affiliation:
Department of Paediatrics and Adolescent Medicine, First Medical Faculty, Charles University in Prague and General University Hospital in Prague, Czech Republic
Tomas Honzik*
Affiliation:
Department of Paediatrics and Adolescent Medicine, First Medical Faculty, Charles University in Prague and General University Hospital in Prague, Czech Republic
*
Correspondence to: Associate Professor T. Honzik, MD, PhD, Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Ke Karlovu 2, 128 08, Praha 2, Prague, Czech Republic. Tel: +420 224 367 792; Fax: +420 224 967 113; E-mail: [email protected]
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Abstract

Cardiomyopathy is a common manifestation in neonates and infants with mitochondrial disorders. In this study, we report two cases manifesting with fatal mitochondrial hypertrophic cardiomyopathy, which include the third known patient with thymidine kinase 2 deficiency and the ninth patient with alanyl-tRNA synthetase 2 deficiency. The girl with thymidine kinase 2 deficiency had hypertrophic cardiomyopathy together with regression of gross motor development at the age of 13 months. Neurological symptoms and cardiac involvement progressed into severe myopathy, psychomotor arrest, and cardiorespiratory failure at the age of 22 months. The imaging methods and autoptic studies proved that she suffered from unique findings of leucoencephalopathy, severe, mainly cerebellar neuronal degeneration, and hepatic steatosis. The girl with alanyl-tRNA synthetase 2 deficiency presented with cardiac failure and underlying hypertrophic cardiomyopathy within 12 hours of life and subsequently died at 9 weeks of age. Muscle biopsy analyses demonstrated respiratory chain complex I and IV deficiencies, and histological evaluation revealed massive mitochondrial accumulation and cytochrome c oxidase-negative fibres in both cases. Exome sequencing in the first case revealed compound heterozygozity for one novel c.209T>C and one previously published c.416C>T mutation in the TK2 gene, whereas in the second case homozygozity for the previously described mutation c.1774C>T in the AARS2 gene was determined. The thymidine kinase 2 mutations resulted in severe mitochondrial DNA depletion (to 12% of controls) in the muscle. We present, for the first time, severe leucoencephalopathy and hepatic steatosis in a patient with thymidine kinase 2 deficiency and the finding of a ragged red fibre-like image in the muscle biopsy in a patient with alanyl-tRNA synthetase 2 deficiency.

Keywords

Alanyl-tRNA synthetase 2thymidine kinase 2mitochondrial cardiomyopathyragged red fibresleucoencephalopathy
Type
Original Articles
Information
Cardiology in the Young , Volume 27 , Issue 5 , July 2017 , pp. 936 - 944
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Copyright
© Cambridge University Press 2016 

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