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Neonatal onset of mitochondrial disorders in 129 patients: clinical and laboratory characteristics and a new approach to diagnosis

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Introduction

Mitochondrial disorders (MD) may manifest in neonates, but early diagnosis is difficult. In this study, clinical and laboratory data were analyzed in 129 patients with neonatal onset of MD to identify any association between specific mitochondrial diseases and their symptoms with the aim of optimizing diagnosis.

Materials and methods

Retrospective clinical and laboratory data were evaluated in 461 patients (331 families) with confirmed MD.

Results

The neonatal onset of MD was reported in 28% of the patients. Prematurity, intrauterine growth retardation and hypotonia necessitating ventilatory support were present in one-third, cardiomyopathy in 40%, neonatal seizures in 16%, Leigh syndrome in 15%, and elevated lactate level in 87%. Hyperammonemia was observed in 22 out of 52 neonates. Complex I deficiency was identified in 15, complex III in one, complex IV in 23, complex V in 31, combined deficiency of several complexes in 53, and PDH complex deficiency was identified in six patients. Molecular diagnosis was confirmed in 49 cases, including a newborn with a 9134A>G mutation in the MTATP6 gene, which has not been described previously.

Conclusion

The most significant finding is the high incidence of neonatal cardiomyopathy and hyperammonemia. Based on our experience, we propose a diagnostic flowchart applicable to critically ill neonates suspicious for MD. This tool will allow for the use of direct molecular genetic analyses without the need for muscle biopsies in neonates with Alpers, Barth, MILS and Pearson syndromes, SCO1, SCO2, TMEM70, ATP5E, SUCLG1 gene mutations and PDH complex deficiency.

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Abbreviations

ATP5E:

Epsilon subunit of F1FO-ATP synthase

BCAA:

Branched-chain amino acids

CMP:

Cardiomyopathy

IEM:

Inborn errors of metabolism

IUGR:

Intrauterine growth retardation

LHON:

Leber hereditary optic neuropathy

L/P:

Lactate/pyruvate ratio

MD:

Mitochondrial disorders

MELAS:

Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes

MERRF:

Myoclonic epilepsy with ragged-red fibers

MILS:

Maternally inherited Leigh syndrome

MMA:

Methylmalonic acid

MNGIE:

Mitochondrial neuro-gastrointestinal encephalomyopathy

MTATP6:

Mitochondrially encoded ATP synthase 6 subunit

mtDNA:

Mitochondrial DNA

MTND1:

Mitochondrially encoded NADH dehydrogenase (complex I) 1 subunit

nDNA:

Nuclear DNA

NARP:

Neuropathy, ataxia and retinitis pigmentosa

NDUFA1, NDUFS1, NDUFS4, NDUFS6:

Complex I subunits

NDUFAF2:

NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, assembly factor 2

OXPHOS:

Oxidative phosphorylation system

PDHc:

Pyruvate dehydrogenase complex

POLG:

Polymerase gamma

SCO1:

Synthesis of cytochrome c oxidase 1, cytochrome c oxidase assembly protein

SCO2:

Synthesis of cytochrome c oxidase 2, cytochrome c oxidase assembly protein

SDH:

Succinate dehydrogenase

SUCLA2:

Succinate-CoA ligase, ADP-forming, beta subunit

SUCLG1:

Succinate-CoA ligase, alpha subunit

SURF1:

Surfeit 1, cytochrome c oxidase assembly protein

TMEM70:

Transmembrane protein 70, F1FO-ATP synthase biogenesis

3-MGA:

3-methylglutaconic acid

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Acknowlegements

The study was supported by grants from the Ministry of Health of the Czech Republic IGA MZ NS 10561-3/2009 (TH, KS), IGA MZ NS 9782-4/2008 (PJ, MM), IGA MZ NT 11186-5/2010 (MT, HH), by Center of Applied Genomics 1 M520 (JZ, KV, LW) from the Ministry of Education, Youth and Sports of the Czech Republic, and by the Vereinigung zur Forschung und Fortbildung, Univ. Kinderklinik Salzburg, Austria (WS, JM).

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Authors and Affiliations

  1. Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Ke Karlovu 2, 120 00, Prague 2, Czech Republic

    Tomas Honzik, Marketa Tesarova, Martin Magner, Pavel Jesina, Katerina Vesela, Laszlo Wenchich, Karol Szentivanyi, Hana Hansikova, Jiri Zeman & Jiri Zeman

  2. Department of Pediatrics, Paracelsus Medical University Salzburg, Müllner Hauptstraße 48, A-5020, Salzburg, Austria

    Johannes Mayr & Wolfgang Sperl

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  1. Tomas Honzik
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  2. Marketa Tesarova
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  3. Martin Magner
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  4. Johannes Mayr
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  10. Wolfgang Sperl
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Correspondence to Jiri Zeman.

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Communicated by: Eva Morava

Competing interest: None declared

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Honzik, T., Tesarova, M., Magner, M. et al. Neonatal onset of mitochondrial disorders in 129 patients: clinical and laboratory characteristics and a new approach to diagnosis. J Inherit Metab Dis 35, 749–759 (2012). https://doi.org/10.1007/s10545-011-9440-3

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  • DOI: https://doi.org/10.1007/s10545-011-9440-3

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