Short clinical reportMitochondrial DNA m.3242G > A mutation, an under diagnosed cause of hypertrophic cardiomyopathy and renal tubular dysfunction?
Highlights
► Two new patients with the recently reported mitochondrial m.3242G > A mutation. ► Mutation was not maternally inherited, but occurred de novo. ► Mutation next to the well known m.3243A > G mutation causing MELAS. ► Different, but characteristic clinical presentation: cardiomyopathy, renal tubular dysfunction.
Introduction
Disorders of the mitochondrial (mt) oxidative phosphorylation (OXPHOS) system can present with virtually any clinical symptom. Combining the biochemical and clinical findings, and recognizing a distinctive disease pattern is a powerful approach to solve the genetic background. Even if the clinical phenotype can be variable; mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is one of these clinically distinctive syndromes (MIM #540 000 [1], [2],). Although MELAS is genetically heterogeneous, most patients harbour the m.3243A > G transition in the MTTL1 gene, encoding the mt tRNA-leu(UUR) [3]. Cardiac involvement is frequent in patients with m.3243A > G, ranging from rhythm disturbances to different forms of cardiomyopathy (CM) [4]. Renal tubular acidosis is a rare finding in OXPHOS disorders and not yet reported in combination with CM (as reviewed in [5]). The first patient with a m.3242G > A transition has been described recently with CM in association with renal tubular dysfunction [6]. Here we report two further patients with a m.3242G > A mutation showing a highly overlapping phenotype.
Section snippets
Methods
For patient 1, parallel with routine enzyme-histochemical analysis, the ATP production from pyruvate oxidation and the activity of the mitochondrial complexes I–V was measured in a fresh muscle biopsy and in cultured fibroblasts, for patient 2 the activities of the complexes I, II, IV were measured in fresh muscle as described previously [7], [8]. The entire mtDNA of patient 1 was evaluated using a standard mitochip analysis (GeneChip® Human Mitochondrial Resequencing Array 2.0, Affymetrix,
Clinical reports
The clinical, radiological, biochemical and genetic details on both patients are summarized in Table 1, Fig. 1 and Supplementary tables 1–3
Patient 1 was the second son of healthy non-consanguineous German parents. The first and third pregnancy ended with fetal loss, the older brother is healthy. The mother, maternal uncle, and the maternal grandmother complained about tension headache/migraine. Pregnancy, delivery and neonatal course were unremarkable. At the age of five months sudden
Genetic investigations
The complete mtDNA sequencing details can be found as Supplementary table 2. Sequencing of the entire mtDNA extracted from muscle from patient 1 revealed the m.3242G > A mutation, pyrosequencing showed homoplasmy in muscle and fibroblasts. Unfortunately, the patient's mother did not agree to participate in further genetic studies. For patient 2 the m.3242G > A mutation was identified by standard sequencing of the mitochondrial genome and shown to be present at a level of 49% heteroplasmy in
Discussion
Mitochondrial disorders, irrespective of whether they are due to nuclear or mitochondrial mutations, can present with virtually any clinical symptom in any severity and combination. However, several clinical distinctive syndromes are well known, e.g. MELAS, Kearns-Sayre (MIM #530000), or myoclonic epilepsy associated with ragged-red fibres (MERRF, MIM #545000) syndrome, but are genetically heterogeneous.
Recently Mimaki et al. reported the first case with a m.3242G > A mtDNA alteration, an
Conflict of interest
Authors declare no conflict of interests.
Acknowledgements
We thank the technicians from the Laboratory of Genetic, Endocrine and Metabolic disorders (LGEM), the Institute of Genetic and Metabolic Disease (IGMD) and the Department of Pathology of the Radboud University Nijmegen Medical Centre for excellent technical assistance. The mitochondrial diagnostic laboratory in Newcastle upon Tyne is funded by the UK NHS Specialised Services to provide the “Rare Mitochondrial Disease of Adults and Children Service”.
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