Whole-blood global DNA methylation is increased in amyotrophic lateral sclerosis independently of age of onset

Abstract

ALS is a heterogeneous disease that is not well understood. Epigenetic rearrangements are important in complex disorders including motor neuron diseases. The aim of this study was to determine whether whole-blood DNA methylation (DNA MET %) is a potential modifier of age at onset in ALS. DNA MET % was measured as incorporation of [³H]dCTP following HpaII cut in 96 ALS patients and 87 controls, comprising: early-onset (< 55 years of age) and late-onset (> 74 years of age). Methionine (Met) and homocysteine (Hcy) plasma levels were assessed by liquid chromatography selected reaction monitoring coupled with isotope-dilution mass spectrometry. Results showed that DNA MET % was increased in ALS patients independently of age of onset. Compared to the other three groups, Hcy plasma levels were reduced in early-onset ALS patients but Met levels were similar. ROC analysis reported Met levels and DNA MET %, respectively, with a slight and moderate discriminative power. In conclusion, increased DNA MET % is a possible marker of epigenetic dysfunction in ALS independently of age of onset. Further studies dissecting biological determinants of phenotypic complexity in ALS may help in developing successful therapeutic strategies.

Key words::

• Amyotrophic lateral sclerosis
• age of onset
• DNA methylation
• epigenetics
• peripheral marker
• methionine
• homocysteine
• blood

Acknowledgements

The authors acknowledge a grant RF-LOM-2007–650716 ‘Genetic and environmental predictors of early onset of amyotrophic lateral sclerosis’.

Declaration of interest: No conflicts of interest related to the present work are declared by all authors. The authors alone are responsible for the content and writing of the paper.