Targeted versus untargeted omics — the CAFSA story
Background In 2009, untargeted metabolomics led to the delineation of a new clinico-biological entity called cerebellar ataxia with elevated cerebrospinal free sialic acid, or CAFSA. In order to elucidate CAFSA, we applied sequentially targeted and untargeted omic approaches. Methods and results Fir...
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Veröffentlicht in: | Journal of inherited metabolic disease 2018-05, Vol.41 (3), p.447-456 |
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Sprache: | eng |
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Zusammenfassung: | Background
In 2009, untargeted metabolomics led to the delineation of a new clinico-biological entity called cerebellar ataxia with elevated cerebrospinal free sialic acid, or CAFSA. In order to elucidate CAFSA, we applied sequentially targeted and untargeted omic approaches.
Methods and results
First, we studied five of the six CAFSA patients initially described. Besides increased CSF free sialic acid concentrations, three patients presented with markedly decreased 5-methyltetrahydrofolate (5-MTHF) CSF concentrations. Exome sequencing identified a homozygous
POLG
mutation in two affected sisters, but failed to identify a causative gene in the three sporadic patients with high sialic acid but low 5-MTHF. Using targeted mass spectrometry, we confirmed that free sialic acid was increased in the CSF of a third known
POLG
-mutated patient. We then pursued pathophysiological analyses of CAFSA using mass spectrometry-based metabolomics on CSF from two sporadic CAFSA patients as well as 95 patients with an unexplained encephalopathy and 39 controls. This led to the identification of a common metabotype between the two initial CAFSA patients and three additional patients, including one patient with Kearns-Sayre syndrome. Metabolites of the CSF metabotype were positioned in a reconstruction of the human metabolic network, which highlighted the proximity of the metabotype with acetyl-CoA and carnitine, two key metabolites regulating mitochondrial energy homeostasis.
Conclusion
Our genetic and metabolomics analyses suggest that CAFSA is a heterogeneous entity related to mitochondrial DNA alterations either through
POLG
mutations or a mechanism similar to what is observed in Kearns-Sayre syndrome. |
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ISSN: | 0141-8955 1573-2665 |
DOI: | 10.1007/s10545-017-0134-3 |