Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Case Reports
. 2013 May;21(5):528-34.
doi: 10.1038/ejhg.2012.202. Epub 2012 Sep 19.

Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency

Konstantina Fragaki  1 , Samira Ait-El-Mkadem, Annabelle Chaussenot, Catherine Gire, Raymond Mengual, Laurent Bonesso, Marie Bénéteau, Jean-Ehrland Ricci, Valérie Desquiret-Dumas, Vincent Procaccio, Agnès Rötig, Véronique Paquis-Flucklinger
Affiliations
Case Reports

Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency

Konstantina Fragaki et al. Eur J Hum Genet. 2013 May.

Abstract

We report two children, born from consanguineous parents, who presented with early-onset refractory epilepsy associated with psychomotor delay, failure to thrive, blindness and deafness. Polarographic and spectrophotometric analyses in fibroblasts and liver revealed a respiratory chain (RC) dysfunction. Surprisingly, we identified a homozygous nonsense mutation in the GM3 synthase gene by using exome sequencing. GM3 synthase catalyzes the formation of GM3 ganglioside from lactosylceramide, which is the first step in the synthesis of complex ganglioside species. Mass spectrometry analysis revealed that the complete absence of GM3 ganglioside and its biosynthetic derivatives was associated with an upregulation of the alternative globoside pathway in fibroblasts. The accumulation of Gb3 and Gb4 globosides likely has a role in RC dysfunction and in the decrease of mitochondrial membrane potential leading to apoptosis, which we observed in fibroblasts. We show for the first time that GM3 synthase deficiency, responsible for early-onset epilepsy syndrome, leads to a secondary RC dysfunction. Our study highlights the role of secondary mitochondrial disorders that can interfere with the diagnosis and the evolution of other metabolic diseases.

PubMed Disclaimer

Figures

Figure 1
Figure 1
(A) Pedigree of the family. Solid symbols represent clinically affected individuals. (B) Brain MRI data from affected children. (a, b) Patient V-5 at 20 months of age. Coronal fluid-attenuated inversion recovery MRI showed symmetric hyperintensities in the deep and subcortical white matter of the temporal (a) and parietal (b) lobes. (c, d) Patient V-6 at 16 months of age. Axial T2-weighted MRI showed diffuse cortical and calcarine sulcus atrophy (c), diffuse subcortical white matter hyperintensities (c, d) and involvement of posterior periventricular white matter (d).
Figure 2
Figure 2
(a) Schematic view of ganglioside biosynthesis. (b) Identification of a homozygous nonsense mutation in the GM3 synthase gene. Sequence analysis of the GM3 synthase gene showing the segregation of the c.862C>T (p.Arg288*) mutation in the family.
Figure 3
Figure 3
MS analysis in the fibroblasts of patient V-5. (a) MALDI-TOF spectrometry analysis in positive mode. Representative spectra from control (upper panel), maximal unit 104 and, patient (lower panel), maximal unit 0.5 × 104. (b) Schematic lactoceramide pathway in control (left) and patient (right).
Figure 4
Figure 4
(a) Measurement of mitochondrial membrane potential in fibroblasts of patient V-5. Mitochondrial membrane potential was estimated by flow cytometry analysis of the catonic dye DiOC6(3) on control and patient fibroblasts. Fluorescence was measured on phosphorylating (basal) and non phosphorylating (state IV, not coupled to ATP synthesis) conditions. (b) Analysis of apoptosis in fibroblasts of patient V-5. Apoptosis was induced by 24 h-rotenone treatment. Ratios of apoptosis were established using untreated cell extracts has having a value of 1. Columns are the mean from three independently performed experiments; bars, SE; *P<0.05 versus control fibroblasts.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Debray F, Lambert M, Chevalier I, et al. Long-term outcome and clinical spectrum of 73 pediatric patients with mitochondrial diseases. Pediatrics. 2007;119:722–733. - PubMed
    1. Khurana D, Salganicoff L, Melvin J, et al. Epilepsy and respiratory chain defects in children with mitochondrial encephalopathy. Neuropediatrics. 2008;39:8–13. - PubMed
    1. Canafoglia L, Francheschetti S, Antozzi C, et al. Epileptic phenotypes associated with mitochondrial disorders. Neurology. 2001;56:1340–1346. - PubMed
    1. Lee Y, Kang H, Lee J, et al. Mitochondrial respiratory chain defects: underlying etiology in various epileptic conditions. Epilepsia. 2008;44:701–707. - PubMed
    1. El Sabbagh S, Lebre A, Bahi-Buisson N, et al. Epileptic phenotypes in children with respiratory chain disorders. Epilepsia. 2010;51:1225–1235. - PubMed

Publication types

MeSH terms

Supplementary concepts