Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency

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.

GM3 synthase deficiency due to ST3GAL5 variants in two Korean female siblings: Masquerading as Rett syndrome‐like phenotype

“…2), although we did not measure the activity of GM3 synthase in vitro. Increased lactate levels seen in the present study might suggest the secondary mitochondrial dysfunction due to GM3 synthase deficiency [Fragaki et al, 2013]. Yoshikawa et al reported that ganglioside GM3 is essential for the proper organization and maintenance of stereocilia in auditory hair cells, and therefore GM3 synthase deficiency can result in hearing loss [Inokuchi, 2011;Yoshikawa et al, 2015].…”

“…As shown in Figure 1C, there have been only two homozygous mutations reported to date: c.862C>T (p.Arg288 Ã ) and c.994G>A (p.Glu332Lys). The protein from the nonsense mutation, c.862C>T, was truncated between L-and S-motifs, which has been reported in Old Order Amish patients [Simpson et al, 2004;Fragaki et al, 2013;Wang et al, 2013]. The other mutation, c.994G>A in an African-American family, was within the S-motif, which might result in disturbed function of S-motif, interacting with the lactosylceramide acceptor and a sugar donor [Boccuto et al, 2014].…”

“…It remains unclear whether the condition is caused by a lack of GM3 and its downstream metabolites or accumulation of lactosylceramide and its alternative metabolites (o-and globoseries) [Kacher and Futerman, 2006]. This condition resulting from the impaired ganglioside biosynthesis pathway can disturb neurodevelopment, which clinically manifest with severe developmental delay/intellectual disability and epilepsy during infancy [Simpson et al, 2004;Fragaki et al, 2013;Wang et al, 2013;Boccuto et al, 2014]. The disease may also present with irritability during early infancy, failure to thrive, cutaneous dyspigmentation, blindness, and deafness [Simpson et al, 2004;Farukhi et al, 2006;Inokuchi, 2011;Fragaki et al, 2013;Wang et al, 2013;Boccuto et al, 2014].…”

“…Diseases from the impaired ganglioside catabolism pathway are widely known, such as the lysosomal storage diseases [Kacher and Futerman, 2006]. However, only a few reports of diseases resulting from disturbance of the ganglioside biosynthesis pathway have been published to date [Simpson et al, 2004;Fragaki et al, 2013;Wang et al, 2013;Boccuto et al, 2014].…”

“…It is characterized clinically by infantile-onset epilepsy, severe intellectual disability, irritability, failure to thrive, blindness, choreoathetosis, and cutaneous dyspigmentation [Simpson et al, 2004;Fragaki et al, 2013;Boccuto et al, 2014].…”