GM3 Synthase Deficiency via the ST3GAL5 Gene

GM3 synthase deficiency (or Amish Infantile Epilepsy Syndrome or Salt and Pepper Mental Retardation Syndrome) is a rare infantile onset neurocutaneous disorder characterized by refractory epilepsy, severe intellectual disability, dysmorphic facial features and hyper- and hypo-pigmented skin maculae on the trunk, face, and extremities. Other variable features include scoliosis, choreoathetosis, spasticity, blindness, deafness, and abnormal EKG (Fragaki et al. 2013; Boccuto et al. 2014).

The onset of epilepsy is accompanied by profound developmental stagnation and regression. Failure to thrive, trouble feeding, and irritability are noticed in the first 2 weeks to 3 months of life. Seizure onset occurs within the first year with multiple type manifestations including generalized tonic-clonic seizures, brief tonic spasms, episodes of eye deviation or startle from sleep. EEG reveals multifocal epileptiform activity. MRI results are initially normal, but show diffuse atrophy as patients age. Mass spectrometry reveals loss of complex gangliosides (Simpson et al. 2004; Fragaki et al. 2013).

GM3 synthase deficiency is inherited in an autosomal recessive manner and is caused by pathogenic variants in the ST3GAL5 gene which encodes GM3 synthase (sialyltransferase). Missense and nonsense variants in ST3GAL5 have been reported in patients with GM3 synthase deficiency. No large deletions/duplications in the ST3GAL5 locus have been reported. Initially described in an Old Order Amish pedigree, GM3 synthase deficiency has subsequently been reported in African-American and French families (Simpson et al. 2004; Fragaki et al. 2013; Boccuto et al. 2014).

GM3 synthase adds sialic acid to lactosylceramide, finally forming ganglioside GM3. The ganglioside GM3 is a glycosphingolipid mainly expressed in neural tissue. One study demonstrated that mitochondrial dysfunction and apoptosis occurred secondary to GM3 synthase deficiency (Fragaki et al. 2013). The authors suggest that mitochondrial defects might contribute to the ganglioside GM3 synthase deficiency phenotype and could explain the clinical similarities between GM3 synthase deficiency and respiratory chain disorders (Fragaki et al. 2013).

Clinical sensitivity of ST3GAL5 in a large cohort of patients with ganglioside GM3 synthase deficiency relevant phenotypes is unavailable in the literature because most of the studies are case reports. Analytical sensitivity should be high because all pathogenic variants reported to date are detectable by sequencing.

This test provides full coverage of all coding exons of the ST3GAL5 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.