GM3 synthase deficiency in non-Amish patients

Area of Science:

• Genetics
• Biochemistry
• Neurology

Background:

• Biallelic loss-of-function variants in ST3GAL5 cause GM3 synthase deficiency (GM3SD).
• Amish infantile epilepsy syndrome is linked to a specific homozygous ST3GAL5 variant due to a founder effect.
• The phenotypical spectrum of GM3SD in non-Amish populations with diverse genetic backgrounds is not well-characterized.

Purpose of the Study:

• To investigate the clinical and molecular characteristics of GM3SD in non-Amish patients.
• To expand the understanding of ST3GAL5 variants and their associated phenotypes.
• To compare the GM3SD phenotype in non-Amish individuals with the previously described Amish infantile epilepsy syndrome.

Main Methods:

• Collected clinical and molecular data from 16 non-Amish patients with pathogenic ST3GAL5 variants.
• Identified 6 ST3GAL5 variants across 12 families from diverse geographical origins (Reunion Island, Ivory Coast, Italy, Algeria).
• Performed genealogical investigations, haplotype analyses, and glycosphingolipid quantification to confirm variant pathogenicity.

Main Results:

• Identified 6 ST3GAL5 variants, 5 novel, with 3 confirmed as founder alleles.
• Confirmed pathogenicity of 4 novel variants through glycosphingolipid analysis.
• Observed severe to profound intellectual disability, hyperkinetic movement disorder, epilepsy, and microcephaly in all patients. Other features included skin pigmentation anomalies, optic atrophy, and hearing loss.

Conclusions:

• The phenotype of GM3SD in non-Amish patients is clinically similar to Amish infantile epilepsy syndrome.
• GM3SD is associated with a narrow and severe clinical spectrum, regardless of genetic background.
• This study broadens the understanding of GM3SD's global impact and genetic diversity.