Introduction
GM3 synthase deficiency is an inborn error of metabolism, previously known as Amish Infantile Epilepsy Syndrome or Salt and Pepper Developmental Regression Syndrome. GM3 synthase is a sialyltransferase encoded by ST3GAL5. Its main function is to synthesize GM3 which is the precursor for most of the gangliosides in human brain. Biallelic pathogenic variants in ST3GAL5 cause GM3 synthase deficiency.  This condition was first described in an Amish population and is characterized by infantile-onset seizures, feeding difficulties, and severe irritability. Other clinical features include growth failure, microcephaly, hypotonia, dystonia, hyperkinetic movements, developmental delay, intellectual disability, scoliosis, skin pigmentation anomalies, as well as visual and hearing impairment. Over one hundred patients with variable phenotypes have been described so far in the literature.

 Here, we describe a patient with GM3 synthase deficiency who underwent a long diagnostic odyssey given her atypical presentation.

Case Presentation
This 15 year old female with history of intellectual disability, absent speech, and G-tube dependence presented to Clinical Genomics for an updated genetic evaluation. Our patient had an unremarkable birth history except for bilateral clubfeet managed with casts and braces. Developmental delay was noted in first year of life which prompted the patient’s initial genetics evaluation at 12 months of age. No definitive diagnosis was made.  At the time of evaluation by our team, she had also been diagnosed with hearing loss and scoliosis. Additionally, her physical exam was notable for microcephaly and spasticity. The family history is notable for consanguineous parents who are 1^st degree cousins of Pakistani ancestry, but otherwise there was no known family history of genetic disorders.

Diagnostic Workup
This patient’s extensive prior evaluation included comprehensive biochemical testing, brain MRI, chromosomal analysis, fragile X analysis, and mitochondrial DNA sequencing all of which were unrevealing. Whole genome sequencing was pursued which identified homozygous pathogenic variant c.862C>T (p.Arg288Ter) in ST3GAL5, consistent with a diagnosis of GM3 synthase deficiency.

 

Treatment and Management
No curative treatment is currently available for GM3 synthase deficiency. Our patient will continue to be managed supportively by neurology team.

Outcome and Follow-Up
The patient has had an evaluation with neurology after her diagnosis was made, plan is to continue follow up for monitoring and supportive management. 

Discussion
We present a case of GM3 synthase deficiency in a fifteen-year-old patient with intellectual disability, G-tube dependence, hearing loss, scoliosis, microcephaly and spasticity, but no seizures.

The most common pathogenic variant (c.862C>T) reported in the literature is an established founder mutation, common within the Amish population. Individuals homozygous for this variant usually present with infantile onset epileptic encephalopathy. However, in our patient, this same homozygous pathogenic variant presented without seizures. Another case of a Pakistani family with the same c.862C>T variant has been reported in the literature. Interestingly, the three Pakistani siblings described by Gordon-Lipkin et al. (2018) also did not have seizures. Their clinical presentation included developmental stagnation, profound intellectual disability, choreoathetosis, failure to thrive, and visual and hearing impairment, as well as ichthyosis and self-injurious behavior.  

Conclusion
This case suggests that GM3 synthase deficiency has a variable phenotype and should be suspected in patients with neurodevelopmental disorder, even in the absence of seizures.