GM3 Synthase Deficiency

Clinical characteristics: Early clinical features of GM3 synthase deficiency include infantile onset of severe irritability with feeding difficulties, early and intractable seizures, growth failure with acquired microcephaly, sensorineural hearing impairment, hypotonia, and poor visual function. Over time, affected individuals experience severe-to-profound developmental delay and intellectual disability, can develop dystonia with hyperkinetic movements, and may develop pigmentary skin changes of the hands and feet. Affected individuals often have frequent ear infections and pneumonia without evidence of immune dysfunction.

Diagnosis/testing: The diagnosis of GM3 synthase deficiency is established in a proband with suggestive findings and biallelic pathogenic variants in ST3GAL5 identified by molecular genetic testing.

Management: Treatment of manifestations: Treatment for new-onset or worsening irritability is based on identification of inciting factors; for example, motility agents for constipation, antibiotic treatment of infections, and standard therapies for GERD, such as proton pump inhibitors. Seizures are treated with anti-seizure medication (ASM), although the majority of electrographic seizures in affected children are clinically silent. No ASM has been demonstrated effective for this condition specifically, ASM treatment may be only partially effective, and multiple ASMs may be required. Feeding therapy may be useful, with consideration of gastrostomy tube placement for persistent poor feeding / growth failure. Hearing aids may be helpful on a case-by-case basis. There is no specific treatment for optic atrophy or cortical blindness, although referral to low vision services is recommended. Dystonia, developmental delay / intellectual disability, sleep disturbances, infectious illnesses, and scoliosis are treated per standard methods.

Surveillance: At each visit: measure growth parameters, evaluate status and safety of oral intake, monitor for new manifestations (seizures, changes in tone, movement disorders), monitor developmental progress, assess for behavioral changes (new-onset or worsening irritability; aggressive or self-injurious behaviors), monitor for constipation/GERD/emesis, monitor for signs/symptoms of pneumonia, and obtain a non-invasive SpO₂. Annually: physical exam for signs/symptoms of scoliosis. As clinically indicated: Audiologic evaluation, ophthalmologic evaluation, and assessment of mobility, physical medicine, and OT/PT needs.

Therapies under investigation: Oral supplementation with GM3 gangliosides did not alter disease course and demonstrated only modest short-term benefit to affected individuals.

Genetic counseling: GM3 synthase deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an ST3GAL5 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the ST3GAL5 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.