Amish infantile epilepsy syndrome

GM3 Synthase Deficiency

Clinical Characteristics

Ocular Features:

Optic atrophy is the primary ocular feature in this disorder. ERG amplitudes and retinal pigmentation are normal. Visual impairment is pronounced with no reactions to threatening visual stimuli. Eye movements are random and uncoordinated. Optic atrophy is present but no retinal abnormalities have been reported.

Systemic Features:

Infants may appear normal at birth but within a few months develop signs of developmental stagnation with onset of tonic-clonic seizures. Irritability, poor feeding, vomiting and failure to thrive are important features. Generalized hypotonia is evident but lower limb deep tendon reflexes may be present. Normal developmental milestones are never achieved and patients are unresponsive to their environment. Older individuals develop non-purposeful choreothetoid movements. The EEG shows multifocal epileptiform discharges and brain MRIs show diffuse atrophy in older patients.

Hypo- and hyperpigmented skin macules in a 'salt and pepper' pattern, have been described. These vary from 2-5 mm in size and are located primarily on the extremities. These are found among children older than 3 years of age and some parents have reported that the hyperpigmentation may decrease after many years. No such lesions were found in mucosal tissue.

Genetics

This is an autosomal recessive disorder secondary to homozygous mutations in (ST3GAL5) (2p11.2) encoding sialytransferase (SIAT9).

The nonsense mutation results in a deficiency of functional GM3 synthase important in the utilization of lactosylceramide necessary for the production of downstream gangliosides.

Pedigree:

Autosomal recessive

Treatment

Treatment Options:

There is no known treatment for the enzyme deficiency. Seizures respond poorly to anti-epileptic medications.

References

Article Title:

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

Lee JS, Yoo Y, Lim BC, Kim KJ, Song J, Choi M, Chae JH. GM3 synthase deficiency due to ST3GAL5 variants in two Korean female siblings: Masquerading as Rett syndrome-like phenotype. Am J Med Genet A. 2016 Aug;170(8):2200-5.

PubMed ID:

27232954

Etiology of vision loss in ganglioside GM3 synthase deficiency

Farukhi F, Dakkouri C, Wang H, Wiztnitzer M, Traboulsi EI. Etiology of vision loss in ganglioside GM3 synthase deficiency. Ophthalmic Genet. 2006 Sep;27(3):89-91.

PubMed ID:

17050284

Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase

Simpson MA, Cross H, Proukakis C, Priestman DA, Neville DC, Reinkensmeier G, Wang H, Wiznitzer M, Gurtz K, Verganelaki A, Pryde A, Patton MA, Dwek RA, Butters TD, Platt FM, Crosby AH. Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase. Nat Genet. 2004 Nov;36(11):1225-9.

PubMed ID:

15502825

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