Early onset or syndromic epilepsy

Gene: HEXA

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Green List (high evidence)

AR Tay Sachs, GM2-gangliosidosis, HEXA pseudodeficiency. Tay Sachs - progressive neurodegenerative disorder which in the classic infantile form is fatal by age 2-3 years. Infant onset of developmental retardation, followed by paralysis, dementia, blindness then death. No mention in the clinical features part of OMIM that any of these cases had seizures. Refs from panel app: Gowda et al, 2018 - 3 year old boy who had a febrile episode and developed myoclonic jerks - hom missense variant detected. Richard et al, 1995 - Non Jewish child - seizures present and is compound het for a missense and a splice site variant. Najmabadi et al, 2011 - Patient M165 - HEXA variant (hom) - had seizures. Are seizures a common feature??

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
GM2-gangliosidosis, several forms, 272800; Tay-Sachs disease, 272800; [Hex A pseudodeficiency], 272800

Publications

• 21937992
• 9222766

Tay-Sachs disease is rare in the general population but has increased frequency in Ashkenazi Jews. Many of the papers do not specify whether patients have seizures/epilpsy and many report on the patient's phenotype as classic infantile (seizures can be a symptom), juvenile or adult late-onset (seizures can be a symptom), which may or may not necessarily mean patients have seizures. I have only included studies that mention seizures/epilepsy specifically.
Three studies have reported 3 patients with different variants in HEXA gene who have seizures (PMID: 30006889, 21937992, 7551830). PMID: 14972682 describe a mouse model of HEXA which also exhibited seizure/epilpsy phenotype.

Created: 22 Nov 2018, 1:52 p.m.

Comment on list classification: Promoted from Amber to Green as seizures is a phenotype of
Tay-Sachs disease is confirmed to be associated with this gene by both OMIM and Gene2Phenotype and seizures is listed in both of these databases.

Created: 15 Nov 2018, 11:43 a.m.

Green List (high evidence)

Seizures are part of the phenotype in this metabolic disorder.

Created: 15 Aug 2018, 1:04 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Tay-Sachs disease, MIM#272800

Variants in this GENE are reported as part of current diagnostic practice