Early onset or syndromic epilepsy

Gene: GLYCTK

I don't know

As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is insufficient evidence to rate this gene Green. Bordeline cases from literature, variable phenotype and needs better genotype:phenotype correlation. Demoted from Green to Amber.

Created: 25 Nov 2019, 8:52 p.m. | Last Modified: 25 Nov 2019, 8:52 p.m.

Panel Version: 1.443

PMID:30637540 (Zehavi et al., 2019) report a male from a consanguineous Arab family with intractable seizures and a homozygous missense pathogenic variant in GLYCTK (p.Leu152Pro).

Created: 21 Nov 2019, 1:47 p.m. | Last Modified: 21 Nov 2019, 1:47 p.m.

Panel Version: 1.412

PMID:28462797 (Swanson et al., 2017) reviewed the Serbian patient from Sass et al., 2010. In addition to p.Phe483SerfsX2 variant in GLYCTK, the patient had an additional Ser117Leu variant in AMT highlighting the co-occurence of two metabolic conditions (D-glyceric aciduria and nonketotic hyperglycinemia).

Created: 21 Nov 2019, 1:47 p.m. | Last Modified: 21 Nov 2019, 1:47 p.m.

Panel Version: 1.412

PMID:20949620 (Sass et al., 2010) report 3 patients of Serbian, Mexican and Turkish origin, including the original 1974 (Serbian) patient. All had homozygous variant in GLYTCK:
Patient A was a Serbian boy with generalized seizures beginning age 8 weeks (p.Phe483SerfsX2 variant).
Patient B was a Mexican girl with focal clonic seizures and a Phe493Cys variant.
Patient C was a Turkish boy where seizures were not noted (p.Leu520CysfsX108 variant).

Created: 21 Nov 2019, 1:47 p.m. | Last Modified: 21 Nov 2019, 1:47 p.m.

Panel Version: 1.412

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: Amber.

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

Panel Version: 1.189

I don't know

AR D-glyceric aciduria - rare AR metabolic disorder with a highly variable phenotype. Some patients have a severe phenotype including seizures and sometimes early death and milder phentoype with only mild speech delay or even normal development. Sass et al 2010 - hom fs mutation identified in a son of non-consang Serbian parents - neonatal hypotonia, delayed psychomotor development, mental retardation and seizures - died aged 3.5 years. However, Swanson et al, 2017 also identified a hom missense AMT variant in cells deried from this patient consistent with a diagnosis of GCE and in vitro studies supported pathogenicity. Confirms 2 inborn errors of metabolism in this patient. Sass et al, 2010 also identified hom mutations in 2 other unrelated patients. Kalim et al,2017 - 2 sibs from a consang Pakistani family - 5 year old boy very severe autism and global dev delay, younger sister asymptomatic and developmentally normal. Both had sim amounts if d-glycerate and both hom for a novel missese variant. They suggest that d-glycerate kinase defic could be a benign disorder with long follow up studies and a greater no of individuals required to confirm.

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
D-glyceric aciduria,220120

Publications

• 30637540

Green List (high evidence)

'treatable' tag, as intervention with a fructose-restricted diet may lead to clinical improvement - PMID:3588091

Created: 16 Mar 2017, 2:53 p.m.

Inclusion of this as a green gene on this panel is appropriate, based on the review in the Undiagnosed metabolic disorders panel and the views of clinical expert, Dr Arianna Tucci, UCL.

Created: 16 Mar 2017, 2:52 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
D-glyceric aciduria 220120

Publications

• 3588091