Early onset or syndromic epilepsy

Gene: D2HGDH

Green List (high evidence)

AR D-2 hydroxyglutaric aciduria - neurometabolic disorder characterised by dev delay, epilepsy, hypotonia and dysmorphic features. Severe pheno associated with EIEE, mild pheno - more variable. Struys et al, 2005 (incl patient from Gibson et al, 1993) - 2 unrelated patients - 1 hom for a missense variant, the other, compound het for missense and splice site, both patients were reported to have seizures. In addition another paper - 3 individuals from 2 unrelated pakistani families - hom variants detected. seizures reported in family 2 not family 1. Kranendijk et al, 2010 - identified presumed pathogenic variants in 24/50 patients with increased levels of D-2 hydroxyglutaric acid - no mention of clinical presentation.

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-2-hydroxyglutaric aciduria, 600721

Publications

• 15609246
• 26178471

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

Comment on list classification: Updated rating from Amber to Green. Green review, and as Zornitza reports, epilepsy is a phenotype of D-2-hydroxyglutaric aciduria. Sufficient unrelated epileptic cases from the literature (2 from PMID:15609246 and 1 from PMID:16037974) to support a diagnostic rating.

Created: 20 Nov 2018, 1:46 p.m.

Struys et al 2005 (PMID:15609246) report two unrelated patients affected with severe D-2-hydroxyglutaric aciduria and disease-causing variants in D2HGDH. Patient one suffered tonic, tonic-clonic, and myoclonic seizures, and was homozygous for missense variant in D2HGDH (c.1331T-->C; p.Val444Ala). Patient 2 presented with generalized tonic-clonic seizures and infantile spasms amongst her symptoms. She was compound heterozygous for a missense mutation (c.440T-->G; p.Ile147Ser) and a splice-site mutation (IVS1-23A-->G) that resulted in a null allele.

Created: 20 Nov 2018, 1:42 p.m.

Struys et al. (2005, PMID:16037974) examined 3 patients from 2 unrelated consanguineous Palestinian families with mild D-2-hydroxyglutaric aciduria and homozygous variants in D2HGDH. In family 1, the two affected siblings were clinically asymptomatic and had the homozygous IVS4‐2A>G variant. Patient C (Family 2) is the only affected member of his family, and at age 8 years he developed absence seizures with myoclonic jerks amongst his symptoms. He had a Homozygous Asn439Asp variant in D2HGDH.

Created: 20 Nov 2018, 1:38 p.m.

Green List (high evidence)

Seizures are a common feature of this metabolic disorder.

Created: 12 Aug 2018, 6:06 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
D-2-hydroxyglutaric aciduria, MIM#600721

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