Early onset or syndromic epilepsy
Gene: D2HGDH
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
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.
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
Source Wessex and West Midlands GLH was added to D2HGDH.
Source NHS GMS was added to D2HGDH.
Zornitza Stark: Seizures are a common feature
Gene: d2hgdh has been classified as Green List (High Evidence).
Phenotypes for gene: D2HGDH were changed from D-2-hydroxyglutaric aciduria, 600721; generalized tonic-clonic seizures; absence seizures; tonic seizures; tonic-clonic seizures; myoclonic seizures, to D-2-hydroxyglutaric aciduria, 600721; generalized tonic-clonic seizures; absence seizures; tonic seizures; tonic-clonic seizures; myoclonic seizures
Phenotypes for gene: D2HGDH were changed from D-2-hydroxyglutaric aciduria, 600721 to D-2-hydroxyglutaric aciduria, 600721; generalized tonic-clonic seizures; absence seizures; tonic seizures; tonic-clonic seizures; myoclonic seizures,
Gene: d2hgdh has been classified as Green List (High Evidence).
Mode of inheritance for gene: D2HGDH was changed from to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: D2HGDH were changed from to D-2-hydroxyglutaric aciduria, 600721
Expert Review Amber was added to D2HGDH. Panel: Genetic Epilepsy Syndromes
D2HGDH was added to Genetic Epilepsy Syndromes panel. Sources: Victorian Clinical Genetics Services
D2HGDH was created by Sarah Leigh