Early onset or syndromic epilepsy

Gene: PDHX

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 Lacticacidemia due to to PDX1 deficiency - Brown et al, 2002 - 2 unrelated patients with compnoent X defic - second patient had tonic clonic seizures.Brown et al, 2006 - 2 sibs both presented with seizures and had a fs variantIvanov et al, 2014 - clinical manifestations of 20 patients from the Roma population in Bulgaria hom for R446* - majority developed seizures in neonatal period or later in infancy in 4/20 seizures were an early manifestation.

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
Lacticacidemia due to PDX1 deficiency, 245349

Publications

• 25087164

Comment when marking as ready: Sufficient variants to associate with disorder. At least 3 cases where seizures are part of the phenotype.

Created: 20 Nov 2018, 11:18 p.m.

Comment on list classification: Numerous variants in this gene associated with Lacticacidemia are reported. 3 cases where seizures are part of the phenotype.

Created: 20 Nov 2018, 10:52 p.m.

PDHX (PDX1) is associated with Lacticacidemia due to PDX1 deficiency in OMIM and Gene2Phenotype. Numerous allelic variants have been reported. Cases with seizures reported include:

Brown et al 2002 (PMID: 11935326). Patient 2 had a homozygous single G>A base substitution in the conserved AG dinucleotide in the splice acceptorsite of intron 8. She presented with tonic-clonic seizures at 10 weeks, which continued throughout the first year.

Brown et al 2006 (PMID: 16904023). Patients 4 and 5 (brother and sister) both presented with seizures. Both have an insertion (c951insA).

Ivanov et al 2014 (PMID: 25087164) Identified a founder mutation p.Arg 446* mutation in PDHX which explains over half of cases with congenital lactic acidosis in Roma children. Seizures were among the early clinical manifestations in 4/20 of the patients that were PDHX p.Arg446* homozygotes.

Created: 20 Nov 2018, 10:51 p.m.

Green List (high evidence)

Seizures are part of the phenotype of this metabolic disorder.

Created: 18 Aug 2018, 10:14 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Lacticacidemia due to PDX1 deficiency, MIM#245349

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