Early onset or syndromic epilepsy

Gene: CAD

Green List (high evidence)

AR EIEE 50 - delayed psychomotor development, early-onset seizures, severe developmental regression and normocytic anemia - onset in first few years of life. Ng et al, 2015 - 4 year old boy with unrelated parents - seizures occurred at 17 months. Compound het mutations in CAD (missense and splicing). Koch et al, 2017 - 5 patients from 3 unrelated families - all developed seizures between 6 months and 2 years, 3 of whom died between 2.5 and 5 years of age. 2 families of Serbian-Roma descent - 1 of these consang. Hom or compound het mutations in CAD. No functional work done - predict LOF. On HGMD Pro - Russo et al, 2018 - patient with congenital dyserythropoietic aneima (CDA) - mild and epilepsy found to be hom for a CAD missense variant.

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
Epileptic encephalopathy early infantile, 616457

Publications

• 28007989

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

Confirmed DD-G2P gene for Uridine-responsive epileptic encephalopathy.

Created: 11 Dec 2018, 10:47 a.m.

Comment on list classification: Updated rating from Grey to Green: 5 patients from 4 families in total (1 patient from PMID:25678555 and 4 more patients from 28007989) all with epileptic seizures (generalized tonic clonic seizures, severe epilepsy, generalised/focal seizures). Note that 2 of the families in PMID:28007989 were Serbian Roma descent with the same homozygous c.98T>G (Met33Arg) transversion, although listed as unrelated. Overall sufficient (>3) unrelated cases of epileptic seizures in patients with CAD variants, for inclusion on diagnostic panel.

Created: 11 Dec 2018, 10:47 a.m.

Green List (high evidence)

Biallelic pathogenic variants in CAD cause Epileptic encephalopathy, early infantile, 50 - MIM 616457.

Overall 5 individuals from 4 unrelated families have been reported in detail in PMIDs 25678555 and 28007989 (table 1 in this article provides a summary).

The phenotype consisted of developmental delay which preceded the onset of seizures (6 months to 2 years) and hematologic anomalies (anemia and anisopoikilocytosis). The patients presented developmental stagnation/regression, which in most cases occurred several months following the seizure onset.

CAD is a tri-functional protein catalyzing the first 3 steps of the de novo pyrimidine biosynthesis.

In total, 5 variants have been reported (2 missense, 1 nonsense and 2 splice-site SNVs) with functional studies (cDNA, metabolites) supporting pathogenicity and disruption of this pathway.

CAD mutations have previously been studied in other model organisms.

Mutations in enzymes catalyzing downstream steps of the same pathway are associated with other syndromes.

The disorder appears to be amenable to dietary intervention (uridine supplementation).

As a result, this gene can be considered for inclusion in the epilepsy panel as green (or amber).
Sources: Literature

Created: 4 Dec 2018, 11:51 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Epileptic encephalopathy, early infantile, 50 - MIM 616457

Publications

• 25678555
• 28007989