Early onset or syndromic epilepsy

Gene: PAH

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 phenylketonuria - seizures are a symptom if left untreated. Tested in UK as part of newborn screening programme.

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
Phenylketonuria 261600; [Hyperphenylalaninemia, non-PKU mild], 261600

Publications

• 8097262
• 25014052

Comment on list classification: Two cases reported in recent literature of variants in PAH in patients that show Phenylketonuria with seizures. Few cases of untreated PKU since newborn screen is now routine in most countries. But many publications state that seizures are a feature of untreated PKU so rating this gene green.

Created: 11 Dec 2018, 4:45 p.m.

Associated with Phenylketonuria in OMIM and Gene2Phenotype and seizures are listed in the clinical phenotype of both.

Through newborn screening most cases are treated today.

Purevsuren et al (2016)(PMID: 27830119) reports one Mongolian child with compound heterozygous variants in PAH and epilepsy.

Schwoerer et al (2018)(PMID: 29560316) - 1 case of Wisconsin Amish child presenting with intellectual disability, seizures, autism, decrease pigmentation, and a history of no newborn screen (case 12). Homogyzosity for a pathogenic variant in PAH was identified.

The European guidelines on phenylketonuria: diagnosis and treatment published by van Wegberg et al 2017 (PMID: 29025426) state that if left untreated PKU results in increased phenylalanine concentrations in blood and brain, which cause severe intellectual disability, epilepsy and behavioural problems.

Chandra et al (2018)(PMID: 29899773) looked at 15 cases of Phenylketonuria with clinical data. Age at diagnosis ranged from 2.5 to 7 years Seizures were reported in 9/15. No variant analysis of the PAH gene but tandem mass spectroscopy showed elevated phenylalanine, normal tyrosine, and elevated phenylalanine/tyrosine ratio in all cases.

Yildiz Celik et al (2018)(PMID: 29579554) - 10 patients (2 related) with PKU reported, all with epilepsy/seizures. Some had febrile seizures but this was in addition to other types of seizure. Age at diagnosis of PKU was 3.5 months to 12 years. However, classic type phenylketonuria was only identified in one patient, 3 others had tetrahydrobiopterin deficiency and this data could not be obtained for other patients. No information about how this distinction was made.

Created: 11 Dec 2018, 4:32 p.m.

I don't know

Seizures are part of the phenotype of untreated PAH, though one hopes diagnosis is through newborn screening.

Created: 18 Aug 2018, 9:11 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Phenylketonuria, MIM#261600

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