Early onset or syndromic epilepsy

Gene: PTS

I don't know

As discussed with members of the GMS Neurology Specialist Test Group on the Webex call 22nd November 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that there is enough evidence to rate this gene Green. Seizures may present before 9 months, and could be the primary presentation in these cases. Since the last group review, PTS has also been promoted to Green on the 'Inborn errors of metabolism' panel (v 1.407). Promoted PTS from Amber to Green on the epilepsy panel.

Created: 25 Nov 2019, 8:44 p.m. | Last Modified: 25 Nov 2019, 8:47 p.m.

Panel Version: 1.437

As discussed with members of the GMS Neurology Specialist Test Group on the Webex call Thursday 8th August 2019 for Clinical Indication R59 Early onset or syndromic epilepsy: Agreed that this gene should be rated Amber to match the rating on the 'Inborn errors of metabolism' panel. The prevailing phenotype is a movement disorder. Demoted from Green to Amber.

Created: 15 Aug 2019, 10:14 a.m. | Last Modified: 15 Aug 2019, 10:14 a.m.

Panel Version: 1.232

Re-reviewed this gene when curating panel for GMS Clinical Indication R59 Early onset or syndromic epilepsy. In summary: Severe Hyperphenylalaninemia, BH4-deficient, is accepted to include seizures (PMID:8801112). Because this condition is diagnosed and treated from an early age, seizures may not be reported frequently. PMID:31000854 (Ahmed et al., 2019)assessed hyperphenylalaninemia patients and found 14/18 (78%) had seizures and ID however genetic analysis to see which of these had PTPS/PTS variants was not performed. PMID:9222757 report 1 case of seizures.

Created: 15 Aug 2019, 10:13 a.m. | Last Modified: 15 Aug 2019, 10:13 a.m.

Panel Version: 1.232

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: Amber.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

I don't know

AR BH4-deficient hyperphenylalaninemia A - most common type. Seizures are a reported feature and as it can be treated - early detection and diagnosis is good - but may also mean fewer patients reported with seizures due to treatment options.

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
Hyperphenylalaninemia BH4-deficient A, 261640

Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 5 variants reported to be associated with severe Hyperphenylalaninemia, BH4-deficient, A 261640, which is accepted to include seizures (PMID 8801112). PMID 9222757 reports first cousins MG & AI, MG who were both homozygous for c.200C>T, p.T67M. MG had two episodes of diazepam responsive convulsions, followed by persistent limb hypertonia, hyperreflexia and myoclonic seizures. The sister of AI died at 21 months following a long course of progressive encephalopathy, microcephaly, Grand Mal convulsions, suggestive of Hyperphenylalaninemia, BH4-deficient, A 261640 (there is no report of DNA analysis). AI, (also diagnosed with Hyperphenylalaninemia, BH4-deficient, A 261640) was also biallelic for c.200C>T, p.T67M. Although she was treated from an early age her motor and intellectual development were severely impaired, with large diurnal fluctuations of clinical symptoms and behavioural disturbance. PMID 9450907 reports four variants in a biallelic state in a total of 9 unrelated cases of severe Hyperphenylalaninemia, BH4-deficient, A 261640, seizures were not mentioned directly in this publication, however, seizures are considered to be a feature of this condition (PMID 8801112). Because this condition is diagnosed and treated from an early age, seizures may not be reported frequently.

Created: 21 Nov 2018, 5:39 p.m.

Green List (high evidence)

Seizures are part of the phenotype of this metabolic disorder.

Created: 20 Aug 2018, 1:54 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Hyperphenylalaninemia, BH4-deficient, A, MIM#261640

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