Early onset or syndromic epilepsy

Gene: CYP27A1

I don't know

AR cerebrotendinous xanthomatosis - no mention of seizure/epilepsy as a feature on OMIM. Szlago et al, 2008 - 2 Argentinian siblings with a novel mutation in this gene - febrile seizures reported follwed by photosensitive epileptic syndrome.

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
Cerebrotendinous xanthomatosis, 213700

Publications

• 2019602
• 22336472

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 insufficient evidence to rate this gene Green. Prominent phenotype is dystonia/ataxia. Demoted from Green to Amber.

Created: 25 Nov 2019, 8:48 p.m. | Last Modified: 26 Nov 2019, 4:08 p.m.

Panel Version: 1.475

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

Comment on list classification: Upgraded rating from Red to Green based on external review by Philip Dawson. Although seizures are not a consistent feature of CTX patients, there are plenty of cases in the literature of seizures reported in CTX cohorts and individual cases (e.g. PMIDs 29484516 and 22336472) to support inclusion on this panel.

Created: 9 Jul 2019, 10:53 a.m. | Last Modified: 9 Jul 2019, 10:53 a.m.

Panel Version: 1.133

PMID:22336472. Koyama et al. 2012. An 18 year old Japanese female with a history of epileptic seizures amongst her phenotypes. She had compound heterozygous variants in CYP27A1: maternally-inherited V413D and paternally-inherited R474W. The variants were not present in Japanese controls.

Created: 9 Jul 2019, 10:41 a.m. | Last Modified: 9 Jul 2019, 10:41 a.m.

Panel Version: 1.132

PMID:24442603. Mignarri et al 2014. In their CTX cohort of 55 patients, 18 were reported with epilepsy (33%). They report 14/54 (26%) and 8/25 (32%) of epilepsy cases in previous cohorts.

Created: 9 Jul 2019, 10:40 a.m. | Last Modified: 9 Jul 2019, 10:40 a.m.

Panel Version: 1.132

PMID:29484516. Wong et al 2018 evaluated 5 cases of cerebrotendinous xanthomatosis (CTX) patients. CTX is an autosomal recessive condition caused by variants in CYP27A1. Seizures reported in 1/5 cases at 24 years old. They also analysed 194 cases from the literature and reported seizures in 37/194 cases (19%).

Created: 9 Jul 2019, 10:40 a.m. | Last Modified: 9 Jul 2019, 10:44 a.m.

Panel Version: 1.132

PMID:18227423. Szlago et al., 2008 report 2 Argentinian siblings with novel compound het CYP27A1 variants: 11_12insTGGGCTGCGC and T395C. Both patients had photosensitive epilepsy. Patient 2 had febrile seizures preceeding the epilepsy. Samples were taken from the parents and a sibling, though full segregation is not discussed. This is the original case discussed by Sarah Leigh.

Created: 9 Jul 2019, 10:40 a.m. | Last Modified: 9 Jul 2019, 10:40 a.m.

Panel Version: 1.132

Green List (high evidence)

1. A 2014 literature review of CTX cases by Mignarri et al identified two earlier cohorts that reported an association with epilepsy (Verrips et al and Pilo de la Fuente et al) and that data was presented along with their own cohort. This showed epilepsy associated with CTX in 26-33% of cases (Mignarri, 18/55 (33%), Verrips, 8/25 (32%), Pilo de la Fuente, 14/54 (26%)) 1
2. In 2018, Wong et al published the results of a PubMed literature review which identified 91 publications and 194 cases which was presented along with their own case series of 5 patients. 37 of the 194 (19.1%) had seizures. They also calculated Cumulative Incidence Function (CIF) for each CTX symptom which gives an indication of the likelihood of a particular symptom having developed at any given age (best- & worst-case scenario) based on a subset of cases where age of symptom onset was available; this shows that epilepsy may develop in both children and adults.
References
1. Mignarri et al, A suspicion index for early diagnosis and treatment of cerebrotendinous xanthomatosis. J Inherit Metab Dis (2014) 37:421-429
2. Wong et al, Natural history of neurological abnormalities in cerebrotendinous xanthomatosis. J Inherit Metab Dis. 2018 Jul;41(4):647-656

Created: 18 Apr 2019, 3 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cerebrotendinous xanthomatosis, 213700, Epilepsy, including childhood onset.

Publications

• 24442603
• 29484516

Red List (low evidence)

Not associated with phenotype in OMIM or in Gen2Phen. At least one variant in a single case in which seizures are a phenotypic feature.
Sources: Literature

Created: 11 Dec 2018, 3:57 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cerebrotendinous xanthomatosis 213700

Publications

• 18227423