Early onset or syndromic epilepsy

Gene: ASAH1

Green List (high evidence)

recognised phenotype with omim number

Created: 7 Oct 2019, 2:08 p.m. | Last Modified: 7 Oct 2019, 2:08 p.m.

Panel Version: 1.352

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
SMA with myoclonic epilepsy

Green List (high evidence)

AR SMA with progressive myoclonic epilepsy. Zhou et al, 2012 - 6 patients from 3 unrelated families. Family 1 - 3 aff sibs of consang turkish parents - progressive myoclonic epilepsy developed around 7 years of age. Family 2 - 2 Italian sisters - unrelated parents both had geralised epileptic seizures and myoclonic jerks from around 12 years of age. Family 3 - 1 aff girl - myoclonic seizures at age 11. First two families - hom missense variant T42M and family 3, compound het for T42M and a gene deletion, expression studies done. Dyment et al, 2014 - girl born of N.European descent - at 10 years, absence and atonic seizures and myoclonic jerks - compound het (missense and a nonsense) and segregated with disease. Other variants reported on HGMD pro with this phenotype - Ruboli et al, 2015, Kernohan et al, 2017.

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
Farber lipogranulomatosis, 228000; Spinal muscular atrophy with progressive myoclonic epilepsy, 159950

Publications

• 8955159
• 22703880
• 27026573

I don't know

The Green rating by Dr Alisdair McNeil (Sheffield Children's Hospital, Yorkshire and North East GLH) supports the current Green rating of ASAH1.

Created: 8 Oct 2019, 9:54 a.m. | Last Modified: 8 Oct 2019, 9:54 a.m.

Panel Version: 1.355

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

Comment on list classification: Updated rating from Red to Green. Confirmed Disease confidence rating in Gene2Phenotype for SPINAL MUSCULAR ATROPHY ASSOCIATED WITH PROGRESSIVE MYOCLONIC EPILEPSY. Relevant disorder in OMIM (Spinal muscular atrophy with progressive myoclonic epilepsy, 159950). Although the three families reported in PMID:22703880 share a haplotype suggesting Founder effect, there are sufficient additional papers reporting cases with additional variants. Note that although most individuals report muscle weakness followed by seizures, PMIDs 27026573 and 30291339 report muscle weakness WITHOUT epilepsy, and PMID:24164096 also report a case with seizures without muscle weakness- there is therefore some heterogeneity in the phenotype. On balance there are plenty of literature reports of seizures in patients with biallelic ASAH1 variants for inclusion on this panel.

Created: 27 Jun 2019, 1:54 p.m. | Last Modified: 27 Jun 2019, 1:54 p.m.

Panel Version: 1.75

Additional cases of seizures associated with SMA were reported in papers including PMIDs 27723502, 26526000, 25847462, 25578555, 31216804.

Created: 27 Jun 2019, 1:49 p.m. | Last Modified: 27 Jun 2019, 1:49 p.m.

Panel Version: 1.74

PMID:27723502 (Oguz et al, 2016) report eyelid myoclonic status epilepticus as an unusual manifestation of SMA-PME in a Turkish girl of consanguineous parents. Ambulatory problems were noted age 4. Generalized seizures developed later.

Created: 27 Jun 2019, 1:48 p.m. | Last Modified: 27 Jun 2019, 1:48 p.m.

Panel Version: 1.74

PMID:29169047: Yidiz et al (2018) report a 13.5 yr old girl with SMA-PME. She was the 8th child born of consanguineous parents. She presented with progressive muscle weakiness age 10, tremor, seizure (generalized epilepsy) and decreased cognitive functions. Screening revelead homozygous missense variant c.173C>T (T58M). The parents or siblings were not tested.

Created: 27 Jun 2019, 1:48 p.m. | Last Modified: 27 Jun 2019, 1:48 p.m.

Panel Version: 1.74

PMID:30291339: Ame van der Beek et al (2019) report an additional case of a mild SMA phenotype with NO myoclonic epilepsy due to variants in ASAH1. She carried two novel ASAH1 variants (Pro26Arg and c.125+1G>A splice variant leading to an unstable transcript lacking exon 2. Segregation analysis confirmed the parental inheritance and acid ceramidase activity was deficient in functional tests.

Created: 27 Jun 2019, 1:31 p.m. | Last Modified: 27 Jun 2019, 1:35 p.m.

Panel Version: 1.74

PMID:27026573: Filosto et al., 2016 studied 2 subjects: a 30yr old pregnant woman and her 17 year old sister affected with slowly progressive SMA since childhood but in the ABSENCE of siezures. Both subjects had a homozygous c.124A>G (T42A) variant in ASAH1.

Created: 27 Jun 2019, 1:31 p.m. | Last Modified: 27 Jun 2019, 1:31 p.m.

Panel Version: 1.73

PMID:24164096: In a girl who presented with absence and atonic seizures age 10, Dyment et al. (2014) identified compound heterozygous mutations in the ASAH1 gene: c.850G>T (G284X) and c.456A>C. Each parent was found to carry one of the variants. Although c.456A>C is predicted to encode a Lys152Asn substitution, it is 2bp away from a splice donor site and fibroblast assays showed an absence of exon 6, suggesting abberant splicing. Note that the patient harboured several hundred rare variants with at least two rare non-synonymous variants within the coding sequence of 4 genes (ASAH1, OC90, CACNA1C and LAMA5) though CACNA1C and OC90 were ruled out because the variants were found to be inherited from a single parent. Unlike the cases from PMID:22703880, this patient presented with seizures as the first symptom, and displayed no significant muscle weakness.

Created: 27 Jun 2019, 1:17 p.m. | Last Modified: 27 Jun 2019, 1:17 p.m.

Panel Version: 1.73

PMID:22703880: In 5 children from 2 families (Family D and Family ITA) with spinal muscular atrophy with progressive myoclonic epilepsy, Zhou et al. (2012) identified a homozygous variant (c.125C>T, T42M) in ASAH1. Another patient from a 3rd family (Family ITB) was found to be compound heterozygous for a maternally-inherited T42M mutation and a paternally-inherited deletion of the ASAH1 gene (the deletion involved ASAH1 only).

Family D was a consanguineous Turkish family with 3 affected and 1 unaffected children.
Family ITA had 2 affected sisters born to unrelated healthy Italian parents.
Family ITB had 1 affected girl born to unrelated healthy Italian parents.

c.125C>T was absent in 95 ethnically-matched controls. c.125C>T was found at a very low frequency (2 out of 10,756 alleles) in the current Exome Variant Server database.

Segregation analysis was performed in all 3 families: In Family D and Family ITA: both parents were heterozygous and affected siblings homozygous. In family ITB: the mother was heterozygous. The father carried a wild type allele and a whole-gene-deletion.

Haplotype analysis revealed an identical haplotype covering 31kb in the affected individuals of the three families, suggesting Founder effect for the c.125C>T mutation.

Created: 27 Jun 2019, 1:03 p.m. | Last Modified: 27 Jun 2019, 1:03 p.m.

Panel Version: 1.73