Early onset or syndromic epilepsy

Gene: PSAP

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 combined SAP deficiency. Harzer et al, 1989 & Schnabel et al, 2002 - first cousin parents - generalised clonic seizure shortly after birth - a second sib similarly aff - hom mutation identified. Hulkova et al, 2001 - fatal infantile storage disorder in a Slovakian infant - developed seizures and died age 3.5 months- hom mutation identified, IHC done. Kuchar et al, 2009 - male infant - developed treatment resistant clonic fits shortly after birth died at 55 days. Second patient - first generalised seizure at 43 months - patient 1 hom for a splicing variant and patient 2 compound het for a splice and a fs variant. Motta et al, 2016 - table 1 - 7 prev reported patients with PSAP defic - 4/7 say seizures. Both patients being reported by the paper have seizures as part of phenotype.

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
Combined SAP deficiency 611721; Gaucher disease, atypical 610539; Krabbe disease, atypical 611722; Metachromatic leukodystrophy due to SAP-b deficiency 249900

Publications

• 19267410

Comment on list classification: Promoting to green after gaining access to PMID: 2514102 and confirming a second case of a patient showing seizures, which along with the mouse knockout model confirms the association with seizures. In addition there is a green expert review.

Created: 5 Dec 2018, 7:31 p.m.

Comment on phenotypes: Only added Combined SAP deficiency as a phenotype as evidence for seizures only found for this disorder.

Created: 5 Dec 2018, 5:18 p.m.

Comment on list classification: Keeping Amber rating, as only 1 confirmed case of a variant in PSAP in an individual with seizures. A mouse knockout model which does develop seizures also exists.

Created: 5 Dec 2018, 5:11 p.m.

A mouse SAP -/- knockout exists (PMID: 8776585) and surviving mice develop intermittent seizures and progress to continual tonic status epilepticus.

Created: 5 Dec 2018, 5:09 p.m.

Metachromatic leukodystrophy due to SAP-b deficiency
2 cases of children with variants in PSAP and saposin B deficiency have been reported in PMID: 8554069 (Henseler et al. 1996) and PMID: 10682309 (Wrobe et al. 2000). Neither child was reported to have seizures.

Created: 5 Dec 2018, 4:54 p.m.

Combined SAP deficiency
PMIDs: 2514102 (Harzer et al. 1989) and 1371116 (Schnabel et al. 1992) report 2 sibs with combined SAP deficiency with a homozygous mutation resulting in a M1L substitution. No precursor and no mature SAPs were detected in the patient's cells. Both parents were heterozygous for the mutation. The first child's clinical phenotype included generalized clonic seizure shortly after birth. The second pregnancy was terminated following diagnosis.

PMID: 11309366 (Hulkova et al. 2001) - In a Slovakian patient with fatal infantile combined SAP deficiency, a homozygous 1 bp deletion in the PSAP gene, inherited from both his parents . Immunohistochemical investigations indicated that saposins A, B, C, and D were all deficient. Generalized seizures developed within minutes of birth.

Created: 5 Dec 2018, 4:53 p.m.

Associated with Combined SAP deficiency and Metachromatic leukodystrophy due to SAP-b deficiency in OMIM both of which have seizures listed as part of their clinical phenotype. Not associated with either of these disorders in Gene2Phentoype.

Created: 5 Dec 2018, 4:53 p.m.

Green List (high evidence)

Seizures are part of the phenotype of these metabolic disorders.

Created: 19 Aug 2018, 11:49 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Metachromatic leukodystrophy due to SAP-b deficiency, MIM#249900; Combined SAP deficiency, MIM#611721

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