Progressive myoclonus epilepsy in Gaucher Disease due to a new Gly-Gly mutation causing loss of an Exonic Splicing Enhancer.
J Neurol
; 266(1): 92-101, 2019 Jan.
Article
in En
| MEDLINE
| ID: mdl-30382391
ABSTRACT
BACKGROUND:
Patients with Gaucher Disease (GD) exhibit three phenotypes, including type 1 (non-neuronopathic), type 2 (acute neuronopathic), and type 3 (subacute neuronopathic).AIM:
Identifying which GBA changes represent benign polymorphisms and which may result in disease-causing mutations is essential for diagnosis and genotype/phenotype correlations but is often challenging.RESULTS:
Here, we describe a patient with type 3 GD, presenting with drug-resistant epilepsy, who bears a set of GBA polymorphic variants including the novel c.363A > G (Gly82Gly) synonymous mutation. In silico predictions, mRNA and functional studies revealed that the new Gly82Gly mutation causes skipping of GBA exon 4, leading to a severe reduction of the wild type GBA mRNA. This is the first report of a synonymous change causing GD through loss of an exonic splicing enhancer sequence. The synonymous mutation is in trans with the Asn188Ser missense mutation, thus making the Asn188Ser responsible for the patient's phenotype and strengthening the association of Asn188Ser with the particular neurological phenotype of type 3 GD.CONCLUSION:
We strengthen the association of Asn188Ser with the type 3 GD phenotype and progressive myoclonus epilepsy. Our data confirm that in silico predictions and mRNA analysis are mandatory in discriminating pathological mutations from the background of harmless polymorphisms, especially synonymous changes.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Myoclonic Epilepsies, Progressive
/
Drug Resistant Epilepsy
/
Gaucher Disease
/
Glucosylceramidase
/
Mutation
Type of study:
Prognostic_studies
Limits:
Adolescent
/
Female
/
Humans
Language:
En
Journal:
J Neurol
Year:
2019
Document type:
Article
Affiliation country:
Italy