Somatic and germline mosaicisms in Severe Myoclonic Epilepsy of Infancy

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Abstract

Severe Myoclonic Epilepsy in Infancy (SMEI) is an intractable epileptic syndrome with onset in the first year of life and is commonly caused by de novo mutations in the SCN1A gene, encoding the α1-subunit of the neuronal voltage-gated sodium channel. We report two unrelated families in which probands were affected by SMEI and their parents showed a single febrile seizure during early childhood or no neurological symptoms. Semiquantitative analysis of SCN1A mutations allowed the detection of a somatic and germline mosaicism in one of the parents. The study provides the first example of parental mosaicisms in SMEI and opens a new insight into the phenotypic variability and complex inheritance of this condition. The identification of germline mosaicisms has important consequences in genetic counseling of SMEI when SCN1A mutations appear to occur de novo with standard screening methods.

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Material and methods

Selection of families and mutational analysis. We selected two families segregating a frameshift and a splice-site SCN1A mutation in two SMEI siblings (Fig. 1) from the screening of 138 patients. Detailed inclusion criteria and screening methods were previously reported [11]. Family 1 has been previously described [5]. We collected different tissue samples from all family members including peripheral lymphocytes, buccal epithelium, hair follicles, and urinary cells. Furthermore, we obtained a

Clinical presentation of the selected families

Detailed clinical histories of the affected subjects from the two families are described in appendix. Briefly, proband of family 1 (subject III:5) and her sib (III:6) started before the age of 10 months suffering from afebrile and febrile, generalized and focal seizures, and myoclonic jerks. Psychomotor delay and ataxia appeared after the onset of epilepsy. Electroencephalograms (EEGs) variably showed focal and generalized epileptic abnormalities. Antiepileptic therapy did not allow seizure

Discussion

In order to determine whether mosaicism could explain the reduced penetrance and variable expressivity of SCN1A mutations in the two SMEI families, we evaluated the amount of mutant cells in different tissues and found a somatic mosaicism in one and a germline mosaicism in another.

In family 1, the mother of two SMEI siblings carries a frameshift mutation in about 70–80% of cells and is not affected by epilepsy. Genotype–phenotype correlations in SCN1A-related disorders have been proved to be

Acknowledgments

We thank the families for their kind cooperation. This work has been supported by the Italian Ministry of Health (F.Z.) and the Pierfranco and Luisa Mariani Foundation ONLUS (F.Z.).

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