Novel LAMC3 pathogenic variant enriched in Finnish population causes malformations of cortical development and severe epilepsy

Anni Saarela; Oskari Timonen; Jarkko Kirjavainen; Yawu Liu; Katri Silvennoinen; Esa Mervaala; Reetta Kälviäinen

doi:10.1002/epd2.20244

Novel LAMC3 pathogenic variant enriched in Finnish population causes malformations of cortical development and severe epilepsy

Epileptic Disord. 2024 May 17. doi: 10.1002/epd2.20244. Online ahead of print.

Authors

Anni Saarela^{1

2}, Oskari Timonen², Jarkko Kirjavainen¹, Yawu Liu², Katri Silvennoinen³, Esa Mervaala^{2

4}, Reetta Kälviäinen^{2

3}

Affiliations

¹ Department of Pediatric Neurology, Kuopio Epilepsy Center., Kuopio University Hospital. Full Member of ERN EpiCARE., Kuopio, Finland.
² Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.
³ Department of Neurology, Kuopio Epilepsy Center, Kuopio University Hospital. Full Member of ERN EpiCARE, Kuopio, Finland.
⁴ Department of Clinical Neurophysiology, Kuopio Epilepsy Center, Kuopio University Hospital. Full Member of ERN EpiCARE, Kuopio, Finland.

PMID: 38758065
DOI: 10.1002/epd2.20244

Abstract

Objective: Recessive LAMC3 mutations are recognized to cause epilepsy with cortical malformations characterized by polymicrogyria and pachygyria. The objective of this study was to describe the clinical picture and epilepsy phenotype of four patients with a previously undescribed LAMC3 variant.

Methods: All epilepsy patients treated in Kuopio Epilepsy Center (located in Kuopio, Finland) are offered the possibility to participate in a scientific study investigating biomarkers in epilepsy (Epibiomarker study). We have collected a comprehensive database of the study population, and are currently re-evaluating our database regarding the patients with developmental and/or epileptic encephalopathy (DEE). If the etiology of epilepsy remains unknown in the clinical setting, we are performing whole exome sequencing to recognize the genetic causes.

Results: Among our study population of 323 DEE patients we recognized three patients with similar homozygous LAMC3 c.1866del (p.(Phe623Serfs*10)) frameshift variant and one patient with a compound heterozygous mutation where the same frameshift variant was combined with an intronic LAMC3 c.4231-12C>G variant on another allele. All these patients have severe epilepsy and either bilateral agyria-pachygyria or bilateral polymicrogyria in their clinical MRI scanning. Cortical malformations involve the occipital lobes in all our patients. Epilepsy phenotype is variable as two of our patients have DEE with epileptic spasms progressing to Lennox-Gastaut syndrome and intellectual disability. The other two patients have focal epilepsy without marked cognitive deficit. The four patients are unrelated. LAMC3 c.1866del p.(Phe623Serfs*10) frameshift variant is enriched in the Finnish population.

Significance: Only a few patients with epilepsy caused by LAMC3 homozygous or compound heterozygous mutations have been described in the literature. To our knowledge, the variants discovered in our patients have not previously been published. Clinical phenotype appears to be more varied than previously assumed and patients with a milder phenotype and normal cognition have probably remained unrecognized.

Keywords: agyria (HPO 0031882); atonic seizure (HPO 0010819); atypical absence seizure (HPO 0007270); atypical absence status epilepticus (HPO 0011151); bilateral tonic–clonic seizure (HPO 0002069); epileptic spasm (HPO 0011097); focal‐onset seizure (HPO 0007359); pachygyria (HPO 0001302); polymicrogyria (HPO 0002126); tonic seizure (HPO 0032792).

Abstract

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