Table 2.

Summary of Molecular Genetic Testing Used in Progressive Myoclonus Epilepsy, Lafora Type

Gene 1 Proportion of Lafora Disease Attributed to Mutation of This GeneTest Method
EPM2A22%-70% 2, 3, 4, 5, 6Sequence analysis 7, 8
Deletion/duplication analysis 9, 10
NHLRC1 (EPM2B)27%-73% 2, 3, 4, 5, 6Sequence analysis 7, 8
Deletion/duplication analysis 9, 10
Unknown 11NANA

See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.


Gómez-Abad et al [2005] found pathogenic variants in 97% (75/77) of families with LD: EPM2A (70%) and NHLRC1 (27%).


Franceschetti et al [2006] found pathogenic variants in 21/22 (95%) of families with LD: EPM2A (22%) and NHLRC1 (73%).


Lohi et al [2006] found pathogenic variants in 88% (75/85) of families with LD: EPM2A (45%) and NHLRC1 (43%).


Singh et al [2006] found pathogenic variants in 84% (23/28) of families with LD: EPM2A (54%) and NHLRC1 (34%).


The marked variations may reflect ethnic differences or chance variation and small sample size.


Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Studies of the combined pathogenic variant detection frequency of sequence analysis of EPM2A and NHLRC1 revealed that between 88% and 97% of pathogenic variants in these two genes can be detected using sequence analysis alone [Gómez-Abad et al 2005, Franceschetti et al 2006, Lohi et al 2006].


Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


The proportion of pathogenic variants in EPM2A and NHLRC1 not detected by sequence analysis that are attributable to deletions is unknown. In the one study that screened for suspected deletions in three individuals with a single heterozygous sequence-detectable pathogenic variant, Lohi et al [2007] found three deletions in three families, one in EPM2A and two in NHLRC1. See also Molecular Genetics. Kecmanović et al reported an affected individual with a homozygous deletion encompassing the entire NHLRC1 gene and with a clinical course more progressive than in most individuals with mutation of NHLRC1 [Kecmanović et al 2013].


Pathogenic variants in at least one other gene also cause LD. Chan et al [2004] described one family with three individuals with biopsy-confirmed LD and no identifiable pathogenic variant in either EPM2A or NHLRC1. Linkage and haplotype analyses excluded both loci from causative involvement in this family, providing indirect evidence for a third locus for LD. The findings were supported by independent studies [Singh et al 2005, Singh et al 2006].

From: Progressive Myoclonus Epilepsy, Lafora Type

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