Clinical and Genetic Findings in 26 Italian Patients with Lafora Disease

Abstract

Summary:Purpose: EPM2B mutations have been found in a variable proportion of patients with Lafora disease (LD). Genotype-phenotype correlations suggested that EPM2B patients show a slower course of the disease, with delayed age at death, compared with EPM2A patients. We herein report clinical and genetic findings of 26 Italian LD patients.Methods: Disease progression was evaluated by means of a disability scale based on residual motor and cognitive functions and daily living and social abilities, at 4 years from the onset. Mutational analysis was performed by sequencing the coding regions of the EPM2A and EPM2B genes.Results: Age at onset ranged from 8.5 to 18.5 years (mean, 13.7 ± 2.6). The mean duration of follow-up was 7.1 ± 3.9 years. Daily living activities and social interactions were preserved in five of 24 patients. The remaining patients showed moderate to extremely severe limitations of daily living and social abilities. Sixteen (72%) of 22 families showed mutations in the EPM2B gene, and five (22%), in the EPM2A gene. One family showed no mutations. A novel EPM2B mutation also was identified.Conclusions: In our series, EPM2B mutations occurred in 72% of families, thus indicating that EPM2B is the major gene for LD in the Italian population. Moreover, we found that six of 17 EPM2B patients preserved daily living activities and social interactions at 4 years from onset, suggesting a slow disease progression. Additional clinical and functional studies will clarify whether specific mutations may influence the course of the disease in LD patients.

Lafora progressive myoclonus epilepsy: A meta-analysis of reported mutations in the first decade following the discovery of theEPM2AandNHLRC1genes

“…Because exon 1 of the EPM2A gene encodes the carbohydrate-binding domain, a role for this domain in the childhood onset symptoms was suspected [Ganesh et al, 2002b]. Although no such report exists for the subdomains of NHLRC1 gene, independent reports have demonstrated that LD patients with NHLRC1 mutations tend to live longer than those with EPM2A mutations [Baykan et al, 2005;Franceschetti et al, 2006;GomezAbad et al, 2005;Singh et al, 2006]. Based on these findings, Singh et al (2006) proposed that not all functions of laforin could be regulated by malin.…”

“…The figure also shows (bottom) the genomic organization of the EPM2A gene and locations of the large deletions associated with LD. Mutations were tabulated from the following PubMed-indexed English articles reporting the mutations [Annesi et al, 2004;Franceschetti et al, 2006;Gomez-Garre et al, 2000Ganesh et al, 2002b;Ianzano et al, 2004;Ki et al, 2003;Lohi et al, 2007;Minassian et al, 1998Minassian et al, , 2000aMinassian et al, , 2000b …”

Lafora Disease: A Case Report

“…Bu durumdaki en büyük etkenin genetik heterojenite olduğu, genel olarak daha iyi seyirli LH tiplerinin NHLRC1'deki D146N mutasyonu ile ilişkili olabileceği ancak genotip-fenotip ilişkilendirmesi yapılmasının farklı kombinasyonlardaki 'farklı' mutasyonlar nedeniyle oldukça zor olduğu ifade edilmektedir. [7][8][9] Hastaların yaklaşık %80'inde genetik analizlerde gen mutasyonu saptanabilmektedir.…”

Phenotype variations in Lafora progressive myoclonus epilepsy: possible involvement of genetic modifiers?

“…For examples, several of the NHLRC1 patients studied showed severe form LD 19 or a late onset LD, 20 and not all EPM2A patients with exon 1 mutations showed an early onset of the LD symptoms. 17,18 Intriguingly, a founder effect mutation for EPM2A in Arab families showed variable age at onset for LD, 21 suggesting that a specific …”

“…6, 16 Here it was suggested that defects in the amino-terminal carbohydrate-binding domain of laforin, mainly coded by the first exon of the EPM2A gene, might underlie the early onset phenotype. 6 Although the proposed models were attractive, subsequent studies have shown that such genotype-phenotype correlations cannot be extended to several other group of patients, 17,18 suggesting that these models, at best, could be applicable to a few LD families. For examples, several of the NHLRC1 patients studied showed severe form LD 19 or a late onset LD, 20 and not all EPM2A patients with exon 1 mutations showed an early onset of the LD symptoms.…”