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Meta-Analysis
. 2023 Sep 2;18(1):263.
doi: 10.1186/s13023-023-02880-6.

Prognostic value of pathogenic variants in Lafora Disease: systematic review and meta-analysis of patient-level data

Federica Pondrelli  1 , Raffaella Minardi  2 , Lorenzo Muccioli  3 , Corrado Zenesini  2 , Luca Vignatelli  2 , Laura Licchetta  2 , Barbara Mostacci  2 , Paolo Tinuper  1 , Craig W Vander Kooi  4 , Matthew S Gentry  4 , Francesca Bisulli  1   2
Affiliations
Meta-Analysis

Prognostic value of pathogenic variants in Lafora Disease: systematic review and meta-analysis of patient-level data

Federica Pondrelli et al. Orphanet J Rare Dis. .

Abstract

Background: Lafora disease (LD) is a fatal form of progressive myoclonic epilepsy caused by biallelic pathogenic variants in EPM2A or NHLRC1. With a few exceptions, the influence of genetic factors on disease progression has yet to be confirmed. We present a systematic review and meta-analysis of the known pathogenic variants to identify genotype-phenotype correlations.

Methods: We collected all reported cases with genetically-confirmed LD containing data on disease history. Pathogenic variants were classified into missense (MS) and protein-truncating (PT). Three genotype classes were defined according to the combination of the variants: MS/MS, MS/PT, and PT/PT. Time-to-event analysis was performed to evaluate survival and loss of autonomy.

Results: 250 cases described in 70 articles were included. The mutated gene was NHLRC1 in 56% and EPM2A in 44% of cases. 114 pathogenic variants (67 EPM2A; 47 NHLRC1) were identified. The NHLRC1 genotype PT/PT was associated with shorter survival [HR 2.88; 95% CI 1.23-6.78] and a trend of higher probability of loss of autonomy [HR 2.03, 95% CI 0.75-5.56] at the multivariable Cox regression analysis. The population carrying the homozygous p.Asp146Asn variant of NHLRC1 genotype was confirmed to have a more favourable prognosis in terms of disease duration.

Conclusions: This study demonstrates the existence of prognostic genetic factors in LD, namely the genotype defined according to the functional impact of the pathogenic variants. Although the reasons why NHLRC1 genotype PT/PT is associated with a poorer prognosis have yet to be fully elucidated, it may be speculated that malin plays a pivotal role in LD pathogenesis.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Schematic representation of the Lafora disease pathogenic variants in EPM2A and NHLRC1 (A), laforin and malin (B). EPM2A gene contains five exons and NHLRC1 consists of one exon. Laforin contains an amino-terminal carbohydrate binding module (CBM) and a carboxy-terminal dual specificity phosphatase domain (DSP). Malin contains a RING finger domain and six NHL repeats
Fig. 2
Fig. 2
Association between genotypes and survival (EPM2A, A; NHLRC1, B) and retention of autonomy (EPM2A, C; NHLRC1, D) according to Kaplan–Meier analysis. Legend: MS, missense pathogenic variants and small in-frame insertions/deletions; PT, nonsense, frameshift, splice site variants, and partial or total gene deletions. MS + PT: genotype composed by one MS variant and one PT variant; 2MS: genotype composed by two MS variants; 2PT: genotype composed by two PT variants
Fig. 3
Fig. 3
Post-hoc analysis comparing survival (A) and probability of retention of autonomy (B) between EPM2A genotypes taken together, NHLRC1 genotype composed by two PT variants (2PT) and the other NHLRC1 genotypes taken together (2MS and MS + PT). Legend: MS, missense pathogenic variants and small in-frame insertions/deletions; PT, nonsense, frameshift, splice site variants, and partial or total gene deletions. MS + PT: genotype composed by one MS variant and one PT variant; 2MS: genotype composed by two MS variants; 2PT: genotype composed by two PT variants
See this image and copyright information in PMC

References

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