NHLRC1 – Lafora Disease

Lafora disease is a fatal, teenage-onset, autosomal recessive progressive myoclonus epilepsy characterized by myoclonus, generalized seizures, and cognitive decline. Biallelic pathogenic variants in NHLRC1, encoding the E3-ubiquitin ligase malin, disrupt glycogen metabolism leading to polyglucosan accumulation and neurodegeneration Gene Symbol – Disease Name.

Genetic studies in 25 patients from 23 families identified NHLRC1 mutations in 21 probands, establishing it as a frequent cause of Lafora disease with an overall milder course than EPM2A-associated cases PMID:15781812. Disease follows autosomal recessive inheritance with complete penetrance in adolescence.

Segregation analysis in a family with four affected siblings homozygous for the p.Asp146Asn variant supports recessive transmission and intra-familial concordance of the phenotype PMID:16190947. Additional segregation data are consistent across multiple reports.

The variant spectrum in NHLRC1 includes missense (e.g., c.436G>A (p.Asp146Asn)), nonsense (c.793C>T (p.Arg265Ter)), frameshift (c.468_469del (p.Gly158fs)), and whole-gene deletions, with recurrent alleles observed in specific populations. Founder effects for c.436G>A have been reported in Apulian and Turkish cohorts.

Functional assays demonstrate that malin mutants fail to ubiquitinate key glycogen regulators (R5/PTG), leading to abnormal glycogen accumulation in cell models. Silencing of NHLRC1 increases ER-stress sensitivity and impairs proteasomal function, paralleling findings in malin-deficient mice that develop Lafora bodies and autophagy defects PMID:19529779; PMID:22186026.

No studies refute the NHLRC1–Lafora disease association. Modifier genes (e.g., PPP1R3C) may modulate disease progression, but NHLRC1 remains the primary genetic determinant.

Integration of clinical, segregation, and functional data supports a strong gene-disease relationship. NHLRC1 genetic testing is essential for definitive diagnosis, family counseling, and stratifying patients for emerging therapies.

Key Take-home: NHLRC1 sequencing should be incorporated into diagnostic workflows for adolescents with progressive myoclonus epilepsy and cognitive decline.

References

• Neurology • 2005 • Lafora disease due to EPM2B mutations: a clinical and genetic study. PMID:15781812
• Epilepsia • 2005 • Late-onset and slow-progressing Lafora disease in four siblings with EPM2B mutation. PMID:16190947
• PLoS One • 2009 • Increased endoplasmic reticulum stress and decreased proteasomal function in lafora disease models lacking the phosphatase laforin. PMID:19529779
• Human Molecular Genetics • 2012 • Lafora bodies and neurological defects in malin-deficient mice correlate with impaired autophagy. PMID:22186026

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