Rapidly progressive phenotype of Lafora disease associated with a novel NHLRC1 mutation

Lafora disease (LD) is a fatal, autosomal recessive form of progressive myoclonus epilepsy that characteristically presents with myoclonic and tonic-clonic seizures and cognitive impairment beginning in the second decade of life.

Diagnosis is based on clinical findings, presence of intracellular polyglucosan inclusion bodies (Lafora bodies) in neuronal and other tissues, and genetic analysis. In genetically confirmed cases of LD, disease-causing mutations have been identified in the EPM2A gene (epilepsy of progressive myoclonus type 2 gene A) encoding a protein phosphatase named laforin, and in a second gene, NHLRC1 (NHL repeat containing 1, also known as EPM2B), encoding the putative E3 ubiquitin ligase malin. NHLRC1 mutations have been shown to be associated with slower disease progression compared to EPM2A mutations with loss of independent living activities mostly not before the second half of the third life decade. In contrast to the majority of genetically identified NHLRC1 phenotypes we found a very rapid progression of therapy-refractory epilepsy and dementia less than two years after symptom onset in the course in association with a novel homozygous NHLRC1 mutation (c.349_350insC;p.His117ProfsX39). This frameshift mutation affects Histidine-117 with a change to Proline that creates a new reading frame ending in a stop at position 39.

The 15-year-old boy was admitted with generalized tonic-clonic seizures and developed myoclonic seizures of the face and upper extremities and a deterioration of cognitive performance. The rapid progressive course of the epileptic encephalopathy together with EEG findings led to the clinical diagnosis of LD confirmed by histological examination with lafora bodies in an axillary skin biopsy.

Based on our observation we speculate that NHLRC1 mutations might result in different phenotypes and might not generally be associated with benign clinical course. Pathophysiologically, involvement of malin in other neurotoxic pathways than functional impairment of laforin might be assumed as an interesting hypothesis of further studies.