The most common
progressive myoclonus epilepsies are the late infantile and late infantile-variant
neuronal ceroid lipofuscinoses (onset before the age of 6 years),
Unverricht-Lundborg disease (onset after the age of 6 years) and
Lafora disease.
Lafora disease is a distinct disorder with uniform course: onset in teenage years, followed by progressively worsening
myoclonus,
seizures, visual hallucinations and
cognitive decline, leading to a
vegetative state in status myoclonicus and death within 10 years. Biopsy reveals Lafora bodies, which are pathognomonic and not seen with any other
progressive myoclonus epilepsies. Lafora bodies are aggregates of polyglucosans, poorly constructed
glycogen molecules with inordinately long strands that render them insoluble.
Lafora disease is caused by mutations in the EPM2A or EPM2B genes, encoding the laforin
phosphatase and the malin
ubiquitin ligase, respectively, two cytoplasmically active
enzymes that regulate
glycogen construction, ensuring symmetric expansion into a spherical shape, essential to its solubility. In this work, we report a new
progressive myoclonus epilepsy associated with Lafora bodies, early-onset
Lafora body disease, map its locus to chromosome 4q21.21, identify its gene and mutation and characterize the relationship of its gene product with laforin and malin. Early-onset
Lafora body disease presents early, at 5 years, with
dysarthria,
myoclonus and ataxia. The combination of early-onset and early
dysarthria strongly suggests late infantile-variant
neuronal ceroid lipofuscinosis, not
Lafora disease. Pathology reveals no
ceroid lipofuscinosis, but Lafora bodies. The subsequent course is a typical
progressive myoclonus epilepsy, though much more protracted than any
infantile neuronal ceroid lipofuscinosis, or
Lafora disease, patients living into the fourth decade. The mutation, c.781T>C (Phe261Leu), is in a gene of unknown function, PRDM8. We show that the PRDM8
protein interacts with laforin and malin and causes translocation of the two
proteins to the nucleus. We find that Phe261Leu-PRDM8 results in excessive sequestration of laforin and malin in the nucleus and that it therefore likely represents a gain-of-function mutation that leads to an effective deficiency of cytoplasmic laforin and malin. We have identified a new
progressive myoclonus epilepsy with Lafora bodies, early-onset
Lafora body disease, 101 years after
Lafora disease was first described. The results to date suggest that PRDM8, the early-onset
Lafora body disease protein, regulates the cytoplasmic quantities of the
Lafora disease enzymes.