PROGRESSIVE MYOCLONUS EPILEPSIES (PME)

Overview

The syndrome progressive myoclonus epilepsies is rare, and composes a group of etiologies that have in common 1) myoclonic seizures that are treatment-resistant, 2) progressive neurological and cognitive deterioration, and 3) slowing of the EEG background that 4) appears in an individual with prior normal development and cognition.

Causes

There are many metabolic and genetic causes of this syndrome. The cause may remain unknown for some patients.

The majority of cases are caused by:

Unverricht-Lundborg disease - the commonest cause, seizures begin <18 years of age, most cases originate from the Scandanavian or Baltic regions of Europe, the condition is usually slowly progressive and may stabilize into adulthood, a repeat expansion in EMP1 is implicated in ~90% of cases, phenytoin can aggravate seizures.

Lafora disease - seizures begin <20 years of age, there is early cognitive decline and the condition is usually rapidly progressive with death in ~10 years from onset in most cases, focal sensory visual seizures are an early feature, pathogenic variants in EPM2A and EPM2B account for nearly all cases, Lafora bodies are found in sweat duct cells.

Neuronal ceroid lipofuscinoses - this is a group of conditions resulting in accumulation of lipopigments (lipofuscin), now classified by the causative gene. The most prevalent is CLN2 disease. This NCL has onset between 2-4 years, can present with speech delay before seizure onset, then there is developmental regression and vision loss, EEG can show a photoparoxysmal response at low flash frequencies, curvilinear bodies can be seen in cells (e.g. skin, lymphocytes).

Mitochondrial disorders - myoclonic epilepsy with ragged-red fibers, POLG-related disorders, and mitochondrial encephalopathy with lactic acidosis and stroke-like episodes.

Less common causes: dentatorubo-pallidoluysian atrophy, juvenile Huntingtons, action-myoclonus-renal failure syndrome, juvenile neuroaxonal dystrophy, pantothenate-kinase associated neurodegeneration, neuroserpin inclusion body disease, leukoencephalopathy with vanishing white matter, early-onset Alzheimers, GOSR2 pathogenic variants and rarer metabolic disorders (GM2 gangliosidoses, tetrahydrobiopterin deficiency, non-infantile neuronopathic Gaucher's disease and Niemann Pick type C).