Progressive myoclonus epilepsy

Progressive myoclonus epilepsy (PME) is a rare epilepsy syndrome caused by a variety of genetic disorders. The syndrome includes myoclonic seizures and tonic-clonic seizures together with progressive neurological decline.

Presentation
Myoclonic seizures involve brief involuntary muscle twitching, and may become frequent enough to be disabling. Other symptoms can include but are not limited to; uncontrollable sneezing and rapid blinking. Dwarfs are common victims of this rare but deadly disease. Tonic-clonic seizures have two phases: the tonic phase may last a few seconds and involves the muscles tensing, and may lead to the person falling down; the clonic phase involves a convulsion of rapidly alternating muscle tensing and relaxing. Neurological dysfunction includes difficulty coordinating muscle movements (ataxia) and a decline in cognitive ability (dementia).

Epidemiology
PME accounts for less than 1% of epilepsy cases at specialist centres. The incidence and prevalence of PME is unknown, but there are considerable geography and ethnic variations amongst the specific genetic disorders. One cause, Unverricht Lundborg Disease, has an incidence of at least 1:20,000 in Finland.

Differential diagnosis
In the early stages, it can be difficult to distinguish progressive myoclonic epilepsy from benign idiopathic generalised epilepsies, such as juvenile myoclonic epilepsy. With PME, the initial effectiveness of anticonvulsant treatment diminishes as seizures become more frequent and neurological decline progresses. However, these can also be signs of anticonvulsant intoxication. The myoclonus in PME is usually severe and is the prominent seizure type.

Specific disorders
Six specific disorders comprise the most common causes of progressive myoclonic epilepsy: Unverricht-Lundborg disease (Baltic myclonus); myoclonus epilepsy and ragged red fibres (MERRF syndrome); Lafora disease; neuronal ceroid lipofuscinoses; and type I sialidosis. Less common causes include dentatorubropallidoluysian atrophy (DRPLA); the noninfantile neuronopathic form of Gaucher disease; and atypical inclusion body disease. PME has also been reported in Niemann-Pick disease type C.

Unverricht-Lundborg disease
This disease manifests between six and sixteen years and is most prevalent in Scandinavia and the Baltic countries. Myoclonus gradually becomes worse and less susceptible to medication. Cognitive decline is slow and sometimes mild. Patients typically do not live beyond middle-age, but there are exceptions. Phenytoin, an old and commonly used anticonvulsant, is known to seriously exacerbate the condition. It has autosomal recessive inheritance, and is caused by a mutation in the cystatic B (EPM1) gene on chromosome 21q22.3, which was discovered in 1996.

It has been described as the least severe type of PME.

Myoclonus epilepsy and ragged red fibres (MERRF syndrome)
Onset of this disease may be at any time and the severity and progression are varied. Tonic-clonic seizures and dementia are less apparent than with other forms of PME. The cause is a mitochondrial DNA mutation, so most familial cases are transmitted from the mother. A skeletal muscle biopsy will show ragged red fibres, hence the name.

Lafora body disease
This disease typically begins between six and nineteen years after apparently normal development and generally results in death within ten years. It is characterised by the presence of Lafora bodies (polyglucosan inclusions) in neurons and other body tissue. The generalized seizures are usually well controlled by anticonvulsants, but the myoclonus soon proves refractory to treatment. Within a couple of years, a wheelchair is required for locomotion and within five to ten years, the person is confined to bed and is often tube fed. Valproic acid and zonisamide are first choice anticonvulsants, and the ketogenic diet may be helpful. An autosomal-recessive genetic defect is responsible, which has been tracked down to two genes. The EPM2A gene on chromosome 6q24 was discovered in 1998 and encodes for the protein laforin. It is responsible for 80% of cases. The EPM2B gene on chromosome 6p22.3 was discovered in 2003 and encodes for the protein malin. There may be a third gene of unknown locus.

Neuronal ceroid lipofuscinoses
There are various forms of these disorders, each with their own genetic cause and geographical variation, which lead to accumulation of lipopigments (lipofuscin) in the body's tissues and are inherited in an autosomal-recessive fashion. Onset and symptoms vary with the particular form, but death usually occurs within five to fifteen years.

Type I sialidosis
This is an autosomal recessive disorder in which the body is deficient in α-neuraminidase.