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Progressive myoclonic epilepsy type 1 (EPM1) has the highest incidence among the progressive myoclonus epilepsies (PMEs), with prevalence reportedly higher in certain geographic areas (Finland, Italy, Tunisia, Algeria, Morocco, and Reunion Island). The prevalence in Finland is estimated at 1/50,000. Whilst the disorder is recognized worldwide, it appears to be underdiagnosed. Both genders are equally affected.

The first symptoms are stimulus-sensitive myoclonus, and tonic-clonic epileptic seizures appearing between 6-15 years of age. Prompt treatment of myoclonic seizures may prevent generalized tonic-clonic seizures (GTCS). Gradually, patients develop additional neurological symptoms including ataxia, dysarthria, intentional tremor, and decreased coordination. Depression is common. Cognitive performance is mostly within the normal range. However, patients may exhibit poor performance in tests dependent on motor functions. The tonic-clonic seizures are well controlled by anti-seizure medications, but the myoclonic jerks are progressive, action activated, treatment resistant and can be severely disabling.

The majority of cases are due to a homozygous expansion of an unstable dodecamer repeat (typically 30 to 125 repeats) in the promoter region of CSTB (21q22.3), resulting in the classic phenotype. In a minority of patients, the dodecamer repeat expansion occurs as a compound heterozygous form with a mutation in the coding region of CSTB. The clinical phenotype is the result of a partial loss of function in CSTB.

Diagnosis is suspected on electroencephalogram demonstrating photosensitivity at onset and action myoclonus detected through polygraphy. Diagnosis is confirmed on targeted molecular genetic testing for the dodecamer expansion of CSTB. When heterozygosity for the dodecamer expansion is found in an affected individual, it is appropriate to pursue molecular genetic testing for other CSTB pathogenic variants either by targeted analysis for a broader panel of pathogenic variants or by sequence analysis.

The initial symptoms may be so mild that a diagnosis of juvenile myoclonic epilepsy is made, and the signs of EPM1 may become evident only with the progression of the disease. Differential diagnosis includes other PMEs with preserved cognition, for example PRICKLE1 and SCARB2-related PME, that have been identified in a few families with a similar clinical phenotype.

The pattern of inheritance is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy. Pre-symptomatic testing is not recommended.

Anti-seizure and anti-myoclonic interventions include valproate, clonazepam, piracetam (the latter only for myoclonus), levetiracetam, brivaracetam, perampanel, topiramate and zonisamide. Phenytoin and fosphenytoin should be avoided as these trigger detrimental neurological side effects. In addition, other sodium channel blockers such as carbamazepine should be excluded as they may negatively contribute to myoclonic seizures.

The disease course is progressive, showing remarkable individual variation, with myoclonus usually presenting as the most disabling symptom. One third of patients become severely incapacitated, wheelchair-bound or even unable to eat on their own. On the other hand, some patients are able to live fully autonomous lives. With modern medical care, the survival rates are comparable to controls up to 40 years of age, but are poorer in the long-term. Death occurs mainly due to respiratory infections. Compound heterozygous mutations are associated with a more severe phenotype than homozygous dodecamer repeat expansions.