Clinical Information

CSTB-related progressive myoclonic epilepsy (PME), also known as progressive myoclonic epilepsy type 1 (EPM1) or Unverricht-Lundborg disease, is the most common and least severe of the collective progressive myoclonic epilepsies. CSTB-related PME is inherited in an autosomal recessive pattern and is associated with inter- and intrafamilial variability. Individuals with CSTB-related PME have normal early development with onset of symptoms typically in the first or second decade of life. CSTB-related PME is characterized by involuntary myoclonus that is action- or stimulus-precipitated. Individuals with the condition are at increased risk for seizures, including tonic-clonic, absence, psychomotor and focal motor. The condition is progressive, leading to wheelchair dependence in some individuals. Later symptoms may also include ataxia, incoordination, intention tremor, dysarthria, mood disorders, and mild cognitive decline.

CSTB-related PME is caused by disease-causing variants in the CSTB gene. An expansion of a dodecamer repeat sequence in the promoter region of the CSTB gene accounts for approximately 90% of disease-causing variants (99% in Finnish individuals). Full penetrance CSTB expansions are greater than or equal to 30 repeats, while normal alleles are typically 2 or 3 repeats. Allele sizes between 5 and 29 repeats are of unclear significance. The remainder of disease-causing variants are sequence variants including missense, nonsense, splice site variants, and small deletions and duplications. Genotype/phenotype correlation suggests that individuals who are homozygous for nonexpansion variants or compound heterozygous for one expansion allele and one nonexpansion allele have earlier onset and more severe symptoms than those individuals with biallelic expansion alleles. Instability of the repeat expansion has been reported with vertical transmission, including both minimal expansion and contraction of repeat sizes. Alleles in the uncertain range are not associated with symptoms of CSTB-related PME but may demonstrate instability with transmission. Since repeat alleles in this size range have rarely been reported, the risk of repeat expansion into the full penetrance allele range (>29 repeats) is not fully understood. Additionally, correlation of repeat size with onset of symptoms is unclear.