Severer Phenotype in Unverricht-Lundborg Disease (EPM1) Patients Compound Heterozygous for the Dodecamer Repeat Expansion and the c.202C>T Mutation in the <i>CSTB</i> Gene

Abstract

Background/Aims: Unverricht-Lundborg disease (EPM1) is caused by mutations in the cystatin B (CSTB) gene. Most patients are homozygous for the expanded dodecamer repeat mutation alleles, but 9 other EPM1-associated mutations have also been identified. We describe the clinical, cognitive and imaging characteristics of 5 Finnish EPM1 patients who are compound heterozygous for the dodecamer repeat expansion and the c.202C>T mutations. Methods: Five compound heterozygous patients and 21 patients homozygous for the expansion mutation, participating in an ongoing nationwide clinical and molecular genetics study, were evaluated using the Unified Myoclonus Rating Scale test and comprehensive neuropsychological testing. All patients underwent MR imaging. The MR data were also compared with those of 24 healthy control subjects. Results: Age at onset of symptoms was significantly lower in the compound heterozygotes than in the homozygous EPM1 patients. They also had severer myoclonus and drug-resistant tonic-clonic seizures. Moreover, they had lower cognitive performance. In MRI a voxel-based morphometry analysis of primary and premotor cortex, supplementary motor cortex and thalami revealed gray matter volume loss when compared with the healthy controls, similar to patients homozygous for the expansion mutation. Conclusion: Patients compound heterozygous for the dodecamer repeat expansion and the c.202C>T mutations seem to have a severer form of EPM1 than patients homozygous for the expansion mutation. These findings have implications for counseling of EPM1 patients with different genetic defects.

Human stefin B normal and patho-physiological role: molecular and cellular aspects of amyloid-type aggregation of certain EPM1 mutants

“…Consistent with this, patients bearing one allele of R68X and the other of the usual dodecamer repeat in the cystatin B gene, show more severe pathology and clinical symptoms (Koskenkorva et al, 2011). These findings raise the question as to whether the oligomers/aggregates are cytotoxic or whether the inclusions are instead protective, as suggested by some (Kopito, 2000).…”

“…Of note, it was reported that patients with an R68X mutation, which leads to expression of a truncated version of stefin B protein, have more severe myoclonus, drug-resistant tonic-clonic seizures and lower cognitive performance. Some were even reported to be psychotic (Koskenkorva et al, 2011). Our results, albeit obtained from experiments on cell cultures, strongly suggest that stefin B becomes more toxic when it forms aggregates and thus should be considered in future human pathological studies.…”

A novel c132‐134del mutation in Unverricht‐Lundborg disease and the review of literature of heterozygous compound patients

“…The homozygous expansion of unstable dodecamer repetition (CCCCGCCCCGCG) in the promoter 5′ untranslated region of CSTB is responsible for the most of the cases of EPM1 causing an almost homogeneous phenotype. In rare cases it can occur in compound heterozygous CSTB point and indel mutations inducing quite different phenotypes, which were recently collected by two case‐series by Koskenkorva et al, Canafoglia et al, and respective colleagues. These reports suggested a more severe phenotype in patients carrying heterozygous mutations with respect to those with homozygous promoter expansions.…”

“…The most common mutation is an expansion of unstable dodecamer repetition (CCCCGCCCCGCG) in the promoter 5′ untranslated region (usually >30 copies), which downregulates CSTB messenger RNA expression, whereas other types of mutation are rare . Among these, heterozygous compound mutations are described to induce a more severe phenotype than that of homozygous dodecameric repetition …”

Unverricht-Lundborg Disease: A Case Report and Literature Review

“…Although individuals with pathogenic variants in CSTB gene show similar clinical phenotype and no correlation has been found between the length of the expanded dodecamer repeat and the age of onset or disease severity, recently severer phenotype was reported in compound heterozygous individuals with repeat expansion and missense mutation. In these patients age at onset of disease is lower in compound heterozygous than homozygous patients [26]. Recently it was shown that repeat numbers have a modulating effect on the age at disease onset, myoclonus severity and cortical neurophysiology [27].…”