Unverricht-Lundborg disease (EPM1) in Finland: A nationwide population-based study.

OBJECTIVE: To investigate the epidemiology and prognosis of Unverricht-Lundborg disease (EPM1) in a nationwide, population-based setting. METHODS: Data from multiple registries were combined and analyzed. Clinical data were obtained from medical records. All patients treated for EPM1 in Finland between January 1, 1998, and December 31, 2016 were included. RESULTS: A total of 135 persons with EPM1 (54% women) were identified and 105 were alive on December 31, 2016 (point prevalence 1.91/100,000 persons). The age-standardized (European Standard Population 2013) prevalence was 1.53/100,000 persons. Annual incidence during the study period was 0.022/100,000 person-years, with a mean age at onset of 9.4 ± 2.3 years (range 7.0-14.6 years, no sex difference). The median age at death (n = 34) was 53.9 years (interquartile range 46.4, 60.3; range 23.2-63.8), with no sex differences. The immediate cause of death was a lower respiratory tract infection in 56% of deaths. The survival rates of the patients were comparable to matched controls up to 40 years of age, but poorer during long-term follow-up (cumulative survival 26.4% vs 78.0%), with a hazard ratio (HR) for death of 4.61. The risk of death decreased with increasing age at onset (HR 0.76 per year, 95% confidence interval 0.65-0.89). In approximately 10% of all cases, the disease progression appeared very mild; some patients retained functional independence for decades. CONCLUSIONS: Unverricht-Lundborg disease is rare in Finland but still more common than anywhere else in the world. The disease course appears somewhat more severe than elsewhere, disability mounts early, and death occurs prematurely.

Refining the phenotype of Unverricht-Lundborg disease (EPM1): a population-wide Finnish study.

OBJECTIVE: This Finnish nationwide study aimed to refine the clinical phenotype variability and to identify factors that could explain the extensive variability in the clinical severity of the symptoms observed among patients with Unverricht-Lundborg disease (progressive myoclonus epilepsy type 1 [EPM1]) homozygous for the dodecamer expansion mutation in the cystatin B (CSTB) gene. METHODS: The study population consisted of 66 (33 men and 33 women) patients with genetically confirmed EPM1 homozygous for the CSTB expansion mutation for whom the sizes of the expanded alleles were determined. The clinical evaluation included videorecorded Unified Myoclonus Rating Scale and retrospectively collected medical history. The navigated transcranial magnetic stimulation test was used to determine motor threshold (MT) and silent period (SP) of the motor cortex. RESULTS: An earlier age at onset for EPM1 and longer disease duration were associated with more severe action myoclonus, lower performance IQ, increased MT, and prolonged SP. The number of dodecamer repeats in CSTB alleles varied between 38 and 77. On average, the size of the longer expanded alleles of patients was independently associated with MT, but exerted only a modulating effect on age at onset, myoclonus severity, and SP. CONCLUSIONS: As a group, earlier disease onset and longer duration are associated with more severe phenotype. Even though the vast majority of patients with EPM1 have a uniform genetic mutation, the actual size of the longer CSTB expansion mutation allele is likely to have a modulating effect on the age at disease onset, myoclonus severity, and cortical neurophysiology.

Progressive myoclonic epilepsies: it takes a village to make a diagnosis.

The progressive myoclonus epilepsies (PMEs) are a devastating group of rare disorders(1) that manifest with increasing action myoclonus, which is also present at rest but activates with stimuli such as noise, light, or touch. Ultimately, patients become wheelchair-bound and experience early death. Neurologic signs that frequently but not reliably coexist include other seizure types (particularly generalized tonic-clonic), progressive ataxia, and dementia. Typically, presentation is in late childhood or adolescence; however, all ages may be affected. Although distinction from more common forms of genetic generalized epilepsy, particularly juvenile myoclonic epilepsy, may be challenging early on, the presence or evolution of 1) progressive neurologic disability, 2) failure to respond to antiepileptic drug therapy, and 3) background slowing on EEG should suggest PME. Importantly, inappropriate therapy in the genetic generalized epilepsies may result in ataxia, impaired cognition, and uncontrolled seizures, which may mimic PME. PMEs should be distinguished from progressive encephalopathies with seizures (due to degenerative conditions such as GM2 gangliosidosis, nonketotic hyperglycinemia, Niemann-Pick type C, juvenile Huntington and Alzheimer disease) and progressive myoclonic ataxias, which affect predominantly adults with progressive ataxia, myoclonus, few if any tonic-clonic seizures, and without evidence of dementia.(2,3.)

Progressive myoclonic epilepsies: definitive and still undetermined causes.

OBJECTIVE: To define the clinical spectrum and etiology of progressive myoclonic epilepsies (PMEs) in Italy using a database developed by the Genetics Commission of the Italian League against Epilepsy. METHODS: We collected clinical and laboratory data from patients referred to 25 Italian epilepsy centers regardless of whether a positive causative factor was identified. PMEs of undetermined origins were grouped using 2-step cluster analysis. RESULTS: We collected clinical data from 204 patients, including 77 with a diagnosis of Unverricht-Lundborg disease and 37 with a diagnosis of Lafora body disease; 31 patients had PMEs due to rarer genetic causes, mainly neuronal ceroid lipofuscinoses. Two more patients had celiac disease. Despite extensive investigation, we found no definitive etiology for 57 patients. Cluster analysis indicated that these patients could be grouped into 2 clusters defined by age at disease onset, age at myoclonus onset, previous psychomotor delay, seizure characteristics, photosensitivity, associated signs other than those included in the cardinal definition of PME, and pathologic MRI findings. CONCLUSIONS: Information concerning the distribution of different genetic causes of PMEs may provide a framework for an updated diagnostic workup. Phenotypes of the patients with PME of undetermined cause varied widely. The presence of separate clusters suggests that novel forms of PME are yet to be clinically and genetically characterized.

Coexistence of Unverricht-Lundborg disease and congenital deafness: molecular resolution of a complex comorbidity.

PURPOSE: We report on genetic analysis of a complex condition in a Serbian family of four siblings, wherein two had progressive myoclonic epilepsy (PME) and congenital deafness (CD), one had isolated congenital deafness (ICD), and one was healthy. METHODS AND RESULTS: Molecular diagnosis performed by Southern blotting confirmed Unverricht-Lundborg disease in the available sibling with PME/CD. In the sibling with ICD (heterozygote for expansion mutation in CSTB) we demonstrated recombination event between the D21S2040 marker and the CSTB gene and identified c.207delC (p.T70Xfs) mutation in the fourth exon of the transmembrane protease, serine-3 (TMPRSS3) gene (maps in close proximity to CSTB), responsible for nonsyndromic deafness in the sibling with PME/CD as well. DISCUSSION: To the best of our knowledge this is the first genetic confirmation of the coexistence of these two mutations.

Seizures, ataxia, and neuronal loss in cystatin B heterozygous mice.

Unverricht-Lundborg disease (EPM1) has been considered to be an autosomal-recessive disease related with loss of function mutations in the gene encoding cystatin B. Although heterozygous carriers are generally asymptomatic, earlier studies in Finnish EPM1 families have reported minor symptoms together with slight changes in the EEG recordings also in near relatives of patients. Here we tested the hypothesis that EPM1 phenotype is expressed also in heterozygous subjects using 17-month-old cystatin B deficient mice as a model of disease. Western blot analysis demonstrated a 50% decrease in cystatin B expression in the cerebellum of these animals. Heterozygous mice showed significantly impaired rotarod performance and were weaker in the grid test. Also the total seizure-rating score of heterozygous animals was higher than in wild-type mice. The stereological analysis revealed a significant decrease in the number of neurons in cerebral cortex and the granule cell layer of cerebellum. These results suggest that partial decrease in cystatin B expression in heterozygous mice could lead to the development of mild EPM1 phenotype.

[Unverricht-Lundborg disease (PME1)]. / La maladie d'Unverricht-Lundborg (EPM1).

Unverricht-Lundborg disease (ULD) is the purest and least severe type of progressive myoclonus epilepsy (PME), and is not associated with progressive cognitive deficit. Symptoms stabilize in adulthood, with a varying degree of permanent, often severe handicap that is mostly due to myoclonus. The disorder follows an autosomal recessive transmission pattern, with onset between 8 and 15 years years of age of generalized tonic-clonic or clonic-tonic-clonic seizures, action myoclonus (massive or segmental), photosensitivity, and often ataxia. Prevalence varies, it is highest in certain isolates (Finland, La Réunion Island) and in region with higher levels of inbreeding (Maghreb). ULD is due to a deficit in cystatin B (stefin B), but the mechanisms leading to the clinical symptoms are not well understood. The causative gene, PME1, was identified in 1991 and localized to chromosome 21q22.3. The mutations are mainly expansions of the CCCCGCCCCGCG dodecamer, but less common point mutations were also found. A variant has been recently reported in a Palestinian family, with localization on chromosome 12. The diagnosis of ULD is made on the basis of family history, age at onset, geographical and ethnic context, and on the typical features of myoclonus and epilepsy, in the absence of cognitive and sensory deficits. Neurophysiological evaluation yields interesting, but unspecific results. There are no biological or pathological markers for ULD. Molecular analysis confirms the diagnosis in most patients. Genetic testing for heterozygotes and even prenatal diagnosis are possible, although seldom performed, if the mutation has been identified. In spite of intensive research, ULD has yet to reveal all of its secrets. It remains a quasi "idiopathic" type of PME, with limited progression. Clinicians and patients are still waiting for an etiologically oriented treatment, which should, ideally, be admnistered early in the course of the disease, if possible before the onset of invalidating symptoms.

Unverricht-Lundborg disease, a condition with self-limited progression: long-term follow-up of 20 patients.

PURPOSE: To assess the long-term evolution of Unverricht-Lundborg disease (ULD), especially concerning myoclonus, seizures, and EEG characteristics. METHODS: We retrospectively evaluated 20 patients (six women, 14 men; mean age, 37.9 years; range, 26-53 years) with ULD who had been closely followed up since the onset of the disease (mean age, 12.3 years; range, 6-17 years) for an average of 25.6 years (range, 13-41 years). ULD was confirmed by genetic tests in all. We used simplified myoclonus and seizure rating scales. RESULTS: The geographic origin of the patients was Northern Africa in nine, France in two, Italy in six, and mixed European in three. Three patients were severely handicapped, six led fully autonomous lives, and 11 required various degrees of social support. Myoclonus progressed only during the first 5 years of disease. Major seizures occurred in 19. Three patients had a single seizure, and eight became seizure free, whereas six had rare seizures, and two had frequent attacks. Overall, seizures became much less frequent after 10 years of evolution. EEG changes abated during follow-up: background activity remained stable or improved, spontaneous discharges disappeared, and photoparoxysmal responses were abolished in all patients but two. CONCLUSIONS: This study shows that ULD progresses only over a limited period and stabilizes thereafter. This self-limited progression may be the consequence of age-related apoptosis of selected neuronal populations.

Univerricht-Lundborg disease: underdiagnosed in the Netherlands.

PURPOSE: Univerricht-Lundborg disease (ULD), with its major symptom of action myoclonus, is supposed to be very rare in the Netherlands and western Europe. We hypothesized that the syndrome may be underdiagnosed in patients with myoclonus epilepsy. METHODS: Mutation analysis of the cystatin B gene was performed in 21 cases with uncontrolled myoclonus. RESULTS: Seven of the 21 evaluated cases carried mutations in the cystatin B gene. Diagnosis of ULD was made with a mean delay of 20 years from symptom onset. CONCLUSIONS: This study from a country without previous reports of ULD suggests that underdiagnosis of the syndrome is likely. These findings also indicate that persons with juvenile-onset myoclonus epilepsy with action myoclonus should be analyzed for ULD.