Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Sipila JOT

PROVIDER: S-EPMC7734927 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Unverricht-Lundborg disease (ULD), also known as progressive myoclonic epilepsy 1 (EPM1), is a rare autosomal recessive neurodegenerative disorder characterized by a complex symptomatology that includes action- and stimulus-sensitive myoclonus and tonic-clonic seizures. The main cause of the onset and development of ULD is a repeat expansion of a dodecamer sequence localized in the promoter region of the gene encoding cystatin B (CSTB), an inhibitor of lysosomal proteases. Although this is the predominant mutation found in most patients, the physio-pathological mechanisms underlying the disease complexity remain largely unknown. In this work, we used patient-specific iPSCs and their neuronal derivatives to gain insight into the molecular and genetic machinery responsible for the disease in two Italian siblings affected by different phenotypes of ULD. Specifically, fragment length analysis on amplified CSTB promoters found homozygous status for dodecamer expansion in both patients and showed that the number of dodecamer repeats is the same in both. Furthermore, the luciferase reporter assay showed that the CSTB promoter activity was similarly reduced in both lines compared to the control. This information allowed us to draw important conclusions: (1) the phenotypic differences of the patients do not seem to be strictly dependent on the genetic mutation around the CSTB gene, and (2) that some other molecular mechanisms, not yet clearly identified, might be taken into account. In line with the inhibitory role of cystatin B on cathepsins, molecular investigations performed on iPSCs-derived neurons showed an increased expression of lysosomal cathepsins (B, D, and L) and a reduced expression of CSTB protein. Intriguingly, the increase in cathepsin expression does not appear to be correlated with the residual amount of CSTB, suggesting that other mechanisms, in addition to the regulation of cathepsins, could be involved in the pathological complexity of the disease.

Project description:BackgroundThe incidence of pediatric inflammatory bowel disease (PIBD) has increased dramatically during the past decades. This implies involvement of environmental factors in etiology but lends no clues about specific agents. We evaluated clustering in time and place of residence at PIBD onset using a case-control setting with comprehensive nationwide register data.MethodsWe included all PIBD cases diagnosed at ages < 18 years during 1992-2017 (3748 cases; median age of 14.6; 2316 (58%) with ulcerative colitis (UC), 1432 with Crohn's, and 18,740 age- and sex-matched controls) and constructed complete residential histories (including coordinates) from the national database until the date of the diagnosis of the case assigned as index date for the controls. Using the coordinates of the addresses of the subjects and the diagnosis/index dates, we evaluated clustering in time and place using the Knox test. Four temporal (2, 4, 6, 12 months) and four distance (0.25, 0.5, 1, 5 km) thresholds were used, and results were calculated separately for Crohn´s disease and UC. Similar analyses were conducted using the addresses at birth and the addresses five years before the diagnosis or index date. Based on the threshold values displaying the most clustering in the Knox test, logistic regression models were built to identify whether sex, age at diagnosis or the year of diagnosis affected the probability of belonging to a cluster. To analyze clustering in time and place throughout the residential histories, we used Jacquez's Q with an open-access python program pyjacqQ.ResultsThe mean number of residencies until the index date was 2.91 for cases and 3.05 for controls (p = 0.0003). Knox test indicated residential clustering for UC with thresholds of 500 m between locations and time-period of four months (p = 0.004). In the regression analysis, sex, age at diagnosis or year of UC diagnosis did not show differences between the clustered and other cases. Jacquez Q analyses showed higher than expected frequency of clustered cases throughout residential histories (p < 10- 8).ConclusionOur findings suggest that the incidence of PIBD, especially of UC, exhibits clustering in locations of residencies over time. For the clustered cases, environmental triggers warrant future studies.

Project description:BackgroundTo date, only a few small studies have assessed the effects of major orthopedic traumas on the subsequent birth rate in fertile-aged woman. We assessed the incidences of traumatic brain injury (TBI) and fractures of the spine, pelvis, and hip or thigh and evaluated their association with the birth rate in fertile-aged woman.MethodsIn this retrospective register-based nationwide cohort study, data on all fertile-aged (15-44 years of age) women who sustained a TBI or fracture of the spine, pelvis, hip or thigh between 1998 and 2013 were retrieved from the Care Register for Health Care. A total of 22,780 women were included in TBI group, 3627 in spine fracture group, 1820 in pelvic fracture group, and 1769 in hip or thigh fracture group. The data were subsequently combined with data from the National Medical Birth Register. We used Cox regression model to analyze the hazard for a woman to give birth during 5-year follow-up starting from a major trauma. Women with wrist fractures (4957 women) formed a reference group. Results are reported as hazard ratios (HR) with 95% confidence intervals (CI).ResultsDuring 5-year follow-up after major trauma, 4324 (19.0%) women in the TBI group, 652 (18.0%) in the spine fracture group, 301 (16.5%) in the pelvic fracture group, 220 (12.4%) in the hip or thigh fracture group, and 925 (18.7%) in the wrist fracture group gave birth. The cumulative birth rate was lower in the hip or thigh fracture group in women aged 15-24 years (HR 0.72, CI 0.58-0.88) and 15-34 years (HR 0.65, CI 0.52-0.82). Women with pelvic fracture aged 25-34 years also had a lower cumulative birth rate (HR 0.79, CI 0.64-0.97). For spine fractures and TBIs, no reduction in cumulative birth rate was observed. Vaginal delivery was the primary mode of delivery in each trauma group. However, women with pelvic fractures had higher rate of cesarean section (23.9%), when compared to other trauma groups.ConclusionsOur results suggest that women with thigh, hip, or pelvic fractures had a lower birth rate in 5-year follow-up. Information gained from this study will be important in clinical decision making when women with previous major trauma are considering becoming pregnant and giving birth.