Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) is characterized by late onset (30-40 years old) cerebellar ataxia, sensory neuronal deafness, narcolepsy-cataplexy and ...dementia. We performed exome sequencing in five individuals from three ADCA-DN kindreds and identified DNMT1 as the only gene with mutations found in all five affected individuals. Sanger sequencing confirmed the de novo mutation p.Ala570Val in one family, and showed co-segregation of p.Val606Phe and p.Ala570Val, with the ADCA-DN phenotype, in two other kindreds. An additional ADCA-DN kindred with a p.GLY605Ala mutation was subsequently identified. Narcolepsy and deafness were the first symptoms to appear in all pedigrees, followed by ataxia. DNMT1 is a widely expressed DNA methyltransferase maintaining methylation patterns in development, and mediating transcriptional repression by direct binding to HDAC2. It is also highly expressed in immune cells and required for the differentiation of CD4+ into T regulatory cells. Mutations in exon 20 of this gene were recently reported to cause hereditary sensory neuropathy with dementia and hearing loss (HSAN1). Our mutations are all located in exon 21 and in very close spatial proximity, suggesting distinct phenotypes depending on mutation location within this gene.
Narcolepsy type 1 (NT1) is a rare central disorder of hypersomnolence characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, hallucinations, and fragmented nocturnal sleep usually ...arising in adolescence or young adulthood. Recently, the childhood NT1 diagnoses have increased for improved disease awareness and for several cases occurring after the H1N1 pandemic influenza or vaccination. As in adults, the occurrence of NT1 in individuals with a genetic predisposition of the immune system (e.g., human leukocyte antigen, HLA-DQB1*0602) together with the role of environmental triggers (e.g., H1N1 influenza virus, streptococcus β hemolyticus) further supports the autoimmune pathogenesis. Children with NT1 close to disease onset show a peculiar cataplexy phenotype characterized by persistent hypotonia with prominent facial involvement (cataplectic facies) and by a complex mosaic of hyperkinetic movement abnormalities that increase during emotional stimulation. This phenotype progressively vanishes along the disease course leading to the typical picture of cataplexy (i.e., muscle weakness exclusively evoked by strong emotions). This possibly explains in part the misdiagnoses and diagnostic delay. Childhood NT1 also shows behavioral abnormalities and psychiatric disorders, encompassing depressive feelings, hyperactive/aggressive behavior, up to psychotic features. The association with obesity and precocious puberty strikingly suggests that NT1 arising in prepubertal children may reflect a wide hypothalamic derangement secondary to hypocretin neuronal loss. The complexity of the childhood NT1 phenotype claims a multidisciplinary assessment and management, taking behavioral and endocrinological features into account. NT1 indeed is a lifelong disorder with a devastating impact on quality of life, especially when arising across developmental age, and targeted school programs, medicolegal and psychological supports are essential for patients care. Controlled studies are mandatory to assess safety and efficacy of the current symptomatic off-label medications on which also relies the treatment for children with NT1, and hopefully future pathogenetic evidences will pave the way to better disease prevention and therapies to modify the disease course.
Abstract
Study Objectives
Narcolepsy is a rare chronic central disorder of hypersomnolence with frequent endocrine-metabolic comorbidities. To address the complex care needs of patients during the ...COVID-19 emergency, we carried out a feasibility study of the TElemedicine for NARcolepsy (TENAR) protocol with the aim of assessing the feasibility of a multidisciplinary care approach via televisit for patients with narcolepsy.
Methods
A feasibility single open-arm study on the multidisciplinary care of children (>7 y.o.) and adults with narcolepsy who required a follow-up visit was realized during the COVID-19 pandemic emergency period in Italy. The study included a sleep, metabolic, and psychosocial assessment via televisit at baseline, at 6, and at 12 months from the study inclusion period (15th May–26th June 2020).
Results
In total 39 out of 44 eligible patients (89%) entered the study (30 adults, nine children); 37 patients (95%) ended the 12-month follow-up. At baseline, the median Epworth sleepiness scale score (ESS) was 10 (IQR 8–14), and the median body mass index (BMI) was 25.6 (IQR 22.1–30.9). During the follow-up period, the ESS score decreased from the 6th month onward (p = 0.003), and BMI decreased at the 1-year follow-up (p = 0.047), while there were no differences in depressive and anxiety symptoms, quality of life, compliance with treatment, adverse drug reactions, or accidents.
Conclusions
High response and retention rates, stability of ESS, and lack of side effects indicate that telemedicine is a feasible and safe approach for adults and children with narcolepsy.
Graphical Abstract
Graphical Abstract
Narcolepsy type 1 (NT1) is a chronic neurological disorder characterized by symptoms such as excessive daytime sleepiness, sudden sleep episodes, disrupted nocturnal sleep, cataplexy, sleep ...paralysis, and hypnagogic hallucinations, which significantly impact the overall well-being and quality of life of individuals. While psychological factors have gained attention, there is limited research on the coping strategies employed by patients with NT1 and their association with quality of life. This study aimed to compare coping strategies in patients with NT1 and controls, as well as assess the relationship between coping strategies and quality of life in patients with NT1. A total of 122 individuals diagnosed with NT1 and 138 controls were enrolled in this cross-sectional study. Participants completed questionnaires assessing coping strategies and health-related quality of life. A Mann-Whitney U test was conducted to compare the use of different coping strategies by patients with NT1 and controls. Spearman's rho correlation was performed to examine the association between coping strategies and quality of life in the NT1 group. Results showed that patients with NT1 exhibited differences in the use of coping strategies compared to controls. They reported lower use of active coping, planning, instrumental, and emotional social support, and higher use of behavioral and mental disengagement. Denial and behavioral disengagement were significantly and negatively associated with quality of life. Identifying coping strategies and their association with quality of life may aid in the development of tailored interventions aimed at improving the adoption of effective coping strategies and reducing the use of maladaptive coping strategies.
Prior research has identified five common genetic variants associated with narcolepsy with cataplexy in Caucasian patients. To replicate and/or extend these findings, we have tested HLA-DQB1, the ...previously identified 5 variants, and 10 other potential variants in a large European sample of narcolepsy with cataplexy subjects.
Retrospective case-control study.
A recent study showed that over 76% of significant genome-wide association variants lie within DNase I hypersensitive sites (DHSs). From our previous GWAS, we identified 30 single nucleotide polymorphisms (SNPs) with P < 10(-4) mapping to DHSs. Ten SNPs tagging these sites, HLADQB1, and all previously reported SNPs significantly associated with narcolepsy were tested for replication.
For GWAS, 1,261 narcolepsy patients and 1,422 HLA-DQB1*06:02-matched controls were included. For HLA study, 1,218 patients and 3,541 controls were included.
None of the top variants within DHSs were replicated. Out of the five previously reported SNPs, only rs2858884 within the HLA region (P < 2x10(-9)) and rs1154155 within the TRA locus (P < 2x10(-8)) replicated. DQB1 typing confirmed that DQB1*06:02 confers an extraordinary risk (odds ratio 251). Four protective alleles (DQB1*06:03, odds ratio 0.17, DQB1*05:01, odds ratio 0.56, DQB1*06:09 odds ratio 0.21, DQB1*02 odds ratio 0.76) were also identified.
An overwhelming portion of genetic risk for narcolepsy with cataplexy is found at DQB1 locus. Since DQB1*06:02 positive subjects are at 251-fold increase in risk for narcolepsy, and all recent cases of narcolepsy after H1N1 vaccination are positive for this allele, DQB1 genotyping may be relevant to public health policy.
Narcolepsy type 1 (NT1) is a chronic and rare sleep disorder typically arising during adolescence and young adulthood. The main symptoms are excessive daytime sleepiness and cataplexy, a prototypical ...fall down elicited by huge emotions. Social relationships, school, work, and general health perception are frequently impaired in patients, who often show lower quality-of-life scores. We report which management strategies a young patient (DMG) adopted to cope with NT1 during his growth, avoiding exhibiting serious impairments to his global functioning.
A clinical psychologist explores the history of the patient's disease and the self-acquired strategies used to cope with the symptoms. The patient's global adaptation to the disease, stress-related managing skills, and overall well-being are assessed by standardized scales Illness Behavior Questionnaire (IBQ); Coping Orientations to Problems Experienced (COPE); and Psychological General Well-Being Index (PGWBI). We conducted a qualitative analysis of the patient's narration of his illness according to the procedure of the Grounded Theory. The MAXQDA software program was used to code the verbatim transcript.
From the qualitative analysis of the interview, three thematic cores emerged: 1) the disease history; 2) the patient's friendship with AD, a friend of his age diagnosed with NT1 since childhood; 3) the strategies used to deal with his symptoms before the diagnosis of NT1 and the related treatment. From the psychometric tests, the patient presents good coping strategies in dealing with stressful problems and events based mainly on acceptance and positive reinterpretation of the stressful situation.
This case shows that comparing peers of the same age and suffering from the same illness improve the patient's self-management ability to cope and live well with NT1.
Recent advances in the identification of susceptibility genes and environmental exposures provide broad support for a post-infectious autoimmune basis for narcolepsy/hypocretin (orexin) deficiency. ...We genotyped loci associated with other autoimmune and inflammatory diseases in 1,886 individuals with hypocretin-deficient narcolepsy and 10,421 controls, all of European ancestry, using a custom genotyping array (ImmunoChip). Three loci located outside the Human Leukocyte Antigen (HLA) region on chromosome 6 were significantly associated with disease risk. In addition to a strong signal in the T cell receptor alpha (TRA@), variants in two additional narcolepsy loci, Cathepsin H (CTSH) and Tumor necrosis factor (ligand) superfamily member 4 (TNFSF4, also called OX40L), attained genome-wide significance. These findings underline the importance of antigen presentation by HLA Class II to T cells in the pathophysiology of this autoimmune disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The brain suprapontine mechanisms associated with human cataplexy have not been clarified. Animal data suggest that the amygdala and the ventromedial prefrontal cortex are key regions in promoting ...emotion-induced cataplectic attacks. Twenty-one drug-naive children/adolescent (13 males, mean age 11 years) with recent onset of narcolepsy type 1 (NT1) were studied with fMRI while viewing funny videos using a "naturalistic" paradigm. fMRI data were acquired synchronously with EEG, mylohyoid muscle activity, and the video of the patient's face. Whole-brain hemodynamic correlates of (1) a sign of fun and amusement (laughter) and of (2) cataplexy were analyzed and compared. Correlations analyses between these contrasts and disease-related variables and behavioral findings were performed.
In this study we reported for the first time in humans the brain structures whose neural activity is specifically and consistently associated with emotion-induced cataplexy. To reach this goal drug-naive children and adolescents with recent onset narcolepsy type 1 were investigated. In narcolepsy caused by hypocretin/orexin deficiency, cataplexy is associated with a marked increase in neural activity in the amygdala, the nucleus accumbens, and the ventromedial prefrontal cortex, which represent suprapontine centers that physiologically process emotions and reward. These findings confirm recent data obtained in the hypocretin knock-out mice and suggest that the absence of hypothalamic hypocretin control on mesolimbic reward centers is crucial in determining cataplexy induced by emotions. Emotion-induced laughter occurred in 16 patients, and of these 10 showed cataplexy for a total of 77 events (mean duration = 4.4 s). Cataplexy was marked by brief losses of mylohyoid muscle tone and by the observation of episodes of facial hypotonia, jaw drop, and ptosis. During laughter (without cataplexy) an increased hemodynamic response occurred in a bilateral network involving the motor/premotor cortex and anterior cingulate gyrus. During cataplexy, suprapontine BOLD signal increase was present in the amygdala, frontal operculum-anterior insular cortex, ventromedial prefrontal cortex, and the nucleus accumbens; BOLD signal increases were also observed at locus ceruleus and in anteromedial pons. The comparison of cataplexy versus laugh episodes revealed the involvement of a corticolimbic network that processes reward and emotion encompassing the anterior insular cortex, the nucleus accumbens, and the amygdala.
The aim of this study was to assess work productivity and activity impairments and to explore their association with excessive daytime sleepiness, body mass index (BMI), depression, and anxiety in ...patients with narcolepsy type 1. We carried out a cross-sectional study in which patients with narcolepsy type 1 and matched controls for sex, age, and education were assessed for occupational features, EDS (Epworth Sleepiness Scale), BMI, depression (Beck Depression Inventory), anxiety (State-Trait Anxiety Inventory), and Work Productivity and Activity Impairment (WPAI). Different statistical approaches were used to investigate differences between groups and correlations between WPAI scores and clinical features. The 127 patients with narcolepsy type 1 (mean age 38.2 ± 15.5, 91.3% taking drugs for narcolepsy) and 131 controls (mean age of 37.4 ± 14.3) included did not differ in terms of occupational features, except for hours worked/week (29.9 in patients vs. 34.9 in controls) and officially recognised disability (30.7% vs. 5.3%). Impairment in all WPAI scores was approximately three times greater in patients. Narcolepsy was associated with work time missed in 27.4% of patients, while 93.2% to 95.5% of them had some impairment while working or during daily activities (vs. 37.5-46.8% of controls). Correlations with WPAI scores were found for excessive daytime sleepiness only in patients, and for both depression and anxiety in patients and controls, with a stronger correlation for activity impairment in patients. These results suggest that, despite treatment, narcolepsy type 1 was associated with extensive impairment especially regarding job effectiveness and daily activities. Future studies should investigate risk factors and effects of interventions on these outcomes.
To investigate potential sex-related differences in patients with narcolepsy type 1, we carried out an analysis of baseline data from 93 women and 89 men with narcolepsy type 1 who participated in ...the TElemedicine for NARcolepsy (TENAR) trial. The following data were considered: sociodemographics; diagnostic (disease history, polysomnography, orexin, human leukocyte antigen) and clinical features, including sleepiness (Epworth Sleepiness Scale), cataplexy and other narcolepsy symptoms; disease severity (Narcolepsy Severity Scale); pharmacological treatment; depressive symptoms (Beck Depression Inventory); and self-reported relevance of eight narcolepsy-related issues. We found that, compared with men, significantly more women reported automatic behaviours (55.4% versus 40%) and had higher Epworth Sleepiness Scale (median 10 versus 9) and Beck Depression Inventory scores (median 10.5 versus 5), and there was a trend for a higher Narcolepsy Severity Scale total score in women (median 19 versus 18, p = 0.057). More women than men were officially recognized as having a disability (38% versus 22.5%) and considered 5/8 narcolepsy-related issues investigated as a relevant problem. More severe sleepiness and a greater narcolepsy-related burden in women could mirror sex differences present in the general population, or may be related to suboptimal management of narcolepsy type 1 or to more severe depressive symptoms in women. Future studies and guidelines should address these aspects.
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