A unique association? A narcolepsy type 1 case comorbid with Primary Biliary Cholangitis.

The aim of the study was to present a woman affected of a narcolepsy with cataplexy (narcolepsy type 1) comorbid with an asymptomatic Primary Biliary Cholangitis (PBC). The HLA haplotype was DRB1*15:01, DQA1*01:02, DQB1*06:02. The allele DQB1*06:02 has been considered until now protective for PBC and dual pathology has not been published. We think the important clinical message of the Case would be of continuing to monitor adults with narcolepsy type 1 for late complications that may be associated with other autoimmune conditions. Clinicians should be aware of the relationship between Narcolepsy and PBC. This highlights the need for screening and management in these individuals.

Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy.

Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®.

Long-Term Outcome of a Series of Patients With Narcolepsy Type 1 and Comorbidity With Immunopathological and Autoimmune Diseases.

Background: The aim of this study was to evaluate the long-term outcome of our series of narcolepsy type 1 (NT1) patients with comorbid autoimmune diseases (ADs) and other immunopathological diseases (IDs), focusing on the incidence of new ADs and IDs in this sample. Methods: A longitudinal observational study was conducted over 6 years (2014 - 2020) in a series of 158 Caucasians NT1 patients (96 males; mean age: 50.1 ± 19.0 years) from the previous study. All but one case (familial case) were HLA-DQB1*06:02-positive. The diagnosis of narcolepsy was made according to the International Classification of Sleep Disorders (ICSD-3). Results: Twenty-one patients have been diagnosed with a new ID, 10 of them with an AD (autoimmune thyroid disease, psoriasis, rheumatoid arthritis, transverse myelitis, granuloma annulare, primary biliary cirrhosis, alopecia areata and antiphospholipid syndrome), and 11 with other IDs (allergic rhinitis, allergic asthma, atopic dermatitis, food allergy, contact dermatitis and drug allergy). One patient was diagnosed with two new ADs. We found IDs in 46 patients (24 females and 22 males) and the overall prevalence in this series is actually 29.11%; 22 of them (13.92%) had an AD, with a percentage higher than estimated in the general population. Conclusions: The prevalence of AD/ID is high in our series, suggesting that NT1 might arise on a background of generalized susceptibility to immune-mediated processes. The occurrence of an ID can in turn influence the development of others in genetically predisposed individuals, which explains the increased associations observed in this long-term study.

Sleep, Respiration and Nocturnal Paroxysmal Events in Joubert Syndrome: A Case Report.

Introduction: Joubert syndrome is a rare disorder, characterized by a complex midbrain malformation caused by defects in the structure and/or function of the primary cilium. Case Report: A 15-year-old boy with mild intellectual disability, hypotonia, mild ataxia, and abnormal eye movements diagnosed as having Joubert Syndrome since childhood, was referred to the Sleep Unit because spells of apnea while sleeping. He did not complain of snoring or daytime somnolence. The macro and microstructure of sleep and the comorbidities such respiratory abnormalities, periodic legs movements (PLM) and paroxysmal motor arousals (PA) and minimal motor events (MME) are described for the first time in Joubert syndrome. Results: EEG was normal. Video-polysomnography revealed a nocturnal disturbed sleep and periods of hyperpnea accompanied by body movements and followed by a periodic breathing lasting several minutes with no oxygen desaturation. The arousals provoked by apneas triggered paroxysmal motor events with dystonic movements in the hand and right foot accompanied by a spontaneous Babinski. Brain MRI showed the typical "molar tooth sign". Conclusion: Joubert syndrome is a heterogeneous disease. Epileptic seizures have been reported in some cases. Video-PSG is mandatory for the identification of nocturnal breathing abnormalities and sleep-related motor paroxysmal episodes.

Idling for Decades: A European Study on Risk Factors Associated with the Delay Before a Narcolepsy Diagnosis.

Purpose: Narcolepsy type-1 (NT1) is a rare chronic neurological sleep disorder with excessive daytime sleepiness (EDS) as usual first and cataplexy as pathognomonic symptom. Shortening the NT1 diagnostic delay is the key to reduce disease burden and related low quality of life. Here we investigated the changes of diagnostic delay over the diagnostic years (1990-2018) and the factors associated with the delay in Europe. Patients and Methods: We analyzed 580 NT1 patients (male: 325, female: 255) from 12 European countries using the European Narcolepsy Network database. We combined machine learning and linear mixed-effect regression to identify factors associated with the delay. Results: The mean age at EDS onset and diagnosis of our patients was 20.9±11.8 (mean ± standard deviation) and 30.5±14.9 years old, respectively. Their mean and median diagnostic delay was 9.7±11.5 and 5.3 (interquartile range: 1.7-13.2 years) years, respectively. We did not find significant differences in the diagnostic delay over years in either the whole dataset or in individual countries, although the delay showed significant differences in various countries. The number of patients with short (≤2-year) and long (≥13-year) diagnostic delay equally increased over decades, suggesting that subgroups of NT1 patients with variable disease progression may co-exist. Younger age at cataplexy onset, longer interval between EDS and cataplexy onsets, lower cataplexy frequency, shorter duration of irresistible daytime sleep, lower daytime REM sleep propensity, and being female are associated with longer diagnostic delay. Conclusion: Our findings contrast the results of previous studies reporting shorter delay over time which is confounded by calendar year, because they characterized the changes in diagnostic delay over the symptom onset year. Our study indicates that new strategies such as increasing media attention/awareness and developing new biomarkers are needed to better detect EDS, cataplexy, and changes of nocturnal sleep in narcolepsy, in order to shorten the diagnostic interval.

Data-Driven Phenotyping of Central Disorders of Hypersomnolence With Unsupervised Clustering.

BACKGROUND AND OBJECTIVES: Recent studies fueled doubts as to whether all currently defined central disorders of hypersomnolence are stable entities, especially narcolepsy type 2 and idiopathic hypersomnia. New reliable biomarkers are needed, and the question arises of whether current diagnostic criteria of hypersomnolence disorders should be reassessed. The main aim of this data-driven observational study was to see whether data-driven algorithms would segregate narcolepsy type 1 and identify more reliable subgrouping of individuals without cataplexy with new clinical biomarkers. METHODS: We used agglomerative hierarchical clustering, an unsupervised machine learning algorithm, to identify distinct hypersomnolence clusters in the large-scale European Narcolepsy Network database. We included 97 variables, covering all aspects of central hypersomnolence disorders such as symptoms, demographics, objective and subjective sleep measures, and laboratory biomarkers. We specifically focused on subgrouping of patients without cataplexy. The number of clusters was chosen to be the minimal number for which patients without cataplexy were put in distinct groups. RESULTS: We included 1,078 unmedicated adolescents and adults. Seven clusters were identified, of which 4 clusters included predominantly individuals with cataplexy. The 2 most distinct clusters consisted of 158 and 157 patients, were dominated by those without cataplexy, and among other variables, significantly differed in presence of sleep drunkenness, subjective difficulty awakening, and weekend-week sleep length difference. Patients formally diagnosed as having narcolepsy type 2 and idiopathic hypersomnia were evenly mixed in these 2 clusters. DISCUSSION: Using a data-driven approach in the largest study on central disorders of hypersomnolence to date, our study identified distinct patient subgroups within the central disorders of hypersomnolence population. Our results contest inclusion of sleep-onset REM periods in diagnostic criteria for people without cataplexy and provide promising new variables for reliable diagnostic categories that better resemble different patient phenotypes. Cluster-guided classification will result in a more solid hypersomnolence classification system that is less vulnerable to instability of single features.

Is memory impaired in narcolepsy type 1?

Memory deficits in narcolepsy with cataplexy type 1 (NT1) have been poorly studied, and the results are controversial. Patients with NT1 usually report memory deficits, which are not seen in objective memory assessments. This study aimed to assess attention and memory processes in NT1 patients using standardised neuropsychological tests and to compare the results with a control group. Performance in memory and attention tests was studied in 12 NT1 patients (diagnosed according to ICSD-3 criteria) and the results compared with those of 14 control subjects. All participants completed questionnaires on sleepiness and depression symptoms. Significant differences were found in the depression symptoms questionnaire. Regarding neuropsychological assessment, NT1 patients performed worse in attention than the control group in that they processed fewer stimuli and achieved fewer correct stimuli. However, no significant differences were found in the memory test results, and the performance was similar between both groups. After application of the Holm-Bonferroni correction, the only differences that remained significant were those in the ESS and in BDI-II scores. Our results showed that memory processes are preserved in NT1 patients and that memory complaints may not be associated with an objective memory deficit. In addition, the significant difference observed for patients in the depression questionnaire could explain the subjective memory complaints.

Kleine-Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci.

Kleine-Levin syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case-control genome-wide association study in 673 KLS cases collected over 14 y, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (rs71947865, Odds Ratio [OR] = 1.48, P = 8.6 × 10-9) within the 3'region of TRANK1 gene locus, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 y, we further stratified our sample by birth years and found that recent cases had a significantly reduced rs71947865 association. While the rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR = 1.54, P = 0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo R2 = 0.15; P < 2.0 × 10-22 at P = 0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, circadian regulation, and bipolar disorder, and indicate that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.

New 2013 incidence peak in childhood narcolepsy: more than vaccination?

Increased incidence rates of narcolepsy type-1 (NT1) have been reported worldwide after the 2009-2010 H1N1 influenza pandemic (pH1N1). While some European countries found an association between the NT1 incidence increase and the H1N1 vaccination Pandemrix, reports from Asian countries suggested the H1N1 virus itself to be linked to the increased NT1 incidence. Using robust data-driven modeling approaches, that is, locally estimated scatterplot smoothing methods, we analyzed the number of de novo NT1 cases (n = 508) in the last two decades using the European Narcolepsy Network database. We confirmed the peak of NT1 incidence in 2010, that is, 2.54-fold (95% confidence interval [CI]: [2.11, 3.19]) increase in NT1 onset following 2009-2010 pH1N1. This peak in 2010 was found in both childhood NT1 (2.75-fold increase, 95% CI: [1.95, 4.69]) and adulthood NT1 (2.43-fold increase, 95% CI: [2.05, 2.97]). In addition, we identified a new peak in 2013 that is age-specific for children/adolescents (i.e. 2.09-fold increase, 95% CI: [1.52, 3.32]). Most of these children/adolescents were HLA DQB1*06:02 positive and showed a subacute disease onset consistent with an immune-mediated type of narcolepsy. The new 2013 incidence peak is likely not related to Pandemrix as it was not used after 2010. Our results suggest that the increased NT1 incidence after 2009-2010 pH1N1 is not unique and our study provides an opportunity to develop new hypotheses, for example, considering other (influenza) viruses or epidemiological events to further investigate the pathophysiology of immune-mediated narcolepsy.

Neuropsychological Alterations in Narcolepsy with Cataplexy and the Expression of Cognitive Deficits.

OBJECTIVES: The objective of our study was to assess attention processes and executive function in patients with narcolepsy with cataplexy (NT1). To do so, we compared the results with those of a control group from the general population using an extensive neuropsychological test battery. METHODS: We studied 28 patients with NT1 and 28 healthy control participants matched for age, gender, and educational level. They all completed questionnaires on sleepiness, anxiety, and depression symptoms. In addition, they underwent neuropsychological tests. The ability to maintain attention was assessed using three computer tasks with different levels of complexity. RESULTS: Patients had significantly more daytime sleepiness than controls. A significant negative correlation between depression and disease duration was found in NT1 patients. The results of the anxiety questionnaire correlated with the presence of sleep paralysis. There were significant differences in information processing speed subtasks. Patients made significantly more omissions and generally reacted slower and more variably than controls in computerized tasks. As for executive function, patients performed worse in phonologic fluency tasks than controls. However, when the influence of processing speed on fluency tasks was statistically controlled, part of this significant difference disappeared. CONCLUSIONS: Our results indicate that the negative correlation between depression and disease duration probably reflects progressive adaptation to the functional burden of the disease. Information processing speed plays a fundamental role in the expression of cognitive deficits. We emphasized the need to control the influence of processing speed and sustained attention in the neuropsychological assessment of NT1 patients.

Aumento de los depósitos cerebrales de hierro en una familia de donantes de sangre con síndrome de piernas inquietas / Brain iron accumulation in a blood donor family with restless legs síndrome

Introducción. La fisiopatología del síndrome de piernas inquietas (SPI) es compleja. El mecanismo a través del cual la ferropenia favorece el desarrollo del SPI no está esclarecido, aunque se sugiere la presencia de una alteración en la homeostasis cerebral del hierro. Casos clínicos. Se presentan los hallazgos inusuales en una familia de donantes de sangre con SPI. Tres miembros de la misma familia fueron diagnosticados de SPI, cumpliendo los criterios definidos por el grupo internacional para el estudio del SPI (International Restless Legs Syndrome Study Group). Todos eran donantes de sangre habituales (rango de donación: 10-40 años) y los síntomas de SPI tenían un curso de 3-5 años. La exploración general y neurológica fue normal en todos los casos, así como los electromiogramas. El estudio fenotípico y genotípico descartó la presencia de hemocromatosis y otras causas genéticas de sobrecarga cerebral de hierro. Los estudios polisomnográficos mostraron sueño nocturno perturbado, con reducción de su eficiencia, y un aumento del índice de movimientos periódicos de las piernas. La resonancia magnética craneal evidenció un aumento de los depósitos cerebrales de hierro en los ganglios basales, la sustancia negra, el núcleo rojo y los dentados. Conclusión. Este aumento patológico de los depósitos cerebrales de hierro sugiere la presencia de un complejo trastorno del metabolismo cerebral del hierro en nuestros pacientes. Futuros estudios deben confirmar estos hallazgos y profundizar en el estudio de su relación con la fisiopatología del SPI

Introduction. The pathophysiology of restless legs syndrome (RLS) is complex. Secondary RLS with iron deficiency - which suggests disturbed iron homeostasis - remains to be elucidated. Case reports. We report the findings from a unique blood donor family with RLS. Three blood donors family members were diagnosed with RLS defined by the International RLS Study Group and without history of neurologic diseases and RLS symptoms in the last 3-5 years (range of blood donation: 10-40 years). The neurological examination and electromyographies were normal. A polisomnography showed disturbed nocturnal sleep with a reduction in sleep efficiency and an increased periodic limbs movement index. The cranial MRI showed brain iron deposits in basal ganglia, substantia nigra, red nuclei and dentate nuclei. Phenotypic and genotypic studies rule out genetic haemochromatosis or iron overload. Conclusion. The abnormal iron accumulation in the basal ganglia indicated a complex iron metabolism disorder of the central nervous system. Further studies are warranted to confirm our findings and its role in the pathophysiology of RLS

Exploring the clinical features of narcolepsy type 1 versus narcolepsy type 2 from European Narcolepsy Network database with machine learning.

Narcolepsy is a rare life-long disease that exists in two forms, narcolepsy type-1 (NT1) or type-2 (NT2), but only NT1 is accepted as clearly defined entity. Both types of narcolepsies belong to the group of central hypersomnias (CH), a spectrum of poorly defined diseases with excessive daytime sleepiness as a core feature. Due to the considerable overlap of symptoms and the rarity of the diseases, it is difficult to identify distinct phenotypes of CH. Machine learning (ML) can help to identify phenotypes as it learns to recognize clinical features invisible for humans. Here we apply ML to data from the huge European Narcolepsy Network (EU-NN) that contains hundreds of mixed features of narcolepsy making it difficult to analyze with classical statistics. Stochastic gradient boosting, a supervised learning model with built-in feature selection, results in high performances in testing set. While cataplexy features are recognized as the most influential predictors, machine find additional features, e.g. mean rapid-eye-movement sleep latency of multiple sleep latency test contributes to classify NT1 and NT2 as confirmed by classical statistical analysis. Our results suggest ML can identify features of CH on machine scale from complex databases, thus providing 'ideas' and promising candidates for future diagnostic classifications.

Alteraciones neuropsicológicas en la narcolepsia con cataplejía: una revisión / Neuropsychological alterations in narcolepsy with cataplexy: a review

Objetivo. Describir el estado actual de conocimiento sobre los principales déficits cognitivos que presentan los pacientes con narcolepsia con cataplejía o narcolepsia de tipo 1. Desarrollo. La mayoría de los estudios ha encontrado que las funciones cognitivas más afectadas son la atención (especialmente el mantenimiento de la atención o atención sostenida), la velocidad de procesamiento de la información y las funciones ejecutivas (en particular, la fluidez verbal y la resistencia a la interferencia de estímulos). Estos datos indican una dificultad para utilizar los recursos cognitivos de los que dispone el sujeto. Estas alteraciones son similares a las presentes en otras hipersomnias, aunque difieren en la intensidad. Por otra parte, la mayoría de los estudios destaca una elevada prevalencia de diferentes trastornos depresivos y ansiosos. Se ha sugerido que la predisposición a la ansiedad forma parte del fenotipo característico de estos pacientes. La ansiedad podría actuar como un factor desencadenante de la enfermedad y ser asimismo una consecuencia de la enfermedad. Conclusiones. Los déficits cognitivos en los pacientes con narcolepsia de tipo 1 se manifiestan en tareas de larga duración o monótonas y en tareas con alta demanda cognitiva, principalmente en tareas de atención sostenida. La presencia de sintomatología depresiva en estos pacientes, junto con la excesiva somnolencia diurna, parecen afectar a su rendimiento en las pruebas neuropsicológicas, y estar estrechamente relacionadas con la apreciación subjetiva de dificultades cognitivas (AU)

Aim. To describe the current state of the art about the main cognitive deficits that appear in patients affected with narcolepsy with cataplexy (NT1). Development. The majority of the studies have found that the most impaired cognitive functions are attention (especially maintenance of attention or sustained attention), speed of information processing and executive functions (in particular, verbal fluency and resistance to the stimuli interference). These data indicate the difficulty to use the available cognitive resources of the patient. These alterations are similar to those present in other hypersomnias, although they might differ in intensity. Moreover, most of the studies emphasize a high prevalence of different depressive and anxious disorders. It has been suggested that predisposition to anxiety could be part of the characteristic phenotype of these patients. Anxiety could act either as a trigger for the disease or a consequence of the disease. Conclusions. Cognitive deficits in patients with NT1 appear in long lasting and/or monotonous tasks and in high cognitive demanding tasks. The presence of depressive symptomatology, together with excessive daytime sleepiness in these patients could affect their performance in neuropsychological test, and it might be related to their subjective perception of the cognitive deficits (AU)

Narcolepsy with cataplexy and pregnancy: a case-control study.

This was a retrospective case-control study in 25 patients with narcolepsy with cataplexy and 75 women in the control group. Patients completed the questionnaire by Maurovich-Horvat et al. (J. Sleep Res., 2013, 22: 496-512). We personally interviewed 25 patients with narcolepsy with cataplexy using the administered questionnaire regarding conception, pregnancy, delivery, perinatal and breastfeeding periods. Patients with narcolepsy with cataplexy reported 59 pregnancies versus 164 in the control group. In 16 cases (27.1%), a disease before pregnancy was present compared with eight cases (4.9%) in the control group (P < 0.001); among them, extrinsic asthma was reported 11 times in the narcolepsy with cataplexy group (P < 0.005). Patients with narcolepsy with cataplexy more often had a single pregnancy compared with controls (P < 0.05). Gestational diabetes was more frequent in patients with narcolepsy with cataplexy (P < 0.05). Induced deliveries were higher in controls (P < 0.009). No differences were found between the groups in terms of duration of pregnancies and complications during and after delivery, as during the puerperium. Neonates from patients had heavier birth weight (P < 0.015). The breastfeeding period was longer in patients (P < 0.01). Modafinil and methylphenidate were the drugs administered in six pregnancies. No significant differences in depression during pregnancy and during puerperium were found between patients and controls. This is the first case-control study in women with narcolepsy with cataplexy related to pregnancy, delivery, childbirth and puerperium. Data suggest that patients have pregnancy outcomes similar to controls. The prevalence of gestational diabetes was higher in women with narcolepsy with cataplexy. Caesarean sections, complications during delivery and normal perinatal period for infants were similar in both groups. Breastfeeding was longer in patients.

Narcolepsia-cataplejía y psicosis: estudio de un caso / Narcolepsy-cataplexy and psychosis: a case study

Objetivo. Describir una paciente que en la adolescencia desarrolló narcolepsia con cataplejía (NT1) y psicosis. Caso clínico. Niña de 14 años remitida a la unidad de sueño por presentar somnolencia diurna, sueño nocturno fragmentado, hambre compulsiva y aumento de peso durante el último año. Tratada inicialmente con modafinilo y oxibato sódico, tuvo que ser hospitalizada por presentar síntomas psicóticos. Se suprimió el tratamiento antinarcoléptico y se administraron antipsicóticos. El único que toleró fue el haloperidol 1 mg/día, con mejoría del delirio, las alucinaciones y los síntomas disfóricos, pero con empeoramiento de los síntomas narcolépticos. La polisomnografía mostró un sueño nocturno muy fragmentado, y en la prueba de latencias múltiples del sueño, la latencia de sueño fue de un minuto, y tuvo cinco adormecimientos directos en la fase del sueño REM. Presentaba HLA-DQB1*06:02 positivo y nivel de hipocretina-1 en el líquido cefalorraquídeo indetectable. La entrevista diagnóstica para estudios genéticos adaptada para narcolepsia (DIGSAN) ayudó a confirmar que presentaba una doble patología de NT1 y síntomas psicóticos. La última revisión de su sueño con tratamiento psicofarmacológico muestra un aumento del índice de eficacia del sueño. Clínicamente presenta somnolencia diurna excesiva, ataques parciales de cataplejía y una obesidad muy importante. No muestra alteraciones del humor, pero tiene fracaso escolar y aislamiento social. Conclusión. La coexistencia de narcolepsia con psicosis es una entidad clínica rara, más frecuente en adolescentes que en adultos. La comorbilidad de ambas enfermedades tiene un mal pronóstico clínico y terapéutico, y sugiere hipótesis fisiopatológicas interesantes (AU)

Aims. To report a challenging patient a girl who developed narcolepsyy with cataplexy (NT1) and a psychosis during adolescence. To discuss diagnostic and therapeutic challenges of the comorbid cases. Case report. A 14-year-old girl was referred to Sleep and Epilepsy Unit for excessive daytime sleepiness, impaired nocturnal sleep, binge eating and weight gain, over the last year. After being diagnosed with a NT1 the patient was treated with modafinil and sodium oxybate. She was hospitalized for psychotic symptoms after starting NT1 treatment. Withdrawal of the narcolepsy treatment and initiation of haloperidol 1 mg/day (the only antipsychotic treatment she could tolerate) improved the delusions, hallucinations and dysphoria but worsened the narcolepsy symptoms. Polysomnography showed fragmented nocturnal sleep and five sleep REM onset periods in MSLT. Positive HLA-QB1*06:02 and undetectable level of hypocretine in the cerebrospinal fluid were found. MRI and CT-scan were normal. Diagnostic Interview for Genetic Studies Adapted for Narcolepsy (DIGSAN) questionnaire confirmed that patient presented a dual diagnostic NT1 and psychotic symptoms. The last sleep follow-up while on psychopharmacological treatment, showed an increased sleep efficiency index. She currently has severe somnolence, obesity, and partial cataplectic attacks along with normal mood, academic failure and social isolation. Conclusion. The coexistence of narcolepsy with psychoses is a rare clinical entity, more frequent in adolescents than in adults. The comorbidity of the two illnesses worsens clinical and therapeutic prognosis and also suggests interesting pathophysiological hypotheses (AU)

Comorbidity of Narcolepsy Type 1 With Autoimmune Diseases and Other Immunopathological Disorders: A Case-Control Study.

BACKGROUND: Several evidences suggest that autoimmune diseases (ADs) tend to co-occur in an individual and within the same family. Narcolepsy type 1 (NT1) is a chronic sleep disorder caused by a selective loss of hypocretin-producing neurons due to a mechanism of neural destruction that indicates an autoimmune pathogenesis, although no evidence is available. We report on the comorbidity of ADs and other immunopathological diseases (including allergy diseases) in narcolepsy. METHODS: We studied 158 Caucasian NT1 patients (60.7% male; mean age 49.4 ± 19.7 years), in whom the diagnosis was confirmed by polysomnography followed by a multiple sleep latency test, or by hypocretin-1 levels measurements. RESULTS: Thirty out of 158 patients (18.99%; 53.3% female; 29 sporadic and one familial cases) had one or more immunopathological diseases associated. A control group of 151 subjects were matched by gender and age with the narcolepsy patients. Results demonstrated that there was a higher frequency of ADs in our series of narcolepsy patients compared to the sample of general population (odds ratio: 3.17; 95% confidence interval: 1.01 - 10.07; P = 0.040). A temporal relationship with the age at onset of the diseases was found. CONCLUSIONS: Cataplexy was significantly more severe in NT1 patients with immunopathological diseases, and immunopathological diseases are a risk factor for severe forms of cataplexy in our series (odds ratio: 23.6; 95% confidence interval: 5.5 - 100.1).

The European Narcolepsy Network (EU-NN) database.

Narcolepsy with cataplexy is a rare disease with an estimated prevalence of 0.02% in European populations. Narcolepsy shares many features of rare disorders, in particular the lack of awareness of the disease with serious consequences for healthcare supply. Similar to other rare diseases, only a few European countries have registered narcolepsy cases in databases of the International Classification of Diseases or in registries of the European health authorities. A promising approach to identify disease-specific adverse health effects and needs in healthcare delivery in the field of rare diseases is to establish a distributed expert network. A first and important step is to create a database that allows collection, storage and dissemination of data on narcolepsy in a comprehensive and systematic way. Here, the first prospective web-based European narcolepsy database hosted by the European Narcolepsy Network is introduced. The database structure, standardization of data acquisition and quality control procedures are described, and an overview provided of the first 1079 patients from 18 European specialized centres. Due to its standardization this continuously increasing data pool is most promising to provide a better insight into many unsolved aspects of narcolepsy and related disorders, including clear phenotype characterization of subtypes of narcolepsy, more precise epidemiological data and knowledge on the natural history of narcolepsy, expectations about treatment effects, identification of post-marketing medication side-effects, and will contribute to improve clinical trial designs and provide facilities to further develop phase III trials.

Novel approach identifies SNPs in SLC2A10 and KCNK9 with evidence for parent-of-origin effect on body mass index.

The phenotypic effect of some single nucleotide polymorphisms (SNPs) depends on their parental origin. We present a novel approach to detect parent-of-origin effects (POEs) in genome-wide genotype data of unrelated individuals. The method exploits increased phenotypic variance in the heterozygous genotype group relative to the homozygous groups. We applied the method to >56,000 unrelated individuals to search for POEs influencing body mass index (BMI). Six lead SNPs were carried forward for replication in five family-based studies (of ∼4,000 trios). Two SNPs replicated: the paternal rs2471083-C allele (located near the imprinted KCNK9 gene) and the paternal rs3091869-T allele (located near the SLC2A10 gene) increased BMI equally (beta = 0.11 (SD), P<0.0027) compared to the respective maternal alleles. Real-time PCR experiments of lymphoblastoid cell lines from the CEPH families showed that expression of both genes was dependent on parental origin of the SNPs alleles (P<0.01). Our scheme opens new opportunities to exploit GWAS data of unrelated individuals to identify POEs and demonstrates that they play an important role in adult obesity.