Electronic consultations with Video Supported PowerPoint versus in-clinic face-to-face, pre-travel consultations: A single-centre, comparative analysis.

BACKGROUND: Pretravel consultation involves a face-to-face visit with a Travel Medicine expert and includes time consuming educating/counseling. Efficacy of electronic consultations for pretravel is unknown. We compared pretravel education via face-to-face consult to an electronic consultations combined with education via Video Supported PowerPoint for select travelers. METHODS: We conducted a prospective trial comparing pre-travel education via electronic consultations versus face-to-face consult. Study was conducted from May 2014 through May 2015. RESULTS: Pretravel surveys were completed by 100 in electronic consult arm and 94 in face-to-face consult arm; 67/100 (67%) in the electronic consult and 51/94 (54.2%) in the face-to-face group completed post-travel surveys. Both groups had similar baseline demographics. 36.2% of the face-to-face group felt the trip preparation could have effectively been accomplished through electronic consult, while 33% felt that a face-to-face consult was needed; in contrast, a majority (63.3%) of electronic consult group preferred the electronic consult. Pre-travel education effectiveness was similar in both groups. No statistically significant differences in responses were noted in both groups to 5 of the 6 knowledge assessment questions. A higher proportion (76/100; 76%) in the electronic consult group compared to 55.4% (51/94) (p = 0.0018) in face-to-face group chose the correct response regarding management of febrile bloody diarrhea. 53% reported behavior change to prevent travel related illnesses, with no statistically significant differences between the groups. CONCLUSIONS: electronic consultation with Video Supported PowerPoint pre-travel education is as effective as education via face-to-face consultations and provides a viable alternative to face-to-face consultations in select travelers.

Non-motor symptoms and quality of life in subjects with mild parkinsonian signs.

BACKGROUND: Mild parkinsonian signs (MPS) are frequent in the elderly population and associated with the presence of risk markers for Parkinson's disease (PD). Both MPS and non-motor signs may be present in prodromal PD and may significantly impair quality of life (QoL). OBJECTIVE: To disentangle the contribution of motor impairment and extra-motor manifestations to QoL in subjects with MPS (n=63), manifest PD (n=69), disorders with motor symptoms due to non-neurodegenerative diseases (n=213) and healthy controls (n=258). METHODS: Subjects with MPS, healthy controls, disease controls (patients with motor impairment due to, eg, arthrosis and spondylosis), and PD patients (total n=603) were selected from a large epidemiological longitudinal study, the EPIPARK cohort. Motor function was determined using the UPDRSIII protocol, and information on depressive symptoms, anxiety, sleep, and QoL was assessed via rating scales and data were analyzed. RESULTS: Depressive symptoms, anxiety, and sleep problems were equally frequent in the MPS group and controls. Health-related QoL was slightly reduced in the MPS group. Motor impairment and its extent was comparable between the MPS group and disease controls (UPDRSIII 5-6 points). Higher motor dysfunction was associated with lower QoL. Depressive symptoms, but not anxiety and daytime sleepiness, was significant predictors of general QoL, independent of motor function. CONCLUSIONS: Quality of life is slightly decreased in an elderly population with MPS. QoL is associated with severity of motor impairment but also with non-motor aspects, ie, depressive symptoms. Follow-up studies in large cohorts are warranted to determine the natural course of MPS and its impact on QoL.

[The Health-Related Quality of Life as Measured with the SF-12v1 in Elderly People Living in Luebeck 2010/11 in Comparison with the German Norm Data in 1994]. / Die bevölkerungsbezogene Lebensqualität gemessen mit dem SF-12v1 bei 51- bis 80-jährigen Lübeckern in den Jahren 2010/11 im Vergleich zur Deutschen Normstichprobe von 1994.

BACKGROUND: Health-related quality of life (HRQL) is deemed to be a meaningful endpoint when evaluating therapy and prevention interventions. For comparison purposes not only patient data but also representative population samples can serve as reference data. We aim to describe differences between the Luebeck population sample (LBS, year 2010/11) and the German norm population from 1994. Moreover, the influence of diabetes mellitus and hypertension on HRQL is analysed. METHODS: The LBS is a representative sample of 10 000 elderly people living in Luebeck aged 51-80 years, an age group susceptible to chronic diseases. Not only the SF-12v1, but also the item "actual health status in comparison to the last year" of the SF-36 and a list of comorbidities have been applied. Descriptive statistics are given for age, sex and disease groups. A comparison with data from the DNSP going back to 1994 is made using unstandardised data as well as age- and gender-standardised data. RESULTS: 5 835 individuals (response rate 60%) did participate in the survey (48% male, mean age 63.9 years, SD 7.7). PSC and MSC could be computed for 80% of them. Unstandardised values are 44.3±10.8 for the PSC and 50.4±10.3 for the MSC. Applying standardisation by age and gender, PSC values were comparable between the LBS and DNSP (except for the age group 51-60 years). MSC values were significantly lower in the LBS. The "general health Status" does not significantly differ whereas the "actual health status in comparison to the last year" is significantly lower in the LBS than in the DNSP (p<0.001). CONCLUSIONS: The LBS comprises more individuals than older studies in an age group relevant for chronic diseases. RESULTS hint to a comparable physical HRQL but a worse mental HRQL in the current data set. It remains unclear why persons between 51 and 60 years assess their physical HRQL worse than in the DNSP. A further open question is why the "actual health status in comparison to the last year" is assessed more negatively. Changed context conditions in working and social life may have an influence.

[Evaluation of Psychiatric Disorders on the Basis of a SCID Screening]. / Evaluation psychiatrischer Störungen anhand eines erweiterten SKID-Screenings.

BACKGROUND: Psychiatric symptoms/syndromes such as depression, apathy, anxiety or psychotic episodes are present in a range of neurological disorders including Parkinson's disease. The Structured Clinical Interview for DSM-IV (SCID) represents the gold standard for the assessment of psychiatric disorders but is often too time-consuming for application in clinical practice. METHODS: 66 participants were examined using the screening items and the first two questions of section A of the SCID as well as the complete version of the SCID, part I. The accuracy of the screening and the complete SCID was evaluated, and logistic regression was conducted to analyze factors associated with measure disagreement between the two procedures. RESULTS: Overall, psychiatric disorders were identified by screening in 40/66 (60.6%), as against 31/66 (47.0%) using the complete SCID. Compared to the complete SCID, the sensitivity and specificity of the screening items were 88% and 59%, respectively. CONCLUSION: Based on its good sensitivity, the SCID screening may be used in clinical practice to yield an overview of psychiatric disorders that may require treatment. Due to its moderate specificity, however, the complete version of the SCID should be subsequently used in cases whenever the SCID screening is positive. In any case, the SCID screening must be regarded as inadequate for the detection of psychotic symptoms.

Acute psychosis in a verified Huntington disease gene carrier with subtle motor signs: psychiatric criteria should be considered for the diagnosis.

Huntington disease (HD) is an inherited, progressive, autosomal dominant disorder. Some patients develop severe chorea or cognitive symptoms. The genetic defect causes progressive atrophy of the striatum, the cortex and extrastriatal structures (Sheperd GM. Corticostriatal connectivity and its role in disease. Nat Rev Neurosci 2013;14:278-91). The precise timing of clinical diagnosis of HD is poorly characterized and is mainly based on motor symptoms (Huntington, Study and Group. Unified Huntington's Disease Rating Scale: reliability and consistency. Huntington Study Group. Mov Discord 1996:136-42). Patients suffering from HD frequently show cognitive or affective symptoms even before manifesting motor signs. Psychiatric symptoms like depression, apathy, aggression, and disinhibition are common, and suicide rates are over four times higher than in the general population (Di Maio L, Squitieri F, Napolitano G, Campanella G, Trofatter JA, Conneally PM. Suicide risk in Huntington's disease. J Med Genet 1993;30:293-5). This case report of a female patient with genetically proven HD is of special interest because motor or cognitive impairment were absent whereas she suffered from symptoms of an acute and severe psychosis likely to be symptomatic signs of HD.

Therapeutic intraspinal microstimulation improves forelimb function after cervical contusion injury.

OBJECTIVE: Intraspinal microstimulation (ISMS) is a promising method for activating the spinal cord distal to an injury. The objectives of this study were to examine the ability of chronically implanted stimulating wires within the cervical spinal cord to (1) directly produce forelimb movements, and (2) assess whether ISMS stimulation could improve subsequent volitional control of paretic extremities following injury. APPROACH: We developed a technique for implanting intraspinal stimulating electrodes within the cervical spinal cord segments C6-T1 of Long-Evans rats. Beginning 4 weeks after a severe cervical contusion injury at C4-C5, animals in the treatment condition received therapeutic ISMS 7 hours/day, 5 days/week for the following 12 weeks. MAIN RESULTS: Over 12 weeks of therapeutic ISMS, stimulus-evoked forelimb movements were relatively stable. We also explored whether therapeutic ISMS promoted recovery of forelimb reaching movements. Animals receiving daily therapeutic ISMS performed significantly better than unstimulated animals during behavioural tests conducted without stimulation. Quantitative video analysis of forelimb movements showed that stimulated animals performed better in the movements reinforced by stimulation, including extending the elbow to advance the forelimb and opening the digits. While threshold current to elicit forelimb movement gradually increased over time, no differences were observed between chronically stimulated and unstimulated electrodes suggesting that no additional tissue damage was produced by the electrical stimulation. SIGNIFICANCE: The results indicate that therapeutic intraspinal stimulation delivered via chronic microwire implants within the cervical spinal cord confers benefits extending beyond the period of stimulation, suggesting future strategies for neural devices to promote sustained recovery after injury.

Phenotype in parkinsonian and nonparkinsonian LRRK2 G2019S mutation carriers.

OBJECTIVES: Using a family study design, we describe the motor and nonmotor phenotype in probands with LRRK2 G2019S mutations and family members and compare these individuals to patients with idiopathic Parkinson disease (iPD) and unrelated controls. METHODS: Probands with G2019S mutations and their first-degree relatives, subjects with iPD, and unrelated control subjects were identified from 4 movement disorders centers. All underwent neurologic examinations and tests of olfaction, color vision, anxiety, and depression inventories. RESULTS: Tremor was more often a presenting feature among 25 individuals with LRRK2-associated PD than among 84 individuals with iPD. Subjects with LRRK2-PD had better olfactory identification compared with subjects with iPD, higher Beck Depression Inventory scores, and higher error scores on Farnsworth-Munsell 100-Hue test of color discrimination. Postural or action tremor was more common among 29 nonmanifesting mutation carriers compared with 53 noncarriers within the families. Nonparkinsonian family members had higher Unified Parkinson's Disease Rating Scale motor scores, more constipation, and worse color discrimination than controls, regardless of mutation status. CONCLUSIONS: Although tremor is a more common presenting feature of LRRK2-PD than iPD and some nonmotor features differed in degree, the phenotype is largely overlapping. Postural or action tremor may represent an early sign. Longitudinal evaluation of a large sample of nonmanifesting carriers will be required to describe any premotor phenotype that may allow early diagnosis.

Progression of subtle motor signs in PINK1 mutation carriers with mild dopaminergic deficit.

BACKGROUND: While homozygous mutations in the PINK1 gene cause recessively inherited early-onset Parkinson disease (PD), heterozygous mutations have been suggested as a susceptibility factor. METHODS: To evaluate this hypothesis, 4 homozygous PINK1 patients with PD and 10 asymptomatic carriers of a single heterozygous mutation from a large German family (family W) were included in this study. Clinical follow-up of the heterozygous mutation carriers 3 years after the initial visit included a detailed videotaped neurologic examination using the Unified Parkinson's Disease Rating Scale III protocol and smell and color discrimination testing. At follow-up, PET with 18-fluorodopa (FDOPA) of 13 family members was obtained in order to evaluate the clinical phenotype in light of nigostriatal dopaminergic functioning. The clinical and PET data were compared to those of healthy controls. RESULTS: While there was mild worsening of clinical signs in previously affected heterozygous mutation carriers upon follow-up, 3 additional individuals had newly developed signs of possible PD. Hyposmia was found in 7 of the heterozygous mutation carriers, diminished color discrimination in 4. The homozygous mutation carriers who were all definitely affected with PD showed a severe, 60% decrease of caudate and putaminal FDOPA uptake; heterozygous offspring also had a significant 20% putaminal FDOPA uptake reduction compared to controls. CONCLUSIONS: Our findings strengthen the hypothesis that heterozygous PINK1 mutations act as a susceptibility factor to develop at least subtle Parkinson disease motor and nonmotor signs, as supported by the finding of a reduced striatal dopaminergic FDOPA uptake not only in homozygous but also, albeit to a lesser extent, in heterozygous mutation carriers.

Pulsión y objeto en la transferencia narcisista. Presentación teórico-clínica / Drive and objetal in the narcissitic transference

El presente trabajo realiza un desarrollo teórico del concepto de transferencias narcisistas a través del análisis de la dinámica de la pulsión de meta inhibida y de la pulsión que busca su descarga en el objeto. Muestra cómo dichas pulsiones intervienen en el balance entre libido del yo, narcisista y libido de objeto. Describe cómo éstas intervienen en la elección y relación de objeto y cómo se traducen en la relación analítica expresándose por medio de la transferencia. Partiendo de postulados freudianos, se destaca la utilidad de plantear el concepto de transferencias narcisistas como herramienta teórica y clínica, basándose en los aportes de varios autores representativos: H.Kohut, B. Grunberger, J. Bergeret y O. Kernberg. Los conceptos teóricos que se describen se ilustran con un caso clínico de una paciente adulta en análisis (AU)

This paper deals with the theoretic study of the concept of narcissistic transference through the analysis of the dynamics of the goal inhibited drive as well as through the study of the drive that looks for discharge in the object. It shows how these drives mediate in the balance between the libido of the narcissistic ego and the libido of the object. The study describes how these drives mediate in the election of the object, and in the object relationship. Also, it shows how they manifest themselves in the transference. From the Freudian postulates, it outstands the concept of narcissistic transference as a basic tool, both theoretically as well as clinically, based on the contributions of a group of representative authors: H. Kohut, B. Grunberger, J. Bergeret and O. Kernberg. The theoretical concepts described are exemplified with a clinical case of an adult patient in analysis (AU)

Validation of photographic food records in children: are pictures really worth a thousand words?

BACKGROUND/OBJECTIVES: Self-reported food records are commonly used to estimate dietary intake. However, diet diaries are time consuming for participants and children are often unfamiliar with standard portion sizes or weights/volume of foods that can add to the error associated with self-reported intake. We hypothesize that photographic food records to assess dietary intake will be as accurate as a standard food diary and will decrease participant/family burden. SUBJECTS/METHODS: A total of 28 healthy subjects, 10-16 years, consumed a weighed diet for 3 days and returned any uneaten items for weigh back on day 4. During the 3 days of weighed diet, subjects recorded all intake both using a standard diet diary and taking photographs before and after consumption. Photographs were analyzed by two independent dieticians for estimation of serving size. The actual amount consumed was compared to the diary and photographic estimates through Spearman's correlation coefficients and confidence intervals. RESULTS: There was no difference between the diet diary and photographic estimates of total energy, carbohydrate, fat, protein, fiber, vitamins A, D and E, calcium, iron or zinc compared to actual intake. However, both participants and their parents reported that the photographic method was quicker, simpler and would be preferred if they were to record dietary intake in the future. In this study cohort, 36% of subjects accurately reported actual daily energy intake (+/-5% of actual intake), only 29% underreported energy intake and 35% overreported energy intake. CONCLUSIONS: Photographic food records can be used to accurately estimate dietary intake in a pediatric population. In addition, this method is less burdensome for the participants and their family.

Premotor Gray Matter Volume is Associated with Clinical Findings in Idiopathic and Genetically Determined Parkinson's Disease.

In the present voxel-based morphometric study, we investigated whether the severity and duration of disease are associated with alterations in gray matter volume (GMV) in symptomatic Parkin mutation carriers (sPARKIN-MC) and patients with idiopathic Parkinson's disease (iPD). Regression analyses revealed different negative correlations between GMV in cortical motor areas and the severity as well as the disease duration in sPARKIN-MC and iPD patients. SPARKIN-MC showed a less involvement of cortical motor areas, in particular in the supplementary motor area (SMA) than iPD patients. Specifically, in iPD patients, but not in sPARKIN-MC, there was a negative correlation between the SMA degeneration and the UPDRS-II item freezing. The different degeneration patterns may mirror diverse kinetics of the disease progress in these two groups of PD patients with different underlying etiologies.

Substantia nigra hyperechogenicity correlates with clinical status and number of Parkin mutated alleles.

To further evaluate (1) transcranial sonography (TCS) for (pre)clinical diagnosis of Parkinson's disease (PD) and (2) to examine asymptomatic carriers of Parkin mutations we investigated substantia nigra (SN) hyperechogenicity in PD patients and unaffected subjects with and without Parkin mutations. The area (aSN) of the hyperechogenic SN were calculated bilaterally and study subjects were assigned to high versus low value groups. Eleven of the (affected and unaffected) mutation carriers had previously undergone 18-fluoro-dopa-(FDOPA)-PET scans. Fifty-eight individuals were investigated, including 24 with clinically definite and 34 without symptoms or signs of PD. Of the patients, three had one mutated and six had two mutated Parkin alleles. Of the unaffected subjects, 13 carried a single Parkin mutated allele. After dichotomization, 21 subjects had high and 37 subjects low values of mean aSN. Regarding the clinical status, 13 (62%) of the individuals with a high mean aSN had PD,while 26 (70%) of the study subjects with low values did not show signs of PD (p = 0.0393). Similarly, probands with high mean aSN values more frequently carried Parkin mutations (58%) than probands with low values (27%, p = 0.0234). A negative correlation between FDOPA uptake in the posterior putamen and maximum aSN was found in the group of mutation carriers (r = -0.809, p = 0.0234). In conclusion, hyperechogenicity of the SN is found in both idiopathic and Parkin-associated PD. Further strengthening the notion of a potential relationship between SN hyperechogenicity and Parkin mutational status, a larger aSN was associated with an increasing number of mutated alleles in our study.

Nongenetic causes of Parkinson's disease.

Study of the nongenetic causes of Parkinson's disease (PD) was encouraged by discovery of a cluster of parkinsonism produced by neurotoxic pyridine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the 1980s. Since that time, epidemiologic investigations have suggested risk factors, though their results do not establish causality. Pesticide exposure has been associated with increased risk in many studies. Other proposed risks include rural residence and certain occupations. Cigarette smoking, use of coffee/caffeine, and non-steroidal antiinflammatory drugs (NSAIDs) all appear to lower risk of PD, while dietary lipid and milk consumption, high caloric intake, and head trauma may increase risk. The cause of PD is likely multifactorial. Underlying genetic susceptibility and combinations of risk and protective factors likely all contribute. The combined research effort by epidemiologists, geneticists, and basic scientists will be needed to clarify the cause(s) of PD.

Motor reorganization in asymptomatic carriers of a single mutant Parkin allele: a human model for presymptomatic parkinsonism.

Mutations in the Parkin gene are the most common known single cause of early-onset parkinsonism. It has been shown that asymptomatic carriers with a single mutant allele have latent presynaptic dopaminergic dysfunction in the striatum. Here we used functional MRI to map movement-related neuronal activity during internally selected or externally determined finger movements in 12 asymptomatic carriers of a Parkin mutation and 12 healthy non-carriers. Mean response times were 63 ms shorter during internally selected movements than during externally guided movements (P = 0.003). There were no differences in mean response times between groups (P > 0.2). Compared with externally determined movements, the internal selection of movements led to a stronger activation of rostral motor areas, including the rostral cingulate motor area (rCMA), rostral supplementary motor area, medial and dorsolateral prefrontal cortices. The genotype had a significant impact on movement-related activation patterns. Asymptomatic carriers showed a stronger increase in movement-related activity in the right rCMA and left dorsal premotor cortex, but only if movements relied on internal cues. In addition, synaptic activity in the rCMA had a stronger influence on activity in the basal ganglia in the context of internally selected movements in asymptomatic carriers relative to non-carriers. We infer that this reorganization of striatocortical motor loops reflects a compensatory effort to overcome latent nigrostriatal dysfunction.

A rare form of narcolepsy (HLA-DR2-) shows possible association with (functionally relevant) alpha-interferon gene polymorphisms.

Narcolepsy is a neuropsychiatric disease caused by complex disturbance of sleep regulation. The main symptoms comprise daytime sleepiness and cataplexy. Although the aetiology remains unclear so far, narcolepsy is genetically characterized by strong linkage to the human leukocyte antigen complex as more than 90% of the patients are typed HLA-DR2+. Recently, it has become apparent that the orexin (hypocretin) neurotransmitter system plays a key role in the pathogenesis of the disease. Canine narcolepsy is caused by mutations in the orexin receptor 2 gene, and narcoleptic patients show specifically decreased cerebrospinal fluid orexin levels. Decreased promotor activity of the prepro-orexin gene is caused by binding of alpha-interferon in vitro. To investigate the possible role of IFNA gene polymorphisms in the pathogenesis of narcolepsy, we have genotyped two single nucleotide polymorphisms in IFNA genes as well as a neighbouring microsatellite. No association was evident in the prevalent DR2+ group. Yet, the IFNA10 single nucleotide polymorphisms and the IFNA microsatellite are associated with the DR2- patient group. Thus, the pathogenetic role of interferons needs to be defined in DR2- narcolepsy.

Increased frequency of migraine in narcoleptic patients: a confirmatory study.

Previously we have reported an increased prevalence of migraine in narcoleptic patients. Because of the theoretical and clinical implications of this finding we recruited an independent new study sample of 100 patients with proven narcolepsy and conducted a structured 26-item interview based on the international diagnostic criteria for headache disorders, the Kiel Headache Questionnaire. Narcolepsy symptoms were measured by means of the Stanford Centre for Narcolepsy Sleep Inventory. Migraine prevalence was twofold to fourfold increased in the narcoleptic patients and amounted to 44.4% in women and 28.3% in men. The onset of narcolepsy symptoms was 12.3 +/- 11.4 years before the onset of migraine symptoms. The results might be regarded as indicative of a common pathophysiological pathway relevant to both of the two disorders.

Narcoleptic and schizophrenic hallucinations. Implications for differential diagnosis and pathophysiology.

The differential diagnosis of narcolepsy versus schizophrenia is sometimes complicated by similar phenomenology, particularly when hallucinations predominate. REM sleep disturbances seem fundamental in the pathophysiology of narcolepsy, and REM sleep intrusions during periods of wakefulness are often associated with hallucinations also in healthy controls and in patients with other brain disorders including schizophrenia. This study used a semistructured interview to investigate different aspects of hallucinations (frequency, modality, content, and dependence on body posture) in 148 patients with narcolepsy, 21 patients with acute exacerbation of a schizophrenic disorder, and 128 healthy subjects. About 80% of patients with narcolepsy, 81% of schizophrenics, and 37% of healthy subjects reported lifetime occurrence of hallucinations (at least once). Auditory hallucinations were reported by 81% of schizophrenic patients (narcoleptics 45%, healthy controls 9%), whereas 83% of narcoleptic patients reported visual hallucinations (schizophrenics 29%, healthy controls 19%). Kinetic hallucinations were experienced by 71% of patients with narcolepsy and 53% of healthy controls in contrast to only 5% of schizophrenics. Accordingly, the content of hallucinations differed substantially between the groups. Most hallucinations in narcoleptics but not in schizophrenics, were sleep-related and dependent on body posture. Taken together, the qualitative aspects of hallucinations in narcolepsy and schizophrenia were so different that a common underlying mechanism of hallucinations in the two conditions is unlikely. Although the clinical separation of patients with narcolepsy and schizophrenia with predominant hallucinations is sometimes difficult, clinical features including the patient's illness history, and careful psychopathological assessments can help to avoid misdiagnoses and treatment failures.

ApoE polymorphisms in narcolepsy.

BACKGROUND: Narcolepsy is a common neuropsychiatric disorder characterized by increased daytime sleepiness, cataplexy and hypnagogic hallucinations. Deficiency of the hypocretin neurotransmitter system was shown to be involved in the pathogenesis of narcolepsy in animals and men. There are several hints that neurodegeneration of hypocretin producing neurons in the hypothalamus is the pathological correlate of narcolepsy. The ApoE4 allele is a major contributing factor to early-onset neuronal degeneration in Alzheimer disease and other neurodegenerative diseases as well. METHODS: To clarify whether the ApoE4 phenotype predisposes to narcolepsy or associates with an earlier disease onset, we have genotyped the ApoE gene in 103 patients with narcolepsy and 101 healthy controls. RESULTS: The frequency of the E4 allele of the ApoE gene was 11% in the patient and 15% in the control groups. Furthermore, the mean age of onset did not differ between the ApoE4+ and ApoE4- patient groups. CONCLUSION: Our results exclude the ApoE4 allele as a major risk factor for narcolepsy.