[Research published prior to 1990 has been excluded.]
L, Hungs M, Mignot E.
Narcolepsy and the HLA region.
J Neuroimmunol. 2001 Jul 2;117(1-2):9-20.
"Narcolepsy was first shown
to be tightly associated with HLA-DR2 and DQ1 in 1983, suggesting a possible autoimmune
mechanism. Early investigations failed to demonstrate this hypothesis, postulating
that HLA-DR2 was only a linkage marker for another, unknown narcolepsy-causing
gene. The autoimmune hypothesis is now being re-evaluated under the light of recent
results. Like many other autoimmune disorders, narcolepsy usually starts during
adolescence, is human leukocyte antigen (HLA)-associated, multigenic and environmentally
influenced. Furthermore, HLA-association studies indicated a primary HLA-DQ effect
with complex HLA class II allele interactions and a partial contribution of HLA
to overall genetic susceptibility. Finally, recent result suggests that human
narcolepsy is associated with the destruction of a small number of hypothalamic
neurons containing the peptide hypocretins (orexins). This data is consistent
with an immune destruction of hypocretin-containing cells as the most common etiology
for human narcolepsy." [Abstract]
Siebold C, Hansen BE, Wyer JR, Harlos K, Esnouf RE, Svejgaard A, Bell JI, Strominger JL, Jones EY, Fugger L
Crystal structure of HLA-DQ0602 that protects against type 1 diabetes and confers strong susceptibility to narcolepsy.
Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):1999-2004.
The MHC class II molecule DQ0602 confers strong susceptibility to narcolepsy but dominant protection against type 1 diabetes. The crystal structure of DQ0602 reveals the molecular features underlying these contrasting genetic properties. Structural comparisons to homologous DQ molecules with differential disease associations highlight a previously unrecognized interplay between the volume of the P6 pocket and the specificity of the P9 pocket, which implies that presentation of an expanded peptide repertoire is critical for dominant protection against type 1 diabetes. In narcolepsy, the volume of the P4 pocket appears central to the susceptibility, suggesting that the presentation of a specific peptide population plays a major role. [Abstract] [Full Text]
LE, Pankratz VS, Oliver L, Boeve BF, Silber MH.
levels in cerebrospinal fluid of patients with narcolepsy: relationship to cataplexy
and HLA DQB1*0602 status.
Sleep. 2002 Nov 1;25(7):733-6.
OBJECTIVES: Hypocretin (orexin) deficiency (< 40 pg/ml) is highly associated
with narcolepsy with cataplexy (89.5%) and more specifically with patients with
cataplexy who are HLA DQB1*0602 positive (95.7%). The relationship between hypocretin-1
levels and narcolepsy without cataplexy or the DQB1*0602 allele is less clear.
METHODS/DESIGN: This study compared cerebrospinal (CSF) hypocretin-1 in 13 patients
with HLA DQB1*0602 allele and cataplexy to 4 HLA negative patients with cataplexy,
3 HLA positive patients without cataplexy, and 6 HLA negative patients without
cataplexy, plus 15 neurologic controls. SETTING: Data were collected at a sleep
disorders center. PATIENTS/PARTICIPANTS: Twenty-six patients with narcolepsy,
with and without HLA DQB1*0602 and with and without cataplexy, as well as 15 neurologic
controls. INTERVENTIONS: N/A. MEASUREMENT & RESULTS: Using analysis of variance
techniques, statistically significant differences were found between the CSF hypocretin-1
levels in HLA positive patients and all other groups (P < 0.01). Although the
sample size was small, subjects with the DQB1*0602 allele without cataplexy had
lower hypocretin-1 levels than did other groups (other than the HLA and cataplexy
positive group). Hypocretin-1 levels were not associated with age at diagnosis,
age at lumbar puncture, body mass index at time of diagnosis, or body mass index
at time of lumbar puncture. CONCLUSION: This data confirms the previous finding
that undetectable hypocretin-1 levels are highly specific for HLA positive narcolepsy
with cataplexy. The data suggests that the pathophysiology and, by extension,
etiology of this disorder are distinctly different from the other conditions studied.
The relationship of the DQB1*0602 allele and reduced hypocretin-1 levels needs
further study." [Abstract]
L, Vodusek DB.
The importance of HLA DQB1*0602 typing in Slovene
patients with narcolepsy.
Cell Mol Biol Lett. 2002;7(2):359-60.
HLA class II region genes DQB1*0602 and DQA1*0102 are currently the best genetic
predictors for narcolepsy in humans (1(. The aim of this study was to identify
the HLA DQ alleles (DQB1*0602 and DQA1*0102) in Slovene sporadic narcoleptic patients.
11 patients who fulfilled ICSD criteria for narcolepsy entered the study. DRB1*1501
DQB1*0602 was present in all the patients while DQA1*0102 was absent in 2 patients.
We propose that DQB1*0602 typing is important in diagnosing narcolepsy in Slovene
SC, Leen-Kim, Park SA, Han JH, Lee SP, Lin L, Okun M, Nishino S, Mignot E.
and hypocretin studies in Korean patients with narcolepsy.
2002 Jun 15;25(4):440-4.
"STUDY OBJECTIVES: Very few studies have evaluated
narcolepsy in Asian countries, outside of Japan. Our goal was to study narcolepsy
at the genetic, clinical and pathophysiological level in Korea. DESIGN: Prospective
study of consecutive patients and age matched controls. Clinical data ascertained
from the Stanford Sleep Inventory, Polysomnography and MSLT data, as well as clinical
notes. High resolution DRB1 and DQB1 typing in all subjects and studies of CSF
hypocretin-1 was also evaluated in a subset of patients. PARTICIPANTS AND SETTING:
20 patients diagnosed at St. Vincent and Korea University Hospitals (Seoul, Korea).
21 Korean control subjects. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: For
narcoleptic subjects, mean age was 28.2 years old and 45% were female. Mean BMI
was 23.9+/-3.4 kg/m2, a significantly higher value than that expected in an age-
and sex-matched sample (p<0.01). All patients had sleepiness and cataplexy
while the prevalence of other symptoms ranged from 60-75%. All but 2 subjects
were HLA-DR15 (DR2), DQB1*0602 positive (90%). This high DQB1*0602 percentage
compared with 24% DQB1*0602 positivity in 21 control Koreans. Protective effects
were observed for the DQB1*0601 and DRB1*0406 alleles, Hypocretin (orexin) CSF
studies were also performed in 6 cataplectic subjects, all of which had undetectable
CSF hypocretin levels. Two of these subjects had started narcolepsy less than
1 year before analysis yet had undetectable hypocretin levels. CONCLUSION: These
results illustrate the similarity of narcolepsy-cataplexy in Korea in comparisons
with other more studied populations. We also identified a new potential HLA protective
subtype, HLA-DRB1*0406." [Abstract]
E, Lin L, Rogers W, Honda Y, Qiu X, Lin X, Okun M, Hohjoh H, Miki T, Hsu S, Leffell
M, Grumet F, Fernandez-Vina M, Honda M, Risch N.
Complex HLA-DR and
-DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups.
J Hum Genet. 2001 Mar;68(3):686-99. Epub 2001 Feb 13.
a sleep disorder associated with a centrally mediated hypocretin (orexin) deficiency,
is tightly associated with HLA-DQB1*0602. Few studies have investigated the influence
that additional HLA class II alleles have on susceptibility to this disease. In
this work, 1,087 control subjects and 420 narcoleptic subjects with cataplexy,
from three ethnic groups, were HLA typed, and the effects of HLA-DRB1, -DQA1,
and -DQB1 were analyzed. As reported elsewhere, almost all narcoleptic subjects
were positive for both HLA-DQA1*0102 and -DQB1*0602. A strong predisposing effect
was observed in DQB1*0602 homozygotes, across all ethnic groups. Relative risks
for narcolepsy were next calculated for heterozygous DQB1*0602/other HLA class
II allelic combinations. Nine HLA class II alleles carried in trans with DQB1*0602
were found to influence disease predisposition. Significantly higher relative
risks were observed for heterozygote combinations including DQB1*0301, DQA1*06,
DRB1*04, DRB1*08, DRB1*11, and DRB1*12. Three alleles-DQB1*0601, DQB1*0501, and
DQA1*01 (non-DQA1*0102)-were found to be protective. The genetic contribution
of HLA-DQ to narcolepsy susceptibility was also estimated by use of lambda statistics.
Results indicate that complex HLA-DR and -DQ interactions contribute to the genetic
predisposition to human narcolepsy but that additional susceptibility loci are
also most likely involved. Together with the recent hypocretin discoveries, these
findings are consistent with an immunologically mediated destruction of hypocretin-containing
cells in human narcolepsy-cataplexy." [Abstract]
OJ, Peled N, Miller K, Pillar G, Peled R, Lavie P, Brautbar C, Amar A.
class II analysis in Jewish Israeli narcoleptic patients.
Immunol. 1995 Dec;44(4):199-202.
"HLA class II was investigated in eight
Jewish narcoleptic patients, representing the total of such patients known in
Israel at present, and in three patients suffering from sleep disturbances other
than narcolepsy. All (11 out of 11) patients carried the serologic specificities
DR2, DQ6 (DQ1). At the DNA level, all narcoleptics were found to be DRB1*1501,
DQA1*0102, DQB1*0602 which indicates that the susceptibility gene may be located
within the HLA class II region, DR, and/or DQ. As for the nonnarcoleptic patients
with idiopathic hypersomnia, they carried different alleles of DR2 and DQ6, namely
DRB1*1502, DQA1*0103, DQB1*0601. This study confirms that the incidence of narcolepsy
in Israel is extremely low and that HLA class II genes or a gene(s) tightly linked
to them are involved in the disease." [Abstract]
ML, Lin L, Pelin Z, Hong S, Mignot E.
Clinical aspects of narcolepsy-cataplexy
across ethnic groups.
Sleep. 2002 Feb 1;25(1):27-35.
OBJECTIVES: The objectives of this study were to compare severity and clinical
presentation for narcolepsy-cataplexy across various ethnic groups. A large sample
of narcoleptic patients was also used to further describe symptomatology and natural
history for this sleep disorder. DESIGN: Retrospective review of clinical data
ascertained from the Stanford Sleep Inventory, polysomnography and MSLT data,
as well as clinical notes. Ethnicity was narrowly defined as African (Black) Americans,
Caucasians, Asians, and Latinos when both parents and the subject identified with
a given ethnic group. SETTING: N/A. PARTICIPANTS: We compared the severity and
clinical presentation of narcolepsy in 64 African Americans, 353 Caucasians, 32
Asians, 26 Latinos, and 9 subjects of mixed ethnicity. Subjects were recruited
through the Stanford center for narcolepsy research. INTERVENTIONS: N/A. MEASUREMENTS
AND RESULTS: A striking similarity in symptomatology, age of onset, and disease
severity was found across ethnic groups. Mean age of onset for sleepiness, hypnagogic
hallucinations, sleep paralysis and cataplexy were 19.20, 19.50, 20.11 and 23.02
years old. We also found that narcoleptic patients have slightly but significantly
elevated body mass index relative to normative data (106.6% of matched controls,
p<0.005) and are born slightly more frequently during the month of March. A
tight correlation between our previously validated cataplexy scale and DQB1*0602
positivity was observed. Two thirds of patients reported having cataplexy with
laughing, 92% of those being DQB1*0602 positive independent of ethnicity. CONCLUSIONS:
These results confirm the similarities in clinical presentation and natural history
of narcolepsy-cataplexy in a large number of patients of various ethnic groups
and cultural backgrounds." [Abstract]
E, Kimura A, Lattermann A, Lin X, Yasunaga S, Mueller-Eckhardt G, Rattazzi C,
Lin L, Guilleminault C, Grumet FC, Mayer G, Dement WC, Underhill P.
HLA class II studies in 58 non-DRB1*15 (DR2) narcoleptic patients with cataplexy.
Antigens. 1997 Apr;49(4):329-41.
"Narcolepsy is a sleep disorder that
has been shown to be tightly associated with HLA DR15 (DR2). In this study, 58
non-DR15 patients with narcolepsy-cataplexy were typed at the HLA DRB1, DQA1 and
DQB1 loci. Subjects included both sporadic cases and narcoleptic probands from
multiplex families. Additional markers studied in the class II region were the
promoters of the DQA1 and DQB1 genes, two CA repeat polymorphisms (DQCAR and DQCARII)
located between the DQA1 and DQB1 genes, three CA repeat markers (G51152, T16CAR
and G411624R) located between DQB1 and DQB3 and polymorphisms at the DQB2 locus.
Twenty-one (36%) of these 58 non-DR15 narcoleptic patients were DQA1*0102 and
DQB1*0602, a DQ1 subtype normally associated with DRB1*15 in DR2-positive narcoleptic
subjects. Additional microsatellite and DQA1 promoter diversity was found in some
of these non-DR15 but DQB1*0602-positive haplotypes but the known allele specific
codons of DQA1*0102 and DQB1*0602 were maintained in all 21 cases. The 37 non-DQA1*0102/DQB1*0602
subjects did not share any particular HLA DR or DQ alleles. We conclude that HLA
DQA1*0102 and DQB1*0602 are the most likely primary candidate susceptibility genes
for narcolepsy in the HLA class II region." [Abstract]
R, Flodman P, Spence MA, Erman MK, Mitler MM.
HLA haplotypes, polysomnography,
and pedigrees in a case series of patients with narcolepsy.
"An ongoing study of the genetics of narcolepsy
ascertains families through a case series of narcoleptic probands using diagnostic
criteria consisting of 1) clinical history of excessive somnolence, 2) a mean
sleep latency on the multiple sleep latency test (MSLT) of less than 7.9 minutes,
3) the rapid eye movement (REM) sleep-related symptom of cataplexy, 4) nocturnal
polysomnography ruling out sleep apnea syndrome, and 5) two or more transitions
to REM sleep on the MSLT. All probands and first-degree relatives received clinical
and laboratory evaluations as well as human leukocyte antigen (HLA) typing. Demographic
characteristics of the 32 probands are as follows: 17 males and 15 females; mean
age was 42.1 years (range 13-70 years). The polysomnographic data confirmed daytime
sleepiness and increased tendency for REM sleep for the 32 probands. Nocturnal
polysomnographic results are as follows: sleep latency, 3.2 minutes; total sleep
time, 442 minutes. MSLT results are as follows: sleep latency, 3.1 minutes; REM
latency, 6.9 minutes; number of REM periods, 3.2. HLA typing revealed the presence
of the HLA haplotypes, DRB1*15 and DQB1*0602, in 21 narcoleptic probands, with
two African-Americans having the DQB1*0602 but not the DRB1*15 allele. Among the
57 relatives of the 32 probands, 1/31 females and 7/26 males were found to be
affected with narcolepsy (p < 0.02), which suggests a higher diagnostic rate
in male relatives. The 21 probands who were positive for the DRB1*15 and DQB1*0602
haplotypes did not differ from the 10 probands who were negative for these alleles
in terms of their nocturnal sleep parameters, MSLT findings, or clinical presentation.
Three families with multiple individuals affected with narcolepsy are presented.
Two families have more than one affected individual who does not have the high-risk
HLA haplotype. In one of these families, the disease is segregating independently
of any HLA haplotype. In the third family, there is cosegregation with HLA DRB1*15
and DQB1*0602. One family contains a pair of DNA-confirmed, monozygotic twins
with narcolepsy who are discordant for cataplexy and have the HLA DR14(Dw9)/DQB1*0503
and DR4(Dw4)/DQB1*0302 haplotypes." [Abstract]
Y, Bazin M, Ondze B, Bera O, Bazin M, Besset A, Billiard M.
of narcolepsy among French of different ethnic origins (south of France and Martinique).
2002 Feb 1;25(1):50-5.
"STUDY OBJECTIVES: The aim of the study was to
describe the clinical and polygraphical characteristics of narcoleptics, with
and without cataplexy and to assess HLA predisposition across two different ethnic
populations. DESIGN AND SETTING: Patients were 126 men and 58 women referred to
the Montpellier Sleep Disorders Center (Mtp) and 12 men and 8 women referred to
the Fort-de-France Sleep Disorders Center (FdF) (Martinique, a French West Indy
island) with symptoms of narcolepsy. PARTICIPANTS: Narcoleptics were included
if they had both excessive daytime sleepiness and clear-cut cataplexy (for the
group with cataplexy), a mean sleep latency of less than 8 minutes and at least
two sleep onset REM periods. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Narcolepsy
without clear-cut cataplexy was rare (12/172) in the Mtp population whereas it
was as frequent as full-blown narcolepsy (10/10) in the FdF population. Comparison
between narcoleptics with cataplexy from the Mtp and FdF populations revealed
a younger age of onset, a trend towards more severe sleepiness and lower frequency
of cataplexy in Martinicans. Comparison between narcoleptics without cataplexy
from the Mtp and FdF population revealed a higher frequency of hypnagogic hallucinations
and sleep paralysis and a trend towards more severe sleepiness in Martinicans.
4.2% of the Mtp and 15% of the FdF patients were negative for HLA DR2. However
all of them were positive for HLA DQ1. Moreover, a tight association with HLA
DRB1*1503 was observed in Martinicans in contrast with DRB1*1501 in the Mtp population.
Association with HLA DQB1*0602 was observed in 99.4% of narcoleptics with cataplexy
and in 89.5% of those without cataplexy. CONCLUSIONS: Narcolepsy is a heterogeneous
clinical syndrome, the more so as ethnic origins are considered. A modulating
effect of HLA and non-HLA genes on symptoms disease may explain these differences."
E, Lin X, Arrigoni J, Macaubas C, Olive F, Hallmayer J, Underhill P, Guilleminault
C, Dement WC, Grumet FC.
DQB1*0602 and DQA1*0102 (DQ1) are better
markers than DR2 for narcolepsy in Caucasian and black Americans.
1994 Dec;17(8 Suppl):S60-7.
"In the present study, we tested 19 Caucasian
and 28 Black American narcoleptics for the presence of the human leucocyte antigen
(HLA) DQB1*0602 and DQA1*0102 (DQ1) genes using a specific polymerase chain reaction
(PCR)-oligotyping technique. A similar technique was also used to identify DRB1*1501
and DRB1*1503 (DR2). Results indicate that all but one Caucasian patient (previously
identified) were DRB1*1501 (DR2) and DQB1*0602/DQA1*102 (DQ1) positive. In Black
Americans, however, DRB1*1501 (DR2) was a poor marker for narcolepsy. Only 75%
of patients were DR2 positive, most of them being DRB1*1503, but not DRB1*1501
positive. DQB1*0602 was found in all but one Black narcoleptic patient. The clinical
and polygraphic results for this patient were typical, thus confirming the existence
of a rare, but genuine form of DQB1*0602 negative narcolepsy. These results demonstrate
that DQB1*0602/DQA1*0102 is the best marker for narcolepsy across all ethnic groups."
Reutens DC, Haddad AP, Cantwell L, Berkovic SF.
negative narcolepsy in Australian Caucasians: clinical features, serology and
sequence specific oligonucleotide typing.
J Neurol Sci.
"An almost invariable association with HLA-DR2
and DQw1 has previously been reported in Japanese and caucasian narcoleptics.
We performed HLA typing in 18 Australian narcoleptics using serological techniques
and sequence specific oligonucleotide probes. HLA-DQw1 was present in 15 patients
and DR2 in 12; 3 patients with cataplectic narcolepsy were DR2-negative. The serological
haplotype most strongly associated with narcolepsy was DRw15 (a subtype of DR2),
DQw1. DRw15-positive patients were positive for the alleles DRB1*1501 and DQB1*0602
defined with oligonucleotide probes. We conclude that the association of narcolepsy
with DR2 and DQw1 is not as strong as previously reported and the absence of DR2
or DQw1 does not preclude the diagnosis of classical narcolepsy, at least in caucasians.
Secondly, DR2-positive narcoleptics possess characteristic serological subtypes
and alleles defined with oligonucleotide probes that are also found in normals.
Thirdly, the occurrence of DR2-negative cataplectic narcoleptics points to the
existence of more than one narcolepsy susceptibility gene." [Abstract]
E, Lin X, Kalil J, George C, Singh S, Billiard M, Montplaisir J, Arrigoni J, Guilleminault
C, Dement WC, et al.
DQB1-0602 (DQw1) is not present in most nonDR2
Sleep. 1992 Oct;15(5):415-22.
narcolepsy is a genetically determined disorder of sleep strongly associated with
the human leucocyte antigens (HLA) DR2 and DQw1. In black narcoleptic patients,
susceptibility for narcolepsy is more closely related to a specific gene subtype
of DQw1, DQB1-0602, than to DR2. About 30% of black narcoleptic patients are nonDR2,
but all carry the HLA DQB1-0602 gene. In the present study, we have tested caucasian
nonDR2 cataplectic patients (6 sporadic cases and 7 familial cases from 3 multiplex
families) for the presence of the HLA DQB1-0602 and DQA1-0102 (DQw1) using a specific
polymerase chain reaction (PCR)-oligotyping technique. None of the patients was
DQB1-0602 or DQA1-0102 positive, thus proving that, in caucasians, DQB1-0602 and
DQA1-0102 (DQw1) are not prerequisites for the diagnosis of narcolepsy. Further
studies with more patients are warranted to exclude the possibility that a few
caucasian patients carry rare haplotypes with DQB1-0602 independently of DR2."
Y, Huang X, Qiu C, et Al.
[Extensive HLA class II studies in Chinese
Zhonghua Nei Ke Za Zhi. 1999 Nov;38(11):757-9.
Narcolepsy is a debilitating, lifelong sleep disorder. Its familial occurrence
suggests that genetic factors may be of importance in the etiology. Narcolepsy
is a very rare disease among Chinese, thus it was of interest to study the association
of narcolepsy with the HLA system in Chinese narcoleptic patients. METHODS: To
explore the role of HLA-DRB genes in the development of narcolepsy, we studied
10 narcoleptic patients and 50 race matched controls in whom HLA-DR typing was
perfomed by the method of DNA amplification with sequence-specific primers (PCR-SSP).
RESULTS: All narcoleptic patients were found to be of DRB1 * 1501 and DRB5 * 0101
genotype. CONCLUSION: These results indicate that HLA-DRB1 * 1501 is a better
primary candidate susceptibility gene for narcolepsy in Chinese." [Abstract]
F, Chen EZ, Wei HL, Dong XS, Li J, Li M, He QY, Ding DJ.
and -DQB allele contribution to narcolepsy susceptibility in Chinese patients
Zhonghua Yi Xue Za Zhi. 2003 Apr 25;83(8):644-6.
To study the association of narcolepsy with HLA class II alleles in Chinese narcoleptic
patients. METHODS: 31 patients with narcolepsy underwent brain computed tomography
(CT) scan and magnetic resonance imaging (MRI) testing. All patients received
a MSLT test following a routine night's sleep, and serological HLA typing for
HLA DR(2). 21 patients received PCR-SSP HLA DR and DQ typing. RESULTS: All patients
had sleepiness and cataplexy. There was no evidence for other functional or structural
diseases. Sleep paralysis was elicited in 45%; hypnagogic hallucinations, in 61%.
Mean sleep latency on MSLT was 2.1 min +/- 1.3 min; sleep-onset rapid eye movement
(SOREM) occurred during 2/5 naps in 30 of 31 patients. The average number and
latency of SOREM episodes were 4.2 +/- 1.0 episodes and 4.0 min +/- 1.8 min, respectively.
All patients but one were HLA DR(2) positive and 86% were HLADRB(1) * 1501-HLADQB(1)*0602
positive. CONCLUSIONS: HLA DR(2) and HLADQw6 are markers for narcolepsy-cataplexy
in Chinese." [Abstract]
D, Puig N, Beneto A, Gomez E, Rubio P, Mirabet V, Bonanad S, Blasco I, Montoro
HLA-DQA, -DQB and -DRB allele contribution to narcolepsy susceptibility.
J Immunogenet. 1997 Dec;24(6):409-21.
"The association of narcolepsy with
HLA class I antigens and HLA class II alleles was studies in a series of Spanish
narcoleptic patients. The haplotype DRB1*1501-DRB5*0101-DQA1*0102-DQB1*0602 was
found to be significantly associated with the disease, while the haplotype DRB1*0701-DRB4*01-DQA1*0201-DQB1*02
might confer a slight protective effect against narcolepsy. Gene dose-effect was
not seen in any of the involved alleles, and linkage disequilibrium between the
positively associated alleles was found to be stronger in patients than in controls.
Statistical analysis applied to identify the HLA allele truly responsible for
the association did not clearly discriminate between the contribution of DRB1*1501
and that of DQB1*0602, but it proved that the association with DQA1*0102 is secondary
to that with DRB1*1501/DQB1*0602. Analysis of the diagnostic value of typing for
the narcolepsy-associated alleles demonstrated a very high negative predictive
value and revealed that this test can be convenient for exclusion of narcolepsy
in cases when the diagnosis is not evident after clinical evaluation and the marker
haplotype is absent. Finally, a family study indicated that narcolepsy is a multifactorial
disorder that involves HLA genes under an incomplete penetrance model, with possible
influences from environmental factors or other genes different to HLA genes."
MC, Hetisimer AH, Ruddy DA, Hansen SL, Kronmal GS, McClelland E, Quintana L, Drayna
DT, Aldrich MS, Mignot E.
HLA class II haplotype and sequence analysis
support a role for DQ in narcolepsy.
systematic haplotype and sequencing analysis of the HLA-DR and -DQ region in patients
with narcolepsy was performed. Five new (CA)n microsatellite markers were generated
and positioned on the physical map across the HLA-DQB1-DQA1-DRB1 interval. Haplotypes
for these new markers and the three HLA loci were established using somatic cell
hybrids generated from patients. A four-marker haplotype surrounding the DQB1(*)0602
gene was found in all narcolepsy patients, and was identical to haplotypes observed
on random chromosomes harboring the DQB1(*)0602 allele. Eighty-six kilobases of
contiguous genomic sequence across the region did not reveal new genes, and analysis
of this sequence for single nucleotide polymorphisms did not reveal sequence variation
among DQB1(*)0602 chromosomes. These results are consistent with other studies,
suggesting that the HLA-DQ genes themselves are among the predisposing factors
in narcolepsy." [Abstract]
E, Young T, Lin L, Finn L.
Nocturnal sleep and daytime sleepiness
in normal subjects with HLA-DQB1*0602.
Sleep. 1999 May 1;22(3):347-52.
a neurological disorder characterized by excessive daytime sleepiness and abnormal
REM sleep, is known to be tightly associated with the Human Leukocyte Antigen
(HLA) DQ allele DQB1*0602. In this study, we have explored the possibility that
normal subjects carrying this HLA allele (25% of the general population) could
display subclinical REM sleep abnormalities and increased daytime sleepiness.
Data from 525 middle-aged adults enrolled in the Wisconsin Sleep Cohort study
were used for this analysis. Nocturnal polysomnography, sleep latency during the
multiple sleep latency test (MSLT), and questionnaire items pertaining to excessive
daytime sleepiness were compared between DQB1*0602 positive (n = 132) and negative
(n = 393) participants. Results indicate shorter REM latency whether or not the
latency was adjusted for wake after sleep onset (p = 0.003) and p = 0.02 respectively),
increased sleep efficiency (p = 0.06) and decreased percent time spent in stage
I sleep (p = 0.02) during nocturnal polysomnography in DQB1*0602 subjects. Data
gathered using the Multiple Sleep Latency Test or the Epworth and Stanford sleepiness
scales did not differentiate between DQB1*0602 positive and negative subjects.
These results support the hypothesis that polymorphisms at the level of HLA DQ
modulates sleep tendencies in humans." [Abstract]
G, Lattermann A, Mueller-Eckhardt G, Svanborg E, Meier-Ewert K.
of HLA genes in multicase narcolepsy families.
J Sleep Res.
"In the past 15 years, 411 sporadic narcolepsy patients
have been diagnosed in the Hephata Klinik, Schwalmstadt, Germany. They were explored
for presence or absence of excessive daytime sleepiness and narcolepsy in their
relatives. A subset of 39 patients were explored for presence or absence of parasomnias.
Six patients had more than one relative affected by narcolepsy-cataplexy. Forty-seven
family members were investigated with the Stanford Center for Narcolepsy Sleep
Inventory and a standardized parasomnia questionnaire. Twenty-four relatives had
nocturnal polysomnographies and Multiple Sleep Latency Tests. HLA class I typing
was performed in all sporadic and familial cases, class II and microsatellite
typing was performed in all members of multicase families. Based on the Finnish
prevalence study by Hublin et al., 1994, the relative risk for first degree relatives
to develop narcolepsy-cataplexy was in our sample 16.5, 34.2 for excessive daytime
sleepiness and 426.9 for parasomnias. Cataplexy, excessive daytime sleepiness
and single narcoleptic symptoms in the multicase families segregate with the DRBI*1501,
CARII:200, CARI: 103, DQBI*0602 haplotype. In two families, members with narcolepsy
and isolated symptoms have inherited the DRBI*1501/DQBI*0602 haplotype from the
nonaffected parent. The observed segregations in these two families may support
the view that narcoleptic symptoms are expressed by DRBI*1501/DQBI*0602 carriers,
independent of haplotype origin. Parasomnias do not segregate with a specific
haplotype. The frequency of parasomnias in narcolepsy is much higher than in the
general population. The empirical risk for first degree family members of narcolepsy
patients to develop cataplexy seems to be low, whereas it is higher for EDS and
highest for parasomnias." [Abstract]
Dormoy A, Froelich N, Parissiadis
A, Cazenave JP, Tongio MM.
Second HLA-A*68 null allele, A*6818 N,
Tissue Antigens. 2002 Jul;60(1):88-90.
second HLA-A*68 null allele, HLA-A*6818 N, was identified in our laboratory after
discrepant results were obtained between class I serological and molecular typing
in a male patient suffering from narcolepsy. HLA-A*6818 N displays a sequence
identical to that of the HLA-A*6802 allele, except in exon 2 where 20 nucleotides
inserted at codon position 48 are a repeat of the 20 preceding nucleotides. This
duplication creates a shift of the reading frame, which leads to a premature non-sense
codon at position 59 of the null allele." [Abstract]
J, Santoso S, Kalb R, Meier-Ewert K, Albert ED, Mueller-Eckhardt G.
deletion in the second exon of an HLA-DRB1 allele found in a DR2-negative narcolepsy
Hum Immunol. 1993 May;37(1):1-6.
report, we describe a new allele of the HLA-DRB 1 gene carrying a form of mutation
that has not been observed before. It appeared in an HLA-DR2-negative narcolepsy
patient who, besides HLA-DR4, revealed a serologic HLA-DR blank segregating with
HLA-DQ1. Oligotyping showed that the new allele belongs to the HLA-DR8 group.
Restriction analysis and DNA sequencing revealed the deletion of 12 bp as well
as the substitution of 9 flanking base pairs between codons 36 and 43. The expression
of the mutated gene was demonstrated by the presence of its messenger RNA and
a few positive reactions with DR8 sera. Without interrupting the reading frame,
the mutation leads to a gene product composed of a modified amino acid sequence.
We anticipate that the mutation influences the conformation of the molecule with
possible consequences concerning immune response." [Abstract]
Wu HS, Guo YH, Zou LP, Han F, Zhang WC, Fang F, Xiao J, Ding CH, Li J, Chen CH
[Diagnosis of childhood narcolepsy and significance of HLA in its diagnosis]
Zhonghua Er Ke Za Zhi. 2004 Apr;42(4):248-51.
OBJECTIVE: Narcolepsy is a lifelong sleep disorder characterized by excessive daytime sleepiness, and features of rapid eye movement (REM) sleep, such as cataplexy, sleep paralysis and hypnagogic hallucinations. The present study aimed to investigate the diagnostic basis of childhood narcolepsy and possible role of HLA Class II alleles in the onset of this disease. METHODS: The clinical data of 40 narcoleptic children were analyzed. All patients received Multiple Sleep Latency Test (MSLT) and they were analyzed in combination with clinical features. Polymerase chain reaction/sequence specific primers (PCR/SSP) methods were used to detect the HLA-DRB1 and DQB1 alleles. RESULTS: Narcolepsy was diagnosed in 40 children. The age range was 3 to 14 years (mean 8.5 +/- 2.5 years), 29 were male and 11 female. Their mean course of disease was 6.5 months, 14 patients (30%) were less than 3 months old, 21 patients (52%) were less than 6 months old. All the patients had excessive daytime sleepiness, cataplexy appeared in 37 cases, hypnagogic hallucination in 22 and sleep paralysis in 6. Mean sleep latency on MSLT was less than 5 min, the average number of sleep-onset rapid eye movement (SOREM) was 4.33 +/- 0.26 episodes (2-5 episodes), the latency of SOREM episodes were 4.0 +/- 1.8 min (0.25-4.9 min). Thirty-five patients were DRB1 1501 and DQB1 0602 positive (Pc < 0.01), 2 were DRB1 1502 and DQB1 0601 positive, while 3 were DRB1 15 and DQB1 6 negative. CONCLUSIONS: Some pediatric patients with narcolepsy were different from adult patients in that the pediatric cases had a sudden onset and shorter disease course. Diagnosis of this disease was based on the clinical manifestations, MSLT and absence of any medical or psychiatric disorder that could account for the symptoms. The authors demonstrated that DRB1 1501 and DQB1 0602 were susceptibility genes for narcolepsy and those who were DRB1 15 negative could not be excluded. [Abstract]
Wieczorek S, Gencik M, Rujescu D, Tonn
P, Giegling I, Epplen JT, Dahmen N.
TNFA promoter polymorphisms and
Tissue Antigens. 2003 Jun;61(6):437-42.
is a debilitating sleep disorder that affects up to 0.05% of individuals in Caucasian
populations. It is highly associated with the HLA-DR2 group antigen or the HLA-DRB1*1501-DQB1*0602
haplotype, respectively. However, the HLA association by itself cannot sufficiently
explain the increased risk to family members, as HLA-DR2 is quite common in the
general population and most people harboring the respective genotype do not develop
any symptoms of narcolepsy. Situated in the HLA class II region, the TNFA gene
is translated into the pro-inflammatory cytokine TNF-alpha. TNFA promoter polymorphisms
have been linked to several inflammatory and autoimmune diseases. We analyzed
three SNP of the TNFA promoter and one adjacent microsatellite in 103 patients
and 96 controls. The T-allele of the C-857T polymorphism was strongly associated
with narcolepsy in the subgroup of DRB1*15/16 (HLA-DR2 type) negative patients,
but not in DRB1*15/16 positive patients. These results point towards an etiological
influence of TNFA alleles in narcolepsy and support previous findings suggesting
genetic heterogeneity and differences in pathophysiological characteristics of
HLA-DR2 positive and negative narcolepsy." [Abstract]
H, Nakayama T, Ohashi J, Miyagawa T, Tanaka H, Akaza T, Honda Y, Juji T, Tokunaga
Significant association of a single nucleotide polymorphism in
the tumor necrosis factor-alpha (TNF-alpha) gene promoter with human narcolepsy.
Antigens. 1999 Aug;54(2):138-45.
"Narcolepsy is a sleep disorder in which
multiple factors, including environmental and genetic factors, are involved. A
genetic factor strongly associated with the disorder has been found in the human
leukocyte antigen (HLA) class II region: the haplotype, DRB1*1501-DQB1*0602, predisposes
to narcolepsy. No susceptibility genes other than the HLA-haplotype have been
found. In this paper, we performed an association study of the tumor necrosis
factor-alpha (TNF-alpha) gene located in the HLA class III region with human narcolepsy,
in which we examined the known single-nucleotide polymorphisms (SNPs) in the promoter
region in 49 narcoleptic patients, who were all positive for DRBI*1501, and 111
healthy control individuals. The results indicated that the frequency of the genotype
at position -857 (-857SNP) was significantly different between the patients and
controls, and the allele frequencies of 857SNP revealed that the frequency of
-857T was significantly increased in the patients as compared with that in the
controls (P=0.0068). In addition, haplotypes presumed from HLA-DRB1, -857SNP and
HLA-B loci suggested that -857T was mainly associated with DRB1 alleles other
than DRB1*1501: the significant increase in frequency of -857T in the patients
was not caused by allelic association with DRB1*1501. Therefore, it is conceivable
that the TNF-alpha with 857T was associated with narcolepsy independently of the
strong association of DRB1*1501 with the disorder. Altogether, the data presented
here lead us to propose that TNF-alpha could be a new susceptibility gene in human
H, Terada N, Nakayama T, Kawashima M, Miyagawa T, Honda Y, Tokunaga K.
study with narcoleptic patients and healthy controls who, like the patients, possess
both HLA-DRB1*1501 and -DQB1*0602.
Tissue Antigens. 2001
"In previous studies, we suggested that the tumor necrosis
factor (TNF-alpha and its receptor 2 (TNFR2) genes could be associated with the
susceptibility to human narcolepsy, and that haplotype carrying DRB1*1502 had
a negative association with the disorder. To further evaluate these associations,
we herein compared narcoleptic patients with healthy individuals who, like the
patients, possessed both DRB1*1501 and DQB1*0602. Results agreed with the negative
association of DRB1*1502 and positive association of the TNF-alpha(-857T) and
TNFR2-196R combination with the disorder. In addition, a significant association
of the TNF-alpha(-857T) homozygote with the disorder and an increase in a rare
haplotype carrying DRB1*1501 and TNF-alpha(-857T) in the patients were also observed
in the present study." [Abstract]
H, Terada N, Miki T, Honda Y, Tokunaga K.
Haplotype analyses with
the human leucocyte antigen and tumour necrosis factor-alpha genes in narcolepsy
Psychiatry Clin Neurosci. 2001 Feb;55(1):37-9.
previous study suggested that the tumour necrosis factor-alpha gene with thymine
residue at position -857 in its promoter region [TNF-alpha(-857T)] could be associated
with human narcolepsy independently of a strong association of the human leucocyte
antigen (HLA)-DRB1*1501 with the disorder. To understand the relationship of DRB1*1501
with TNF-alpha(-857T) in narcoleptic patients, we investigated 28 members of four
Japanese narcolepsy families and determined the haplotypes with the HLA-B, TNF-alpha(-857C/T)
and HLA-DRB1 in the members. The resultant haplotypes indicated that not only
the DRB1*1501-TNF-alpha(-857C) haplotype but also the DRB1*1501-TNF-alpha(-857T)
haplotype, which is rare in healthy individuals and may have a strong predisposition
to the disorder, were present in the affected members. From the chromosomal recombination
observed in a few members, it is possible that chromosomal recombination could
play a role in the generation of the rare DRB1*1501-TNF-alpha(-857T) haplotype."
T, Honda M, Kuwata S, Juji T, Fukuda M, Honda Y, Kato N.
for a mutation in the tumour necrosis factor-alpha gene in narcolepsy.
Clin Neurosci. 1999 Jun;53(3):421-3.
"The discovery of almost 100% association
of narcolepsy with human leukocyte antigens (HLA) DR2 antigen prompted molecular
biological research of this disorder. In the HLA class II gene cluster, the gene
for tumour necrosis factor-alpha (TNF-alpha), which plays a role in the regulation
of normal human sleep, is located. The present study searched for a mutation in
the TNF-alpha gene by single-strand conformation polymorphism analysis (SSCP)
in patients with narcolepsy. No mutation was detected in exons and introns of
the TNF-alpha gene by SSCP and sequencing." [Abstract]
T, Honda M, Kuwata S, Juji T, Kunugi H, Nanko S, Fukuda M, Honda Y.
polymorphism in the promoter region of the tumor necrosis factor alpha gene: No
association with narcolepsy.
Am J Med Genet. 1999 Aug 20;88(4):301-4.
striking evidence of almost 100% association of narcolepsy with human leukocyte
antigens (HLA) DR2(DR15) antigen is an important clue to elucidate the molecular
basis of this sleep disorder. The gene for tumor necrosis factor alpha (TNF alpha)
is located in the HLA class II gene cluster. Recent studies have indicated that
TNF alpha plays an important role in the regulation of normal human sleep, and
regulation of this cytokine may be disturbed in narcolepsy. We searched for a
mutation associated with narcolepsy in the promoter region of the TNF alpha gene
by single-strand conformation polymorphism analysis. A novel polymorphism, C-850T,
was found in narcoleptic patients. Genotype frequency was examined by restriction
fragment length polymorphism method. No significant difference of genotype distribution
was found between 92 patients with narcolepsy and 91 normal controls. These results
do not support our hypothesis that genetic abnormality of TNF alpha production
is pathogenetic for narcolepsy." [Abstract]
S, Dahmen N, Jagiello P, Epplen JT, Gencik M.
Polymorphisms of the
tumor necrosis factor receptors: no association with narcolepsy in German patients.
Mol Med. 2003 Feb;81(2):87-90. Epub 2003 Feb 11.
"Narcolepsy is a debilitating
sleep disorder characterized by daytime sleepiness and cataplexy. The strong association
of narcolepsy with the HLA system suggests an autoimmune cause. Tumor necrosis
factor is a cytokine involved in both regulation of immune mechanisms and sleep.
Several studies were undertaken to determine a contribution of tumor necrosis
factor and its receptors to the pathogenesis of narcolepsy. A significant increase
in the 196R allele, a functionally relevant polymorphism in the TNFR2 gene, has
been found in Japanese patients, indicating altered transduction of tumor necrosis
factor signals. Here we explore polymorphisms in both tumor necrosis factor receptor
genes as risk factors in a German population sample. Neither the polymorphism
in the TNFR1 nor that in the TNFR2 gene was associated with narcolepsy. Our findings
contrast to those previously published and thus provide evidence for genetic heterogeneity
between different narcolepsy populations." [Abstract]
H, Terada N, Kawashima M, Honda Y, Tokunaga K.
of the tumor necrosis factor receptor 2 (TNFR2) gene with human narcolepsy.
Antigens. 2000 Nov;56(5):446-8.
"We report on the association study of
the tumor necrosis factor receptor 2 (TNFR2) gene with human narcolepsy. A single-nucleotide
polymorphism in TNFR2, which is involved in an amino acid substitution [methionine(M)/arginine(R)]
at position 196, was investigated in 149 Japanese narcoleptic patients and 204
healthy individuals as controls. Results reveal that the frequency of the TNFR2-196R
allele significantly increased in the patients as compared with that in the controls
(P=0.029), suggesting that TNFR2 is likely associated with the susceptibility
to narcolepsy. In addition, the analyses of the relationship of TNFR2 and TNF-alpha
with the susceptibility to narcolepsy indicate the possibility that an additive
effect on the susceptibility to the disorder lies between TNFR2-196R and TNF-alpha(-857T)
Wieczorek S, Dahmen N, Kasten M, Epplen JT, Gencik M
A rare form of narcolepsy (HLA-DR2-) shows possible association with (functionally relevant) alpha-interferon gene polymorphisms.
Psychiatr Genet. 2004 Mar;14(1):47-51.
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. [Abstract]
J, Miura M, Honda M, Miki T, Honda Y, Arinami T.
Linkage of human
narcolepsy with HLA association to chromosome 4p13-q21.
2000 Apr 1;65(1):84-6.
"Although narcolepsy is highly associated with
human leukocyte antigen (HLA) DQ6/DQB1*0602 and/or DR2/DRB1*1501, most individuals
with the HLA haplotype are free of narcolepsy. This indicates that HLA alone makes
a relatively small contribution to the development of narcolepsy and that a non-HLA
gene(s) can contribute to the genetic predisposition even in narcoleptic cases
with HLA association. We conducted a genome-wide linkage search for narcolepsy
in eight Japanese families with 21 DR2-positive patients (14 narcoleptic cases
with cataplexy and 7 cases with an incomplete form of narcolepsy). A lod score
of 3.09 suggested linkage to chromosome 4p13-q21. A lod score of 1.53 was obtained
at the HLA-DRB1 locus, though this lod score may be biased since all the affected
patients and many of the family members were DR2-positive. No other loci including
hypocretin, hypocretin receptor 1, and hypocretin receptor 2 had lod scores greater
than 1.0. The present study suggests that chromosome 4p13-q21 contains a second
locus for HLA-associated human narcolepsy." [Abstract]
M, Dauvilliers Y.
Pharmacogenomics in the treatment of narcolepsy.
"Narcolepsy is a neurological disorder characterized
by excessive daytime sleepiness and cataplexy. Available treatments of narcolepsy
include stimulants and antidepressants but the recent discovery of orexin/hypocretin
deficiency in narcolepsy opens up new perspectives. Narcolepsy is a complex disorder
involving genetic, immune and environmental factors. Although only a strong association
is found with the HLA DQB1*0602 gene, other genetic susceptibility factors might
be involved. Among these, the functional polymorphism of the catechol-O-methyltransferase
(COMT) gene is critically involved in the severity of narcolepsy and in the response
to the stimulant modafinil. Other pharmacogenetic targets include the orexinergic,
noradrenergic and possibly the serotonergic pathways." [Abstract]
Y, Neidhart E, Lecendreux M, Billiard M, Tafti M.
MAO-A and COMT
polymorphisms and gene effects in narcolepsy.
"Narcolepsy presents one of the tightest associations
with a specific HLA antigen (DQB1*0602) but there is strong evidence that non-HLA
genes also confer susceptibility. Recent observations have implicated the hypocretin/orexin
system in narcolepsy in both humans and animals. In addition, the implication
of monoaminergic systems in the pathophysiology of narcolepsy is well established
and a significant association between the monoamine oxydase-A (MAO-A) gene and
human narcolepsy has recently provided a possible genetic link. We investigated
polymorphisms of MAO-A and catechol-O-methyltransferase (COMT) in 97 Caucasians
with well-defined narcolepsy-cataplexy and sought for genotypic effects on disease
symptoms. No evidence of association between genotype or allele frequencies of
both MAO-A or COMT gene and narcolepsy was found. However, a sexual dimorphism
and a strong effect of COMT genotype on disease severity were found. Women narcoleptics
with high COMT activity fell asleep twice as fast as those with low COMT activity
during the multiple sleep latency test (MSLT) while the opposite was true for
men. COMT genotype also strongly affected the presence of sleep paralysis and
the number of REM sleep onsets during the MSLT. In agreement with well-documented
pharmacological results in canine narcolepsy, this study reports the first genetic
evidence for the critical involvement of the dopaminergic and/or noradrenergic
systems in human narcolepsy." [Abstract]
Y, Neidhart E, Billiard M, Tafti M.
Sexual dimorphism of the catechol-O-methyltransferase
gene in narcolepsy is associated with response to modafinil.
"The gene for catechol-O-methyltransferase (COMT) plays
a key modulatory role in dopaminergic and noradrenergic neurotransmission. Recent
evidence suggests that modafinil, like other stimulants, might act through the
dopaminergic system. We have reported a sexual dimorphism and a strong effect
of the COMT genotype on narcolepsy symptoms and hypothesized that response to
modafinil treatment may be associated with the COMT genotype. Here we confirm
that COMT genotype distribution between men and women narcoleptics is associated
with response to modafinil. In addition, the optimal daily dose of modafinil is
approximately 100 mg lower in women narcoleptics and lower in all narcoleptics
with low activity COMT genotype. Our results suggest that a sexual dimorphism
in COMT activity affects the response to modafinil and probably to other dopaminergic
Wieczorek S, Jagiello P, Arning L, Dahmen N, Epplen JT
Screening for candidate gene regions in narcolepsy using a microsatellite based approach and pooled DNA.
J Mol Med. 2004 Oct;82(10):696-705.
Narcolepsy is a complex sleep disorder characterized by excessive daytime sleepiness and cataplexy. Mutations in genes of the hypocretin (orexin) neurotransmitter system cause narcoleptic symptoms in animal models. The absence of hypocretin in the cerebrospinal fluid of human patients is hypothesized to originate from destruction of hypocretinergic cells in the hypothalamus, the cause of which remains unknown. Due to strong HLA association autoimmune models of narcolepsy pathogenesis are still mostly favored. Genetic predisposition factors other than HLA are likely to play a role in causing the disorder. We screened three sets of gene regions ( n=254) for association with narcolepsy using a microsatellite based approach and pooled DNA: genes related to immunity, particularly apoptosis; genes related to regulation of circadian rhythmicity; genes coding for several factors of neurotransmission. In relation to apoptosis an association was found for the BAG1 gene region. Interestingly, microsatellites representing four genomic regions related to neurotransmission revealed association with narcolepsy: COMT, DRD2, GABBR1, and HTR2A. These results, although exploratory and still to be confirmed in independent samples, support a complex pathogenetic model for narcolepsy, including disturbances of neurotransmission rather than involvement of autoimmunity. [Abstract]
Dauvilliers Y, Blouin JL, Neidhart E, Carlander B, Eliaou JF, Antonarakis SE, Billiard M, Tafti M
A narcolepsy susceptibility locus maps to a 5 Mb region of chromosome 21q.
Ann Neurol. 2004 Sep;56(3):382-8.
The genetic basis of human narcolepsy remains poorly understood. Multiplex families with full-blown narcolepsy-cataplexy are rare, whereas families with both narcolepsy-cataplexy and excessive daytime sleepiness without cataplexy are more common. We performed a genomewide linkage analysis in a large French family with four members affected with narcolepsy-cataplexy and 10 others with isolated recurrent naps or lapses into sleep. Only three regions showed logarithm of odds (LOD) scores greater than 1 in two-point linkage analysis (D6S1960, D11S2359, and D21S228). Genotyping additional markers provided support for linkage to 9 markers on chromosome 21 (maximum two-point LOD score, 3.36 at D21S1245). The multipoint linkage analysis using SimWalk2 provided further evidence for linkage to the same region (maximum parametric LOD score, 4.00 at 21GT26K). A single haplotype was shared by all affected individuals and informative crossovers indicated that the elusive gene that confers susceptibility to narcolepsy is likely to be located between markers D21S267 and ABCG1, in a 5.15 Mb region of 21q. [Abstract]
Narcolepsy: differential diagnosis or etiology in some cases
of bipolar disorder and schizophrenia?
CNS Spectr. 2003
"Does narcolepsy, a neurological disease, need to be considered
when diagnosing major mental illness? Clinicians have reported cases of narcolepsy
with prominent hypnagogic hallucinations that were mistakenly diagnosed as schizophrenia.
In some bipolar disorder patients with narcolepsy, the HH resulted in their receiving
a more severe diagnosis (ie, bipolar disorder with psychotic features or schizoaffective
disorder). The role of narcolepsy in psychiatric patients has remained obscure
and problematic, and it may be more prevalent than commonly believed. Classical
narcolepsy patients display the clinical "tetrad"--cataplexy, hypnagogic
hallucinations, daytime sleep attacks, and sleep paralysis. Over 85% also display
the human leukocyte antigen marker DQB1*0602 (subset of DQ6). Since 1998, discoveries
in neuroanatomy and neurophysiology have greatly advanced the understanding of
narcolepsy, which involves a nearly total loss of the recently discovered orexin/hypocretin
(hypocretin) neurons of the hypothalamus, likely by an autoimmune mechanism. Hypocretin
neurons normally supply excitatory signals to brainstem nuclei producing norepinephrine,
serotonin, histamine, and dopamine, with resultant suppression of sleep. They
also project to basal forebrain areas and cortex. A literature review regarding
the differential diagnosis of narcolepsy, affective disorder, and schizophrenia
is presented. Furthermore, it is now possible to rule out classical narcolepsy
in difficult psychiatric cases. Surprisingly, psychotic patients with narcolepsy
will likely require stimulants to fully recover. Many conventional antipsychotic
drugs would worsen their symptoms and make them appear to become a "chronic
psychotic," while in fact they can now be properly diagnosed and treated."
T, Hohjoh H, Honda Y, Juji T, Tokunaga K.
Identification of a telomeric
boundary of the HLA region with potential for predisposition to human narcolepsy.
"We report on a study performed to determine a
boundary of the region with the potential to contribute to the predisposition
to human narcolepsy (the susceptibility region) in the human leukocyte antigen
(HLA) region. We investigated a Japanese narcolepsy family, in which a de novo
chromosomal recombination occurred between the HLA-DRB1 and HLA-B genes in the
proband. The recombinant chromosome carrying HLA-DRB1*1501 was transmitted to
the affected child and grandchild, suggesting that a strong genetic factor(s)
predisposing to the disorder was (were) present on the chromosome, and that the
recombination breakpoint could be regarded as a boundary to the susceptibility
region. To search for the breakpoint, we carried out allele typing at various
polymorphic sites, e.g., microsatellite repeat polymorphisms, restriction fragment
length polymorphisms, and single-nucleotide polymorphisms in the HLA region, and
examined haplotypes with the polymorphic sites in the family members. Haplotype
analyses revealed that the recombination breakpoint was present approximately
50 kb to the telomeric side of the palmitoyl-protein thioesterase-2 (PPT2) gene
in the HLA class III region. From the gene map of the HLA region, the cyclic AMP
response element-binding protein-related protein gene (CREB-RP) appeared to be
located at the telomeric end in the 50-kb region. Therefore, the data presented
here suggest that the susceptibility region for the disorder in the family is
present on the centromeric side of the CREB-RP gene in the recombinant Chromosome
6 carrying HLA-DRB1*1501." [Abstract]
A, Shigenari A, Naruse TK, Sugaya K, Juji T, Honda Y, Ikemura T, Inoko H.
repeat polymorphism within the NOTCH4 gene located near the junction of the HLA
class II and class III regions in narcolepsy.
"A polymorphic (CTG)n microsatellite repeat was
found in the signal peptide domain of the NOTCH4 gene located near the junction
of the class II and class III regions of the human major histocompatibility complex.
This gene belongs to a multigene family of NOTCH originally identified as a differential
factor of neuronal cells. To ascertain whether the NOTCH4 gene is involved in
the development of neurogenic disease, narcolepsy, which is known to be tightly
associated with HLA-DR15, this microsatellite polymorphism of the (CTG)n repeat
was analyzed in Japanese patients with narcolepsy One allele, 9 repetitions of
CTG (Leu) was significantly increased in the patient group. However, the significant
increase of this allele in the patient group could be explained by a strong linkage
disequilibrium with the HLA class II alleles, DRB1*1501, DQA1*0102 and DQB1*0602,
which were more strongly associated with the disease. These results suggest that
the (CTG)n repeat polymorphism in NOTCH4 does not primarily determine the susceptibility
to narcolepsy." [Abstract]
Singh SM, George CF, Ott RN, Rattazzi C, Guilleminault
C, Dement WC, Mignot E.
IgH (mu-switch and gamma-1) region restriction
fragment length polymorphism in human narcolepsy.
Immunol. 1996 Jul;16(4):208-15.
"To determine if the IgH locus is involved
in genetic predisposition to human narcolepsy, restriction fragment length polymorphisms
specific for the IgM and IgG cluster within this locus were studied in sporadic
cases of the disease, as well as in five families with two or more affected individuals.
Comparisons were made between control populations and both familial and sporadic
cases and for patients with and without HLA-DR15 and DQB1*0602. RFLP analysis
at the S mu and gamma-1 loci, which cover over 200 kb of 14q32.3, indicates that
there is no evidence for any association between the IgH region and human narcolepsy."
M, Dahmen N, Wieczorek S, Kasten M, Gencikova A, Epplen JT.
polymorphisms in narcolepsy.
BMC Med Genet. 2001;2(1):9.
Epub 2001 Aug 09.
"SUMMARY: 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." [Full
Fehr C, Schleicher A, Szegedi A, Anghelescu
I, Klawe C, Hiemke C, Dahmen N.
Serotonergic polymorphisms in patients
suffering from alcoholism, anxiety disorders and narcolepsy.
Neuropsychopharmacol Biol Psychiatry. 2001 Jul;25(5):965-82.
in the serotonergic neurotransmission have been frequently described for patients
suffering from alcoholism, anxiety disorders and narcolepsy. 2. The authors tested
for association of the 5-HT2A receptor polymorphism (T102C) and the intron 7 tryptophan
hydroxylase (TPH) polymorphism (A218C) among 176 alcohol dependent patients, 35
patients with panic disorder, 50 patients with generalized anxiety disorder, 55
patients with narcolepsy and 87 healthy controls. 3. Allele and genotype frequencies
of the 5-HT2A receptor polymorphism (T102C), the intron 7 TPH polymorphism (A218C)
were almost similar between the patients suffering from alcohol dependence, panic
disorder, generalized anxiety disorder and narcolepsy. 4. There was no association
between the 5-HT2A receptor polymorphism (T102C), the intron 7 TPH (A218C) polymorphisms
and alcohol dependence, panic disorder, generalized anxiety disorder and narcolepsy
in our subsets of German patients." [Abstract]
C, Szegedi A, Anghelescu I, Klawe C, Hiemke C, Dahmen N.
in allelic frequencies of the 5-HT2C Cys23Ser polymorphism in psychiatric patients
and healthy volunteers: findings from an association study.
Genet. 2000 Jun;10(2):59-65.
"Polymorphisms in the serotonergic system
are believed to play a role in the etiology and treatment of different psychiatric
illnesses. The 5-HT2C receptor gene is X-linked, with a frequent mutation at nucleotide
68 leading to a Ser-->Cys transition at amino acid 23. Recent studies have
demonstrated an impaired function of 5-HT2C receptors and an increased production
of the major noradrenergic metabolite 3-methoxy-4-hydroxyphenylethyleneglycol
in the cerebrospinal fluid among the subjects carrying the Ser23 allele (Lappalainen
et al., 1999). Biol. Psychiatry 46:821). We genotyped patients with alcohol dependence,
panic disorder without agoraphobia, generalized anxiety disorder, narcolepsy and
normal healthy volunteers for the 5-HT2C Cys23Ser polymorphism. 5-HT2C Cys23Ser
allele frequencies and genotypes did not differ among patients with alcohol dependence,
panic disorder, generalized anxiety disorder, narcolepsy and normal healthy volunteers.
In an overall analysis, female subjects (n = 173) displayed a higher frequency
of 5-HT2C Ser23 alleles as compared to males (n = 298, P = 0.0178). The potential
mechanisms of the observed gender difference in allele frequencies, including
transmission ratio distortion, are discussed." [Abstract]
M., Dahmen, N., Wieczorek, S., Kasten, M., Bierbrauer, J., Anghelescu, I., Szegedi,
A., Menezes Saecker, A. M., Epplen, J. T.
A prepro-orexin gene polymorphism
is associated with narcolepsy
Neurology 2001 56: 115-117
orexin (hypocretin) neurotransmitter system was recently shown to be directly
involved in the pathogenesis of narcolepsy in two animal models. Furthermore,
decreased levels of orexin A in the CSF were shown in narcoleptic patients. To
define any genetic contribution of orexin to the etiology of narcolepsy, the authors
screened the entire prepro-orexin gene for mutations or polymorphisms in 133 patients
suffering from narcolepsy. They report an association of a rare polymorphism in
the prepro-orexin gene with narcolepsy in a cohort of 178 patients."
mutation analysis in the prepro-orexin revealed a sequence variation C3250T (reference
accession number AF118885) in the 5' UTR, 22 bp 5' from the start codon. The 3250T
allele was present in six of 178 narcoleptic patients, as well as in one healthy
control subject out of 189 (p < 0.05, OR = 6.5)." [Full
Hungs, Marcel, Lin, Ling, Okun, Michele,
Polymorphisms in the vicinity of the hypocretin/orexin
are not associated with human narcolepsy
"Human narcolepsy/cataplexy is associated with reduced hypocretin
(orexin) transmission. A common preprophypocretin (HCRT) polymorphism (-909C/T)
was identified and tested in 502 subjects (105 trio families, 80 Caucasian narcolepsy
cases, and 107 Caucasian control subjects). This polymorphism was not associated
with the disease. The promoter and 5' untranslated (5'URT) regions of the HCRT
gene (-320 to +21 from ATG) were also sequenced in 281 subjects. None of the subjects
carried -22T, a rare 5'UTR polymorphism previously reported to be associated with
narcolepsy. The HCRT locus is not a major narcolepsy susceptibility locus."
Black JL, Silber MH, Krahn LE, Avula RK, Walker DL, Pankratz VS, Fredrickson PA, Slocumb NL
Studies of humoral immunity to preprohypocretin in human leukocyte antigen DQB1*0602-positive narcoleptic subjects with cataplexy.
Biol Psychiatry. 2005 Sep 15;58(6):504-9.
BACKGROUND: Canine models for narcolepsy have mutations of the hypocretin receptor 2 gene, and preprohypocretin knockout murine lines exhibit narcoleptic-like behaviors. Human narcolepsy with cataplexy is associated with human leukocyte antigen DQB1*0602 and reduced hypocretin levels in cerebrospinal fluid, suggesting an autoimmune diathesis. We tested the hypothesis that DQB1*0602-positive narcoleptic subjects with cataplexy have immunoglobulin (Ig)G reactive to human preprohypocretin and its cleavage products. METHODS: Serum samples of 41 DQB1*0602-positive narcoleptic subjects with cataplexy and 55 control subjects were studied, as were 19 narcoleptic and 13 control samples of cerebrospinal fluid. We tested for IgG reactive to preprohypocretin and its major cleavage products (including hypocretin 1 and 2), using immunoprecipitation assays (IP), immunofluorescence microscopy (IF) of Chinese hamster ovarian cells expressing preprohypocretin, and Western blots. RESULTS: There was no evidence for IgG reactive to preprohypocretin or its cleavage products in CSF of subjects with narcolepsy as measured by IPs, Western blots, and IF. Although the IP with CSF and the C-terminal peptide showed significant differences by two methods of comparison, the control subjects had higher counts per minute than narcoleptic subjects, which was opposite to our hypothesis. CONCLUSIONS: The hypothesis that DQB1*0602-positive narcoleptic subjects with cataplexy have IgG reactive to preprohypocretin or its cleavage products was not supported. [Abstract]
Khatami R, Maret S, Werth E, Rétey J, Schmid D, Maly F, Tafti M, Bassetti CL
Monozygotic twins concordant for narcolepsy-cataplexy without any detectable abnormality in the hypocretin (orexin) pathway.
Lancet. 2004 Apr 10;363(9416):1199-200.
Narcolepsy with cataplexy is thought to be a hypocretin ligand or hypocretin receptor deficiency syndrome caused by genetic and environmental factors. We looked for an abnormality of the hypocretin pathway in HLA-DQB1*0602-positive monozygotic twins who were concordant for narcolepsy-cataplexy. They had normal cerebrospinal fluid concentrations of hypocretin-1, and we found no mutation in the prepro-hypocretin gene or either hypocretin receptor gene. Our finding points to the existence of presumably genetic forms of narcolepsy with cataplexy without any demonstrable defect in the hypocretin pathway. [Abstract]
Moreira F, Pedrazzoli M, Dos Santos Coelho FM, Pradella-Hallinan M, Lopes da Conceição MC, Pereira Peregrino AJ, de Oliveira EC, Tufik S
Clock gene polymorphisms and narcolepsy in positive and negative HLA-DQB1*0602 patients.
Brain Res Mol Brain Res. 2005 Oct 31;140(1-2):150-4.
Narcolepsy is a chronic sleep disorder. It is linked to the HLA-DQB1*0602 allele. A recent report established a genetic linkage between narcolepsy and the chromosomal region 4p13-q21 that contains the Clock gene. We studied two SNPs in the Clock gene aiming to find any association with narcolepsy. We did not find differences in genetic frequencies in the patients group. We concluded that these two SNPs are not associated with narcolepsy. [Abstract]