Utilize este identificador para referenciar este registo: http://hdl.handle.net/10400.18/2231
Título: How genetic characterization of Narcolepsy and hypersomnia is useful on phenotype definition
Autor: Martins da Silva, A.
Lopes, J.
Ramalheira, J.
Carvalho, C.
Costa, P.P.
Silva, B.M.
Palavras-chave: Doenças Genéticas
Data: 16-Mar-2013
Editora: Cesar Viguera
Citação: Rev Neurol.2013;57(1):37-43
Resumo: Introduction. The determination of HLA class II genotype is widely used to confirm the diagnosis of narcolepsy with or without cataplexy. It is known from studies carried out in the 80’s and 90’s that genetic markers, particularly HLA-DR2 (HLA-DRB1*15) and later DQB1*06:02, are strongly associated with susceptibility to narcolepsy (N). First studies in 1984 showed values of 100% of positive HLA-DR2 (Langdon et al; Lancet 1984) in narcoleptic patients with cataplexy (NC). Mignot et al (Sleep 1997) found values of 76.1% of HLA-DQB1*06:02 positive in NC and 40.9% in N. More recent studies emphasize difference between children and adults for HLA-DQB1*06:02. Values of 93.7% (adults) vs 92.6% (children) in NC and a frequency of 78,6% in adults vs 52.9% in children were found in N (Nevsimalova et al; J Neurol 2013). The dissemination of HLA genotyping was the result of two convergent reasons: i) the method is reliable, easy to perform and reassures the clinician; ii) the assay is less invasive than other methodologies, namely those involving cerebrospinal fluid (CSF) samples. Another contributing factor is the wide acceptance of the hypothesis of an autoimmune origin for Narcolepsy (a clinical field in which the relevance of HLA system is generally accepted). This hypothesis finds support in the virtually absent levels of hypocretin peptides in the CSF of patients with NC, which is postulated to be due to the autoimmune destruction of hypocretin producing neurons (Burgess et al; J Neurosci 2012). Aims. To evaluate the contribution of genetic markers (HLA) to the differential diagnosis between narcolepsy with (NC) or without cataplexy (N) and hypersomnia (H) and their relevance in the context of our population (Northern Portugal). Patients and methods. A cohort of 113 patients with sleep and hypersomnia complaints were observed at the Outpatient Sleep Clinic from Hospital Santo Antonio/CH Porto and were assessed by clinical, night sleep polygraphic recording, MSLT on the following day, blood sampling in a routine method. Data from laboratory parameters was confronted with the clinical diagnostic hypothesis. Clinical reevaluation of the patients was considered if results did not match. Of these patients, classified as NC, N or H (according to ICSD2, 2005), 38 were NC (age at testing: mean, 32.8 years; median, 30 years); 13 N (age at testing: mean, 34.2 years; median: 36 years); 62 patients had H (age at testing: mean, 38.2 years; median, 40 years). We used a control population (CP) of 206 reportedly healthy individuals from the same geographic origin. The allele frequencies of the control population were confirmed and compared with a larger cohort of another population (2500 individuals) from the central and south regions of the country. Results. The frequency of HLA-DQB1*06:02 allele was overrepresented in N and NC patients (46% and 71% respectively), as expected, and the p value is extremely significant for NC (p < 0.0000). HLA-DQB1*02 frequency was also increased in the population with H when compared with the CP (55% vs 34%; p = 0.00396). Interestingly the frequency of the HLADQB1*03 allele was decreased in the NC vs CP group (34% vs 56%; p =0.012153). No differences were found in the HLA-DQB1*06:03 frequency between the cohort of patients and the control population. Conclusions. The HLA-DQB1*06:02 allele, a susceptibility factor to other autoimmune disorders (e.g.: MS, SLE, sarcoidosis, sclerosing cholangitis), was confirmed as a susceptibility allele also to NC in our population. The frequency of this allele in our NC patients (71%) is within the range of other studies. This value is lower when compared to studies concerning only patients with severe cataplexy (frequencies between 85-95%). Some of the differences could be due to phenotypic uncertainty or to the clinical picture evolution in different age groups (Nevsimalova et al; J Neurol 2013). Also a modification of hypocretin levels, by circadian or other oscillations and the influence of environmental factors (infections, head trauma, immunization) can be involved. The role of the potential regeneration of CNS tissue is also a subject to be explored. Given these uncertainties, genetic characterization has the potential to enhance the ability to carry out differential diagnosis among diverse excessive daytime sleepiness phenotypes, helping in the distinction of diverse entities corresponding to fundamentally different biological processes. Finally a matter to be explored is the role of HLADQB1*06:03 allele, considered by some authors as a protective factor to NC (Hor et al; Nat Genet 2010) (Van der Heide et al; Sleep 2012). Our study did not confirm this assumption.
Peer review: no
URI: http://hdl.handle.net/10400.18/2231
ISSN: 0210-0010
Versão do Editor: http://www.revneurol.com/sec/resumen.php?i=i&id=2013176&vol=57&num=01
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