Steven Jervis*, Anthony Payton, Arpana Verma, Marcus Lowe, Rachel Thomasson and Kay Poulton
Narcolepsy is hypothesized to be an autoimmune disease targeting the hypocretin/orexin producing neurons within the hypothalamus and is categorised into subsets based on the symptoms presented. Epidemiological studies have proposed that there is an additional requirement for an environmental trigger combined with potential genetic predisposition to trigger the onset of this spectrum of disorders. Despite epidemiological evidence which suggests the condition arises due to a breach of immunological tolerance, the absence of a defined autoantigen remains an element of debate in the aetiology of the disorder. Currently there are no definitive diagnostically useful genetic variants observed in narcolepsy suffers which could be exploited at disease onset to support its diagnosis or clinical management
The most impactful genetic risk factor is the presence of human leukocyte antigen (HLA) allele, DQB1*06:02, which increases the risk of Narcolepsy over 20-fold. The discovery of the strong association of HLADQB1* 06:02 and disease onset was the original trigger to shift the focus from its classification as a neurological disease to that of an immunemediated condition. However, the presence of HLA-DQB1*06:02 alone cannot be the sole genetic risk factor to explain disease onset. Primarily, not all narcolepsy patients express DQB1*06:02 (>95%) and more importantly not all people who express DQB1*06:02 suffer from narcolepsy – only 16% of the global population who express DQB1*06:02 suffer from Narcolepsy. This has resulted in low usage of this definition test in the clinical setting due to its lack of specificity and because it is of most clinical utility if the result is negative, reducing the likelihood of a diagnosis of narcolepsy.
The diagnosis of narcolepsy is often suspected from the clinical history of the patient, supported by the results of a multiple sleep latency test (MSLT). Combined with the determination of hypocretin/orexin in the cerebral spinal fluid, these two tests are still considered the gold standard tests for diagnosis. However, there are also documented issues surrounding both tests in terms of level of sensitivity, specificity and potential complications which limit their reliability as a diagnostic resource. This review focuses on emerging evidence of genetic and environmental risk factors linked with narcolepsy onset, their link to its pathophysiology and we speculate how genetic traits could be better utilised to effectively aid a diagnosis.
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