The first clinical reports of chronic excessive daytime sleepiness (EDS) with abrupt loss of muscle tone date back to the late 19th century, with publications from the German psychiatrist Karl Friedrich Otto Westphal and French neurologist Jean Baptiste Edouard Gélineau [1]. In these reports, patients presented with multiple sleep attacks throughout the day and episodes of loss of muscle tone, known as cataplexy, which could be triggered by strong positive emotions. This pathognomonic association of clinical findings observed nearly 150 years ago is attributed to a rare sleep disorder called narcolepsy type 1 (NT1), which also includes disturbances in rapid eye movement (REM) sleep with the presence of hallucinations upon falling asleep (hypnagogic) or waking up (hypnopompic), in addition to sleep attacks and or sleep paralysis [2]. As a rare neurological disease, the prevalence of NT1 varies from 12.6 to 50 cases per 100,000 individuals [3], [4], [5], and onset follows a bimodal distribution with peaks at ages 15 and 35, though it is more frequently observed during adolescence [6].

The pathophysiology of NT1 is attributed to a deficit of hypocretin (HCRT), also named orexin [7], [8], [9]. This excitatory neuropeptide, essential for wakefulness and stabilizing the REM/non-REM state, is secreted by HCRT-producing neurons in the lateral hypothalamus with long-range projections throughout the central nervous system (CNS) [10]. Active HCRT is secreted in two forms, HCRT-1 and HCRT-2 (also known as orexin-A and orexin-B, respectively), and binds to homologous receptors HCRTR1 and HCRTR2 [8], [11]. In addition to a deficit in HCRT [7], [9], in the case of NT1, it is suggested that there is a selective loss of HCRT-producing neurons in the hypothalamus [2]. Anatomopathological studies have shown that NT1 patients have an 85–95 % reduction in the number of HCRT neurons in the lateral hypothalamus, while neighboring melanin-concentrating hormone neurons are spared [12], [13]. However, recent evidence also suggested a loss of corticotropin-releasing hormone (CRH)-positive neurons in the paraventricular nucleus (PVN) in patients with NT1 [14]. Familial cases of patients with NT1 are rare (1–2 %) and monozygotic twins are concordant for NT1 in only 25 % of cases [15].

Selective genetic ablation of HCRT-producing neurons in mice results in a narcoleptic phenotype [12], [16]. Similar to Parkinson’s disease wherein motor signs appear after at least a 30 % loss of dopaminergic neurons in substantia nigra [17], data from animal models indicate that classical NT1 symptoms appear with progressive loss of HCRT-neurons. Indeed, EDS appears after a 80 % neuronal loss, while cataplexy would appear after a loss exceeding 95 % [18], [19], [20]. Consequently, the cerebrospinal fluid (CSF) concentration of HCRT (<110 pg/mL) is used as a diagnostic biomarker for NT1. Although this review is focused solely on NT1, there is an additional form of narcolepsy, narcolepsy type 2, which is characterized by EDS in the absence of cataplexy and without decreased levels of HCRT in the CSF. A subset of these patients may later develop HCRT deficiency and thus be reclassified as NT1 [21].

The mechanisms leading to selective loss of HCRT in NT1 are not yet fully understood. Notably, the remaining spared HCRT-secreting neurons in the lateral hypothalamus do not show protein aggregates similar to those found in other degenerative CNS pathologies, such as tauopathy or alpha-synucleinopathy [22]. Additionally, neuropathological examination in post-mortem studies and positron emission tomography (PET) imaging of idiopathic NT1 patients have not detected inflammatory infiltration [10], [23]. Despite the lack of mechanistic understanding of HCRT-secreting neuron destruction in NT1, it is widely suspected that NT1 is an autoimmune disorder with both genetic and environmental components (Fig. 1). Highlighting the autoimmune aspect of NT1 pathogenesis, collective research involving animal models and human studies has aimed to elucidate the mechanisms underlying this hypothesis. Here, we highlight recent data from both hypothesis-driven and hypothesis-generating approaches that may offer new insights into the pathogenesis of the disease, and may potentially lead to targeted immunotherapies.