Wilson’s Disease Coexisting with Narcolepsy Type 1: Evidence for a Multifactorial Cause of Excessive Daytime Sleepiness from a Case Report

Abstract

Background

Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism that frequently involves the central nervous system and may be associated with secondary sleep disturbances. Excessive daytime sleepiness (EDS) in WD is typically attributed to metabolic or structural brain injury rather than primary sleep–wake dysregulation. Narcolepsy type 1 (NT1), caused by autoimmune loss of hypothalamic hypocretin neurons, is a distinct primary sleep disorder. The coexistence of WD and NT1 has not previously been reported.

Case Presentation

We describe a 23-year-old woman with a 15-year history of WD who developed long-standing EDS accompanied by emotionally triggered cataplexy, sleep paralysis, and hypnagogic hallucinations. Genetic analysis identified pathogenic ATP7B variants (p.R778L and p.R919G). Brain MRI revealed symmetric signal abnormalities involving the basal ganglia, midbrain nuclei, cerebellar dentate nuclei, and hypothalamus, suggesting chronic neurotoxicity. Comprehensive sleep evaluation supported a diagnosis clinically consistent with NT1, further corroborated by HLA-DQB1*06:02 positivity. Importantly, hepatic encephalopathy and other secondary causes of hypersomnolence were excluded.

Conclusion

This case suggests the possibility that NT1 can coexist with WD as an independent primary sleep disorder rather than a secondary manifestation of metabolic or structural brain disease. The findings support a multifactorial neurobiological mechanism in which copper-related neurotoxicity and genetic susceptibility converge on hypothalamic injury. Clinicians should maintain a high index of suspicion for primary sleep–wake disorders when patients with WD present with cataplexy or other REM-related symptoms, as accurate differentiation has important implications for diagnosis, management, and prognosis.

Infographic available for this article.

Infographic

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1007/s40120-026-01011-0.

Digital Features

This article is published with digital features, including an Infographic, to facilitate understanding of the article. To view digital features for this article, go to https://doi.org/10.6084/m9.figshare.33106673.

Key Summary Points

Why carry out this study?

Excessive daytime sleepiness in Wilson’s disease (WD) is typically attributed to metabolic or structural causes, while coexisting primary sleep disorders are rarely considered.

Hypothalamic involvement in WD raises the possibility of overlapping mechanisms affecting sleep–wake regulation.

This study was prompted by a patient with WD who presented with cataplexy, a symptom not explained by copper toxicity alone, raising the question of whether narcolepsy type 1 (NT1) could coexist as an independent disorder.

What was learned from the study?

This case is clinically consistent with NT1 in a patient with WD, based on typical REM-related features and sleep study findings.

The case highlights diagnostic uncertainty and the need to consider both primary and secondary mechanisms.

Introduction

Wilson’s disease (WD) is an autosomal recessive disorder caused by impaired copper excretion, resulting in toxic copper accumulation in the liver and central nervous system [1]. Neurological involvement commonly includes movement disorders, cognitive impairment, and secondary sleep disturbances, which typically arise from copper-induced structural brain injury or hepatic encephalopathy rather than primary dysregulation of the sleep–wake system [2]. Excessive daytime sleepiness (EDS) is defined as an increased tendency to fall asleep during the daytime and a reduced ability to maintain wakefulness, reflecting dysfunction of the sleep–wake regulatory system [3]. In contrast, fatigue is a subjective sensation of reduced physical or mental energy and diminished endurance, which is not necessarily associated with an increased propensity for sleep.

Narcolepsy type 1 (NT1) is a primary sleep disorder characterized by EDS and cataplexy. NT1 is caused by autoimmune loss of hypothalamic hypocretin-producing neurons, resulting in profound sleep–wake instability [4]. Diagnosis requires objective sleep study criteria, including a mean sleep latency of ≤ 8 min on the multiple sleep latency test (MSLT) and the presence of ≥ 2 sleep-onset rapid eye movement periods (SOREMPs), in addition to clinical features such as cataplexy or low cerebrospinal fluid hypocretin-1 levels. Its pathogenesis is unrelated to copper metabolism. The coexistence of WD and NT1 is exceptionally rare. Although the mechanisms underlying EDS differ fundamentally between conditions, EDS is a hallmark symptom of NT1 [5]. Therefore, EDS in patients with WD may sometimes be misdiagnosed as NT1, and vice versa.

This report describes a patient with WD presenting with clinical features consistent with NT1, highlighting the diagnostic challenge in distinguishing primary and secondary causes of hypersomnolence.

Case Presentation

A 23-year-old female patient with a 15-year history of abnormal liver function and a prior diagnosis of WD presented to our hospital for follow-up evaluation and ongoing treatment in November 2, 2025. There was no family history of narcolepsy, sleep disorders, or autoimmune diseases. The patient was identified to have abnormal liver function during a routine examination at the age of 7. In 2011 (age 9), her body mass index (BMI) was 18.4. Laboratory tests showed ALT 181 U/L, AST 71U/L (rate method), blood ammonia 23 μmol/L (normal 9–30 μmol/L), 24-h urinary copper 365.13 μg/24 h, serum protein electrophoresis showing albumin 63.26% (normal 53–71.3%), α1-globulin 2.52% (1.4–4.2%), α2-globulin 8.54% (4–8.8%), β-globulin 13.37% (8–12.5%), γ-globulin 12.31% (11–22.5%), and coagulation parameters including PT 12.1 s, INR 1.12, APTT 34.0 s, fibrinogen 3.21 g/L, TT 17.7 s. Her Child–Pugh score was 5, indicating preserved hepatic synthetic function and making hepatic encephalopathy unlikely at that time. Laboratory testing showed markedly abnormal liver enzymes, with ALT 175 U/L, AST 103 U/L, and a low level of ceruloplasmin at 0.091 g/L (reference 0.23–0.44 g/L). The patient was diagnosed with WD in 2011 on the basis of the aforementioned test results. In 2013, liver function tests again showed elevated ALT (164 U/L) and AST (86 U/L), blood ammonia remained normal at 21 μmol/L, and 24-h urinary copper was 318.64 μg/24 h.

The patient had been treated continuously with penicillamine since the diagnosis of WD. There was no history of sedative, hypnotic, or other medications that could account for hypersomnolence prior to symptom onset. The patient has been receiving long-term copper-chelation therapy since the age of 9, treated with penicillamine at a dosage of 20 mg/kg/day. At age 12 (2015), the patient developed EDS with emotionally triggered cataplexy, which was not evaluated at the time.

The episodes were characterized by sudden bilateral lower limb muscle atonia leading to falls, consistent with cataplexy, while consciousness and awareness remained fully preserved during the events, without any loss or alteration of consciousness. Between ages 13 and 14, her BMI increased to 30.1, while sleepiness and cataplexy persisted; menarche occurred at age 13. By age 16, she developed amenorrhea and type 2 diabetes mellitus, with ongoing EDS and REM-related symptoms, including sleep paralysis. At age 19, BMI further increased to 31.2, and sleep, metabolic, and reproductive abnormalities persisted. At age 23 (2025), BMI reached 33.8, and she presented with severe EDS (Epworth score 19), cataplexy episodes were less frequent but remained intermittently present, while EDS and other REM-related symptoms persisted. Brain MRI showed hypothalamic involvement, and genetic testing identified compound heterozygous ATP7B mutations (p.R778L and p.R919G), consistent with WD.

During this admission, Epworth Sleepiness Scale (© MW Johns 1990–1997. Used under License) [6] was 19 points. Neurological examination revealed increased muscle tone in both upper limbs, consistent with basal ganglia involvement. No other focal neurological deficits were observed. Then, she presented at our institution with persistent EDS and fragmented nighttime sleep, along with ongoing episodes of sleep paralysis and hallucinations before sleep. A brain MRI scan performed in November 2025 demonstrated symmetric signal abnormalities in the bilateral dentate nuclei of the cerebellum, red nuclei, substantia nigra, globus pallidus, and hypothalamus, characterized by mildly hyperintense signals on T1-weighted imaging and hypointense signals on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences. Susceptibility-weighted imaging (SWI) was not performed (Fig. 1).

Fig. 1.

Brain magnetic resonance imaging (MRI) of the patient (November 2025). Symmetric signal abnormalities were observed in the bilateral dentate nuclei of the cerebellum, red nuclei, substantia nigra, globus pallidus, and hypothalamus characterized by mildly hyperintense signals on T1-weighted imaging and hypointense signals on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences. A–C T2-weighted imaging (T2WI), T1-weighted imaging (T1WI), and T2-fluid-attenuated inversion recovery (T2-FLAIR) demonstrate symmetric isointense or slightly hyperintense signals on T1WI and hypointense signals on T2WI and T2-FLAIR in the bilateral substantia nigra (solid arrows) and red nuclei (open arrows). D–F T2WI, T1WI, and T2-FLAIR show symmetric patchy isointense or slightly hyperintense signals on T1WI and hypointense signals on T2WI and T2-FLAIR in the bilateral globus pallidus (solid arrows). G–H Coronal T2-FLAIR images demonstrate symmetric patchy hypointense signals in the bilateral globus pallidus (solid arrows) and linear hypointense signals in the bilateral hypothalamus (long arrows)

Polysomnography (PSG) performed on the night preceding the multiple sleep latency test (MSLT) demonstrated a sleep onset latency of 3.5 min, with poor sleep continuity after sleep onset. The distribution of sleep stages was as follows: rapid eye movement (REM) sleep accounted for 19.0% of total sleep time, with a REM sleep latency of 6.5 min; non-rapid eye movement (NREM) sleep stages N1, N2, and N3 comprised 26.3%, 37.1%, and 17.6% of total sleep time, respectively. The total sleep time was 419.5 min, and sleep efficiency was 87.5%. The apnea–hypopnea index (AHI) was 5.6, and the minimum oxygen saturation during sleep was 90% (Fig. 2). The subsequent MSLT consisted of five nap opportunities and revealed a mean sleep latency of 4.5 min. SOREMPs were observed in three naps, occurring during the first, second, and fourth nap opportunities, with REM sleep latencies of 1.5 min, 5.5 min, and 1.5 min, respectively. Clinically, the patient exhibited marked EDS (Table S1). HLA-DQB1*06:02 testing returned positive results via PCR electrophoresis, supporting the diagnosis clinically consistent with NT1. PSG and MSLT during this hospitalization were clinically consistent with NT1, supported by HLA-DQB1*06:02 positivity.

Fig. 2.

Polysomnography and multiple sleep latency test (MSLT) findings (November 2025). W = wakefulness; R = rapid eye movement (REM) sleep; N1, N2, and N3 = non-rapid eye movement sleep stages 1, 2, and 3. A Overnight polysomnography on the night preceding the MSLT, showing a sleep onset latency of 3.5 min, a REM sleep latency of 6.5 min, and a total sleep time of 419.5 min. B The MSLT, in which sleep-onset REM periods (SOREMPs) occurred during the first, second, and fourth nap opportunities; REM sleep latencies were 1.5 min in the first nap, 5.5 min in the second nap, and 1.5 min in the fourth nap

The current treatment plan continues to focus on promoting copper excretion with intravenous sodium dimercaptopropane sulfonate (0.125 g/vial) administered at 5 mg/kg/day. In addition, trazodone was given at 50 mg nightly at 22:00 to reduce nighttime sleep fragmentation and improve nocturnal sleep fragmentation and sleep continuity, thereby enhancing daytime alertness. This choice was based on an individualized treatment strategy, as first-line wake-promoting agents were avoided because of concerns regarding potential exacerbation of dopaminergic dysfunction and movement-related symptoms in the context of WD. The patient was also advised to take scheduled naps during the day to manage her excessive sleepiness. Given the relatively low-stress nature of her current job, stimulant medications were not prescribed.

The patient was discharged on December 4, 2025 and transitioned to penicillamine at 1000 mg/day, administered orally three times daily. Following discharge, she will undergo regular monitoring of liver function tests, 24-h urinary copper excretion, and Epworth Sleepiness Scale scores. Ongoing follow-up visits will allow for continuous assessment of both WD and narcolepsy, with timely adjustments to her therapeutic regimen based on clinical response and any newly emerging symptoms.

Sanger sequencing of the ATP7B gene (Fig. 3) in January 2026 identified two heterozygous missense variants in the patient. A c.2333G>T substitution in exon (corresponding exon number, if applicable) resulted in a p.Arg778Leu amino acid change (Fig. 3A). In addition, a c.2755C>G substitution was detected, leading to a p.Arg919Gly amino acid change (Fig. 3B).

Fig. 3.

Sanger sequencing analysis of the ATP7B gene. A Partial chromatograms showing the heterozygous c.2333G>T (p.Arg778Leu) missense mutation in the patient (bottom) compared to the wild-type control (top). B Partial chromatograms showing the heterozygous c.2755C>G (p.Arg919Gly) missense mutation in the patient (bottom) compared to the control (top). Black arrows indicate the positions of the nucleotide substitutions

The patient’s demographic data, longitudinal clinical course, laboratory findings, neuroimaging results, and genetic testing across key time points from childhood to adulthood are shown in Table 1.

Table 1.

Longitudinal clinical, laboratory, and management profile of the patient

Age (year)	Clinical features	Laboratory/imaging/genetic findings	Management
7–9 years (2009–2011)	Abnormal liver function detected at age 7; BMI 18.4 at age 9	ALT 181 U/L, AST 71 U/L; ceruloplasmin 0.091 g/L; 24-h urinary copper 365.13 μg/24 h	Diagnosis of Wilson’s disease; initiation of penicillamine (20 mg/kg/day)
12 years (2015)	EDS; emotionally triggered cataplexy; sleep paralysis; BMI 23.4	No sleep studies performed at this stage	Continued penicillamine; no specific sleep treatment
13–14 years (2016–2017)	Persistent sleepiness and cataplexy; menarche at age 13; BMI increased to 30.1	Liver function (2013): ALT 164 U/L, AST 86 U/L; 24-h urinary copper 318.64 μg/24 h	Maintenance penicillamine therapy
16–19 years (2018–2021)	Amenorrhea at age 16; type 2 diabetes mellitus diagnosed; persistent sleep-related symptoms; BMI 31.2 at age 19	Stable compensated liver function during follow-up	Continued chelation therapy
23 years (2025–2026)	Severe EDS (ESS 19); sleep fragmentation; sleep paralysis; hypnagogic hallucinations; BMI 33.8; increased muscle tone in upper limbs	MRI: symmetric lesions in basal ganglia and hypothalamus; PSG: AHI 5.6, sleep efficiency 87.5%; MSLT: mean latency 4.5 min, 3 SOREMPs; HLA-DQB1*06:02 positive; ATP7B mutations (p.R778L, p.R919G)	IV sodium dimercaptopropane sulfonate; low-dose trazodone (50 mg nightly); avoidance of stimulants

AHI apnea–hypopnea index, ALT alanine aminotransferase, AST aspartate aminotransferase, ATP7B ATPase copper transporting beta polypeptide, BMI body mass index, EDS excessive daytime sleepiness, ESS Epworth Sleepiness Scale, HLA human leukocyte antigen, IV intravenous, MRI magnetic resonance imaging, MSLT multiple sleep latency test, PSG polysomnography, SOREMP sleep-onset rapid eye movement period

This case was approved by the Medical Ethics Committee of the First Affiliated Hospital of Anhui University of Chinese Medicine (2024AH-06-01). Written informed consent for publication of this case report and any accompanying images was obtained from the patient.

Discussion

This case suggests the coexistence of WD and NT1 and supports a hypothesis-generating multifactorial model of hypothalamic dysfunction underlying narcolepsy pathophysiology. In this framework, genetic susceptibility represents a vulnerable substrate, copper-related neurotoxicity acts as a principal trigger, and metabolic-endocrine stress may function as a secondary amplifying factor contributing to hypothalamic dysfunction. The patient was positive for HLA-DQB1*06:02, a well-established genetic marker associated with increased susceptibility to NT1. However, this allele is also present in a proportion of healthy individuals and is therefore not sufficient for disease causation on its own, but rather reflects genetic susceptibility in the context of other environmental or immunological factors [7]. While NT1 is generally associated with autoimmune-mediated hypocretin neuron loss, cerebrospinal fluid hypocretin-1 (orexin-A) measurement was not performed in this patient, as lumbar puncture was not undertaken; therefore, CSF biomarker confirmation of NT1 was not available. In WD, copper accumulation in basal ganglia and related structures induces oxidative stress and neuroinflammation, and potential extension to hypothalamic involvement remains speculative.

Distinguishing primary NT1 from secondary narcolepsy related to hypothalamic dysfunction is challenging in this case. Although the patient exhibited typical NT1 features, including cataplexy and SOREMPs on MSLT, the absence of CSF hypocretin-1 limits diagnostic certainty. Hypothalamic abnormalities on MRI further raise the possibility of structural contribution, and secondary narcolepsy related to WD cannot be excluded [8]. Therefore, the diagnosis is best defined as clinically consistent with NT1 rather than definitively established.

Obesity, diabetes mellitus, and amenorrhea in this patient likely reflect hypothalamic dysfunction rather than independent predisposing factors. While weight gain may occur in a subset of patients with NT1, but this association is not universal, WD-related metabolic disruption may have contributed to early hypothalamic dysregulation. Obesity and metabolic disturbances may further induce low-grade inflammation and insulin resistance, potentially exacerbating hypothalamic vulnerability, although direct causal evidence for progressive orexin neuron loss is lacking [9]. Menstrual disturbance also supports involvement of the hypothalamic-pituitary axis [10]. Thus, even if metabolic abnormalities initially emerge as downstream consequences of hypothalamic injury, once established they may perpetuate a potential interaction that further compromises the survival of residual hypocretin neurons. We propose a hypothesis-generating model integrating genetic susceptibility, copper-induced neurotoxicity, and metabolic stress. These factors may converge to create a pathophysiological cascade affecting hypothalamic integrity. However, the hypothesis-generating model proposed in this report should be interpreted with caution. Although NT1 is characterized by hypocretin neuron loss within the hypothalamus, the evidence for hypothalamic involvement in WD remains indirect and primarily based on imaging findings. Therefore, a shared hypothalamic dysfunction between the two conditions cannot be established on the basis of the current data. In this framework, metabolic-endocrine disturbances function more as sustaining modifiers than primary etiological drivers. This model may help explain early onset of EDS and REM-related phenomena (cataplexy, sleep paralysis, hypnagogic hallucinations), distinguishing this presentation from typical secondary hypersomnolence in WD [11]. Stress and inflammatory processes have been proposed as potential contributors to hypothalamic vulnerability and orexin neuron dysfunction in previous studies. In the present case, these mechanisms are inferred indirectly from clinical features and comorbid metabolic abnormalities rather than direct biological measurements. However, this proposed model remains speculative and is not supported by direct CSF orexin measurements or other objective biomarkers in the present case. Therefore, rather than supporting a specific mechanistic model, this case raises the possibility that both primary and secondary mechanisms should be considered when evaluating EDS in patients with WD. Further clinical and mechanistic studies are required to determine whether this observation represents a coincidental coexistence or reflects a broader biological association.

From a clinical perspective, this case illustrates diagnostic overshadowing and anchoring bias. In WD, symptoms such as fatigue, movement disorders, and hepatic dysfunction may lead to misattribution of hypersomnolence [2]. In this patient, emotionally triggered cataplexy and hypnagogic hallucinations were initially misattributed to neurological manifestations of WD, leading to a diagnostic delay exceeding 10 years. Differentiating NT1-related cataplexy from movement abnormalities caused by basal ganglia involvement requires careful clinical evaluation. In contrast to cataplexy, which presents as brief episodes of emotionally triggered muscle weakness with preserved consciousness, WD-related movement disorders are generally characterized by persistent extrapyramidal manifestations rather than transient REM sleep-related muscle atonia.

Early brain MRI showed no typical WD lesions or hypothalamic abnormalities; however, conventional imaging is insensitive to functional hypothalamic dysfunction in NT1. These findings therefore do not clarify the temporal relationship between the two conditions. Considering the potential inflammatory effects of copper neurotoxicity, we propose a hypothesis-generating model in which metabolic-endocrine dysregulation and hypothalamic vulnerability interact to shape disease expression. Functional impairment may thus precede structural changes detectable on imaging, and sublethal copper toxicity with metabolic stress may suppress hypocretin signaling before irreversible neuronal loss occurs. Accordingly, a normal early MRI does not exclude hypothalamic involvement, and NT1 should remain a diagnostic consideration in patients with WD presenting with REM-related symptoms.

Hypothalamic MRI signal abnormalities are non-specific and may reflect metabolic or microstructural changes. They do not distinguish primary NT1 from secondary hypersomnolence. Copper-related oxidative stress may impair hypocretin neurons directly or via disruption of ascending arousal pathways [12]. However, the exact relationship between imaging findings and clinical phenotype remains uncertain. Copper-induced oxidative stress may also affect blood–brain barrier integrity in the hypothalamic region, potentially increasing vulnerability, although direct evidence in this patient is lacking [13].

Several investigations relevant to NT1 were not performed. CSF hypocretin-1 levels were not measured because lumbar puncture was declined, and inflammatory or autoimmune biomarkers were not systematically assessed. Although the diagnosis clinically consistent with NT1 was supported by characteristic symptoms, polysomnography/MSLT findings, and HLA-DQB1*06:02 positivity, the absence of these data limits diagnostic certainty. Likewise, the proposed mechanistic interpretations are based on indirect clinical observations and existing literature rather than direct biological evidence and should therefore be regarded as hypothesis-generating.

Conclusion

This case suggests that NT1 may coexist with WD as an independent primary sleep disorder rather than solely representing secondary hypersomnolence. The findings raise the possibility that copper-related neurotoxicity, genetic susceptibility, and metabolic stress may interact at the level of the hypothalamus, although a causal relationship cannot be established on the basis of a single case. This report may highlight the importance of considering primary sleep–wake disorders in patients with WD who present with REM-related symptoms, as accurate differentiation may have implications for diagnosis and management.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Zhenjing Xu conceived the original idea, analyzed the data, and drafted the manuscript, including the design of the mechanistic illustration. Yanxin Wang and Chunsheng Xu contributed to the acquisition of clinical data and interpretation of the neuroimaging and polysomnographic findings. Zhifeng Hou performed the genetic analysis and literature review. Wenming Yang supervised the study, provided critical revision of the manuscript for important intellectual content, and obtained funding. Zhenjing Xu, Yanxin Wang, Chunsheng Xu, Zhifeng Hou, and Wenming Yang read and approved the final manuscript and agreed to be accountable for all aspects of the work.

Funding

This study was supported by the National Natural Science Foundation of China Regional Innovation Development Joint Fund Project (U22A20366) Anhui Province Traditional Chinese Medicine Science and Technology Research Special Project (202303a07020004). The journal’s Rapid Service Fee will be funded by Zhenjing Xu.

Data Availability

All data generated or analyzed during this study are included in this published article.

Declarations

Conflict of Interests

Zhenjing Xu declares no conflict of interest. Yanxin Wang declares no conflict of interest. Chunsheng Xu declares no conflict of interest. Zhifeng Hou declares no conflict of interest. Wenming Yang declares no conflict of interest.

Ethical Approval

This case was approved by the Medical Ethics Committee of the First Affiliated Hospital of Anhui University of Chinese Medicine (2024AH-06-01). Written informed consent for publication of this case report and any accompanying images was obtained from the patient.