Introduction

Niemann-Pick type C (NP-C) is a lysosomal storage disorder (LSD) resulting from bi-allelic mutations in NP-C1 or NP-C2 gene, with clinical manifestations that may begin from perinatal to adult life [27]. NP-C1 and NP-C2 genes code for NP-C1 and NP-C2 proteins, localized respectively in the lysosome membrane and lumen, functioning together for cholesterol export from the lysosome, and leading when altered to subsequent cholesterol lysosomal accumulation, but also ganglioside secondary lysosomal accumulation especially in the nervous system. NP-C1 is involved in 95% of patients, whereas NP-C2 is involved in 5%, with reported more severe disease and exceptional adult onset forms. The prognosis of the disease, apart from the potentially fatal visceral neonatal form, is clearly related to the age of neurological onset, that defines the different forms of NP-C (ie early infantile, late infantile, juvenile, or adolescent/adult). Children with NP-C, especially younger patients, may experience a very severe neurological disease with a psychomotor regression leading to death after a few years, associated with overt systemic disease (splenomegaly, hepatomegaly, sometimes lung disease), whereas adults have a more protracted course with survival possible along several decades. In addition to prognosis, clinical picture is clearly different in adults: NP-C mainly presents as a neuropsychiatric degenerative disease, that associates motor (cerebellar ataxia, dystonia, myoclonus), cognitive and psychiatric manifestations with no or little systemic involvement [26]. Blood diagnostic biomarkers are now currently used for NP-C screening, with high sensitivity and specificity [22, 30]. Achieving an early diagnosis is crucial since patients can benefit from miglustat treatment, a substrate reduction therapy that has shown efficacy in stabilizing or slowing the disease progression, particularly in adults when neurological disability is not yet severe (ie, before the onset of dementia, loss of ambulation, or need of gastrostomy feeding) [26, 29]. However, first NP-C manifestations are often non-specific, delaying diagnosis and treatment introduction.

Psychiatric manifestations in NP-C disease have been reported for more than two decades now, especially in the form of acute psychotic episodes, often as the initial manifestation of the disease [9, 26, 29]. However, as diagnosis of NP-C is usually achieved several years later, clues about the semiological key points of the first acute psychotic episode are scarce. There is nonetheless a need to rationally identify those patients who could benefit from a blood NP-C screening among the numerous ones presenting with an acute psychotic episode of unknown origin. Beyond psychosis, behavioral symptoms are less often reported, however we observed that these could represent a major burden in some NP-C patients, even more than motor and cognitive impairment [9]. Therefore, we aimed to study the specific characteristics of behavioral manifestations in NP-C, during the first acute psychotic episode and beyond. For this, we report here detailed retrospective data from medical charts, including semi-structured interviews, psychometric scales and neuropsychological evaluations from a single-center French cohort of adult patients with NP-C.

Material and methods

Participants

This retrospective study was performed from 2016 to 2020 in the department of Neurology of Pitié-Salpêtrière hospital in Paris, France, hosting the Lysosomal Diseases Reference Center and a behavioral neuropsychiatric ward.

Patients included were seen in our center between 2016 and 2020, or were identified in the Lysosomal Diseases Reference Center database as NP-C patients who experienced a psychotic episode (30 NP-C patients in the database in 2020, all referred to our reference center). All included patients had a genetically confirmed NP-C disease (two mutations). Data from medical charts were reviewed and collected for all patients. This included demographical data, key items concerning NP-C disease (diagnosis, clinical features, evolution), description of the psychiatric manifestations, psychometric scales data and neuropsychological evaluation data. Notably, psychiatric manifestations were collected from psychiatric reports in different French centers involved along the whole psychiatric history of the patients, and from semi-structured interviews (patients and/or parents) performed in the behavioral neuropsychiatric ward in Pitié-Salpêtrière Hospital (during consultations or phone calls). Psychotropic drugs were listed, including all classes of psychotropic medication. Absence of Anti-psychotic (AP) efficacy was defined as the persistence of symptoms despite more than 2 trials of adequate dose and duration of antipsychotic medication with documented adherence. Psychotropic drug intolerance was defined by the occurrence of well-known side effects related to the specific psychotropic medication prescribed to the patient and reported in the patient’s medical records.

Statistical analysis

Data analysis was performed using SPSS 26 (IBM). Concerning continuous values: Mean and median values, standard deviation, and range were reported using SPSS data description function. Concerning categorical values: absolute or relative frequencies of categorical variables were reported using SPSS data description function.

Ethical statement

This study was conducted according to French legislation and authorized by the National Commission on Informatics and Liberty (no. 2211991). The patients were informed about the utilization of their anonymized data in this study.

Results

Nineteen patients with NP-C followed in our center were included in the study (see demographic and NP-C related data in Table 1), with ten of them having experienced at least one acute psychotic episode. Due to missing data, we report the ratio of patients in whom a symptom was reported out of all the patients for whom the data was available. Whereas all patients were considered as adult-onset NP-C (onset above 10 years-old), we observed subtle previous manifestations during childhood before onset of overt disease in 10/18 patients, including psychomotor delay in 6/17, learning disorder in 6/17, and autistic symptoms in 3/13.

Table 1 General characteristics and psychiatric manifestations in 19 adult NP-C patients
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For the ten patients with an acute psychotic episode (see Table 2), this was considered as the first neuropsychiatric manifestation of the disease in six of them, even though patient 9 also suffered from hearing loss in early childhood of unknown origin (and probably related to NP-C). Globally, the first acute psychotic episode occurred at a median age of 20.5 years old (yo) (range = 16–30). In 9/10 psychotic patients, NP-C diagnosis was made after the first psychotic episode, with a median delay of 5 years (range = 0–16 years). Only patient 1 suffered from their first psychotic symptoms after NP-C diagnosis, with occurrence of isolated visual hallucinations in a sleep disorder context (diagnosed secondary narcolepsy) that both lasted a few months before spontaneous regression without anti-psychotic drug use. Delirium was frequently associated (8/10) as well as delusions (8/10) which were most frequently complex (5/8; defined as a delusion including multiple themes concomitantly), persecution-type being systematically reported. Auditory hallucinations were frequent (7/10 including four patients with no verbal hallucinations, i.e. hearing non-discriminative noises), as well as visual hallucinations (5/9). During the acute psychotic episode, behavioral symptoms classically associated with frontal dysfunction were frequently observed: emotional hyperreactivity (7/10), excessive spending (5/10), impaired social cognition (7/7), affective blunting (4/8), disinhibition (7/9), social retreat (8/9), apathy (9/10) and stereotyped behaviors (4/4). 9/10 patients with psychosis received several psychotropic drugs (median = 8 different molecules, range = 3–13), especially antipsychotic agents (median = 4, range = 1–6) as lack of efficacy was frequently reported (8/9 patients). One patient suffered from antipsychotic intolerance. Along a median follow-up of 9 years (range = 1–17) after NP-C diagnosis, 5/10 patients experienced a psychotic episode relapse, including all three patients who had never been treated with miglustat. Miglustat was associated with better control of psychotic symptoms, including decreased of antipsychotic agents need (number and/or dosage) in 5/6 patients (excluding patient 1, see above). To qualitatively illustrate semiological specificities and evolution of psychosis in NP-C, we detail the anamnesis of three patients with inaugural psychosis (patients 5, 8 and 10; see Box 1) (Additional file 1).

Table 2 Semiological characteristics of the psychotic episodes in 10 adult NP-C patients
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Box 1 Detailed history of three NP-C patients who suffered from psychotic episodes
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Beyond psychosis, most of the patients suffered from behavioral (15/17) and cognitive disorders (18/19). The only patient without a cognitive complaint (whereas not formally tested) was one out of the two without any behavioral disorder detected. MMSE [10] mean score was 19.75 (SD ± 5.93, 9–28, n = 12), whereas FAB [11] mean score was 10.64 (SD ± 4.48, 3–15, n = 11) (see Fig. 1). Executive functions (based on frontal lobe functioning) were altered in 11/12 patients tested. Numerous frontal abnormal behaviors were observed in our cohort: apathy (13/17), impaired social cognition (11/13) and stereotyped behaviors (5/10). For five patients (patients 4, 8, 12, 15 and 16) quality of life was markedly impaired by these abnormal behaviors, being the principal burden of the disease, as detailed for patient 15 (see Box 2). As for psychometric and neuropsychological tests evaluating social cognition underlying frontal behavioral disorders, facial emotion recognition test (FER) [14] was by far the most frequently performed (n = 8), as FER require minimal cognitive skills. FER scores were abnormal in all of tested patients (see Fig. 1).

Fig. 1
figure 1

Scores of individuals NP-C patients for Starkstein auto-evaluation scales, FAB (Frontal Assessment Battery), FER (Facial Emotion Recognition), and MMSE (Mini Mental State Examination), displayed as box plots indicating median, interquartile range, and extreme values for each test. The blue line indicates the normal value limit (normal below the blue line for Starkstein, above for FAB, above for FER, and above for MMSE)

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Box 2 detailed history of one NP-C patient whose main disability was related to a frontal behavior manifestations
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Discussion

We report a high frequency of psychiatric symptoms in NP-C encompassing acute psychotic manifestations, presenting often early in the course of the disease with atypical features, and disabling behavioral manifestations mostly due to frontal dysfunction.

Psychotic disorders are frequent in the general population, with a pool incidence of 26.6 per 100,000 person-years [18]. More interestingly, prevalence of Clinical High-Risk for Psychosis (defined by the presence of attenuated psychotic symptoms, functional impairment for more than a year and an accumulation of numerous risk factors for psychosis in a patient) is estimated at 1.7% in the general population and 19.2% in clinical samples [32]. Psychosis in childhood and in young adults is mostly related to paranoid schizophrenia but may sometimes be part of an inborn error of metabolism, rare genetic diseases that in some cases may have disease-modifying therapies, such as in NP-C [6,7,8, 13, 15],Psychotic symptoms in NP-C patients has been reported in up to 55% of patients [23]. Thus, diagnosing NP-C disease in patients presenting with an acute psychotic episode is critical but challenging for psychiatrists.

This series of NP-C patients aimed to reveal some atypical clinical features that should lead to blood biomarker screening for NP-C disease in patients with an acute psychotic episode: i) history of psychomotor delay and/or autistic symptoms before the onset of psychosis; ii) associated neurological symptoms (including delirium, cognitive symptoms and frontal behavioral symptoms); iii) complex delusion, defined as a delusion including multiple themes concomitantly; iv) exclusive visual hallucinations and v) antipsychotic lack of efficiency and/or intolerance.

Concerning childhood reported manifestations, there is growing evidence of an overlap between autistic spectrum disorder and schizophrenia [4, 19, 34], and individuals at ultra-high risk for psychosis may present mild psychiatric or neurological symptoms during the prodromal phase such as thoughts, language, perception and motor disturbances, disorders of emotion and affect or impaired social ability [1, 2, 33]. Nevertheless, these prodromal neurodevelopmental symptoms remain relatively mild and do not impair psychomotor development until late teenage years and young adulthood in patients with classical paranoid schizophrenia, which is not the case in NP-C patients with psychosis. In addition, schizophrenic patients may present with neurological soft signs, ie subtle deficits in sensory integration, motor coordination, and sequencing of complex motor acts altered. NP-C patients also suffer from motor manifestations, mainly cerebellar ataxia and dystonia (that may be thought to be of iatrogenic origin), which are more prominent and disabling than the so-called neurological “soft signs”. A characteristic manifestation of NP-C is Vertical supranuclear gaze palsy (VSGP), that was present in all NP-C patients in this series. Unfortunately, this data was almost never available at first presentation, but as VSGP is described as an early manifestation of NP-C often without complaint, we consider that VSGP should be specifically looked for in evaluating psychotic patients, especially when atypical signs are described.

Considering the nature of the psychotic symptoms, although delusions (especially persecutory) are a hallmark of schizophrenia and one of the main diagnostic criteria for the disorder [3, 21], complex delusions are rather rare. Nonetheless, it was a frequent clinical feature reported in our patients. Exclusive visual hallucinations are classically highly suggestive of an associated organic disease, since visual hallucinations in schizophrenia are mostly complex and co-occur with auditory hallucinations [35]. Interestingly, patients did not report being aware of the hallucination process, similarly to schizophrenic patients.

Furthermore, almost all of our patients reported treatment resistance (antipsychotic lack of efficiency) and/or treatment intolerance referred an atypical clinical feature in NP-C, but only in retrospective studies [31].

Little is known about the underlying mechanisms involved in such resistance. One hypothesis may be that the defect in transporting cholesterol and other fatty substances (lipids) inside of cells as seen in NP-C (leading to an abnormal accumulation of cholesterol) may play a role in AP efficacy. Some recent studies have raised that a change in polyinsaturated fatty acid levels may be associated with diminished AP treatment response in chronic psychosis [20]. Such association may explain why NP-C patients commonly report AP resistance.

In our NP-C patients, cognitive disorder was common (18/19) and in eight patients, extensive neuropsychological evaluation was performed, where at least one abnormal cognitive test pointing out frontal dysfunction was present in all eight patients. Although this has already been described by Heitz et al. [17], we present additional data regarding behavioral manifestations, that were present in 15/17 patients. Interestingly, the main processes involved specifically in social cognition (facial emotion recognition and Theory of Mind) were altered in all patients who underwent the tests. Considered together, one may argue that frontal lobe dysfunction may participate in the development of behavioral symptoms in addition to cognitive impairment in NP-C patients, since social cognition impairment is related to orbitofrontal dysfunction [16, 28]. Moreover, cognitive impairment may contribute to the occurrence of psychotic symptoms, through the combination of two cognitive bias: the “jumping to conclusions” bias (tendency to make rushed and premature decisions on the basis of little evidence) and the “evidence integration” bias (impaired integration of disambiguating evidence) [24].

Cognitive/behavioral impairment in NP-C may be due to disruption in brain development, neurodegeneration, or a combination of both. Neurodevelopmental disorders are often associated with psychiatric features (psychotic and/or autistic symptoms) and have a major impact on cognition as the frontal lobe is developing until adulthood. Social cognition impairment is common to psychosis and autistic spectrum disorder [16, 28]. Neurodegeneration with specific involvement of fronto-striatal circuits may also contribute to frontal lobe-predominant cognitive/behavioral impairment in NP-C patients, as some clinical characteristics (motor manifestations, executive dysfunction, apathy) may resemble Frontotemporal Dementia (FTD) [5, 12, 25, 36]. No correlation can be made in our study in terms of the specific brain area involved, but further studies may help correlate MRI abnormalities and psychometric tests.

Miglustat has a positive impact on global cognition [17], and thus could be of great impact on frontal lobe dysfunction and its underlying behavioral disorders, at least to avoid progressive worsening. We did not have access to longitudinal specific psychometric scales to observe evolution of behavioral disorders. On the other hand, only 2/7 patients had a psychotic relapse under Miglustat treatment, and one of them (patient 8) occurred after rapid reduction of anti-psychotics and cannabis use. Therefore, miglustat seemed to prevent psychotic relapse, and this may could be partly explained by its effect on cognition.

Conclusion

Psychiatric symptoms in NP-C disease are common and can frequently appear in the form of an acute psychotic episode. Associated atypical signs, such as a history of psychomotor delay and/or autistic symptoms before the onset of psychosis, complex delusions, isolated visual hallucinations, treatment resistance or intolerance, and/or neurological symptoms may prompt NP-C screening to permit the early initiation of appropriate treatment, and may protentially prevent psychotic relapses. Behavioral manifestations in the form of a frontal syndrome may have a higher burden on quality of life that classically described motor and cognitive symptoms in NP-C patients.