Box 1 Detailed history of three NP-C patients who suffered from psychotic episodes

Patient 5

A 25-year-old man was referred to our Neurology Unit presenting with a 9-year treatment-resistant schizophrenia, and experiencing recent gait disturbances. He was a single child. His parents reported a speech delay and learning difficulties in his childhood. He dropped out of school at the age of 15. He was described as introverted, usually playing alone, with restricted interests (with very specialized knowledge in insects and horses). At the age of 16, the patient showed behavioral changes. He described that “cyber-devils” were spying on him, which led him to jump out of a window from the first floor in order to escape them. He started to behave strangely, getting out of a supermarket with a shopping cart full of food he did not pay for, or suddenly getting naked in front of his parents at home without being able to explain his behavior. He also presented with social isolation, apathy, and anosognosia. The patient was hospitalized in a Psychiatric Unit, with a diagnosis of acute psychotic episode. He was treated with Risperidone 2 mg od, with partial efficacy. To be noted, his psychiatrist already reported a comorbid space and time disorientation and reversible acute faecal incontinence at this time. A second acute psychotic episode occurred at the age of 19, with similar psychotic symptoms, along with irritability, fluctuating space and time disorientation, hyperphagia, emotional blunting and discrete gait disturbances. A diagnosis of schizophrenia was eventually made. Various psychotropic drugs were prescribed (among which amisulpride, valproic acid, paroxetine, fluoxetine), alone or in association, without efficacy but with significant side effects such as extrapyramidal syndrome, dyskinesia and akathisia. It led to a switch for clozapine 200 mg od, with partial efficacy. A significant change in his behavior convinced his psychiatrist to refer him to a neurologist. He experienced stereotyped behaviors, endlessly repeating daily rituals (hairdressing, taking a shower several times a day, singing songs for hours for no reason, with uncontrollable laughter) and stereotyped speech (saying “that’s it” at the end of each sentence). His neurologist confirmed the presence of an associated cerebellar ataxia, with global slowness of movement, vertical supranuclear palsy, developmental delay and a more recent cognitive frontal syndrome. A diagnosis of Niemann-Pick type C disorder associated with autism spectrum disorder with psychotic features was eventually made with positive NP-C biomarkers (oxysterols) and genetic sequencing

Patient 8

A 25-year-old man was referred to our Neurology outpatient Clinics for exploration of a gait disturbance with cerebellar ataxia, dysarthria, dysphagia and behavioral changes. The patient reported a first psychotic episode at the age of 22, associated with a chronic history of cannabis abuse, leading to an admission in psychiatric wards. At this period of time, he expressed a polythematic delusion (with persecution, megalomania, mysticism, shouting “I am not a fundamentalist!” and autobiographic misconceptions “I am Bryan’s father, a sick son who was born premature”), auditory hallucinations, along with anosognosia. He was agitated, with disinhibition (dealing drugs in the hospital), apathy, impairment in social cognition, affective blunting, sleep disturbances and social retreat. Neurological symptoms were already identified, with cognitive impairment, dysarthria, dysphagia, gait disturbance and oculomotor dysfunction. He was first treated with various antipsychotics without clinical improvement until Clozapine 200 mg once daily (od) was introduced, allowing the patient to clinically improve. Her sister was diagnosed with paranoid schizophrenia. A diagnosis of Niemann-Pick type C disorder associated with a frontal lobe syndrome was eventually made after complementary investigations. Miglustat was introduced shortly after (200 mg three times per day), reducing drastically the course of the disease. The patient maintained a good level of autonomy through the years, with mild residual symptoms such as a dysexecutive syndrome, gait disturbance and impulsivity. He could walk without help. The patient discontinued the miglustat treatment after 3 years for a period of five months, leading to a worsening of the neurologic and psychiatric symptoms (acute psychotic relapse, severe dysphagia). A clinical improvement was reported after having reintroduced the Miglustat and Clozapine. After two years of psychotic remission, Clozapine was discontinued by his psychiatrist, due to a severe apathetic syndrome. Clinical remission was obtained for three more years, until an acute psychotic relapse was diagnosed, in a context of cannabis use. The patient described a persecutory delusion towards his parents, accusing them of stealing money from him, showing an aggressive behavior and elated mood. The patient was hospitalised and successfully treated with Risperidone 4 mg od and Quetiapine 200 mg od. Until now, the patient has been treated with Miglustat and antipsychotic medication

Patient 10

A 41-year-old woman was referred to our Neurology Unit with a 10-year treatment-resistant schizophrenia associated with recently screened cognitive impairment. She did not report any psychiatric episode until the age of 30. She was working in a supermarket, and lived with her husband and two children. Her sister was described as physically disabled since the age of 10

The patient experienced her first acute psychotic episode at the age of 30. At first, she reported insomnia, fatigue and loss of appetite leading to weight loss, for several days after having been a victim of a robbery at work. Then, the patient experienced behavioral changes. She became apathetic, crying every day. She told her husband that one of her colleagues was jealous of her, insulting her at work. She also believed her husband had poisoned their son, which led her to make her son vomit. She was convinced that her neighbors wanted to kill her and her family. Along with these delusions of persecution, she felt guilty at work. She feared being blamed for her incompetence at work, incompetence which was not confirmed by her staff. She did not criticize these ideas. She was first treated with haloperidol 10 mg od and cyamemazine 50 mg twice daily when admitted to the Psychiatric Unit

During the next years, the patient was hospitalized 8 times, after having re-experienced psychotic symptoms of persecution associated with auditory hallucinations. A diagnosis of schizoaffective disorder was made. Various psychotropic drugs were prescribed (among which Amisulpride, Chlorpromazine, Valproic Acid, Fluoxetine, Clomipramine), alone or in association, without efficacy for more than two months. At the age of 40, the patient discontinued her treatment, leading to a relapse of an acute psychotic episode. She was first treated with Olanzapine 10 mg od. This treatment led to numerous side effects, including somnolence and acute delirium. A switch for Risperidone 1 mg od was eventually decided. At this time, one of the psychiatrists screened the patient for cognitive impairment. It revealed a dysexecutive and attentional syndrome, along with apraxia. A Brain Magnetic Resonance Imaging (MRI) was performed, revealing a right frontal lobe atrophy. She was then referred to a neurologist, who found a cerebellar ataxia and a vertical supranuclear palsy. The cognitive impairment was confirmed by the neuropsychological assessment. A diagnosis of Niemann Pick type C disease with psychotic features was eventually made after a positive filipin test on a cutaneous biopsy and genetic sequencing