Adult Niemann-Pick disease type C in France: clinical phenotypes and long-term miglustat treatment effect

Abstract

BackgroundNiemann-Pick disease type C (NP-C) is a neurodegenerative lysosomal lipid storage disease caused by autosomal recessive mutations in the NPC1 or NPC2 genes. The clinical presentation and evolution of NP-C and the effect of miglustat treatment are described in the largest cohort of patients with adolescent/adult-onset NP-C studied to date.MethodsObservational study based on clinical chart data from adult patients with NP-C (> 18 year old) diagnosed in France between 1990 and 2015. Retrospective data from patients at diagnosis, onset of miglustat therapy (if applicable), and last follow up were analysed.ResultsIn France, patients with an adolescent-adult neurological form constituted approximately 25% of all NP-C cases diagnosed during the study period. Forty-seven patients (46 with NP-C1 and one with NP-C2; 53% female) were included. Mean ± SD (range) ages at neurological onset and diagnosis were 23.9 ± 12.5 (8–56) years and 34 ± 13.5 (15–65) years, respectively. At presentation, patients mainly had 1) impaired gait due to cerebellar ataxia and/or dystonia, 2) and/or cognitive/behavioural manifestations, 3) and/or psychotic signs. Initially, almost half of patients had only one of the above three neuro-psychiatric manifestations. Vertical supranuclear gaze palsy, usually occurring without patient complaint, was only detected on careful clinical examination and was recorded in most patients (93%) at the time of diagnosis, several years after neurological onset. Thirty-seven patients (79%) received miglustat, among whom seventeen (46%) continued beyond 2 years (at last follow up) to a maximum of 9.8 years. Eight patients (22%) discontinued treatment early due to side effects (n = 3) or perceived lack of efficacy (n = 5).Miglustat treatment duration correlated significantly with reduced neurological worsening (p < 0.001). Treatment for≥2 years was associated with improved patient survival (p = 0.029). Good responses to miglustat were associated with less severe neurological disability at the start of miglustat treatment (p = 0.02).ConclusionThe proportion of adolescent/adult-onset NP-C cases diagnosed in France increased 2.5-fold since 2009 compared with the 2000–2008 period due to improved awareness. Adolescent/adult-onset NP-C frequently presented initially with a non-specific isolated neuro-psychiatric manifestation (motor, cognitive or psychotic). Patients with less severe neurological disability responded better to miglustat therapy.Electronic supplementary materialThe online version of this article (10.1186/s13023-018-0913-4) contains supplementary material, which is available to authorized users.

Very Late‐Onset Niemann Pick Type C Disease: Example of Progressive Supranuclear Palsy Look‐Alike Disorder

“…In the adult‐onset group (>15 years), visceral symptoms are less common and typically there is the co‐occurrence of cognitive impairment, psychiatric symptoms, VSGP and progressive ataxia, or movement disorders . Movement disorders are common in adult‐onset NPC; dystonia is the most frequent, followed by chorea, myoclonus, and parkinsonism . When present in NPC, parkinsonism is mild, consisting in bradykinesia, axial rigidity, hypomimia, or isolated rest tremor .…”

“…7,9 Movement disorders are common in adult-onset NPC; dystonia is the most frequent, followed by chorea, myoclonus, and parkinsonism. 7,10 When present in NPC, parkinsonism is mild, consisting in bradykinesia, axial rigidity, hypomimia, or isolated rest tremor. 7 Gelastic cataplexy is sensitive for NPC diagnosis, but is present in only 16% of these patients.…”

Transcript, protein, metabolite and cellular studies in skin fibroblasts demonstrate variable pathogenic impacts of NPC1 mutations

“…Detailed data on clinical phenotypes are available in [3] for 21 of them (for correspondence see Table S1). The phenotype classification of patients #5 and #24 was revised and reclassified according to Nadjar and colleagues [39] as late infantile and adolescent/adult, respectively. Juvenile NP-C was by far the most common clinical phenotype.…”

Nosology and Phenomenology of Psychosis in Movement Disorders

“…199 Psychosis may present as paranoid delusions, thought disorder, and visual, auditory, or somatic hallucinations. [200][201][202][203] Psychosis as the initial presentation was reported in several cases and may be the only symptom for several years, resulting in misdiagnosis of schizophrenia. 174,[200][201][202]204,205 In these cases, diagnosis of NP disease may be delayed, especially when patients develop dyskinesias after neuroleptic use, which can be mistakenly interpreted as a drug-induced movement disorder rather than clinical manifestation of NP disease.…”

“…201,206 The presence of neurological manifestations, (e.g., vertical supranuclear gaze palsy, gelastic cataplexia, ataxia, dystonia, and seizures), treatment-resistant psychosis, or paradoxical worsening of psychosis with neuroleptics suggest an organic cause like NP disease. 205,207,208 Psychosis is frequently associated with other psychiatric symptoms, such as depression 203,204,208 and cognitive decline. 200,202,205,208 Postictal psychosis was also reported in NP disease type C, generally limited to a psychotic disorder that follows complex partial or generalized seizure activity, or a cluster of seizures.…”