La maladie de Niemann-Pick de type C (NPC) est une maladie neuro-viscérale rare, de transmission autosomique récessive, ayant une présentation clinique extrêmement hétérogène. La forme adulte de la maladie, d’expression habituellement neurologique, peut également se manifester sous la forme de troubles psychiatriques isolés et non spécifiques. Depuis 2009, la mise sur le marché du miglustat a permis d’en améliorer l’évolution. Nous exposerons le cas d’une fratrie suivie au sein d’un même service de psychiatrie et présentant une clinique psychotique atypique. Le frère, chez qui a initialement été diagnostiquée une schizophrénie, est atteint d’une maladie de NPC. Il est actuellement stabilisé sous miglustat. Sa sœur aînée, également traitée pour une schizophrénie, est hétérozygote pour une des deux mutations portées par son frère mais présente aussi des symptômes neurologiques qui nous ont interrogés. Parce qu’il s’agit d’une maladie à transmission autosomique récessive, les sujets hétérozygotes, ne transportant qu’une seule mutation pathogène du gène, sont généralement asymptomatiques. Plusieurs hypothèses sont discutées : expression psychiatrique chez des hétérozygotes, facteur génétique de prédisposition à la schizophrénie, comorbidité ou association fortuite. Des investigations supplémentaires auprès des patients et de leurs familles seraient nécessaires pour nous orienter vers une réponse.

Niemann-Pick type C disease (NPC) is a rare, neurovisceral, autosomal recessive disease, with an extremely heterogeneous clinical presentation. The adult form of the disease is usually expressed as a neurological form. Non-specific psychiatric symptoms are often associated with NPC. For some cases, it can also be expressed as an isolated psychiatric disorder form. Since 2009, the launching of a medicine called miglustat has helped to improve the disease evolution.

We report two siblings followed-up in the same department of psychiatry and with an atypical psychotic symptomatology. Case 1 is a 27-year-old French male. He was hospitalised several times due to disordered behaviour, psychomotor excitation, mood instability and wandering. He was originally diagnosed with schizophrenia. However, the patient's psychosis proved refractory to treatment. He also exhibited a number of neurological signs (pyramidal signs and abnormal movements of the hands, head and limbs), which were considered related to his antipsychotic medication. Three years later, a full physical, neurological and neuropsychological examination revealed various neurological and visceral symptoms. He was diagnosed with NPC based on a classical biochemical NPC-phenotype following filipin staining in cultured skin fibroblasts. NPC1 gene sequencing revealed that he was a compound heterozygote for the p.S954L and p.N1156S mutations. The patient's psychiatric and neurological symptoms are currently stabilized by miglustat, allowing the patient to cease antipsychotic medication. Case 2 is the elder sister of Case 1. She was hospitalised several times due to acute delirium, hallucinations and suicidal tendencies. She was diagnosed with paranoid schizophrenia at 22 years of age. She has received a variety of typical and atypical antipsychotics. Many of these drugs proved initially effective but the patient's symptoms repeatedly returned. The patient shows persistent and worsening gait disorder and abnormal arm movements. A follow-up neurological examination at age 29 did not detect any ataxia, cataplexy or vertical supra-nuclear gaze palsy. Direct NPC1 gene sequencing detected a mutant NPC1 allele held in common with her brother, but full sequencing of both the NPC1 and NPC2 genes and multiplex ligation-dependent probe amplification (MLPA) did not detect any other pathogenic mutation or other anomalies.

Because NPC is an autosomal recessive condition, heterozygous individuals carrying only one causal gene mutation are usually asymptomatic. Thus, while the accepted wisdom would suggest that patient 2 is not affected by the disease, it is interesting to consider why she has developed neurological and psychiatric disorders like her brother. Several hypotheses are discussed: mental expression in heterozygous genetic factor predisposing to schizophrenia, comorbidity or fortuitous association. It is not currently known whether a patient with a single NPC gene mutation can express NPC in full, partially, or perhaps just to a minimal degree. This case of a patient with a heterozygous “carrier” NPC genotype and neuropsychiatric disorders suggestive of the disease raises the possibility that symptomatic heterozygous NPC patients may exist. On the other hand, if the heterozygous genotype of patient 2 does not give rise to symptomatic disease, it is pertinent to question whether it could be a predisposing factor for the development of psychiatric pathologies. There are currently no published data on the occurrence of heterozygous NPC1 or NPC2 mutations among patients with atypical psychiatric presentations combined with neurological symptoms. Conversely, there are no published data demonstrating an increased frequency of psychiatric disorders in families affected by NPC. Finally, in view of the history of psychiatric disorders in this family, it is possible that psychosis simply occurred concomitantly with symptomatic NPC in patient 1 by chance, and that schizophrenia occurred simultaneously with an asymptomatic NPC carrier genotype in patient 2. To investigate this further, NPC patients’ carrier family members (parents and siblings) should be fully screened for signs suggestive of the disease.