Early detection of Niemann-pick disease type C with cataplexy and orexin levels: continuous observation with and without Miglustat

Abstract Study objectives Niemann-Pick type C (NPC) is an autosomal recessive and congenital neurological disorder characterized by the accumulation of cholesterol and glycosphingolipids. Symptoms include hepatosplenomegaly, vertical supranuclear saccadic palsy, ataxia, dystonia, and dementia. Some cases frequently display narcolepsy-like symptoms, including cataplexy which was reported in 26% of all NPC patients and was more often recorded among late-infantile onset (50%) and juvenile onset (38%) patients. In this current study, we examined CSF orexin levels in the 10 patients of NPC with and without cataplexy, which supports previous findings. Methods Ten patients with NPC were included in the study (5 males and 5 females). NPC diagnosis was biochemically confirmed in all 10 patients, from which 8 patients with NPC1 gene were identified. We compared CSF orexin levels among NPC, narcoleptic and idiopathic hypersomnia patients. Results Six NPC patients with cataplexy had low or intermediate orexin levels. In 4 cases without cataplexy, their orexin levels were normal. In 5 cases with Miglustat treatment, their symptoms stabilized or improved. For cases without Miglustat treatment, their conditions worsened generally. The CSF orexin levels of NPC patients were significantly higher than those of patients with narcolepsy-cataplexy and lower than those of patients with idiopathic hypersomnia, which was considered as the control group with normal CSF orexin levels. Discussion Our study indicates that orexin level measurements can be an early alert of potential NPC. Low or intermediate orexin levels could further decrease due to reduction in the neuronal function in the orexin system, accelerating the patients’ NPC pathophysiology. However with Miglustat treatment, the orexin levels stabilized or improved, along with other general symptoms. Although the circuitry is unclear, this supports that orexin system is indeed involved in narcolepsy-cataplexy in NPC patients. Conclusion The NPC patients with cataplexy had low or intermediate orexin levels. In the cases without cataplexy, their orexin levels were normal. Our study suggests that orexin measurements can serve as an early alert for potential NPC; furthermore, they could be a marker of therapy monitoring during a treatment.

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Novel compound heterozygous mutation in NPC1 gene cause Niemann–Pick disease type C with juvenile onset

Journal of Genetics ◽

10.1007/s12041-020-01198-7 ◽

2020 ◽

Vol 99 (1) ◽

Author(s):

Maria Cristina Costanzo ◽

Antonio Gennaro Nicotera ◽

Mirella Vinci ◽

Aurelio Vitello ◽

Agata Fiumara ◽

...

Keyword(s):

Disease Type ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Juvenile Onset ◽

Niemann Pick Disease ◽

Npc1 Gene ◽

Type C ◽

Niemann Pick ◽

Pick Disease

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Hearing Loss is an Early Consequence of Npc1 Gene Deletion in the Mouse Model of Niemann–Pick Disease, Type C

Journal of the Association for Research in Otolaryngology ◽

10.1007/s10162-014-0459-7 ◽

2014 ◽

Vol 15 (4) ◽

pp. 529-541 ◽

Cited By ~ 9

Author(s):

Kelly A. King ◽

Sandra Gordon-Salant ◽

Karen S. Pawlowski ◽

Anna M. Taylor ◽

Andrew J. Griffith ◽

...

Keyword(s):

Hearing Loss ◽

Mouse Model ◽

Gene Deletion ◽

Disease Type ◽

Niemann Pick Disease ◽

Npc1 Gene ◽

Type C ◽

Niemann Pick ◽

Pick Disease

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Niemann-Pick disease type C: a case series of Brazilian patients

Arquivos de Neuro-Psiquiatria ◽

10.1590/0004-282x20130249 ◽

2014 ◽

Vol 72 (3) ◽

pp. 214-218 ◽

Cited By ~ 2

Author(s):

Paulo José Lorenzoni ◽

Elaine Cardoso ◽

Ana C. S. Crippa ◽

Charles Marques Lourenço ◽

Fernanda Timm Seabra Souza ◽

...

Keyword(s):

Treatment Response ◽

Laboratory Data ◽

Disease Onset ◽

Disease Type ◽

Niemann Pick Disease ◽

Npc1 Gene ◽

Variant Pattern ◽

Type C ◽

Niemann Pick ◽

Pick Disease

The aim of the study was to analyze a series of Brazilian patients with Niemann-Pick disease type C (NP-C). Method Correlations between clinical findings, laboratory data, molecular findings and treatment response are presented. Result The sample consisted of 5 patients aged 8 to 26 years. Vertical supranuclear gaze palsy, cerebellar ataxia, dementia, dystonia and dysarthria were present in all cases. Filipin staining showed the “classical” pattern in two patients and a “variant” pattern in three patients. Molecular analysis found mutations in the NPC1 gene in all alleles. Miglustat treatment was administered to 4 patients. Conclusion Although filipin staining should be used to confirm the diagnosis, bone marrow sea-blue histiocytes often help to diagnosis of NP-C. The p.P1007A mutation seems to be correlated with the “variant” pattern in filipin staining. Miglustat treatment response seems to be correlated with the age at disease onset and disability scale score at diagnosis.

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Intracerebroventricular Treatment with 2-Hydroxypropyl-β-Cyclodextrin Decreased Cerebellar and Hepatic Glycoprotein Nonmetastatic Melanoma Protein B (GPNMB) Expression in Niemann–Pick Disease Type C Model Mice

International Journal of Molecular Sciences ◽

10.3390/ijms22010452 ◽

2021 ◽

Vol 22 (1) ◽

pp. 452

Author(s):

Madoka Fukaura ◽

Yoichi Ishitsuka ◽

Seiichi Shirakawa ◽

Naoki Ushihama ◽

Yusei Yamada ◽

...

Keyword(s):

Elevated Serum ◽

Disease Type ◽

Therapeutic Effects ◽

Niemann Pick Disease ◽

Potential Biomarker ◽

Npc1 Gene ◽

Type C ◽

Niemann Pick ◽

Pick Disease ◽

Protein B

Niemann–Pick disease type C (NPC) is a recessive hereditary disease caused by mutation of the NPC1 or NPC2 gene. It is characterized by abnormality of cellular cholesterol trafficking with severe neuronal and hepatic injury. In this study, we investigated the potential of glycoprotein nonmetastatic melanoma protein B (GPNMB) to act as a biomarker reflecting the therapeutic effect of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) in an NPC mouse model. We measured serum, brain, and liver expression levels of GPNMB, and evaluated their therapeutic effects on NPC manifestations in the brain and liver after the intracerebroventricular administration of HP-β-CD in Npc1 gene-deficient (Npc1−/−) mice. Intracerebroventricular HP-β-CD inhibited cerebellar Purkinje cell damage in Npc1−/− mice and significantly reduced serum and cerebellar GPNMB levels. Interestingly, we also observed that the intracerebral administration significantly reduced hepatic GPNMB expression and elevated serum ALT in Npc1−/− mice. Repeated doses of intracerebroventricular HP-β-CD (30 mg/kg, started at 4 weeks of age and repeated every 2 weeks) drastically extended the lifespan of Npc1−/− mice compared with saline treatment. In summary, our results suggest that GPNMB level in serum is a potential biomarker for evaluating the attenuation of NPC pathophysiology by intracerebroventricular HP-β-CD treatment.

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Niemann-Pick disease type C: mutations of NPC1 gene and the course of disease

Paediatria Croatica ◽

10.13112/pc.2014.45 ◽

2014 ◽

Vol 58 (4) ◽

pp. 255-61

Author(s):

Ljerka Cvitanović Šojat ◽

◽

Maša Malenica ◽

Monika Kukuruzović ◽

Tamara Žigman ◽

...

Keyword(s):

Disease Type ◽

Course Of Disease ◽

Niemann Pick Disease ◽

Npc1 Gene ◽

Type C ◽

Niemann Pick ◽

Pick Disease

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Niemann-Pick Disease Type C: Mutation Spectrum and Novel Sequence Variations in the Human NPC1 Gene

Molecular Neurobiology ◽

10.1007/s12035-019-1528-z ◽

2019 ◽

Vol 56 (9) ◽

pp. 6426-6435 ◽

Cited By ~ 2

Author(s):

Márcia Polese-Bonatto ◽

Hugo Bock ◽

Ana Carolina S. Farias ◽

Rafaella Mergener ◽

Maria Cristina Matte ◽

...

Keyword(s):

Disease Type ◽

Mutation Spectrum ◽

Niemann Pick Disease ◽

Sequence Variations ◽

Npc1 Gene ◽

Type C ◽

Niemann Pick ◽

Pick Disease

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NPC1 gene mutations in Japanese patients with Niemann-Pick disease type C

Human Genetics ◽

10.1007/s004399900059 ◽

1999 ◽

Vol 105 (1-2) ◽

pp. 10-16 ◽

Cited By ~ 3

Author(s):

Toshiyuki Yamamoto ◽

Eiji Nanba ◽

Haruaki Ninomiya ◽

Katsumi Higaki ◽

Miyako Taniguchi ◽

...

Keyword(s):

Gene Mutations ◽

Japanese Patients ◽

Disease Type ◽

Niemann Pick Disease ◽

Npc1 Gene ◽

Type C ◽

Niemann Pick ◽

Pick Disease

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NPC1 gene mutations in Japanese patients with Niemann-Pick disease type C

Human Genetics ◽

10.1007/s004390051057 ◽

1999 ◽

Vol 105 (1-2) ◽

pp. 10-16 ◽

Cited By ~ 22

Author(s):

T. Yamamoto ◽

E. Nanba ◽

H. Ninomiya ◽

K. Higaki ◽

H. Zhang ◽

...

Keyword(s):

Gene Mutations ◽

Japanese Patients ◽

Disease Type ◽

Niemann Pick Disease ◽

Npc1 Gene ◽

Type C ◽

Niemann Pick ◽

Pick Disease

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Niemann–Pick disease type C in Palestine: genotype and phenotype of sixteen patients and report of a novel mutation in the NPC1 gene

BMC Medical Genomics ◽

10.1186/s12920-021-01072-0 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Imad Dweikat ◽

Othman Thaher ◽

Abdulrahman Abosleem ◽

Almotazbellah Zeer ◽

Ameer Abo Mokh

Keyword(s):

Novel Mutation ◽

Tertiary Care ◽

Disease Onset ◽

Disease Type ◽

Cerebellar Hemisphere ◽

Niemann Pick Disease ◽

Npc1 Gene ◽

Type C ◽

Niemann Pick ◽

Pick Disease

Abstract Background Niemann–Pick disease type C (NPC) is an autosomal recessive, neurodegenerative disease caused by mutations in either the NPC1 or NPC2 genes. Mutations in these genes are associated with abnormal endosomal–lysosomal trafficking, resulting in the accumulation of tissue-specific lipids in lysosomes. Methods We described sixteen patients with NPC diagnosed between the age of 1 month and 30 years at two tertiary care centers in Palestine. The clinical phenotype, brain magnetic resonance imaging (MRI), and molecular genetic analysis data were reviewed. Results The diagnosis was confirmed by molecular analysis in all patients. Fourteen out of sixteen patients were homozygous for the NPC1 p.G992W variant. Among them, most were categorized as having the late-infantile neurological form of disease onset. They predominantly manifested with early-onset visceral manifestations in the form of hepatosplenomegaly and prolonged neonatal jaundice, and late-onset neuropsychiatric manifestations in the form of vertical supranuclear gaze palsy (VSGP), ataxia, cognitive impairment and seizures. Brain MRI in 6 patients was normal in 5 or consistent with cerebellar hemisphere atrophy in 1 of them. Two other mutations were identified in the NPC1 gene, of which p.V845Cfs*24 was novel. Conclusions Our results revealed phenotypic heterogeneity of NPC even within the same genotype, and add to the increasingly recognized evidence that cholestatic jaundice and hepatosplenomegaly during infancy, should alert the physician for the possibility of NPC. We reported a novel mutation in the NPC1 gene further expanding its genotype.

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