Niemann–Pick type C disease with a novel intronic mutation: three Turkish cases from the same family

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Gonca Kılıç Yıldırım ◽  
Coşkun Yarar ◽  
Berna Şeker Yılmaz ◽  
Serdar Ceylaner
Keyword(s):  
Age At Onset ◽  
Point Mutations ◽  
Intronic Mutation ◽  
Novel Variant ◽  
Progressive Neurodegeneration ◽  
History Of ◽  
Type C ◽  
Exon 9 ◽  
Vertical Supranuclear Gaze Palsy ◽  
Niemann Pick

Abstract Objectives Niemann–Pick type C (NPC) disease is a rare progressive neurodegenerative condition that is characterized by the accumulation of cholesterol, glycosphingolipids, and sphingosine in lysosomes. Patients have various systemic and neurological findings depending on their age at onset. This disease is caused by the autosomal recessive transmission of mutations in the NPC1 and NPC2 genes; patients have mutations mainly in the NPC1 gene (95%) and the majority of them are point mutations located in the exonic regions. Case presentation Here, we presented three cousins with hepatosplenomegaly and progressive neurodegeneration who were diagnosed with visceral-neurodegenerative NPC disease. Their parents were relatives, and they had a history of sibling death with similar complaints. Bone marrow smear showed foamy cells in patient 1. Vertical supranuclear gaze palsy was not present in all cases. Sphingomyelinase (SM) activities were almost normal to exclude NPA or NPB. Filipin staining was performed in patient 2 and showed a massive accumulation of unesterified cholesterol The NPC1 gene analysis of the three patients showed a novel homozygous c.1553+5G>A intronic mutation. cDNA analysis was performed from the patient 3 and both parents. It was observed that exon 9 was completely skipped in the homozygous mutant baby. Both the normal and the exon 9-skipped transcripts have been detected in the parents. Conclusions When combined with the filipin staining and the patients’ clinical outcomes, this mutation is likely to be deleterious. Moreover, cDNA sequencing supports the pathogenicity of this novel variant.

scholarly journals Involvement of the Choroid Plexus in the Pathogenesis of Niemann-Pick Disease Type C

2021 ◽  
Vol 15 ◽  
Author(s):  
Lien Van Hoecke ◽  
Caroline Van Cauwenberghe ◽  
Kristina Dominko ◽  
Griet Van Imschoot ◽  
Elien Van Wonterghem ◽  
...  
Keyword(s):  
Choroid Plexus ◽  
Premature Death ◽  
Loss Of Function ◽  
Lipid Storage Disease ◽  
Niemann Pick Disease ◽  
Progressive Neurodegeneration ◽  
Type C ◽  
Niemann Pick

Niemann-Pick type C (NPC) disease, sometimes called childhood Alzheimer’s, is a rare neurovisceral lipid storage disease with progressive neurodegeneration leading to premature death. The disease is caused by loss-of-function mutations in the Npc1 or Npc2 gene which both result into lipid accumulation in the late endosomes and lysosomes. Since the disease presents with a broad heterogenous clinical spectrum, the involved disease mechanisms are still incompletely understood and this hampers finding an effective treatment. As NPC patients, who carry NPC1 mutations, have shown to share several pathological features with Alzheimer’s disease (AD) and we and others have previously shown that AD is associated with a dysfunctionality of the blood-cerebrospinal fluid (CSF) barrier located at choroid plexus, we investigated the functionality of this latter barrier in NPC1 pathology. Using NPC1–/– mice, we show that despite an increase in inflammatory gene expression in choroid plexus epithelial (CPE) cells, the blood-CSF barrier integrity is not dramatically affected. Interestingly, we did observe a massive increase in autophagosomes in CPE cells and enlarged extracellular vesicles (EVs) in CSF upon NPC1 pathology. Additionally, we revealed that these EVs exert toxic effects on brain tissue, in vitro as well as in vivo. Moreover, we observed that EVs derived from the supernatant of NPC1–/– choroid plexus explants are able to induce typical brain pathology characteristics of NPC1–/–, more specifically microgliosis and astrogliosis. Taken together, our data reveal for the first time that the choroid plexus and CSF EVs might play a role in the brain-related pathogenesis of NPC1.

scholarly journals Clinical and Molecular Features of Early Infantile Niemann Pick Type C Disease

2020 ◽  
Vol 21 (14) ◽  
pp. 5059 ◽  
Author(s):  
Berna Seker Yilmaz ◽  
Julien Baruteau ◽  
Ahad A. Rahim ◽  
Paul Gissen
Keyword(s):  
Neurological Symptoms ◽  
Novel Therapy ◽  
Clinical Patient ◽  
Molecular Features ◽  
Niemann Pick Disease ◽  
Exon 1 ◽  
Type C ◽  
Vertical Supranuclear Gaze Palsy ◽  
Niemann Pick ◽  
Prolonged Jaundice

Niemann Pick disease type C (NPC) is a neurovisceral disorder due to mutations in NPC1 or NPC2. This review focuses on poorly characterized clinical and molecular features of early infantile form of NPC (EIF) and identified 89 cases caused by NPC1 (NPC1) and 16 by NPC2 (NPC2) mutations. Extra-neuronal features were common; visceromegaly reported in 80/89 NPC1 and in 15/16 NPC2, prolonged jaundice in 30/89 NPC1 and 7/16 NPC2. Early lung involvement was present in 12/16 NPC2 cases. Median age of neurological onset was 12 (0–24) and 7.5 (0–24) months in NPC1 and NPC2 groups, respectively. Developmental delay and hypotonia were the commonest first detected neurological symptoms reported in 39/89 and 18/89 NPC1, and in 8/16 and 10/16 NPC2, respectively. Additional neurological symptoms included vertical supranuclear gaze palsy, dysarthria, cataplexy, dysphagia, seizures, dystonia, and spasticity. The following mutations in homozygous state conferred EIF: deletion of exon 1+promoter, c.3578_3591 + 9del, c.385delT, p.C63fsX75, IVS21-2delATGC, c. 2740T>A (p.C914S), c.3584G>T (p.G1195V), c.3478-6T>A, c.960_961dup (p.A321Gfs*16) in NPC1 and c.434T>A (p.V145E), c.199T>C (p.S67P), c.133C>T (p.Q45X), c.141C>A (p.C47X) in NPC2. This comprehensive analysis of the EIF type of NPC will benefit clinical patient management, genetic counselling, and assist design of novel therapy trials.

46. The natural history of Niemann–Pick disease type C

2008 ◽  
Vol 93 (2) ◽  
pp. 25
Author(s):  
Elizabeth Jacklin ◽  
Jackie Imrie ◽  
Suprana Dasgupta ◽  
Guy Besley ◽  
Harris Chris ◽  
...  
Keyword(s):  
Natural History ◽  
Disease Type ◽  
Niemann Pick Disease ◽  
History Of ◽  
Type C ◽  
Niemann Pick ◽  
Pick Disease

Vertical supranuclear gaze palsy in Niemann-Pick type C disease

2012 ◽  
Vol 33 (6) ◽  
pp. 1225-1232 ◽  
Author(s):  
Ettore Salsano ◽  
Chizoba Umeh ◽  
Alessandra Rufa ◽  
Davide Pareyson ◽  
David S. Zee
Keyword(s):  
Type C ◽  
Vertical Supranuclear Gaze Palsy ◽  
Niemann Pick ◽  
Gaze Palsy

scholarly journals The mind’s eye: A neuro-ophthalmological perspective on Niemann-Pick type C disease

2019 ◽  
Vol 78 (1) ◽  
Author(s):  
Priyanka Beedasy ◽  
Anand Moodley ◽  
Adrian D. Marais
Keyword(s):  
Skin Biopsy ◽  
Neuropsychiatric Symptoms ◽  
Poor Response ◽  
Course Of Illness ◽  
Niemann Pick Disease ◽  
Clinical Clue ◽  
Type C ◽  
Vertical Supranuclear Gaze Palsy ◽  
Niemann Pick ◽  
Gaze Palsy

Niemann-Pick disease type C (NPC) is a rare autosomal recessive genetic disease caused by mutations in the NPC1 and NPC2 genes with an estimated incidence of 1:120 000 live births. The clinical presentations vary across the ages. Children present with visceral symptoms related to cholesterol accumulation in the liver and adults have predominantly neuropsychiatric features such as dementia. However, vertical supranuclear gaze palsy can be present from the first year of life and is a strong feature in the diagnosis of NPC, which can be confirmed by a skin biopsy. A 36-year-old female with long-standing depression was referred for an evaluation of dystonia. She had progressive cognitive decline, dysarthria, dysphonia, dystonia of the trunk and limbs, ataxia and supranuclear gaze palsy. A similar course of illness affected her brother. Her parents were first cousins. She had positive Filipin stain of fibroblasts cultured from her skin biopsy, confirming the diagnosis of NPC. Miglustat, the approved drug for treatment, was not accessible. She had been on simvastatin since diagnosis, with a poor response, and had ongoing severe cognitive and physical disability. There are few conditions that present with neuropsychiatric symptoms and supranuclear gaze palsy. This patient had been managed as chronic depression with psychosis since her teenage years and her diagnosis was reviewed only when she had developed dystonia. Supranuclear gaze palsy is an early diagnostic clinical clue that could be present from infancy and should be sought in patients with neurocognitive presentations.

Efficient Investigation and Differential Diagnosis of Childhood Onset Niemann-Pick Type C

2012 ◽  
Vol 7 (3) ◽  
pp. 153
Author(s):  
Alasdair Parker ◽  
Keyword(s):  
Genetic Testing ◽  
Age Of Onset ◽  
Unmet Need ◽  
Lysosomal Storage ◽  
Cultured Skin ◽  
Specificity And Sensitivity ◽  
Niemann Pick Disease ◽  
History Of ◽  
Type C ◽  
Niemann Pick

Niemann-Pick disease type C (NPC) is a fatal, neurodegenerative, lysosomal storage disorder. It is rare with a broad phenotypic spectrum and variable age of onset. This complicates diagnosis, which is often delayed by several years after presentation of the first symptoms. It is a treatable condition if detected early, therefore reliable means of diagnosis are essential. Clinical diagnosis of NPC involves identifying characteristic neurological features, taking a detailed history of the patient’s details, and must be confirmed by biochemical and/or genetic testing. The key laboratory diagnostic test for NPC is filipin staining of cultured skin fibroblasts, which shows free cholesterol accumulation in lysosomes resulting from impaired intracellular cholesterol transport. Genetic testing for mutations in theNPC1andNPC2genes is also important for confirmation of the diagnosis. However, there is an unmet need for cheaper diagnostic tests with greater specificity and sensitivity

Niemann-Pick Disease Type C

2016 ◽  
Author(s):  
Frédéric Sedel
Keyword(s):  
Disease Type ◽  
Lipid Storage Disease ◽  
Niemann Pick Disease ◽  
Exact Function ◽  
Type C ◽  
Endosomal Transport ◽  
Vertical Supranuclear Gaze Palsy ◽  
Niemann Pick ◽  
Npc2 Gene ◽  
Pick Disease

Niemann-Pick disease type C (NPC) is a fatal neurovisceral lipid storage disease of autosomal inheritance resulting from mutations in either the NPC1 (95% of families) or NPC2 gene. The encoded proteins appear to be involved in lysosomal/late endosomal transport of cholesterol, glycolipids, and other molecules, but their exact function is still unknown. The clinical spectrum of the disease ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease characterized prominently by psychiatric disorders, cerebellar ataxia, cognitive decline, and vertical supranuclear gaze palsy. Miglustat is the only treatment approved to date which has been demonstrated to slow or halt disease progression.

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