Niemann-Pick Type C 1 (NPC1) and NPC2 Gene Variability in Demented Patients with Evidence of Brain Amyloid Deposition

2021 ◽  
pp. 1-11
Author(s):  
Federica Sorrentino ◽  
Andrea Arighi ◽  
Maria Serpente ◽  
Beatrice Arosio ◽  
Marina Arcaro ◽  
...  
Keyword(s):  
Psychiatric Symptoms ◽  
Amyloid Β ◽  
Elderly Subjects ◽  
Targeted Next Generation Sequencing ◽  
Modifying Factors ◽  
Pathogenic Variants ◽  
Type C ◽  
Niemann Pick ◽  
Npc2 Gene ◽  
Gene Variability

Background: Variants in Niemann-Pick Type C genes (NPC1 and NPC2) have been suggested to play a role as risk or disease modifying factors for Alzheimer’s disease (AD). Objective: The aim of this study was to analyze NPC1 and NPC2 variability in demented patients with evidence of brain amyloid-β 1–42 (Aβ) deposition and to correlate genetic data with clinical phenotypes. Methods: A targeted Next Generation Sequencing panel was customized to screen NPC1, NPC2, and main genes related to neurodegenerative dementias in a cohort of 136 demented patients with cerebrospinal fluid (CSF) low Aβ levels or positive PET with Aβ tracer and 200 non-demented geriatric subjects. Results: Seven patients were carriers of NPC variants in heterozygosis. Four of them displayed pathogenic variants previously found in NPC patients and one AD patient had a novel variant. The latter was absent in 200 non-demented elderly subjects. Five of seven patients (70%) exhibited psychiatric symptoms at onset or later as compared with 43%in non-carriers (p >  0.05). Conclusion: The frequency of NPC1 and NPC2 heterozygous variants in patients with CSF evidence of Aβ deposition is higher than in the general population.

Psychiatric Manifestations of Niemann-pick Type c Disease – Two Case Reports

2016 ◽  
Vol 33 (S1) ◽  
pp. 1-1 ◽  
Author(s):  
J. Rebelo ◽  
M. Oliveira ◽  
P. Nunes
Keyword(s):  
Metabolic Diseases ◽  
Psychiatric Symptoms ◽  
Case Reports ◽  
Clinical Manifestations ◽  
Specific Treatment ◽  
Autosomal Recessive Inheritance ◽  
Ataxic Gait ◽  
Type C ◽  
Niemann Pick ◽  
Psychiatric Manifestations

IntroductionNiemann-Pick type C disease (NPCD) is a rare metabolic illness, with autosomal recessive inheritance. NPCD has a heterogeneous presentation, with non-specific psychiatric symptoms, mostly affective and psychotic features and also cognitive deficits.Objectives and methodsWe present the case reports of two brothers with an adolescent-adult onset and discuss the evolution of their neuropsychiatric manifestations.ResultsThe patients have now 35 and 31 years old and the youngest was the first to develop clinical manifestations of the disease. From 16 years old, he developed unspecified neurological impairment with gait imbalance. In the next years, the neurologic manifestations exacerbated, with dysarthria, ataxic gait, and his academic performance declined. With 24 years old, he presented acute psychosis, with unstructured delusion and auditory hallucinations. The acute psychotic symptomatology remitted with olanzapine but he revealed social withdrawal, apathy and progressive cognitive decline that persist until now. His brother, whose diagnosis was made in the course of the family genetic study, developed the first signs of the NPCD with 19 years old. He presented neuropsychiatric compromise, with impaired learning, social isolation and insomnia. They are receiving specific treatment with miglustat and symptomatic treatment for the psychiatric manifestations.ConclusionsNPCD is a rare metabolic disease, with neuropsychiatric compromise. No general psychopathological profile has been associated to NPCD. Sometimes psychiatric symptoms dominate the initial clinical presentation, with neuro-visceral signs appearing later. An atypical psychiatric symptomatology should be extensively investigated in order to exclude organic causes, including metabolic diseases like NPCD.Disclosure of interestThe authors have not supplied their declaration of competing interest.

scholarly journals Enrichment of gene variants associated with treatable genetic disorders in psychiatric populations

2018 ◽  
Author(s):  
Venuja Sriretnakumar ◽  
Ricardo Harripaul ◽  
John B. Vincent ◽  
James L. Kennedy ◽  
Joyce So
Keyword(s):  
Psychotic Disorders ◽  
Psychiatric Symptoms ◽  
Psychiatric Patients ◽  
Genetic Disorders ◽  
Acute Intermittent Porphyria ◽  
Inborn Errors ◽  
Pathogenic Variants ◽  
Niemann Pick Disease ◽  
Poor Treatment ◽  
Niemann Pick

ABSTRACTPurposeMany genetic conditions can mimic mental health disorders, with psychiatric symptoms that are difficult to treat with standard psychotropic medications. This study tests the hypothesis that psychiatric populations are enriched for pathogenic variants associated with selected treatable genetic disorders.MethodsUsing next-generation sequencing, 2046 psychiatric patients were screened for variants in genes associated with four inborn errors of metabolism (IEMs), Niemann-Pick disease type C (NPC), Wilson disease (WD), homocystinuria (HOM), and acute intermittent porphyria (AIP).ResultsAmong the 2046 cases, carrier rates of 0·83%, 0·98%, 0·20%, and 0·24% for NPC, WD, HOM, and AIP were seen respectively. An enrichment of known and likely pathogenic variants in the genes associated with NPC and AIP was found in the psychiatric cohort, and especially in schizophrenia patients.ConclusionThe results of this study support that rare genetic disease variants, such as those associated with IEMs, may contribute to the pathogenesis of psychiatric disorders. IEMs should be considered as possible causative factors for psychiatric presentations, especially in psychotic disorders, such as schizophrenia, and in the context of poor treatment response.

scholarly journals Genetic screening for Niemann-Pick disease type C in adults with neurological and psychiatric symptoms: findings from the ZOOM study

2013 ◽  
Vol 22 (21) ◽  
pp. 4349-4356 ◽  
Author(s):  
P. Bauer ◽  
D. J. Balding ◽  
H. H. Klunemann ◽  
D. E. J. Linden ◽  
D. S. Ory ◽  
...  
Keyword(s):  
Genetic Screening ◽  
Psychiatric Symptoms ◽  
Disease Type ◽  
Niemann Pick Disease ◽  
Type C ◽  
Niemann Pick ◽  
Pick Disease

scholarly journals Characterization of a Spontaneous Novel Mutation in the NPC2 Gene in a Cat Affected by Niemann Pick Type C Disease

PLoS ONE ◽  
2014 ◽  
Vol 9 (11) ◽  
pp. e112503 ◽  
Author(s):  
Stefania Zampieri ◽  
Ezio Bianchi ◽  
Carlo Cantile ◽  
Roberta Saleri ◽  
Bruno Bembi ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Type C ◽  
Niemann Pick ◽  
Npc2 Gene

scholarly journals Exome sequence analysis of siblings affected with Niemann-Pick type C disease

2021 ◽  
Author(s):  
◽  
Shaun Carswell
Keyword(s):  
Disease Severity ◽  
Age Of Onset ◽  
Monogenic Disease ◽  
Chromosome 11 ◽  
Unesterified Cholesterol ◽  
Pulmonary Tissue ◽  
Sibling Pairs ◽  
Type C ◽  
Niemann Pick ◽  
Npc2 Gene

<p>Mutations in either the Niemann-Pick type C1 or C2 (NPC1/NPC2) gene result in a fatal lysosomal storage disorder, Niemann-Pick type C (NP-C) disease, for which there is no effective cure. The disease is characterized by systemic and neurodegenerative symptoms arising from toxic accumulation of unesterified cholesterol within the late endosome and lysosome, with a common cause of death for patients being respiratory failure or recurrent infection of pulmonary tissue. Interestingly, the disease symptoms are heterogeneous, with age of onset and severity varied, even among siblings with the same mutations in the NPC1 or NPC2 gene causing this monogenic disease. To date there is no clear explanation for disease severity in siblings with the same mutation. As siblings are raised in the same environment, the major hypothesis of this thesis is that there are genetic modifiers that explain variation in disease severity within siblings. To determine if there are genetic variants associated with disease severity, exomes were sequenced from five sibling pairs exhibiting divergent onset and progression of NPC disease. Out of 23,105 genes, 26 variants were identified that were predicted to have functional consequences in NP-C patients, of which homozygous MUC5B and MARCH8 variants segregated across siblings that exhibited increased and decreased severity of disease, respectively. A cluster of variants was discovered on chromosome 11 belonging to the matrix metalloproteinase (MMP) family. Further investigation of one of these variants, a frameshift insertion in MMP-12, confirmed that this locus regulates the accumulation of unesterified cholesterol in primary neurons derived from a murine model of NPC disease. However, this region on chromosome 11 did not have any statistically significant copy number alteration detectable through a depth of coverage analysis. Overall, these results provide groundwork into the sequence variants mediating disease severity, which with further investigations, may be novel pharmacological targets to treat NPC disease.</p>

scholarly journals Exome sequence analysis of siblings affected with Niemann-Pick type C disease

2021 ◽  
Author(s):  
◽  
Shaun Carswell
Keyword(s):  
Disease Severity ◽  
Age Of Onset ◽  
Monogenic Disease ◽  
Chromosome 11 ◽  
Unesterified Cholesterol ◽  
Pulmonary Tissue ◽  
Sibling Pairs ◽  
Type C ◽  
Niemann Pick ◽  
Npc2 Gene

<p>Mutations in either the Niemann-Pick type C1 or C2 (NPC1/NPC2) gene result in a fatal lysosomal storage disorder, Niemann-Pick type C (NP-C) disease, for which there is no effective cure. The disease is characterized by systemic and neurodegenerative symptoms arising from toxic accumulation of unesterified cholesterol within the late endosome and lysosome, with a common cause of death for patients being respiratory failure or recurrent infection of pulmonary tissue. Interestingly, the disease symptoms are heterogeneous, with age of onset and severity varied, even among siblings with the same mutations in the NPC1 or NPC2 gene causing this monogenic disease. To date there is no clear explanation for disease severity in siblings with the same mutation. As siblings are raised in the same environment, the major hypothesis of this thesis is that there are genetic modifiers that explain variation in disease severity within siblings. To determine if there are genetic variants associated with disease severity, exomes were sequenced from five sibling pairs exhibiting divergent onset and progression of NPC disease. Out of 23,105 genes, 26 variants were identified that were predicted to have functional consequences in NP-C patients, of which homozygous MUC5B and MARCH8 variants segregated across siblings that exhibited increased and decreased severity of disease, respectively. A cluster of variants was discovered on chromosome 11 belonging to the matrix metalloproteinase (MMP) family. Further investigation of one of these variants, a frameshift insertion in MMP-12, confirmed that this locus regulates the accumulation of unesterified cholesterol in primary neurons derived from a murine model of NPC disease. However, this region on chromosome 11 did not have any statistically significant copy number alteration detectable through a depth of coverage analysis. Overall, these results provide groundwork into the sequence variants mediating disease severity, which with further investigations, may be novel pharmacological targets to treat NPC disease.</p>

scholarly journals Variants in the NPC1 Gene in Egyptian Patients with Niemann-Pick Type C

2020 ◽  
Vol 8 (A) ◽  
pp. 134-145
Author(s):  
Mona L. Essawi ◽  
Asmaa F. Abdel-aleem ◽  
Mohamed A. Badawy ◽  
Maha S. Zaki ◽  
Magda F. Mohamed ◽  
...  
Keyword(s):  
Molecular Analysis ◽  
Mutational Analysis ◽  
Polymerase Chain Reaction Amplification ◽  
Clinical Criteria ◽  
Npc1 Gene ◽  
Egyptian Patients ◽  
Type C ◽  
Niemann Pick ◽  
Npc2 Gene ◽  
Biallelic Mutations

BACKGROUND: Niemann-Pick disease type C (NPC) is a rare, autosomal recessive, progressive neuro-visceraldisease caused by biallelic mutations in either NPC1gene (95% of cases) or NPC2 gene. AIM: This caseseries study aimed at the molecular analysis of certain hot spots of NPC1 genein NPC Egyptian patients. METHODS: The study included 15 unrelated NPC patients and selected parents,as well as20 healthy controls of matched sex and age. Clinical investigations were performed according to well established clinical criteria. Assessment of the chitotriosidase level, as an initial screening tool for NPC, was done in all cases. Polymerase chain reaction amplification of NPC1 exons (17–25) encountering the hotspot residues (855–1098 and1038–1253) was carried out followed by direct sequencingfor mutational analysis. RESULTS: All includedpatients with mainly neurovisceral involvement were characterized. The onset of the disease varied from early-infantile (58.3%) to late-infantile (26.7%) and juvenile-onset (6.7%). Ahigh chitotriosidase level wasobservedin all patients. Molecular analysis of NPC1 (exons 17–25) confirmed 15 mutant alleles out of 30 studied ones. They included two novel homozygous missense variants (p.Ser1169Arg and p.Ser1197Phe) and previously reportedfour mutations (p.Arg958*, p.Gly910Ser, p.Ala927Glyfs*38, and andp.Cys1011*). CONCLUSION: The two studied amino acid residues (855–1098 and 1038–1253) could beconsidered aspotential hotspot regions in NPC1 Egyptian patients.

scholarly journals Accumulation and Aggregation of Amyloid β-Protein in Late Endosomes of Niemann-Pick Type C Cells

2000 ◽  
Vol 276 (6) ◽  
pp. 4454-4460 ◽  
Author(s):  
Tsuneo Yamazaki ◽  
Ta-Yuan Chang ◽  
Christian Haass ◽  
Yasuo Ihara
Keyword(s):  
Amyloid Β ◽  
Amyloid Β Protein ◽  
C Cells ◽  
Late Endosomes ◽  
Β Protein ◽  
Type C ◽  
Niemann Pick
Sign in / Sign up

Export Citation Format

Share Document