Materiały źródłowe

• #1 Consensus clinical management guidelines for Niemann-Pick disease type C | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-018-0785-7

  Niemann-Pick Type C (NPC) is a progressive and life limiting autosomal recessive disorder caused by mutations in either the NPC1 or NPC2 gene. Mutations in these genes are associated with abnormal endosomal-lysosomal trafficking, resulting in the accumulation of multiple lipids in the lysosomes. […] NPC has an estimated incidence of ~1: 100,000 and the rarity of the disease translate into misdiagnosis, delayed diagnosis and barriers to good care. […] The information contained in these guidelines was obtained through a systematic review of the literature and the experiences of the authors in their care of patients with NPC. […] These guidelines can inform care providers, care funders, patients and their carers of best practice of care for patients with NPC. […] The guidelines refer to the management of patients suspected or diagnosed with NPC disease at any age.

• #2 Advancing diagnosis and treatment of Niemann-Pick C disease through biomarker discovery

  https://www.explorationpub.com/Journals/ent/Article/100412

  Niemann-Pick C disease is a rare neurodegenerative, lysosomal storage disease caused by accumulation of unesterified cholesterol. Diagnosis of the disease is often delayed due to its rarity, the heterogeneous presentation, and the early non-specific symptoms. The discovery of disease-specific biomarkers cholestane-3,5,6-triol (C-triol), trihydroxycholanic acid glycinate (TCG) and N-palmitoyl-O-phosphocholineserine [PPCS, initially referred to as lysosphingomyelin-509 (lysoSM-509)] has led to development of non-invasive, blood-based diagnostics. […] Diagnosis of NPC is challenging due to the rarity of the disorder, the heterogeneity of disease onset and presentation, its non-specific early symptoms, and the complexity of the laboratory testing. Consequently, diagnosis is typically delayed 4-5 years for the late-infantile and juvenile forms of the disease, during which time opportunities for early intervention are lost.

• #3 Clinical disease characteristics of patients with Niemann-Pick Disease Type C: findings from the International Niemann-Pick Disease Registry (INPDR) | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-022-02200-4

  Niemann-Pick Disease Type C (NPC) is an autosomal recessive rare disease characterised by progressive neurovisceral manifestations. The INPDR is a web-based, patient-led independent registry for the collection of prospective and retrospective clinical data from Niemann-Pick Disease patients. The mean age (SD) at diagnosis was 11.2 years (14.2). Among the 97 patients with identified NPC1 variants, the most common variant was the c. 3182TC variant responsible for the p.lle1061Thr protein change, reported in 35.1% (N=34) of patients. The age at diagnosis and death increased with increased age of neurological symptom onset. The clinical spectrum of NPC encompasses a range of non-specific neurological and systemic manifestations at an early stage and varying by age of onset and organ involvement. The classification of NPC by age of neurological onset is as follows: early infantile (2 years) (visceral-neurodegenerative form); late-infantile (2-6 years) and juvenile (6-15 years) (neurodegenerative form); adult (15 years) (psychiatric-neurodegenerative form). The rarity, varied age of onset, heterogeneous and non-specific manifestations of the disease pose significant challenges in understanding the natural course of NPC. The INPDR is a patient led registry designed to: (a) better understand the natural history of Niemann-Pick disease worldwide; (b) provide an inventory of patients for recruitment to observational and interventional studies; (c) establish genotype-phenotype correlations; (d) provide support for education of health professionals and empowerment of patients. The p.I1061T variant was the most common variant in this population, with detection in 28.6% of patients. Disease classification based on the age of onset of the first neurological symptoms has been accepted as a guide to clinicians in providing day to day care, genetic counselling and to estimate the trajectory of the disease course. The type and onset of visceral symptoms varied across the age groups with decreased occurrence with an increasing age. Clinical assessment of disease burden and rate of progression in time or regression with disease modifying therapy is challenging when dealing with progressive diseases such as NPC. The composite disability scores were notably higher in patients with early onset neurological signs, particularly in late infantile patients. Mortality data was available for 59 patients and the duration of survival after disease onset varies with age spectrum of the disease. The most common therapy was Miglustat, a potential disease modifying therapy specifically indicated for NPC, reported in 85 (62.4%) patients, with a mean duration of just over 4 years.

• #4 Recommendations for the detection and diagnosis of Niemann-Pick disease type C

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5800709/

  Niemann-Pick disease type C (NP-C) is a neurovisceral disorder that may be more prevalent than earlier estimates. Diagnosis of NP-C is often delayed; a key aim for clinical practice is to reduce this delay. Recently, substantial progress has been made in the field of NP-C screening and diagnosis, justifying an update to the existing recommendations for clinical practice. […] New biomarker profiling and genetic analysis technologies are included as first-line diagnostic tests for NP-C. Most diagnoses can now be confirmed by combination of biomarker and genetic analyses. Filipin staining may facilitate diagnosis in uncertain cases. Recommendations are provided for psychiatrists, neuro-ophthalmologists, and radiologists, and on screening within specific at-risk patient cohorts. The NP-C diagnostic algorithm has been updated and simplified.

• #5 Recommendations for the detection and diagnosis of Niemann-Pick disease type C

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5800709/

  The NP-C Diagnostic Recommendations Expert Panel met in May 2016 to assess the impact of recently published data and to reach consensus on the best approaches to diagnosing NP-C. The following sections of the previous recommendations were updated: differential diagnosis and initial detection, diagnosis, and the NP-C diagnostic algorithm. Three approaches to the detection and diagnosis of patients with NP-C were established: clinical assessment, biomarker testing, and genetic analysis. […] All patients with suspicion of NP-C require rigorous and detailed clinical assessment, as described in the 2012 diagnostic recommendations. All undiagnosed patients with any manifestation of NP-C should be referred to regional or national centers specializing in inherited metabolic disorders. […] The NP-C Suspicion Index (NP-C SI) quantifies the diagnostic weight of NP-C signs and symptoms, individually and in combination.

• #6 A Rare Case of Late Adult-Onset Niemann-Pick Disease Type C

  https://www.e-jmd.org/journal/view.php?number=278

  Niemann-Pick disease type C (NPC) is an autosomal recessive neurodegenerative disorder caused by mutation of either NPC1 (95% of cases) or NPC2. […] Early diagnosis of NPC is important because treatment with miglustat has been shown to stabilize disease progression. […] The NPC suspicion index score was 100, indicating its high probability. […] The genetic testing was also compatible with the recently proposed diagnostic criteria for NPC in which the diagnosis can be confirmed by the identification of two known or likely pathogenic alleles. […] In adult-onset NPC, diagnostic delay is common and often 5 years or more, as seen in our case. […] VSGP is present in approximately 70-80% of the patients across all age at onset categories, which suggests that clinicians should consider NPC in the differential diagnosis of VSGP, regardless of age at onset. […] Thus, the absence of VSGP cannot rule out the diagnosis of NPC, and eye movements need to be checked regularly in patients with suspected NPC, but without VSGP.

• #7 Niemann-Pick disease – Diagnosis and treatment – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/niemann-pick/diagnosis-treatment/drc-20355890

  Diagnosis of Niemann-Pick disease begins with a physical exam. The exam may show an early warning sign such as a liver or spleen that is too large. Your healthcare professional talks with you about symptoms and your family health history. Niemann-Pick disease is rare, and its symptoms can be similar to those of other health conditions, so testing is needed to get the right diagnosis. […] Diagnostic tests depend on the type of Niemann-Pick disease. […] Using blood or a tiny sample of skin, experts measure how much sphingomyelinase is in white blood cells. Sphingomyelinase is an enzyme that breaks down and uses fat. […] Experts use a blood sample to measure levels of a specific type of cholesterol called oxysterol. In rare cases, a small sample of skin also can be used to tell how the cells move and store cholesterol.

• #8 Niemann-Pick disease | UM Health-Sparrow

  https://www.uofmhealthsparrow.org/departments-conditions/conditions/niemann-pick-disease

  Diagnosis of Niemann-Pick disease begins with a physical exam. The exam may show an early warning sign such as a liver or spleen that is too large. Your healthcare professional talks with you about symptoms and your family health history. Niemann-Pick disease is rare, and its symptoms can be similar to those of other health conditions, so testing is needed to get the right diagnosis. […] Diagnostic tests depend on the type of Niemann-Pick disease. […] Using blood or a tiny sample of skin, experts measure how much sphingomyelinase is in white blood cells. Sphingomyelinase is an enzyme that breaks down and uses fat. […] Experts use a blood sample to measure levels of a specific type of cholesterol called oxysterol. In rare cases, a small sample of skin also can be used to tell how the cells move and store cholesterol.

• #9 Recommendations for the detection and diagnosis of Niemann-Pick disease type C

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5800709/

  The NP-C Diagnostic Recommendations Expert Panel met in May 2016 to assess the impact of recently published data and to reach consensus on the best approaches to diagnosing NP-C. The following sections of the previous recommendations were updated: differential diagnosis and initial detection, diagnosis, and the NP-C diagnostic algorithm. Three approaches to the detection and diagnosis of patients with NP-C were established: clinical assessment, biomarker testing, and genetic analysis. […] All patients with suspicion of NP-C require rigorous and detailed clinical assessment, as described in the 2012 diagnostic recommendations. All undiagnosed patients with any manifestation of NP-C should be referred to regional or national centers specializing in inherited metabolic disorders. […] The NP-C Suspicion Index (NP-C SI) quantifies the diagnostic weight of NP-C signs and symptoms, individually and in combination.

• #10 Niemann-Pick Disease | Causes, signs, symptoms & treatment

  https://cpdonline.co.uk/knowledge-base/care/niemann-pick-disease/

  How is Niemann-Pick disease diagnosed? […] Given the huge range of symptoms and the many overlaps with other conditions, it can be difficult to get a diagnosis of Niemann-Pick disease. Clinicians do have tools that help them to identify the signs and symptoms but there needs to be suspicion of the condition before these will be used. The tools include: The NPC Suspicion Index Tool, NPS Clinical Severity Scale (NPCCSS), The Assessment and Rating of Ataxia (SARA) scale. […] There are also biomarkers than can be tested. These include bile acids and lysoSM-509. However, there are no biomarkers that will tell you of any CNS (central nervous system) manifestations or whether there has been disease progression. […] The difficulty in diagnosing NPC (Niemann-Pick type C) means that there are often years of delays in receiving a diagnosis. On average, this is just over 4 years.

• #11 Niemann-Pick Disease | Causes, signs, symptoms & treatment

  https://cpdonline.co.uk/knowledge-base/care/niemann-pick-disease/

  How is Niemann-Pick disease diagnosed? […] Given the huge range of symptoms and the many overlaps with other conditions, it can be difficult to get a diagnosis of Niemann-Pick disease. Clinicians do have tools that help them to identify the signs and symptoms but there needs to be suspicion of the condition before these will be used. The tools include: The NPC Suspicion Index Tool, NPS Clinical Severity Scale (NPCCSS), The Assessment and Rating of Ataxia (SARA) scale. […] There are also biomarkers than can be tested. These include bile acids and lysoSM-509. However, there are no biomarkers that will tell you of any CNS (central nervous system) manifestations or whether there has been disease progression. […] The difficulty in diagnosing NPC (Niemann-Pick type C) means that there are often years of delays in receiving a diagnosis. On average, this is just over 4 years.

• #12 Consensus clinical management guidelines for Niemann-Pick disease type C | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-018-0785-7

  The guidelines have been developed by experts with extensive experience of European, Australian and North American healthcare systems and populations. […] The clinical spectrum of NPC disease ranges from a neonatal rapidly progressive fatal disorder to an adult-onset chronic neurodegenerative disease. Based on data gathered from a large cohort of French NPC patients, the age of onset of neurological symptoms predicts the severity of the disease and determines life expectancy. […] The symptoms and signs of NPC vary with age at disease onset. There are numerous conditions raising the suspicion of NPC and other age appropriate diseases should also be excluded. […] NPC-specific disease severity scores are useful adjuncts to clinical judgement in assessing disease burden, response to therapy and determining prognosis.

• #13 Niemann-Pick Disease | Causes, signs, symptoms & treatment

  https://cpdonline.co.uk/knowledge-base/care/niemann-pick-disease/

  How is Niemann-Pick disease diagnosed? […] Given the huge range of symptoms and the many overlaps with other conditions, it can be difficult to get a diagnosis of Niemann-Pick disease. Clinicians do have tools that help them to identify the signs and symptoms but there needs to be suspicion of the condition before these will be used. The tools include: The NPC Suspicion Index Tool, NPS Clinical Severity Scale (NPCCSS), The Assessment and Rating of Ataxia (SARA) scale. […] There are also biomarkers than can be tested. These include bile acids and lysoSM-509. However, there are no biomarkers that will tell you of any CNS (central nervous system) manifestations or whether there has been disease progression. […] The difficulty in diagnosing NPC (Niemann-Pick type C) means that there are often years of delays in receiving a diagnosis. On average, this is just over 4 years.

• #14 Clinical disease characteristics of patients with Niemann-Pick Disease Type C: findings from the International Niemann-Pick Disease Registry (INPDR) | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-022-02200-4

  Niemann-Pick Disease Type C (NPC) is an autosomal recessive rare disease characterised by progressive neurovisceral manifestations. The INPDR is a web-based, patient-led independent registry for the collection of prospective and retrospective clinical data from Niemann-Pick Disease patients. The mean age (SD) at diagnosis was 11.2 years (14.2). Among the 97 patients with identified NPC1 variants, the most common variant was the c. 3182TC variant responsible for the p.lle1061Thr protein change, reported in 35.1% (N=34) of patients. The age at diagnosis and death increased with increased age of neurological symptom onset. The clinical spectrum of NPC encompasses a range of non-specific neurological and systemic manifestations at an early stage and varying by age of onset and organ involvement. The classification of NPC by age of neurological onset is as follows: early infantile (2 years) (visceral-neurodegenerative form); late-infantile (2-6 years) and juvenile (6-15 years) (neurodegenerative form); adult (15 years) (psychiatric-neurodegenerative form). The rarity, varied age of onset, heterogeneous and non-specific manifestations of the disease pose significant challenges in understanding the natural course of NPC. The INPDR is a patient led registry designed to: (a) better understand the natural history of Niemann-Pick disease worldwide; (b) provide an inventory of patients for recruitment to observational and interventional studies; (c) establish genotype-phenotype correlations; (d) provide support for education of health professionals and empowerment of patients. The p.I1061T variant was the most common variant in this population, with detection in 28.6% of patients. Disease classification based on the age of onset of the first neurological symptoms has been accepted as a guide to clinicians in providing day to day care, genetic counselling and to estimate the trajectory of the disease course. The type and onset of visceral symptoms varied across the age groups with decreased occurrence with an increasing age. Clinical assessment of disease burden and rate of progression in time or regression with disease modifying therapy is challenging when dealing with progressive diseases such as NPC. The composite disability scores were notably higher in patients with early onset neurological signs, particularly in late infantile patients. Mortality data was available for 59 patients and the duration of survival after disease onset varies with age spectrum of the disease. The most common therapy was Miglustat, a potential disease modifying therapy specifically indicated for NPC, reported in 85 (62.4%) patients, with a mean duration of just over 4 years.

• #15 Recommendations for the detection and diagnosis of Niemann-Pick disease type C

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5800709/

  Biomarker screening methods can now be considered a first-line step in the NP-C diagnostic process. […] It is crucial to genetically confirm a diagnosis in patients with high clinical suspicion and/or a biomarker profile consistent with NP-C. […] Positive genetic testing results, or positive biomarker testing results combined with molecular genetic analysis, are now deemed sufficient to diagnose NP-C in most cases.

• #16 NPC Diagnostic Test | Metabolomics | Washington University in St. Louis

  https://metabolomics.wustl.edu/npc-diagnostic-test/

  Niemann-Pick disease type C (NPC) is a fatal, neurodegenerative, cholesterol storage disorder. The current diagnostic standard for NPC includes clinical assessment, biomarker testing, and genetic analysis. All patients with suspicion of NPC and patient groups with an increased risk of NPC are recommended to receive biomarker profiling or genetic test that are first-line diagnostic tests for NPC. The most well validated NPC diagnostic biomarkers include cholestane-3b,5a,6b-triol (C-triol), lysoSM-509 (N-palmitoyl-O-phosphocholineserine), and the glycinated bile acid (N-(3,5,6-trihydroxy-cholan-24-oyl)glycine). The diagnosis of patients with high clinical suspicion and/or a biomarker profile should be confirmed with genetic test. […] The test report will be sent to the contact person who requests the analyses. Any patient samples with glycinated bile acid levels 18.5 ng/mL are considered to require follow-up with genetic analysis. […] Sphingomyelinase and lysosomal lipase assays as well as genetic test are required to further differentiate NPC from ASMD and LALD.

• #17 Niemann-Pick disease – Diagnosis and treatment – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/niemann-pick/diagnosis-treatment/drc-20355890

  Diagnosis of Niemann-Pick disease begins with a physical exam. The exam may show an early warning sign such as a liver or spleen that is too large. Your healthcare professional talks with you about symptoms and your family health history. Niemann-Pick disease is rare, and its symptoms can be similar to those of other health conditions, so testing is needed to get the right diagnosis. […] Diagnostic tests depend on the type of Niemann-Pick disease. […] Using blood or a tiny sample of skin, experts measure how much sphingomyelinase is in white blood cells. Sphingomyelinase is an enzyme that breaks down and uses fat. […] Experts use a blood sample to measure levels of a specific type of cholesterol called oxysterol. In rare cases, a small sample of skin also can be used to tell how the cells move and store cholesterol.

• #18 Niemann-Pick Disease – Pediatrics – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/pediatrics/inherited-disorders-of-metabolism/niemann-pick-disease

  Diagnosis is by DNA analysis and/or enzyme analysis of white blood cells. […] Diagnosis of Niemann-Pick disease can be confirmed by DNA analysis and/or sphingomyelinase assay on white blood cells and can be made prenatally by using amniocentesis or chorionic villus sampling. […] DNA tests also can be done to diagnose carriers.

• #19 Niemann-Pick disease: MedlinePlus Medical EncyclopediaLock

  https://medlineplus.gov/ency/article/001207.htm

  A blood or bone marrow test can be done to diagnose types A and B. The test can tell who has the disease, but does not show if you are a carrier. DNA tests can be done to diagnose carriers of types A and B. […] A skin biopsy is usually done to diagnose types C and C1. A technician watches how the skin cells grow, move, and store cholesterol. DNA tests may also be done to look for the 2 genes that cause this type of the disease. […] Other tests might include: Bone marrow aspiration, Liver biopsy (usually not needed), Slit-lamp eye exam, Tests to check level of ASM.

• #20 Sphingomyelinase Deficiency Workup: Approach Considerations, Acid Sphingomyelinase, Histologic Findings

  https://emedicine.medscape.com/article/951564-workup

  Targeted mutation analysis for 4 common SMPD1 mutations is available in clinical laboratories. […] Sequence and deletion/duplication analysis of SMPD1 are available in clinical laboratories and permit identification of rare and private gene mutations. […] Bone marrow examination is not necessary for the diagnosis of NPD. […] Once ASMD has been diagnosed, a biomarker assay may be useful to monitor disease progression. […] Plasma lysosphingolipids, such as lysosphingomyelin, are increased in patients with ASMD and may serve as biomarkers to monitor disease activity.

• #21 Advancing diagnosis and treatment of Niemann-Pick C disease through biomarker discovery

  https://www.explorationpub.com/Journals/ent/Article/100412

  Until recently, the standard for diagnosis of NPC disease was filipin staining of unesterified cholesterol in cultured skin fibroblasts obtained from patients. The filipin test identifies approximately 80-85% classical NPC patients; however, the test does not provide a clear result in patients with variant phenotypes. […] Over the past decade, the discovery of disease-specific, blood-based biomarkers has transformed the diagnosis of NPC, supplanting filipin as first-line diagnostics. The first generation of these markers were non-enzymatic oxidation products of cholesterol known as oxysterols. […] To date, the oxysterol assay has been implemented in 50 clinical laboratories worldwide and widely adopted in NPC diagnostic algorithms. […] The infeasibility of using C-triol or other oxysterol species for newborn screening in NPC disease prompted us to pursue further biomarker discovery.

• #22 Niemann-Pick disease – Diagnosis and treatment – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/niemann-pick/diagnosis-treatment/drc-20355890

  Diagnosis of Niemann-Pick disease begins with a physical exam. The exam may show an early warning sign such as a liver or spleen that is too large. Your healthcare professional talks with you about symptoms and your family health history. Niemann-Pick disease is rare, and its symptoms can be similar to those of other health conditions, so testing is needed to get the right diagnosis. […] Diagnostic tests depend on the type of Niemann-Pick disease. […] Using blood or a tiny sample of skin, experts measure how much sphingomyelinase is in white blood cells. Sphingomyelinase is an enzyme that breaks down and uses fat. […] Experts use a blood sample to measure levels of a specific type of cholesterol called oxysterol. In rare cases, a small sample of skin also can be used to tell how the cells move and store cholesterol.

• #23 Niemann-Pick type C: contemporary diagnosis and treatment of a classical disorder | Practical Neurology

  https://pn.bmj.com/content/19/5/420

  Serum oxysterol can be used as a first-line test with subsequent genetic confirmation and has a positive predictive value of 97%. […] Testing for serum oxysterol can give a rapid diagnosis. […] Niemann-Pick type C is a rare lysosomal storage disorder of which all neurologists should be aware, as it is treatable. […] Serum biomarkers such as oxysterol have become available since previous reports based on the Filipin test, which is labour intensive, making diagnosis easier.

• #24 Advancing diagnosis and treatment of Niemann-Pick C disease through biomarker discovery

  https://www.explorationpub.com/Journals/ent/Article/100412

  In comparison to oxysterols, the TCA and TCG bile acids exhibit robust ionization, do not require chemical derivatization, and are readily detected and stable at room temperature in plasma and dried blood spots. […] The discovery of NPC-specific blood-based biomarkers and their rapid dissemination over the past decade into clinical laboratories have transformed the approach to disease diagnosis. The circulating biomarkers most widely used in clinical laboratories C-triol, TCG and PPCS all have high sensitivity for identifying NPC disease. However, in contrast to C-triol and PPCS, TCG has significant advantages with respect to sample handling and stability and offers higher specificity for discrimination between carriers and NPC patients. For these reasons, the plasma TCG assay is recommended as the first-line diagnostic.

• #25 NPC Diagnostic Test | Metabolomics | Washington University in St. Louis

  https://metabolomics.wustl.edu/npc-diagnostic-test/

  Niemann-Pick disease type C (NPC) is a fatal, neurodegenerative, cholesterol storage disorder. The current diagnostic standard for NPC includes clinical assessment, biomarker testing, and genetic analysis. All patients with suspicion of NPC and patient groups with an increased risk of NPC are recommended to receive biomarker profiling or genetic test that are first-line diagnostic tests for NPC. The most well validated NPC diagnostic biomarkers include cholestane-3b,5a,6b-triol (C-triol), lysoSM-509 (N-palmitoyl-O-phosphocholineserine), and the glycinated bile acid (N-(3,5,6-trihydroxy-cholan-24-oyl)glycine). The diagnosis of patients with high clinical suspicion and/or a biomarker profile should be confirmed with genetic test. […] The test report will be sent to the contact person who requests the analyses. Any patient samples with glycinated bile acid levels 18.5 ng/mL are considered to require follow-up with genetic analysis. […] Sphingomyelinase and lysosomal lipase assays as well as genetic test are required to further differentiate NPC from ASMD and LALD.

• #26 Challenges in the Definitive Diagnosis of Niemann–Pick Type C—Leaky Variants and Alternative Transcripts

  https://www.mdpi.com/2073-4425/14/11/1990

  However, N-palmitoyl-O-phosphocholineserine, (PPCS, previously known as lysosphingomyelin-509) has been shown to be elevated in the plasma and dried blood spots of NPC patients. […] The increased availability of NGS has also contributed to the update of the overall NPC diagnostic algorithm while actively contributing to an increase in the number of positive molecular NPC diagnoses. Currently, there are a number of fully described diagnostic workflows for NPC, which may slightly vary between different labs depending on the tests each of them has available. However, NPC1 and NPC2 molecular analysis is mandatory in all of them and usually represents the ultimate step towards diagnosis. […] Indeed, a rapid molecular diagnosis of a potential NPC patient is essential, not just for swift access to available therapies (currently miglustat is the only one approved within the European Union) but also to slow the progression of the disease and ultimately because it is the sole method of offering prenatal diagnosis to affected families.

• #27 Advancing diagnosis and treatment of Niemann-Pick C disease through biomarker discovery

  https://www.explorationpub.com/Journals/ent/Article/100412

  In comparison to oxysterols, the TCA and TCG bile acids exhibit robust ionization, do not require chemical derivatization, and are readily detected and stable at room temperature in plasma and dried blood spots. […] The discovery of NPC-specific blood-based biomarkers and their rapid dissemination over the past decade into clinical laboratories have transformed the approach to disease diagnosis. The circulating biomarkers most widely used in clinical laboratories C-triol, TCG and PPCS all have high sensitivity for identifying NPC disease. However, in contrast to C-triol and PPCS, TCG has significant advantages with respect to sample handling and stability and offers higher specificity for discrimination between carriers and NPC patients. For these reasons, the plasma TCG assay is recommended as the first-line diagnostic.

• #28 Advancing diagnosis and treatment of Niemann-Pick C disease through biomarker discovery

  https://www.explorationpub.com/Journals/ent/Article/100412

  In comparison to oxysterols, the TCA and TCG bile acids exhibit robust ionization, do not require chemical derivatization, and are readily detected and stable at room temperature in plasma and dried blood spots. […] The discovery of NPC-specific blood-based biomarkers and their rapid dissemination over the past decade into clinical laboratories have transformed the approach to disease diagnosis. The circulating biomarkers most widely used in clinical laboratories C-triol, TCG and PPCS all have high sensitivity for identifying NPC disease. However, in contrast to C-triol and PPCS, TCG has significant advantages with respect to sample handling and stability and offers higher specificity for discrimination between carriers and NPC patients. For these reasons, the plasma TCG assay is recommended as the first-line diagnostic.

• #29 Niemann-Pick disease type C | MedLink Neurology

  https://www.medlink.com/articles/niemann-pick-disease-type-c

  Substantial progress has been achieved for laboratory screening and diagnosis of Niemann-Pick disease type C. Several plasma metabolites have emerged as sensitive Niemann-Pick disease type C biomarkers, and their study, completed by sequencing of the NPC1 and NPC2 genes, constitutes the recommended first-line testing once Niemann-Pick disease type C is suspected clinically. […] The clinical diagnosis of Niemann-Pick disease type C is relatively easy in patients with the most typical symptoms, such as combined splenomegaly, ataxia, and vertical gaze palsy. However, strikingly different clinical presentations exist, especially in infants and neonates. […] The „filipin test” (ie, demonstration in cultured cells of an accumulation of unesterified cholesterol in perinuclear vesicles, visualized by fluorescence microscopy after staining with filipin) was considered the gold standard diagnostic assay for Niemann-Pick disease type C.

• #30 Challenges in the Definitive Diagnosis of Niemann–Pick Type C—Leaky Variants and Alternative Transcripts

  https://www.mdpi.com/2073-4425/14/11/1990

  Overall, the wide range of clinical phenotypes and the different ages of onset it may present with, together with the rarity of the disease and the fact it may be caused by mutations in two different genes, make its diagnosis a significant challenge. […] That is why a definitive NPC diagnosis must rely on additional laboratorial analyses. The classical method of establishing a NPC diagnosis relies on the filipin staining of cultured fibroblasts from skin biopsies. This is a microscopy-based test that takes advantage of the fact that filipin specifically binds to unesterified cholesterol, allowing the evaluation of cholesterol accumulation in the perinuclear vesicular compartments. […] Nevertheless, even the most severely affected patients may fail to be diagnosed through this method. […] Recent advances in the field are actively contributing to an increase in the detection of NPC patients. Among those advances is the development of rapid and reliable biomarkers, including oxysterols, lysosphingomyelin derivatives, and bile acids, even though none of them are specific to NPC.

• #31 Advancing diagnosis and treatment of Niemann-Pick C disease through biomarker discovery

  https://www.explorationpub.com/Journals/ent/Article/100412

  Until recently, the standard for diagnosis of NPC disease was filipin staining of unesterified cholesterol in cultured skin fibroblasts obtained from patients. The filipin test identifies approximately 80-85% classical NPC patients; however, the test does not provide a clear result in patients with variant phenotypes. […] Over the past decade, the discovery of disease-specific, blood-based biomarkers has transformed the diagnosis of NPC, supplanting filipin as first-line diagnostics. The first generation of these markers were non-enzymatic oxidation products of cholesterol known as oxysterols. […] To date, the oxysterol assay has been implemented in 50 clinical laboratories worldwide and widely adopted in NPC diagnostic algorithms. […] The infeasibility of using C-triol or other oxysterol species for newborn screening in NPC disease prompted us to pursue further biomarker discovery.

• #32 Consensus clinical management guidelines for Niemann-Pick disease type C | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-018-0785-7

  Once NPC is suspected clinically, diagnosis can be confirmed by the combination of biochemical and molecular genetic studies. […] Assessment of biomarkers should be considered as a first-line test to screen for NPC. […] Mutation analysis of NPC1 and NPC2 genes is mandatory to confirm the diagnosis of NPC. […] Filipin test is no longer considered a first line test for the diagnosis of NPC. […] Brain imaging changes in individuals with NPC are variable and non-specific, but the most commonly reported changes are reductions in volume of the cerebellum, hippocampus, and subcortical grey matter, in addition to subtle changes in most white matter regions. […] NPC is a progressive condition and patients require regular follow up. Treatment goals should be established at diagnosis and reviewed regularly, aimed at improving or maintaining the physical and psychosocial wellbeing of individuals with NPC and their families.

• #33 Recommendations for the detection and diagnosis of Niemann-Pick disease type C

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5800709/

  Biomarker screening methods can now be considered a first-line step in the NP-C diagnostic process. […] It is crucial to genetically confirm a diagnosis in patients with high clinical suspicion and/or a biomarker profile consistent with NP-C. […] Positive genetic testing results, or positive biomarker testing results combined with molecular genetic analysis, are now deemed sufficient to diagnose NP-C in most cases.

• #34 Consensus clinical management guidelines for Niemann-Pick disease type C | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-018-0785-7

  Once NPC is suspected clinically, diagnosis can be confirmed by the combination of biochemical and molecular genetic studies. […] Assessment of biomarkers should be considered as a first-line test to screen for NPC. […] Mutation analysis of NPC1 and NPC2 genes is mandatory to confirm the diagnosis of NPC. […] Filipin test is no longer considered a first line test for the diagnosis of NPC. […] Brain imaging changes in individuals with NPC are variable and non-specific, but the most commonly reported changes are reductions in volume of the cerebellum, hippocampus, and subcortical grey matter, in addition to subtle changes in most white matter regions. […] NPC is a progressive condition and patients require regular follow up. Treatment goals should be established at diagnosis and reviewed regularly, aimed at improving or maintaining the physical and psychosocial wellbeing of individuals with NPC and their families.

• #35 Invitae Niemann-Pick Disease Types A and B Panel | Test catalog | Invitae

  https://www.invitae.com/us/providers/test-catalog/test-06190

  The Invitae Niemann-Pick Disease Types A and B Test analyzes the SMPD1 gene; which causes both conditions. SMPD1 encodes the lysosomal enzyme acid sphingomyelinase (ASM), and varying degrees of residual enzyme activity results in a clinical spectrum of acid sphingomyelinase deficiency. Niemann-Pick disease type A (NPA) and Niemann-Pick disease type B (NPB) are different manifestations along this clinical continuum and are due to differing amounts of residual ASM activity. […] This panel is indicated for any individual in whom NPA or NPB is suspected based on clinical or laboratory findings. Genetic testing of SMPD1 may confirm a diagnosis and help guide treatment and management decisions. Identification of disease-causing variants provides accurate risk assessment and carrier status of at-risk relatives. […] For individuals with a clinical and biochemical diagnosis of Niemann Pick Disease Type A or Type B, the detection rate of pathogenic variants in SMPD1 is greater than 95%.

• #36 An uncommon diagnosis of a common clinical presentation – Visceral Niemann–Pick disease – Wadia Journal of Women and Child Health

  https://wjwch.com/an-uncommon-diagnosis-of-a-common-clinical-presentation-visceral-niemannpick-disease/

  NiemannPick (NP) disease is a diverse spectrum of disorders, autosomal recessive in nature, characterized by failure to thrive, visceral involvement in the form of hepatosplenomegaly and neurodegenerative changes. […] Diagnosis of Types A and B NP disease is confirmed by molecular genetic testing which is positive for Sphingomyelin Phosphodiesterase-1 (SMPD1) gene. NP type C is detected on biomarker screening for oxysterols. […] Bone marrow aspiration shows macrophages. Diagnosis of Types A and B NP disease is confirmed by molecular genetic testing which is positive for SMPD1 gene mutations. NP type C is detected on biomarker screening for oxysterols.

• #37 Invitae Niemann-Pick Disease Types A and B Panel | Test catalog | Invitae

  https://www.invitae.com/us/providers/test-catalog/test-06190

  The Invitae Niemann-Pick Disease Types A and B Test analyzes the SMPD1 gene; which causes both conditions. SMPD1 encodes the lysosomal enzyme acid sphingomyelinase (ASM), and varying degrees of residual enzyme activity results in a clinical spectrum of acid sphingomyelinase deficiency. Niemann-Pick disease type A (NPA) and Niemann-Pick disease type B (NPB) are different manifestations along this clinical continuum and are due to differing amounts of residual ASM activity. […] This panel is indicated for any individual in whom NPA or NPB is suspected based on clinical or laboratory findings. Genetic testing of SMPD1 may confirm a diagnosis and help guide treatment and management decisions. Identification of disease-causing variants provides accurate risk assessment and carrier status of at-risk relatives. […] For individuals with a clinical and biochemical diagnosis of Niemann Pick Disease Type A or Type B, the detection rate of pathogenic variants in SMPD1 is greater than 95%.

• #38 Invitae Niemann-Pick Disease Type C Panel | Test catalog | Invitae

  https://www.invitae.com/us/providers/test-catalog/test-06176

  Test code: 06176 […] This panel is indicated for any individual in whom NPC is suspected based on clinical, radiologic, or laboratory findings. […] Of individuals with a clinical diagnosis of NPC, 95% will have two pathogenic variants in NPC1 and approximately 4% will have biallelic pathogenic variants in NPC2. Less than 1% of cases with clinical and biochemical findings will have pathogenic variants in neither NPC1 or NPC2. […] Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS). […] Based on validation study results, this assay achieves 99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions 15bp in length, and exon-level deletions and duplications. Invitae’s methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. […] Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test.

• #39 A Rare Case of Late Adult-Onset Niemann-Pick Disease Type C

  https://www.e-jmd.org/journal/view.php?number=278

  Niemann-Pick disease type C (NPC) is an autosomal recessive neurodegenerative disorder caused by mutation of either NPC1 (95% of cases) or NPC2. […] Early diagnosis of NPC is important because treatment with miglustat has been shown to stabilize disease progression. […] The NPC suspicion index score was 100, indicating its high probability. […] The genetic testing was also compatible with the recently proposed diagnostic criteria for NPC in which the diagnosis can be confirmed by the identification of two known or likely pathogenic alleles. […] In adult-onset NPC, diagnostic delay is common and often 5 years or more, as seen in our case. […] VSGP is present in approximately 70-80% of the patients across all age at onset categories, which suggests that clinicians should consider NPC in the differential diagnosis of VSGP, regardless of age at onset. […] Thus, the absence of VSGP cannot rule out the diagnosis of NPC, and eye movements need to be checked regularly in patients with suspected NPC, but without VSGP.

• #40 Clinical disease characteristics of patients with Niemann-Pick Disease Type C: findings from the International Niemann-Pick Disease Registry (INPDR) | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-022-02200-4

  Niemann-Pick Disease Type C (NPC) is an autosomal recessive rare disease characterised by progressive neurovisceral manifestations. The INPDR is a web-based, patient-led independent registry for the collection of prospective and retrospective clinical data from Niemann-Pick Disease patients. The mean age (SD) at diagnosis was 11.2 years (14.2). Among the 97 patients with identified NPC1 variants, the most common variant was the c. 3182TC variant responsible for the p.lle1061Thr protein change, reported in 35.1% (N=34) of patients. The age at diagnosis and death increased with increased age of neurological symptom onset. The clinical spectrum of NPC encompasses a range of non-specific neurological and systemic manifestations at an early stage and varying by age of onset and organ involvement. The classification of NPC by age of neurological onset is as follows: early infantile (2 years) (visceral-neurodegenerative form); late-infantile (2-6 years) and juvenile (6-15 years) (neurodegenerative form); adult (15 years) (psychiatric-neurodegenerative form). The rarity, varied age of onset, heterogeneous and non-specific manifestations of the disease pose significant challenges in understanding the natural course of NPC. The INPDR is a patient led registry designed to: (a) better understand the natural history of Niemann-Pick disease worldwide; (b) provide an inventory of patients for recruitment to observational and interventional studies; (c) establish genotype-phenotype correlations; (d) provide support for education of health professionals and empowerment of patients. The p.I1061T variant was the most common variant in this population, with detection in 28.6% of patients. Disease classification based on the age of onset of the first neurological symptoms has been accepted as a guide to clinicians in providing day to day care, genetic counselling and to estimate the trajectory of the disease course. The type and onset of visceral symptoms varied across the age groups with decreased occurrence with an increasing age. Clinical assessment of disease burden and rate of progression in time or regression with disease modifying therapy is challenging when dealing with progressive diseases such as NPC. The composite disability scores were notably higher in patients with early onset neurological signs, particularly in late infantile patients. Mortality data was available for 59 patients and the duration of survival after disease onset varies with age spectrum of the disease. The most common therapy was Miglustat, a potential disease modifying therapy specifically indicated for NPC, reported in 85 (62.4%) patients, with a mean duration of just over 4 years.

• #41

  https://link.springer.com/article/10.1007/s11011-019-00445-w

  The filipin staining test was the first one, which has been used for identification of NPC individuals for over 30 years. […] Since filipin test is invasive, long lasting and laborious there was an expectation on fast and easy tests in blood. […] In 1994, Hollak et al. revealed chitotriosidase to be a novel biomarker for Gaucher disease but it soon was demonstrated that moderate elevation of chitotriosidase activity can be found in patients with some other lysosomal diseases and among them also in NPC. […] Since early 1990, molecular analyses based on polymerase chain reaction method (PCR) are available in the diagnostic process of NPC. […] Results of biochemical biomarkers testing alone provide a very high suspicion of NPC which in several cases must be confirmed by genetic testing. […] The most commonly used diagnostic molecular method for NPC is Sanger sequencing, which uses the polymerase chain reaction (PCR). […] All biochemical and molecular techniques described in this review are summarized in Table 2.

• #42 Invitae Niemann-Pick Disease Types A and B Panel | Test catalog | Invitae

  https://www.invitae.com/us/providers/test-catalog/test-06190

  The Invitae Niemann-Pick Disease Types A and B Test analyzes the SMPD1 gene; which causes both conditions. SMPD1 encodes the lysosomal enzyme acid sphingomyelinase (ASM), and varying degrees of residual enzyme activity results in a clinical spectrum of acid sphingomyelinase deficiency. Niemann-Pick disease type A (NPA) and Niemann-Pick disease type B (NPB) are different manifestations along this clinical continuum and are due to differing amounts of residual ASM activity. […] This panel is indicated for any individual in whom NPA or NPB is suspected based on clinical or laboratory findings. Genetic testing of SMPD1 may confirm a diagnosis and help guide treatment and management decisions. Identification of disease-causing variants provides accurate risk assessment and carrier status of at-risk relatives. […] For individuals with a clinical and biochemical diagnosis of Niemann Pick Disease Type A or Type B, the detection rate of pathogenic variants in SMPD1 is greater than 95%.

• #43 Niemann-Pick disease – Diagnosis and treatment – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/niemann-pick/diagnosis-treatment/drc-20355890

  DNA testing of a blood sample may show the specific gene changes that cause Niemann-Pick disease types A, B and C. […] An MRI of the brain may show loss of brain cells. But in the early stages of Niemann-Pick disease, an MRI may not show any changes because symptoms usually show up before the loss of brain cells. […] An eye exam may show changes that could be caused by Niemann-Pick disease, such as problems with eye movements in type C and changes inside the eyes in types A and B. […] Ultrasound during pregnancy can show the large liver and spleen caused by Niemann-Pick disease type C. […] Genetic testing and counseling for families with a child with Niemann-Pick disease can give information about risks and family planning options.

• #44 Consensus clinical management guidelines for Niemann-Pick disease type C | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-018-0785-7

  Once NPC is suspected clinically, diagnosis can be confirmed by the combination of biochemical and molecular genetic studies. […] Assessment of biomarkers should be considered as a first-line test to screen for NPC. […] Mutation analysis of NPC1 and NPC2 genes is mandatory to confirm the diagnosis of NPC. […] Filipin test is no longer considered a first line test for the diagnosis of NPC. […] Brain imaging changes in individuals with NPC are variable and non-specific, but the most commonly reported changes are reductions in volume of the cerebellum, hippocampus, and subcortical grey matter, in addition to subtle changes in most white matter regions. […] NPC is a progressive condition and patients require regular follow up. Treatment goals should be established at diagnosis and reviewed regularly, aimed at improving or maintaining the physical and psychosocial wellbeing of individuals with NPC and their families.

• #45 Niemann-Pick disease | UM Health-Sparrow

  https://www.uofmhealthsparrow.org/departments-conditions/conditions/niemann-pick-disease

  DNA testing of a blood sample may show the specific gene changes that cause Niemann-Pick disease types A, B and C. People who have only one copy of the gene change but do not have the condition are called carriers. DNA tests can show carriers for all types of Niemann-Pick disease if the gene changes have been identified in the first person in a family to have the condition. The gene change can be passed on to children. […] An MRI of the brain may show loss of brain cells. But in the early stages of Niemann-Pick disease, an MRI may not show any changes because symptoms usually show up before the loss of brain cells. MRI also can be used to look at the liver and spleen to see if they are large and to measure their size. […] An eye exam may show changes that could be caused by Niemann-Pick disease, such as problems with eye movements in type C and changes inside the eyes in types A and B.

• #46 Diagnosis And Treatment For Niemann-Pick Disease – Klarity Health Library

  https://my.klarity.health/diagnosis-and-treatment-for-niemann-pick-disease/

  Niemann-Pick disease involves a combination of clinical evaluation, laboratory testing, genetic analysis, and imaging studies: […] Laboratory tests: Enzyme activity assays to measure ASM activity in blood leukocytes are used for Type A and Type B. Genetic testing confirms the diagnosis by identifying mutations in the SMPD1 gene (Type A and Type B) or NPC1/NPC2 genes (Type C) […] Imaging studies: MRI and CT scans are employed to evaluate organomegaly (enlarged liver) and detect neurological abnormalities. The cholesterol esterification test aids in diagnosing Type C by assessing cholesterol metabolism in cultured fibroblasts or other cells […] Neurological testing: This type of test can evaluate the function of the brain and nervous system, not only aiding in the diagnosis but also determining the severity of the disease […] Liver and spleen biopsy: This involves collecting a small sample of liver or spleen tissue and examining it under a microscope to look for abnormalities.

• #47 Niemann-Pick disease – Diagnosis and treatment – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/niemann-pick/diagnosis-treatment/drc-20355890

  DNA testing of a blood sample may show the specific gene changes that cause Niemann-Pick disease types A, B and C. […] An MRI of the brain may show loss of brain cells. But in the early stages of Niemann-Pick disease, an MRI may not show any changes because symptoms usually show up before the loss of brain cells. […] An eye exam may show changes that could be caused by Niemann-Pick disease, such as problems with eye movements in type C and changes inside the eyes in types A and B. […] Ultrasound during pregnancy can show the large liver and spleen caused by Niemann-Pick disease type C. […] Genetic testing and counseling for families with a child with Niemann-Pick disease can give information about risks and family planning options.

• #48 Niemann-Pick disease type A – Metabolic Support UKAccessibility ToolsIncrease TextDecrease TextGrayscaleHigh ContrastNegative ContrastLight BackgroundLinks UnderlineReadable FontReset

  https://metabolicsupportuk.org/condition/niemann-pick-disease-type-a/

  ASMD NP- A can also be diagnosed by taking a skin biopsy. This test involves a health care professional taking a small sample of your skin to measure how the cells move and store components in your child’s body. […] Other tests may include an eye exam by an ophthalmologist, identifying a cherry red spot within the eye may be an indicator for Nieman pick type A disease although genetic testing would need to be performed in conjunction with this for the correct diagnosis.

• #49 Niemann-Pick disease | UM Health-Sparrow

  https://www.uofmhealthsparrow.org/departments-conditions/conditions/niemann-pick-disease

  DNA testing of a blood sample may show the specific gene changes that cause Niemann-Pick disease types A, B and C. People who have only one copy of the gene change but do not have the condition are called carriers. DNA tests can show carriers for all types of Niemann-Pick disease if the gene changes have been identified in the first person in a family to have the condition. The gene change can be passed on to children. […] An MRI of the brain may show loss of brain cells. But in the early stages of Niemann-Pick disease, an MRI may not show any changes because symptoms usually show up before the loss of brain cells. MRI also can be used to look at the liver and spleen to see if they are large and to measure their size. […] An eye exam may show changes that could be caused by Niemann-Pick disease, such as problems with eye movements in type C and changes inside the eyes in types A and B.

• #50 Orphanet: Niemann-Pick disease type C

  https://www.orpha.net/en/disease/detail/646

  The diagnosis of NPDC must be confirmed by mutation analysis and, if necessary, filipin test (based on the reaction of unesterified cholesterol with fluorescent antibiotic filipin). Several biomarkers are used alone or in combination as a first-line test to screen for NPDC: oxysterols (cholestane-3, 5, 6-triol); lyso-SM-509 and lyso-sphingomyelin. Foam cells and sea-blue histiocytes are usually present in the bone marrow. […] Prenatal diagnosis of NPDC should be offered to couples at risk. Molecular genetic analysis is the preferred strategy. […] Genetic counseling should be offered to at-risk couples informing them that there is a 25% risk of having an affected child at each pregnancy.

• #51 An uncommon diagnosis of a common clinical presentation – Visceral Niemann–Pick disease – Wadia Journal of Women and Child Health

  https://wjwch.com/an-uncommon-diagnosis-of-a-common-clinical-presentation-visceral-niemannpick-disease/

  NiemannPick (NP) disease is a diverse spectrum of disorders, autosomal recessive in nature, characterized by failure to thrive, visceral involvement in the form of hepatosplenomegaly and neurodegenerative changes. […] Diagnosis of Types A and B NP disease is confirmed by molecular genetic testing which is positive for Sphingomyelin Phosphodiesterase-1 (SMPD1) gene. NP type C is detected on biomarker screening for oxysterols. […] Bone marrow aspiration shows macrophages. Diagnosis of Types A and B NP disease is confirmed by molecular genetic testing which is positive for SMPD1 gene mutations. NP type C is detected on biomarker screening for oxysterols.

• #52 Microcytosis Leads to Niemann-Pick Disease Type C Diagnosis for Toddler

  https://www.ajmc.com/view/microcytosis-leads-to-niemann-pick-disease-type-c-diagnosis-for-toddler

  A young child with Niemann-Pick Disease type C (NPDC) was diagnosed after first presenting with neurodevelopmental delay and persistent microcytosis, according to a new case report. […] The authors added that BMA is widely available in most medical centers, and in this case revealed, the presence of foamy histiocytes indicating lipidosis, and also showed that the child was iron deficient despite having normal- high ferritin levels. […] As this (microcytosis) may be another frequent manifestation of [NPDC], being aware of it may allow for an early diagnosis and thus avoid unnecessary tests, they wrote.

• #53 Diagnosis And Treatment For Niemann-Pick Disease – Klarity Health Library

  https://my.klarity.health/diagnosis-and-treatment-for-niemann-pick-disease/

  Niemann-Pick disease involves a combination of clinical evaluation, laboratory testing, genetic analysis, and imaging studies: […] Laboratory tests: Enzyme activity assays to measure ASM activity in blood leukocytes are used for Type A and Type B. Genetic testing confirms the diagnosis by identifying mutations in the SMPD1 gene (Type A and Type B) or NPC1/NPC2 genes (Type C) […] Imaging studies: MRI and CT scans are employed to evaluate organomegaly (enlarged liver) and detect neurological abnormalities. The cholesterol esterification test aids in diagnosing Type C by assessing cholesterol metabolism in cultured fibroblasts or other cells […] Neurological testing: This type of test can evaluate the function of the brain and nervous system, not only aiding in the diagnosis but also determining the severity of the disease […] Liver and spleen biopsy: This involves collecting a small sample of liver or spleen tissue and examining it under a microscope to look for abnormalities.

• #54 Genetic Testing – NPUK

  https://www.npuk.org/niemann-pick-diseases/genetic-testing/

  Prenatal diagnosis for Niemann-Pick disease is possible. If the DNA mutations of both parents are known, then the process of prenatal diagnosis can be much quicker. […] Carrier testing is conducted to determine if a person is a carrier for a specific autosomal recessive disease, such as Niemann-Pick disease. This kind of testing is primarily used by couples who are considering becoming pregnant to determine the risks of their child inheriting a genetic disorder.

• #55 Orphanet: Niemann-Pick disease type C

  https://www.orpha.net/en/disease/detail/646

  The diagnosis of NPDC must be confirmed by mutation analysis and, if necessary, filipin test (based on the reaction of unesterified cholesterol with fluorescent antibiotic filipin). Several biomarkers are used alone or in combination as a first-line test to screen for NPDC: oxysterols (cholestane-3, 5, 6-triol); lyso-SM-509 and lyso-sphingomyelin. Foam cells and sea-blue histiocytes are usually present in the bone marrow. […] Prenatal diagnosis of NPDC should be offered to couples at risk. Molecular genetic analysis is the preferred strategy. […] Genetic counseling should be offered to at-risk couples informing them that there is a 25% risk of having an affected child at each pregnancy.

• #56 Niemann-Pick Disease – Children’s Health Issues – Merck Manual Consumer Version

  https://www.merckmanuals.com/home/children-s-health-issues/hereditary-metabolic-disorders/niemann-pick-disease

  Niemann-Pick disease types A and B occur when the body lacks enzymes needed to break down sphingomyelin. […] The diagnosis is based on blood tests. […] Before birth, Niemann-Pick disease types A and B can be diagnosed in the fetus by using the prenatal screening tests chorionic villus sampling or amniocentesis. […] After birth, the diagnosis of Niemann-Pick disease types A and B may be diagnosed in some states in the United States by routine newborn screening tests. […] Doctors also measure levels of sphingomyelinase in white blood cells for types A and B. […] Genetic testing, which is used to determine whether a couple is at increased risk of having a baby with a hereditary genetic disorder, is also available for all 3 types. […] Tests of DNA (the building blocks of genes) may be done to identify carriers.

• #57 Niemann-Pick Disease | Baby’s First Test | Newborn Screening | Baby Health

  https://babysfirsttest.org/newborn-screening/conditions/niemann-pick-disease

  Your babys doctor may ask you if your baby is showing any of the signs of Niemann-Pick disease (see Early Signs below). If your baby has certain signs, your babys doctor may suggest starting immediate treatment. […] If your babys newborn screening result for Niemann-Pick disease (NPD) was out of the normal range, your babys doctor or the state screening program will contact you to arrange for your child to have additional testing. It is important to remember that an out-of-range screening result does not necessarily mean that your child has the condition. […] However, as a few babies do have the condition, it is very important that you go to your follow-up appointment for a confirmatory test. Because the harmful effects of untreated NPD can occur soon after birth, follow-up testing must be completed as soon as possible to determine whether or not your baby has the condition.

• #58 Newborn Screening Program – Niemann-Pick Disease

  http://www.idph.state.il.us/healthwellness/fs/niemann_pick.htm

  Niemann-Pick disease is an inherited metabolic disorder in which harmful amounts of a sphingolipid called sphingomyelin accumulate within lysosomes of cells. […] Niemann-Pick disease is categorized into four types: A, B, C and D. Only types A and B are detected by newborn screening. […] Statewide screening of newborns for lysosomal storage disorders is scheduled to begin in 2014. […] It is important to reassure parents that not all infants identified by newborn screening as having low ASM activity will turn out to have Niemann-Pick disease. If the child needs additional testing or diagnostic evaluation, make certain the parents understand the importance of following the pediatricians and/or specialists recommendations for additional testing and referrals. […] These guidelines should be followed after a diagnosis of Niemann-Pick disease has been confirmed: Follow up with the child’s metabolic disease specialist. Use a multidisciplinary approach for long-term management including specialists from pediatrics, genetics, and others experienced with managing individuals with Niemann-Pick disease. Ensure that parents understand that treatment for Niemann-Pick disease is not curative and that morbidity cannot always be prevented. Recommend genetic counseling services to help the parents understand the complexity surrounding the carrier state and inheritance of this disease.

• #59 Niemann-Pick Disease | Baby’s First Test | Newborn Screening | Baby Health

  https://babysfirsttest.org/newborn-screening/conditions/niemann-pick-disease

  Follow-up testing will involve checking your babys blood for signs of NPD. When a child has a lysosomal storage disorder, an enzyme that helps the body breakdown fats is either missing or not working properly. Evaluating the activity of this enzyme in your babys body can help doctors determine if your baby has the condition. Deficient activity of the enzyme, acid sphingomyelinase (ASM), in the blood may indicate that your baby has NPD. Your babys doctor may also want to confirm the diagnosis with clinical genetic testing. […] Early detection and proper treatment can help improve the quality of life in babies with NPD-A and the long term outcome of babies with NPD-B. This is why newborn screening for NPD is so important. […] Healthcare professionals can learn more about confirmatory testing by reading the American College of Medical Genetics and Genomics’ Algorithm for Diagnosis and ACT Sheet, a guide for follow-up after newborn screening.

• #60 Genetic Testing – NPUK

  https://www.npuk.org/niemann-pick-diseases/genetic-testing/

  Prenatal diagnosis for Niemann-Pick disease is possible. If the DNA mutations of both parents are known, then the process of prenatal diagnosis can be much quicker. […] Carrier testing is conducted to determine if a person is a carrier for a specific autosomal recessive disease, such as Niemann-Pick disease. This kind of testing is primarily used by couples who are considering becoming pregnant to determine the risks of their child inheriting a genetic disorder.

• #61 Genetic Testing – NPUK

  https://www.npuk.org/niemann-pick-diseases/genetic-testing/

  Niemann-Pick diseases are acquired through autosomal recessive inheritance, which means that the affected individual inherits two faulty (mutated) genes, one from each parent. If an individual has a single copy of the mutated gene, they are known as a carrier, and it will have no noticeable effect on their everyday lives and health. […] Genetic counselling is recommended for all couples in which both partners are known to be carriers, or if one partner is a known carrier and the others status is uncertain. […] Genetic testing (or screening) is a type of medical test that aims to identify changes in chromosomes, genes or proteins. The results of these tests can confirm or rule out a suspected genetic condition (such as Niemann-Pick disease), or help determine a persons chance of developing or passing on a genetic disorder.

• #62 Newborn Screening Program – Niemann-Pick Disease

  http://www.idph.state.il.us/healthwellness/fs/niemann_pick.htm

  Niemann-Pick disease is an inherited metabolic disorder in which harmful amounts of a sphingolipid called sphingomyelin accumulate within lysosomes of cells. […] Niemann-Pick disease is categorized into four types: A, B, C and D. Only types A and B are detected by newborn screening. […] Statewide screening of newborns for lysosomal storage disorders is scheduled to begin in 2014. […] It is important to reassure parents that not all infants identified by newborn screening as having low ASM activity will turn out to have Niemann-Pick disease. If the child needs additional testing or diagnostic evaluation, make certain the parents understand the importance of following the pediatricians and/or specialists recommendations for additional testing and referrals. […] These guidelines should be followed after a diagnosis of Niemann-Pick disease has been confirmed: Follow up with the child’s metabolic disease specialist. Use a multidisciplinary approach for long-term management including specialists from pediatrics, genetics, and others experienced with managing individuals with Niemann-Pick disease. Ensure that parents understand that treatment for Niemann-Pick disease is not curative and that morbidity cannot always be prevented. Recommend genetic counseling services to help the parents understand the complexity surrounding the carrier state and inheritance of this disease.

• #63 Niemann-Pick Disease | Causes, signs, symptoms & treatment

  https://cpdonline.co.uk/knowledge-base/care/niemann-pick-disease/

  How is Niemann-Pick disease diagnosed? […] Given the huge range of symptoms and the many overlaps with other conditions, it can be difficult to get a diagnosis of Niemann-Pick disease. Clinicians do have tools that help them to identify the signs and symptoms but there needs to be suspicion of the condition before these will be used. The tools include: The NPC Suspicion Index Tool, NPS Clinical Severity Scale (NPCCSS), The Assessment and Rating of Ataxia (SARA) scale. […] There are also biomarkers than can be tested. These include bile acids and lysoSM-509. However, there are no biomarkers that will tell you of any CNS (central nervous system) manifestations or whether there has been disease progression. […] The difficulty in diagnosing NPC (Niemann-Pick type C) means that there are often years of delays in receiving a diagnosis. On average, this is just over 4 years.

• #64 Advancing diagnosis and treatment of Niemann-Pick C disease through biomarker discovery

  https://www.explorationpub.com/Journals/ent/Article/100412

  Niemann-Pick C disease is a rare neurodegenerative, lysosomal storage disease caused by accumulation of unesterified cholesterol. Diagnosis of the disease is often delayed due to its rarity, the heterogeneous presentation, and the early non-specific symptoms. The discovery of disease-specific biomarkers cholestane-3,5,6-triol (C-triol), trihydroxycholanic acid glycinate (TCG) and N-palmitoyl-O-phosphocholineserine [PPCS, initially referred to as lysosphingomyelin-509 (lysoSM-509)] has led to development of non-invasive, blood-based diagnostics. […] Diagnosis of NPC is challenging due to the rarity of the disorder, the heterogeneity of disease onset and presentation, its non-specific early symptoms, and the complexity of the laboratory testing. Consequently, diagnosis is typically delayed 4-5 years for the late-infantile and juvenile forms of the disease, during which time opportunities for early intervention are lost.

• #65 Recommendations for the detection and diagnosis of Niemann-Pick disease type C

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5800709/

  Niemann-Pick disease type C (NP-C) is a neurovisceral disorder that may be more prevalent than earlier estimates. Diagnosis of NP-C is often delayed; a key aim for clinical practice is to reduce this delay. Recently, substantial progress has been made in the field of NP-C screening and diagnosis, justifying an update to the existing recommendations for clinical practice. […] New biomarker profiling and genetic analysis technologies are included as first-line diagnostic tests for NP-C. Most diagnoses can now be confirmed by combination of biomarker and genetic analyses. Filipin staining may facilitate diagnosis in uncertain cases. Recommendations are provided for psychiatrists, neuro-ophthalmologists, and radiologists, and on screening within specific at-risk patient cohorts. The NP-C diagnostic algorithm has been updated and simplified.

• #66 Recommendations for the detection and diagnosis of Niemann-Pick disease type C

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5800709/

  The NP-C Diagnostic Recommendations Expert Panel met in May 2016 to assess the impact of recently published data and to reach consensus on the best approaches to diagnosing NP-C. The following sections of the previous recommendations were updated: differential diagnosis and initial detection, diagnosis, and the NP-C diagnostic algorithm. Three approaches to the detection and diagnosis of patients with NP-C were established: clinical assessment, biomarker testing, and genetic analysis. […] All patients with suspicion of NP-C require rigorous and detailed clinical assessment, as described in the 2012 diagnostic recommendations. All undiagnosed patients with any manifestation of NP-C should be referred to regional or national centers specializing in inherited metabolic disorders. […] The NP-C Suspicion Index (NP-C SI) quantifies the diagnostic weight of NP-C signs and symptoms, individually and in combination.

• #67 Recommendations for the detection and diagnosis of Niemann-Pick disease type C

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5800709/

  Biomarker screening methods can now be considered a first-line step in the NP-C diagnostic process. […] It is crucial to genetically confirm a diagnosis in patients with high clinical suspicion and/or a biomarker profile consistent with NP-C. […] Positive genetic testing results, or positive biomarker testing results combined with molecular genetic analysis, are now deemed sufficient to diagnose NP-C in most cases.

• #68 Consensus clinical management guidelines for Niemann-Pick disease type C | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-018-0785-7

  Once NPC is suspected clinically, diagnosis can be confirmed by the combination of biochemical and molecular genetic studies. […] Assessment of biomarkers should be considered as a first-line test to screen for NPC. […] Mutation analysis of NPC1 and NPC2 genes is mandatory to confirm the diagnosis of NPC. […] Filipin test is no longer considered a first line test for the diagnosis of NPC. […] Brain imaging changes in individuals with NPC are variable and non-specific, but the most commonly reported changes are reductions in volume of the cerebellum, hippocampus, and subcortical grey matter, in addition to subtle changes in most white matter regions. […] NPC is a progressive condition and patients require regular follow up. Treatment goals should be established at diagnosis and reviewed regularly, aimed at improving or maintaining the physical and psychosocial wellbeing of individuals with NPC and their families.

• #69 Recommendations for the detection and diagnosis of Niemann-Pick disease type C

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5800709/

  The NP-C Diagnostic Recommendations Expert Panel met in May 2016 to assess the impact of recently published data and to reach consensus on the best approaches to diagnosing NP-C. The following sections of the previous recommendations were updated: differential diagnosis and initial detection, diagnosis, and the NP-C diagnostic algorithm. Three approaches to the detection and diagnosis of patients with NP-C were established: clinical assessment, biomarker testing, and genetic analysis. […] All patients with suspicion of NP-C require rigorous and detailed clinical assessment, as described in the 2012 diagnostic recommendations. All undiagnosed patients with any manifestation of NP-C should be referred to regional or national centers specializing in inherited metabolic disorders. […] The NP-C Suspicion Index (NP-C SI) quantifies the diagnostic weight of NP-C signs and symptoms, individually and in combination.

• #70 A new test for diagnosing Niemann–Pick disease

  https://www.asbmb.org/asbmb-today/science/060116/a-new-test-for-diagnosing-niemann%E2%80%93pick-disease

  NiemannPick disease is a rare genetic disease with devastating effects. Until recently, the first-line diagnostic test for NPC disease involved a skin biopsy and filipin staining, which is invasive, cumbersome and expensive. Patients with NPC often go up to five years without a diagnosis, drastically limiting the possibility of early interventions. Importantly, the new noninvasive assay produces results within a day instead of months. The team used mass spectrometry to analyze dried blood spots collected at various times after birth from patients known to have NPC. They found three bile acid biomarkers that could distinguish NPC patients from people without the disease. Ory says the assay already is being used at Washington University in St. Louis, Mo., as a diagnostic test. For its use in newborn screening, Ory says researchers will need to put the assay to the test in the undiagnosed newborn population to ensure its usefulness for that age group. The approach weve taken over the last 10 years, I feel like, its getting close to bearing fruit.

• #71 Challenges in the Definitive Diagnosis of Niemann–Pick Type C—Leaky Variants and Alternative Transcripts

  https://www.mdpi.com/2073-4425/14/11/1990

  However, N-palmitoyl-O-phosphocholineserine, (PPCS, previously known as lysosphingomyelin-509) has been shown to be elevated in the plasma and dried blood spots of NPC patients. […] The increased availability of NGS has also contributed to the update of the overall NPC diagnostic algorithm while actively contributing to an increase in the number of positive molecular NPC diagnoses. Currently, there are a number of fully described diagnostic workflows for NPC, which may slightly vary between different labs depending on the tests each of them has available. However, NPC1 and NPC2 molecular analysis is mandatory in all of them and usually represents the ultimate step towards diagnosis. […] Indeed, a rapid molecular diagnosis of a potential NPC patient is essential, not just for swift access to available therapies (currently miglustat is the only one approved within the European Union) but also to slow the progression of the disease and ultimately because it is the sole method of offering prenatal diagnosis to affected families.

• #72

  https://link.springer.com/article/10.1007/s11011-019-00445-w

  The filipin staining test was the first one, which has been used for identification of NPC individuals for over 30 years. […] Since filipin test is invasive, long lasting and laborious there was an expectation on fast and easy tests in blood. […] In 1994, Hollak et al. revealed chitotriosidase to be a novel biomarker for Gaucher disease but it soon was demonstrated that moderate elevation of chitotriosidase activity can be found in patients with some other lysosomal diseases and among them also in NPC. […] Since early 1990, molecular analyses based on polymerase chain reaction method (PCR) are available in the diagnostic process of NPC. […] Results of biochemical biomarkers testing alone provide a very high suspicion of NPC which in several cases must be confirmed by genetic testing. […] The most commonly used diagnostic molecular method for NPC is Sanger sequencing, which uses the polymerase chain reaction (PCR). […] All biochemical and molecular techniques described in this review are summarized in Table 2.

• #73 Niemann-Pick Disease Type C Diagnosed Using Neonatal Cholestasis Gene Panel

  https://www.kjg.or.kr/journal/view.html?doi=10.4166/kjg.2021.079

  Niemann-Pick disease type C (NPC) is a neurovisceral lysosomal storage disorder caused by mutations in the NPC1 and NPC2 genes. These mutations cause the accumulation of unesterified cholesterol and other lipids in the lysosomes. […] Genetic analysis of the NPC1 and NPC2 genes provides a definitive diagnosis of NPC. Biomarkers, such as oxysterols, lyso-sphingomyelin, and lyso-sphingomyelin 509, can also be helpful in the diagnostic process. […] The neonatal cholestasis gene panel revealed two novel likely pathogenic variants in the NPC1 gene: c.1145CG (p.Ser382*) and c.2231_2233del (p.Val744del), leading to a diagnosis of NPC. […] In conclusion, NPC must be considered in infants who present with neonatal cholestasis. In addition, the neonatal cholestasis gene panel may be crucial in the diagnostic process.

• #74 Challenges in the Definitive Diagnosis of Niemann–Pick Type C—Leaky Variants and Alternative Transcripts

  https://www.mdpi.com/2073-4425/14/11/1990

  However, N-palmitoyl-O-phosphocholineserine, (PPCS, previously known as lysosphingomyelin-509) has been shown to be elevated in the plasma and dried blood spots of NPC patients. […] The increased availability of NGS has also contributed to the update of the overall NPC diagnostic algorithm while actively contributing to an increase in the number of positive molecular NPC diagnoses. Currently, there are a number of fully described diagnostic workflows for NPC, which may slightly vary between different labs depending on the tests each of them has available. However, NPC1 and NPC2 molecular analysis is mandatory in all of them and usually represents the ultimate step towards diagnosis. […] Indeed, a rapid molecular diagnosis of a potential NPC patient is essential, not just for swift access to available therapies (currently miglustat is the only one approved within the European Union) but also to slow the progression of the disease and ultimately because it is the sole method of offering prenatal diagnosis to affected families.

• #75 A Rare Case of Late Adult-Onset Niemann-Pick Disease Type C

  https://www.e-jmd.org/journal/view.php?number=278

  Niemann-Pick disease type C (NPC) is an autosomal recessive neurodegenerative disorder caused by mutation of either NPC1 (95% of cases) or NPC2. […] Early diagnosis of NPC is important because treatment with miglustat has been shown to stabilize disease progression. […] The NPC suspicion index score was 100, indicating its high probability. […] The genetic testing was also compatible with the recently proposed diagnostic criteria for NPC in which the diagnosis can be confirmed by the identification of two known or likely pathogenic alleles. […] In adult-onset NPC, diagnostic delay is common and often 5 years or more, as seen in our case. […] VSGP is present in approximately 70-80% of the patients across all age at onset categories, which suggests that clinicians should consider NPC in the differential diagnosis of VSGP, regardless of age at onset. […] Thus, the absence of VSGP cannot rule out the diagnosis of NPC, and eye movements need to be checked regularly in patients with suspected NPC, but without VSGP.

• #76 Clinical disease characteristics of patients with Niemann-Pick Disease Type C: findings from the International Niemann-Pick Disease Registry (INPDR) | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-022-02200-4

  Niemann-Pick Disease Type C (NPC) is an autosomal recessive rare disease characterised by progressive neurovisceral manifestations. The INPDR is a web-based, patient-led independent registry for the collection of prospective and retrospective clinical data from Niemann-Pick Disease patients. The mean age (SD) at diagnosis was 11.2 years (14.2). Among the 97 patients with identified NPC1 variants, the most common variant was the c. 3182TC variant responsible for the p.lle1061Thr protein change, reported in 35.1% (N=34) of patients. The age at diagnosis and death increased with increased age of neurological symptom onset. The clinical spectrum of NPC encompasses a range of non-specific neurological and systemic manifestations at an early stage and varying by age of onset and organ involvement. The classification of NPC by age of neurological onset is as follows: early infantile (2 years) (visceral-neurodegenerative form); late-infantile (2-6 years) and juvenile (6-15 years) (neurodegenerative form); adult (15 years) (psychiatric-neurodegenerative form). The rarity, varied age of onset, heterogeneous and non-specific manifestations of the disease pose significant challenges in understanding the natural course of NPC. The INPDR is a patient led registry designed to: (a) better understand the natural history of Niemann-Pick disease worldwide; (b) provide an inventory of patients for recruitment to observational and interventional studies; (c) establish genotype-phenotype correlations; (d) provide support for education of health professionals and empowerment of patients. The p.I1061T variant was the most common variant in this population, with detection in 28.6% of patients. Disease classification based on the age of onset of the first neurological symptoms has been accepted as a guide to clinicians in providing day to day care, genetic counselling and to estimate the trajectory of the disease course. The type and onset of visceral symptoms varied across the age groups with decreased occurrence with an increasing age. Clinical assessment of disease burden and rate of progression in time or regression with disease modifying therapy is challenging when dealing with progressive diseases such as NPC. The composite disability scores were notably higher in patients with early onset neurological signs, particularly in late infantile patients. Mortality data was available for 59 patients and the duration of survival after disease onset varies with age spectrum of the disease. The most common therapy was Miglustat, a potential disease modifying therapy specifically indicated for NPC, reported in 85 (62.4%) patients, with a mean duration of just over 4 years.

• #77 Sphingomyelinase Deficiency: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/951564-overview

  Acid sphingomyelinase deficiency (ASMD) is a rare lipid storage disorder with a genetic etiology. It is commonly known as Niemann-Pick disease (NPD) type A, type B, or type A/B. The diagnosis of NPD is confirmed with measurement of enzyme activity in peripheral white blood cells or in cultured fibroblasts. Targeted mutation analysis for four common SMPD1 mutations is available in clinical laboratories. The pathologic hallmark in NPD types A and B is the histochemically characteristic lipid-laden foam cell, often termed the Niemann-Pick cell, on bone marrow examination. Pancytopenia may be present secondary to the enlarged spleen in patients with NPD, and reduced high-density lipoprotein cholesterol (HDL-C) fraction is common in NPD type B. […] The first disease-specific enzyme replacement treatment for noncentral nervous system (non-CNS) ASMD, olipudase alfa, was approved by the US Food and Drug Administration (FDA) in August 2022. Other medical and surgical care for NPD types A and B are mainly focused on supportive care.

• #78

  https://www.jscreen.org/hereditary-diseases/niemann-pick-disease?srsltid=AfmBOopRpNhY63esf_6at091sUp_Z6NgBRQRhgTzGn0pSLpdPTmPmFeO

  Genetic testing plays a crucial role in diagnosing Niemann-Pick disease and finding carriers. Early diagnosis allows for prompt intervention and access to treatments that can slow down the diseases progression. […] There is an enzyme replacement treatment for Niemann-Pick disease that was approved for use in late summer 2022. It can be used for types A and B but does not treat neurological symptoms. […] The prognosis for a person with Niemann-Pick disease type A is poor without treatment. It is a severe disease which is typically fatal by the age of 2 or 3. People with Niemann-Pick disease type B often survive into adulthood; however, lifespan will likely be affected.

• #79 Clinical disease characteristics of patients with Niemann-Pick Disease Type C: findings from the International Niemann-Pick Disease Registry (INPDR) | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-022-02200-4

  Niemann-Pick Disease Type C (NPC) is an autosomal recessive rare disease characterised by progressive neurovisceral manifestations. The INPDR is a web-based, patient-led independent registry for the collection of prospective and retrospective clinical data from Niemann-Pick Disease patients. The mean age (SD) at diagnosis was 11.2 years (14.2). Among the 97 patients with identified NPC1 variants, the most common variant was the c. 3182TC variant responsible for the p.lle1061Thr protein change, reported in 35.1% (N=34) of patients. The age at diagnosis and death increased with increased age of neurological symptom onset. The clinical spectrum of NPC encompasses a range of non-specific neurological and systemic manifestations at an early stage and varying by age of onset and organ involvement. The classification of NPC by age of neurological onset is as follows: early infantile (2 years) (visceral-neurodegenerative form); late-infantile (2-6 years) and juvenile (6-15 years) (neurodegenerative form); adult (15 years) (psychiatric-neurodegenerative form). The rarity, varied age of onset, heterogeneous and non-specific manifestations of the disease pose significant challenges in understanding the natural course of NPC. The INPDR is a patient led registry designed to: (a) better understand the natural history of Niemann-Pick disease worldwide; (b) provide an inventory of patients for recruitment to observational and interventional studies; (c) establish genotype-phenotype correlations; (d) provide support for education of health professionals and empowerment of patients. The p.I1061T variant was the most common variant in this population, with detection in 28.6% of patients. Disease classification based on the age of onset of the first neurological symptoms has been accepted as a guide to clinicians in providing day to day care, genetic counselling and to estimate the trajectory of the disease course. The type and onset of visceral symptoms varied across the age groups with decreased occurrence with an increasing age. Clinical assessment of disease burden and rate of progression in time or regression with disease modifying therapy is challenging when dealing with progressive diseases such as NPC. The composite disability scores were notably higher in patients with early onset neurological signs, particularly in late infantile patients. Mortality data was available for 59 patients and the duration of survival after disease onset varies with age spectrum of the disease. The most common therapy was Miglustat, a potential disease modifying therapy specifically indicated for NPC, reported in 85 (62.4%) patients, with a mean duration of just over 4 years.

• #80 Consensus clinical management guidelines for Niemann-Pick disease type C | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-018-0785-7

  Once NPC is suspected clinically, diagnosis can be confirmed by the combination of biochemical and molecular genetic studies. […] Assessment of biomarkers should be considered as a first-line test to screen for NPC. […] Mutation analysis of NPC1 and NPC2 genes is mandatory to confirm the diagnosis of NPC. […] Filipin test is no longer considered a first line test for the diagnosis of NPC. […] Brain imaging changes in individuals with NPC are variable and non-specific, but the most commonly reported changes are reductions in volume of the cerebellum, hippocampus, and subcortical grey matter, in addition to subtle changes in most white matter regions. […] NPC is a progressive condition and patients require regular follow up. Treatment goals should be established at diagnosis and reviewed regularly, aimed at improving or maintaining the physical and psychosocial wellbeing of individuals with NPC and their families.

• #81 Clinical Guidelines – International Niemann-Pick Disease Alliance (INPDA)

  https://www.inpda.org/inpda-portal/clinical-practice/clinical-guidelines/

  Consensus Clinical Management Guidelines for Niemann-Pick disease type C (2018) […] Recent Advances in the Diagnosis and Treatment of Niemann-Pick Disease Type C in Children: A Guide to Early Diagnosis for the General Pediatrician (2015) […] Recommendations for the Diagnosis and Management of Niemann-Pick disease type C (2012) […] Elsevier: Recommendations on the Diagnosis and Management of Niemann-Pick disease (2009) […] Argentinean Consensus on the Diagnosis and Treatment of Niemann-Pick Disease type C (2023) […] Looking for a diagnostic centre in your country? Visit Orphanet! Orphanet is a unique resource, aiming to provide high-quality information on rare diseases, and ensure equal access to knowledge for all stakeholders.

• #82 Consensus clinical management guidelines for Niemann-Pick disease type C | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-018-0785-7

  Once NPC is suspected clinically, diagnosis can be confirmed by the combination of biochemical and molecular genetic studies. […] Assessment of biomarkers should be considered as a first-line test to screen for NPC. […] Mutation analysis of NPC1 and NPC2 genes is mandatory to confirm the diagnosis of NPC. […] Filipin test is no longer considered a first line test for the diagnosis of NPC. […] Brain imaging changes in individuals with NPC are variable and non-specific, but the most commonly reported changes are reductions in volume of the cerebellum, hippocampus, and subcortical grey matter, in addition to subtle changes in most white matter regions. […] NPC is a progressive condition and patients require regular follow up. Treatment goals should be established at diagnosis and reviewed regularly, aimed at improving or maintaining the physical and psychosocial wellbeing of individuals with NPC and their families.

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