-
Molecular Genetics and Metabolism 2017The eponym Niemann-Pick disease (NPD) refers to a group of patients who present with varying degrees of lipid storage and foam cell infiltration in tissues, as well as... (Review)
Review
The eponym Niemann-Pick disease (NPD) refers to a group of patients who present with varying degrees of lipid storage and foam cell infiltration in tissues, as well as overlapping clinical features including hepatosplenomegaly, pulmonary insufficiency and/or central nervous system (CNS) involvement. Due to the pioneering work of Roscoe Brady and co-workers, we now know that there are two distinct metabolic abnormalities that account for NPD. The first is due to the deficient activity of the enzyme acid sphingomyelinase (ASM; "types A & B" NPD), and the second is due to defective function in cholesterol transport ("type C" NPD). Herein only types A and B NPD will be discussed. Type A NPD patients exhibit hepatosplenomegaly in infancy and profound CNS involvement. They rarely survive beyond 2-3years of age. Type B patients also have hepatosplenomegaly and pathologic alterations of their lungs, but there are usually no CNS signs. The age of onset and rate of disease progression varies greatly among type B patients, and they frequently live into adulthood. Intermediate patients also have been reported with mild to moderate neurological findings. All patients with types A and B NPD have mutations in the gene encoding ASM (SMPD1), and thus the disease is more accurately referred to as ASM deficiency (ASMD). Herein we will review the clinical, pathological, biochemical, and genetic findings in types A and B NPD, and emphasize the seminal contributions of Dr. Brady to this disease. We will also discuss the current status of therapy for this disorder.
Topics: Age of Onset; Animals; Cholesterol; Disease Progression; Female; History, 20th Century; History, 21st Century; Humans; Male; Mutation; Niemann-Pick Diseases; Sphingomyelin Phosphodiesterase
PubMed: 28164782
DOI: 10.1016/j.ymgme.2016.12.008 -
Journal of Inherited Metabolic Disease Nov 2021Niemann-Pick disease type C (NPC) is a rare, genetic, progressive neurodegenerative disorder with high unmet medical need. We investigated the safety and efficacy of... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of arimoclomol in Niemann-Pick disease type C: Results from a double-blind, randomised, placebo-controlled, multinational phase 2/3 trial of a novel treatment.
Niemann-Pick disease type C (NPC) is a rare, genetic, progressive neurodegenerative disorder with high unmet medical need. We investigated the safety and efficacy of arimoclomol, which amplifies the heat shock response to target NPC protein misfolding and improve lysosomal function, in patients with NPC. In a 12-month, prospective, randomised, double-blind, placebo-controlled, phase 2/3 trial (ClinicalTrials.gov identifier: NCT02612129), patients (2-18 years) were randomised 2:1 to arimoclomol:placebo, stratified by miglustat use. Routine clinical care was maintained. Arimoclomol was administered orally three times daily. The primary endpoint was change in 5-domain NPC Clinical Severity Scale (NPCCSS) score from baseline to 12 months. Fifty patients enrolled; 42 completed. At month 12, the mean progression from baseline in the 5-domain NPCCSS was 0.76 with arimoclomol vs 2.15 with placebo. A statistically significant treatment difference in favour of arimoclomol of -1.40 (95% confidence interval: -2.76, -0.03; P = .046) was observed, corresponding to a 65% reduction in annual disease progression. In the prespecified subgroup of patients receiving miglustat as routine care, arimoclomol resulted in stabilisation of disease severity over 12 months with a treatment difference of -2.06 in favour of arimoclomol (P = .006). Adverse events occurred in 30/34 patients (88.2%) receiving arimoclomol and 12/16 (75.0%) receiving placebo. Fewer patients had serious adverse events with arimoclomol (5/34, 14.7%) vs placebo (5/16, 31.3%). Treatment-related serious adverse events (n = 2) included urticaria and angioedema. Arimoclomol provided a significant and clinically meaningful treatment effect in NPC and was well tolerated.
Topics: Adolescent; Child; Child, Preschool; Disease Progression; Double-Blind Method; Female; Humans; Hydroxylamines; Internationality; Male; Niemann-Pick Disease, Type C; Prospective Studies; Severity of Illness Index; Treatment Outcome; Young Adult
PubMed: 34418116
DOI: 10.1002/jimd.12428 -
Orphanet Journal of Rare Diseases Apr 2023Acid Sphingomyelinase Deficiency (ASMD) is a rare autosomal recessive disorder caused by mutations in the SMPD1 gene. This rarity contributes to misdiagnosis, delayed...
BACKGROUND
Acid Sphingomyelinase Deficiency (ASMD) is a rare autosomal recessive disorder caused by mutations in the SMPD1 gene. This rarity contributes to misdiagnosis, delayed diagnosis and barriers to good care. There are no published national or international consensus guidelines for the diagnosis and management of patients with ASMD. For these reasons, we have developed clinical guidelines that defines standard of care for ASMD patients.
METHODS
The information contained in these guidelines was obtained through a systematic literature review and the experiences of the authors in their care of patients with ASMD. We adopted the Appraisal of Guidelines for Research and Evaluation (AGREE II) system as method of choice for the guideline development process.
RESULTS
The clinical spectrum of ASMD, although a continuum, varies substantially with subtypes ranging from a fatal infantile neurovisceral disorder to an adult-onset chronic visceral disease. We produced 39 conclusive statements and scored them according to level of evidence, strengths of recommendations and expert opinions. In addition, these guidelines have identified knowledge gaps that must be filled by future research.
CONCLUSION
These guidelines can inform care providers, care funders, patients and their carers about best clinical practice and leads to a step change in the quality of care for patients with ASMD with or without enzyme replacement therapy (ERT).
Topics: Adult; Humans; Consensus; Mutation; Niemann-Pick Disease, Type A; Niemann-Pick Diseases; Sphingomyelin Phosphodiesterase; Systematic Reviews as Topic
PubMed: 37069638
DOI: 10.1186/s13023-023-02686-6 -
Progress in Lipid Research Apr 2023Disturbances of lipid homeostasis in cells provoke human diseases. The elucidation of the underlying mechanisms and the development of efficient therapies represent... (Review)
Review
Disturbances of lipid homeostasis in cells provoke human diseases. The elucidation of the underlying mechanisms and the development of efficient therapies represent formidable challenges for biomedical research. Exemplary cases are two rare, autosomal recessive, and ultimately fatal lysosomal diseases historically named "Niemann-Pick" honoring the physicians, whose pioneering observations led to their discovery. Acid sphingomyelinase deficiency (ASMD) and Niemann-Pick type C disease (NPCD) are caused by specific variants of the sphingomyelin phosphodiesterase 1 (SMPD1) and NPC intracellular cholesterol transporter 1 (NPC1) or NPC intracellular cholesterol transporter 2 (NPC2) genes that perturb homeostasis of two key membrane components, sphingomyelin and cholesterol, respectively. Patients with severe forms of these diseases present visceral and neurologic symptoms and succumb to premature death. This synopsis traces the tortuous discovery of the Niemann-Pick diseases, highlights important advances with respect to genetic culprits and cellular mechanisms, and exposes efforts to improve diagnosis and to explore new therapeutic approaches.
Topics: Humans; Sphingolipids; Niemann-Pick Disease, Type C; Lipid Metabolism; Lysosomes; Cholesterol
PubMed: 37003582
DOI: 10.1016/j.plipres.2023.101225 -
Orphanet Journal of Rare Diseases Feb 2017Acid sphingomyelinase deficiency (ASMD), a rare lysosomal storage disease, is an autosomal recessive genetic disorder caused by different SMPD1 mutations. Historically,... (Review)
Review
Acid sphingomyelinase deficiency (ASMD), a rare lysosomal storage disease, is an autosomal recessive genetic disorder caused by different SMPD1 mutations. Historically, ASMD has been classified as Niemann-Pick disease (NPD) types A (NPD A) and B (NPD B). NPD A is associated with a uniformly devastating disease course, with rapidly progressing psychomotor degeneration, leading to death typically by the age of 3 years, most often from respiratory failure. In contrast, the clinical phenotype and life expectancy of patients with NPD B may vary widely. Almost all patients have hepatosplenomegaly and an atherogenic lipid profile, and most patients have interstitial lung disease with progressive impairment of pulmonary function and hematologic abnormalities including cytopenias. Other common clinical manifestations include liver dysfunction, heart disease, skeletal abnormalities and growth delays. Some patients with ASMD who survive beyond early childhood have intermediate phenotypes (variant NPD B) characterized by combinations of non-neurologic and mild to severe neurologic symptoms. The physical and psychosocial burden of illness in patients with NPD B is substantial. Common symptoms include shortness of breath, joint or limb pain, abdominal pain, bleeding and bruising. The disease often leads to chronic fatigue, limited physical or social activity and difficulties in performing daily activities or work. Many patients die before or in early adulthood, often from pneumonia/respiratory failure or liver failure. Available treatments are limited to symptom management and supportive care. An enzyme replacement therapy currently in clinical development is expected to be the first treatment addressing the underlying pathology of the disease. Early diagnosis and appropriate management are essential for reducing the risk of complications. While knowledge about ASMD is evolving, more evidence about ASMD and the natural history across the disease spectrum is needed, to improve disease recognition, timely diagnosis and appropriate disease management.
Topics: Cause of Death; Cost of Illness; Humans; Incidence; Niemann-Pick Diseases; Rare Diseases; Sphingomyelin Phosphodiesterase
PubMed: 28228103
DOI: 10.1186/s13023-017-0572-x -
International Journal of Molecular... Nov 2020Biomedical research aims to understand the molecular mechanisms causing human diseases and to develop curative therapies. So far, these goals have been achieved for a... (Review)
Review
Biomedical research aims to understand the molecular mechanisms causing human diseases and to develop curative therapies. So far, these goals have been achieved for a small fraction of diseases, limiting factors being the availability, validity, and use of experimental models. Niemann-Pick type C (NPC) is a prime example for a disease that lacks a curative therapy despite substantial breakthroughs. This rare, fatal, and autosomal-recessive disorder is caused by defects in NPC1 or NPC2. These ubiquitously expressed proteins help cholesterol exit from the endosomal-lysosomal system. The dysfunction of either causes an aberrant accumulation of lipids with patients presenting a large range of disease onset, neurovisceral symptoms, and life span. Here, we note general aspects of experimental models, we describe the line-up used for NPC-related research and therapy development, and we provide an outlook on future topics.
Topics: Animals; Disease Models, Animal; Humans; Mammals; Models, Biological; Niemann-Pick Disease, Type C; Stem Cells
PubMed: 33256121
DOI: 10.3390/ijms21238979 -
Journal of Neurology Mar 2022To investigate the safety and efficacy of N-acetyl-L-leucine (NALL) on symptoms, functioning, and quality of life in pediatric (≥ 6 years) and adult Niemann-Pick... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To investigate the safety and efficacy of N-acetyl-L-leucine (NALL) on symptoms, functioning, and quality of life in pediatric (≥ 6 years) and adult Niemann-Pick disease type C (NPC) patients.
METHODS
In this multi-national, open-label, rater-blinded Phase II study, patients were assessed during a baseline period, a 6-week treatment period (orally administered NALL 4 g/day in patients ≥ 13 years, weight-tiered doses for patients 6-12 years), and a 6-week post-treatment washout period. The primary Clinical Impression of Change in Severity (CI-CS) endpoint (based on a 7-point Likert scale) was assessed by blinded, centralized raters who compared randomized video pairs of each patient performing a pre-defined primary anchor test (8-Meter Walk Test or 9-Hole Peg Test) during each study periods. Secondary outcomes included cerebellar functional rating scales, clinical global impression, and quality of life assessments.
RESULTS
33 subjects aged 7-64 years with a confirmed diagnosis of NPC were enrolled. 32 patients were included in the primary modified intention-to-treat analysis. NALL met the CI-CS primary endpoint (mean difference 0.86, SD = 2.52, 90% CI 0.25, 1.75, p = 0.029), as well as secondary endpoints. No treatment-related serious adverse events occurred.
CONCLUSIONS
NALL demonstrated a statistically significant and clinical meaningfully improvement in symptoms, functioning, and quality of life in 6 weeks, the clinical effect of which was lost after the 6-week washout period. NALL was safe and well-tolerated, informing a favorable benefit-risk profile for the treatment of NPC. CLINICALTRIALS.
GOV IDENTIFIER
NCT03759639.
Topics: Adolescent; Adult; Child; Double-Blind Method; Humans; Leucine; Middle Aged; Niemann-Pick Disease, Type C; Quality of Life; Treatment Outcome; Young Adult
PubMed: 34387740
DOI: 10.1007/s00415-021-10717-0 -
Journal of Inherited Metabolic Disease May 2020Niemann-Pick disease type C (NPC) and Tangier disease are genetically and clinically distinct rare inborn errors of metabolism. NPC is caused by defects in either NPC1...
Niemann-Pick disease type C (NPC) and Tangier disease are genetically and clinically distinct rare inborn errors of metabolism. NPC is caused by defects in either NPC1 or NPC2; whereas Tangier disease is caused by a defect in ABCA1. Tangier disease is currently without therapy, whereas NPC can be treated with miglustat, a small molecule inhibitor of glycosphingolipid biosynthesis that slows the neurological course of the disease. When a Tangier disease patient was misdiagnosed with NPC and treated with miglustat, her symptoms improved. This prompted us to consider whether there is mechanistic convergence between these two apparently unrelated rare inherited metabolic diseases. In this study, we found that when ABCA1 is defective (Tangier disease) there is secondary inhibition of the NPC disease pathway, linking these two diseases at the level of cellular pathophysiology. In addition, this study further supports the hypothesis that miglustat, as well as other substrate reduction therapies, may be potential therapeutic agents for treating Tangier disease as fibroblasts from multiple Tangier patients were corrected by miglustat treatment.
Topics: 1-Deoxynojirimycin; ATP Binding Cassette Transporter 1; Adult; Humans; Intracellular Signaling Peptides and Proteins; Middle Aged; Niemann-Pick C1 Protein; Niemann-Pick Disease, Type C; Treatment Outcome
PubMed: 31707734
DOI: 10.1002/jimd.12191 -
Orphanet Journal of Rare Diseases Apr 2018Niemann-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... (Review)
Review
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 tissue specific lipids in the lysosomes. The clinical spectrum of NPC disease ranges from a neonatal rapidly progressive fatal disorder to an adult-onset chronic neurodegenerative disease. The age of onset of the first (beyond 3 months of life) neurological symptom may predict the severity of the disease and determines life expectancy.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. For these reasons, we have developed clinical guidelines that define standard of care for NPC patients, foster shared care arrangements between expert centres and family physicians, and empower patients. 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. We adopted the Appraisal of Guidelines for Research & Evaluation (AGREE II) system as method of choice for the guideline development process. We made a series of conclusive statements and scored them according to level of evidence, strengths of recommendations and expert opinions. These guidelines can inform care providers, care funders, patients and their carers of best practice of care for patients with NPC. In addition, these guidelines have identified gaps in the knowledge that must be filled by future research. It is anticipated that the implementation of these guidelines will lead to a step change in the quality of care for patients with NPC irrespective of their geographical location.
Topics: Humans; Niemann-Pick Disease, Type C; Practice Guidelines as Topic
PubMed: 29625568
DOI: 10.1186/s13023-018-0785-7 -
California Medicine Apr 1971Sphingolipidoses are an heterogeneous group of inherited disorders of lipid metabolism affecting primarily the central nervous system. These disorders occur chiefly in...
Sphingolipidoses are an heterogeneous group of inherited disorders of lipid metabolism affecting primarily the central nervous system. These disorders occur chiefly in the pediatric population, and the degenerative nature of the disease processes is generally characterized by diffuse and progressive involvement of neurones (gray matter) with psychomotor retardation and myoclonus or of fiber tracts (white matter) with weakness and spasticity. Biochemical research has identified the defects in the sphingolipidoses to specific lysosomal enzymes. For example, Niemann-Pick disease lacks sphingomyelinase; Krabbe's disease lacks galactocerebrosidase; Gaucher's disease lacks beta-D-glucosidase; metachromatic leukodystrophy lacks sulfatase; Tay-Sachs disease lacks hexosaminidase A; and generalized gangliosidosis lacks beta-galactosidase. Although there are no currently available modes of rendering corrective therapy in these disorders, a definitive diagnosis is possible both antepartum as well as postpartum. This information provides a sound and accurate basis for genetic counseling.
Topics: Brain; Diffuse Cerebral Sclerosis of Schilder; Gangliosides; Gaucher Disease; Humans; Infant; Lipid Metabolism; Lipid Metabolism, Inborn Errors; Lipidoses; Niemann-Pick Diseases
PubMed: 5551302
DOI: No ID Found