Molecular and biochemical biomarkers for diagnosis and therapy monitorization of Niemann‐Pick type C patients

Hammerschmidt, Tatiane Grazieli; Ribas, Graziela de Oliveira Schmitt; Saraiva-Pereira, Maria Luiza; Bonatto, Márcia Polese; Kessler, Rejane Gus; Souza, Fernanda Timm Seabra; Trapp, Franciele Barbosa; Michelin‐Tirelli, Kristiane; Burin, Maira Graeff; Giugliani, Roberto; Vargas, Carmen Regla

doi:10.1016/j.ijdevneu.2017.11.007

Cited by 24 publications

(23 citation statements)

References 42 publications

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“…Currently, lyso-sphingomyelin-509 (LysoSM-509) is used for the primary diagnosis of Niemann-Pick disease type C [104]. Another biomarker is cholestane-3β,5α,6β-triol [105]. Both biomarkers, however, also accumulate in Niemann-Pick disease types A and B [103].…”

Section: Niemann-pick Disease Type Cmentioning

confidence: 99%

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Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

Breiden

Sandhoff

2020

IJMS

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Gangliosidoses are caused by monogenic defects of a specific hydrolase or an ancillary sphingolipid activator protein essential for a specific step in the catabolism of gangliosides. Such defects in lysosomal function cause a primary accumulation of multiple undegradable gangliosides and glycosphingolipids. In reality, however, predominantly small gangliosides also accumulate in many lysosomal diseases as secondary storage material without any known defect in their catabolic pathway. In recent reconstitution experiments, we identified primary storage materials like sphingomyelin, cholesterol, lysosphingolipids, and chondroitin sulfate as strong inhibitors of sphingolipid activator proteins (like GM2 activator protein, saposin A and B), essential for the catabolism of many gangliosides and glycosphingolipids, as well as inhibitors of specific catabolic steps in lysosomal ganglioside catabolism and cholesterol turnover. In particular, they trigger a secondary accumulation of ganglioside GM2, glucosylceramide and cholesterol in Niemann-Pick disease type A and B, and of GM2 and glucosylceramide in Niemann-Pick disease type C. Chondroitin sulfate effectively inhibits GM2 catabolism in mucopolysaccharidoses like Hurler, Hunter, Sanfilippo, and Sly syndrome and causes a secondary neuronal ganglioside GM2 accumulation, triggering neurodegeneration. Secondary ganglioside and lipid accumulation is furthermore known in many more lysosomal storage diseases, so far without known molecular basis.

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Section: Niemann-pick Disease Type Cmentioning

confidence: 99%

“…Several biomarkers have been investigated for GD, however, none of them is perfect. Chitotriosidase activity levels have been considered as a classic biomarker [105]. They are used as an indicator of disease severity and its response to therapy.…”

Section: Gaucher Diseasementioning

confidence: 99%

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

Breiden

Sandhoff

2020

IJMS

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“…Oxysterols are formed in the body through enzymatic and non-enzymatic reactions involving reactive oxygen species (ROS). The latter reaction seems to be driving the enhanced levels of oxysterols in NPC [45,46,47,48,49]. Moderate elevation of oxysterol levels is also observed in other cholesterol-related storage diseases, such as atherosclerosis, obesity, and diabetes [50,51,52].…”

Section: Gaucher Cell Biomarkers: Lipidsmentioning

confidence: 99%

Glycoprotein Non-Metastatic Protein B: An Emerging Biomarker for Lysosomal Dysfunction in Macrophages

Lienden

Gaspar

Boot

et al. 2018

IJMS

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Several diseases are caused by inherited defects in lysosomes, the so-called lysosomal storage disorders (LSDs). In some of these LSDs, tissue macrophages transform into prominent storage cells, as is the case in Gaucher disease. Here, macrophages become the characteristic Gaucher cells filled with lysosomes laden with glucosylceramide, because of their impaired enzymatic degradation. Biomarkers of Gaucher cells were actively searched, particularly after the development of costly therapies based on enzyme supplementation and substrate reduction. Proteins selectively expressed by storage macrophages and secreted into the circulation were identified, among which glycoprotein non-metastatic protein B (GPNMB). This review focusses on the emerging potential of GPNMB as a biomarker of stressed macrophages in LSDs as well as in acquired pathologies accompanied by an excessive lysosomal substrate load in macrophages.

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“…Additionally, in line with previous reports, cerebrospinal tau proteins were elevated in Case 1 [ 16 ] and the laboratory values of copper metabolism slightly deviated or were close to the lower limit of the normal levels [ 17 ]. Recently, it has been reported that plasma oxysterol (cholestane-3β,5α,6β-triol) is informative in the detection of NPC [ 18 ]. Additionally, lysosphingolipids have been proposed as a potential biomarker for NPC [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Phenotypic variability of Niemann-Pick disease type C including a case with clinically pure schizophrenia: a case report

et al. 2018

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BackgroundNiemann-Pick disease type C (NPC) is a lysosomal storage disorder with severe prognosis. Disease-specific therapy is crucial to prevent disease progression; however, diagnosing NPC is quite difficult because of remarkably variable clinical presentations. The NPC Suspicion Index (NPC-SI) was developed to overcome this problem. Identifying preclinical cases is important for prevention and therapy. Here, we report three newly diagnosed NPC cases, one typical juvenile-onset case and the cases of two sisters with symptoms neurologically/psychiatrically indistinguishable from dystonia and schizophrenia, respectively.Case presentationIn Case 1, a 25-year-old man presented with a 14-year history of intellectual disability, clumsiness, spastic ataxia, dysphagia, and frequent falls. Neurological examination revealed vertical supranuclear gaze palsy and involuntary movements. Ultrasonography revealed mild splenomegaly, and filipin staining of skin fibroblasts was positive with a variant staining pattern. NPC1 gene analysis showed compound heterozygous mutations, including c.1421C > T (p.P474L), a known causative mutation, and c.3722 T > C (p.L1241S), a new mutation. In Case 2, a 28-year-old woman, the proband, who had marked splenomegaly in her childhood, survived well, contrary to the expected severe prognosis of infantile NPC. She had minor neuropsychiatric symptoms including auditory hallucinations, nocturnal urination, and sleep paralysis. At the age of 28 years, she presented with a 1-year history of orofacial and oromandibular painful dystonia. The patient’s 35-year-old sister (Case 3) was diagnosed with schizophrenia. In both cases, filipin staining of skin fibroblasts was positive with variant staining patterns, as well as elevated levels of urinary bile acids. NPC1 gene analysis showed compound heterozygous mutations including c.3011C > T (p.S1004 L), a known causative mutation, and c.160_161insG (p.D54GfsX4), a new mutation. Their mother, who was under therapy with modafinil for narcolepsy, shared the latter mutation.ConclusionsMarked clinical variability was observed in our three cases. NPC could masquerade as a pure neuropsychiatric disorder such as dystonia or schizophrenia. Abdominal ultrasonography, history evaluation, and neurological examination were quite important in the diagnostic process.

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Molecular and biochemical biomarkers for diagnosis and therapy monitorization of Niemann‐Pick type C patients

Abstract: Taken together, the present data show that cholestane-3β,5α,6β-triol analysis has a high potential to be an important NP-C screening assay, and also can be used for therapy monitorization with miglustat in NP-C patients.

Cited by 24 publications

References 42 publications

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

Glycoprotein Non-Metastatic Protein B: An Emerging Biomarker for Lysosomal Dysfunction in Macrophages

Phenotypic variability of Niemann-Pick disease type C including a case with clinically pure schizophrenia: a case report

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