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Article: Autopsy pathology of infantile neurovisceral ASMD (Niemann-Pick Disease type A): Clinicopathologic correlations of a case report.

Thurberg, Beth L

Molecular genetics and metabolism reports

2020 Volume 24, Page(s) 100626

Abstract: Acid sphingomyelinase deficiency (ASMD; also known as Niemann-Pick Disease [NPD] A and B) is a rare lysosomal storage disease characterized by the pathological accumulation of sphingomyelin within multiple cell types throughout the body. The infantile ... ...

Abstract	Acid sphingomyelinase deficiency (ASMD; also known as Niemann-Pick Disease [NPD] A and B) is a rare lysosomal storage disease characterized by the pathological accumulation of sphingomyelin within multiple cell types throughout the body. The infantile neurovisceral (ASMD type A, also known as Niemann-Pick Disease type A) form of the disease is characterized by markedly low or absent enzyme levels resulting in both visceral and severe neurodegenerative involvement with death in early childhood. We report here the clinical course and autopsy findings in the case of a 3 year old male patient with infantile neurovisceral ASMD. A comprehensive examination of the autopsy tissue was conducted, including routine paraffin processing and staining, high resolution light microscopy and staining for sphingomyelin, and ultrastructural examination by electron microscopy. Profound sphingomyelin accumulation was present in virtually every organ and cell type. We report the clinicopathologic correlations of these findings and discuss the relevance of these results to the clinical practice of physicians following all patients with ASMD. This case represents one of the most extensive and detailed examinations of ASMD type A to date.
Language	English
Publishing date	2020-07-16
Publishing country	United States
Document type	Case Reports
ZDB-ID	2821908-9
ISSN	2214-4269
ISSN	2214-4269
DOI	10.1016/j.ymgmr.2020.100626
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Article ; Online: Autopsy pathology of infantile neurovisceral ASMD (Niemann-Pick Disease type A)

Beth L. Thurberg

Molecular Genetics and Metabolism Reports, Vol 24, Iss , Pp 100626- (2020)

Clinicopathologic correlations of a case report

2020

Abstract	Acid sphingomyelinase deficiency (ASMD; also known as Niemann-Pick Disease [NPD] A and B) is a rare lysosomal storage disease characterized by the pathological accumulation of sphingomyelin within multiple cell types throughout the body. The infantile neurovisceral (ASMD type A, also known as Niemann-Pick Disease type A) form of the disease is characterized by markedly low or absent enzyme levels resulting in both visceral and severe neurodegenerative involvement with death in early childhood. We report here the clinical course and autopsy findings in the case of a 3 year old male patient with infantile neurovisceral ASMD. A comprehensive examination of the autopsy tissue was conducted, including routine paraffin processing and staining, high resolution light microscopy and staining for sphingomyelin, and ultrastructural examination by electron microscopy. Profound sphingomyelin accumulation was present in virtually every organ and cell type. We report the clinicopathologic correlations of these findings and discuss the relevance of these results to the clinical practice of physicians following all patients with ASMD. This case represents one of the most extensive and detailed examinations of ASMD type A to date.
Keywords	Niemann-Pick Disease type A ; Acid sphingomyelinase deficiency ; Sphingomyelin ; Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2020-09-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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Article ; Online: Clinical relevance of globotriaosylceramide accumulation in Fabry disease and the effect of agalsidase beta in affected tissues.

Tøndel, Camilla / Thurberg, Beth L / DasMahapatra, Pronabesh / Lyn, Nicole / Maski, Manish / Batista, Julie L / George, Kelly / Patel, Hiren / Hariri, Ali

Molecular genetics and metabolism

2022 Volume 137, Issue 4, Page(s) 328–341

Abstract: Fabry disease (FD) is a rare lysosomal storage disorder, characterized by a reduction in α-galactosidase A enzyme activity and the progressive accumulation of globotriaosylceramide (GL3) and its metabolites in the cells of various organs. Agalsidase beta, ...

Abstract	Fabry disease (FD) is a rare lysosomal storage disorder, characterized by a reduction in α-galactosidase A enzyme activity and the progressive accumulation of globotriaosylceramide (GL3) and its metabolites in the cells of various organs. Agalsidase beta, an enzyme replacement therapy (ERT), is approved for use in patients with FD in Europe, Canada, Australia, South America, and Asia, and is the only ERT approved for use in the United States. In this review, we discuss the clinical relevance of GL3 accumulation, the effect of agalsidase beta on GL3 in target tissues, and the association between treatment-related tissue GL3 clearance and long-term structure, function, or clinical outcomes. Accumulation of GL3 in the kidney, heart, vasculature, neurons, skin, gastrointestinal tract and auditory system correlates to cellular damage and irreversible organ damage, as a result of sclerosis, fibrosis, apoptosis, inflammation, and endothelial dysfunction. Damage leads to renal dysfunction and end-stage renal disease; myocardial hypertrophy with heart failure and arrhythmias; ischemic stroke; neuropathic pain; skin lesions; intestinal ischemia and dysmotility; and hearing loss. Treatment with agalsidase beta is effective in substantially clearing GL3 in a range of cells from the tissues affected by FD. Agalsidase beta has also been shown to slow renal decline and lower the overall risk of clinical progression, demonstrating an indirect link between treatment-related GL3 clearance and stabilization of FD.
Language	English
Publishing date	2022-10-29
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1418518-0
ISSN	1096-7206 ; 1096-7192
ISSN (online)	1096-7206
ISSN	1096-7192
DOI	10.1016/j.ymgme.2022.10.005
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Article ; Online: Peripheral Nerve Microscopic Changes Related to Study Procedures: Two Nonclinical Case Studies.

Bangari, Dinesh S / Pardo, Ingrid D / Sellers, Rani / Johnson, Jennifer A / Ryan, Susan / Thurberg, Beth L

Toxicologic pathology

2019 Volume 48, Issue 1, Page(s) 220–227

Abstract: Peripheral nerves are routinely examined microscopically during the nonclinical safety assessment of therapeutics. In addition to test article-related on- or off-target changes, microscopic changes in peripheral nerves may also be caused by study ... ...

Abstract	Peripheral nerves are routinely examined microscopically during the nonclinical safety assessment of therapeutics. In addition to test article-related on- or off-target changes, microscopic changes in peripheral nerves may also be caused by study procedures, such as parenteral test article administration and blood or tissue sampling. We present 2 nonclinical case studies in which nonstandard peripheral nerves had study procedure-related histologic changes. The first case study describes mouse trigeminal nerve changes as a result of blood sampling via retro-orbital sinus puncture. These changes included minimal-to-mild nerve fiber (axonal) degeneration associated with macrophage infiltration. The second case study presents rat brachial plexus changes associated with animal handling and blood sampling. Brachial plexus changes included minimal-to-moderate inflammation, focal hemorrhage, and nerve fiber degeneration. In both cases, the histological changes were morphologically indistinguishable from those that might be due to test article. Therefore, careful consideration of the incidence and severity across groups and a review of study procedures to rule out handling-related nerve damage are essential before identifying a test article-related effect on peripheral nerves. Study design considerations to avoid such procedure-related changes will be discussed, as well as sampling strategies to help distinguish these from test article-related effects.
MeSH term(s)	Animals ; Humans ; Mice ; Nerve Degeneration ; Peripheral Nerves/pathology ; Peripheral Nervous System Diseases ; Rats
Language	English
Publishing date	2019-07-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	841009-4
ISSN	1533-1601 ; 0192-6233
ISSN (online)	1533-1601
ISSN	0192-6233
DOI	10.1177/0192623319854328
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Article ; Online: Histologic abnormalities of placental tissues in Fabry disease: a case report and review of the literature.

Thurberg, Beth L / Politei, Juan M

Human pathology

2012 Volume 43, Issue 4, Page(s) 610–614

Abstract: Fabry disease is an X-linked lysosomal storage disease caused by deficiency of α-galactosidase A, resulting in the accumulation of globotriaosylceramide. Many women experience symptoms, but the understanding of placental and fetal aspects of the disease ... ...

Abstract	Fabry disease is an X-linked lysosomal storage disease caused by deficiency of α-galactosidase A, resulting in the accumulation of globotriaosylceramide. Many women experience symptoms, but the understanding of placental and fetal aspects of the disease is limited. We report the pregnancy outcome in and placental pathology of a 37-year-old woman with Fabry disease. She became pregnant 2 years after starting enzyme replacement therapy and continued therapy throughout her pregnancy. At 38 weeks' gestation, she gave birth to a healthy boy with the same maternal Fabry mutation. The present case describes more extensive placental involvement by Fabry disease than has been previously reported. Globotriaosylceramide deposits were found within multiple cell types of the placenta, cord, and membranes. Because of the small numbers of cases described in the literature for comparison, it remains unclear if placental tissues are also targeted by enzyme replacement therapy.
MeSH term(s)	Adult ; Enzyme Replacement Therapy ; Extraembryonic Membranes/metabolism ; Extraembryonic Membranes/pathology ; Fabry Disease/drug therapy ; Fabry Disease/genetics ; Fabry Disease/pathology ; Female ; Humans ; Infant, Newborn ; Isoenzymes/therapeutic use ; Male ; Mutation, Missense ; Placenta/drug effects ; Placenta/metabolism ; Placenta/pathology ; Pregnancy ; Pregnancy Complications/enzymology ; Pregnancy Complications/genetics ; Pregnancy Complications/pathology ; Pregnancy Outcome ; Treatment Outcome ; Trihexosylceramides/metabolism ; Umbilical Cord/metabolism ; Umbilical Cord/pathology ; alpha-Galactosidase/genetics ; alpha-Galactosidase/metabolism ; alpha-Galactosidase/therapeutic use
Chemical Substances	Isoenzymes ; Trihexosylceramides ; globotriaosylceramide (71965-57-6) ; alpha-Galactosidase (EC 3.2.1.22) ; agalsidase beta (RZD65TSM9U)
Language	English
Publishing date	2012-04
Publishing country	United States
Document type	Case Reports ; Journal Article ; Review
ZDB-ID	207657-3
ISSN	1532-8392 ; 0046-8177
ISSN (online)	1532-8392
ISSN	0046-8177
DOI	10.1016/j.humpath.2011.07.020
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Zs.A 722: Show issues

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Article ; Online: Long-term efficacy of olipudase alfa in adults with acid sphingomyelinase deficiency (ASMD): Further clearance of hepatic sphingomyelin is associated with additional improvements in pro- and anti-atherogenic lipid profiles after 42 months of treatment.

Thurberg, Beth L / Diaz, George A / Lachmann, Robin H / Schiano, Thomas / Wasserstein, Melissa P / Ji, Allena J / Zaher, Atef / Peterschmitt, M Judith

Molecular genetics and metabolism

2020 Volume 131, Issue 1-2, Page(s) 245–252

Abstract: The liver is a major site of lipoprotein synthesis and metabolism. Liver manifestations of chronic visceral ASMD include hepatomegaly, fibrosis, elevated liver enzymes and a pro-atherogenic lipid profile. Measurements of sphingomyelin (SM) levels in ... ...

Abstract	The liver is a major site of lipoprotein synthesis and metabolism. Liver manifestations of chronic visceral ASMD include hepatomegaly, fibrosis, elevated liver enzymes and a pro-atherogenic lipid profile. Measurements of sphingomyelin (SM) levels in liver biopsies and lyso-SM in plasma were used as pharmacodynamic biomarkers. Five adult patients with chronic visceral ASMD were enrolled in a 26-week phase 1b trial of enzyme replacement therapy (ERT) with olipudase alfa (NCT01722526) followed by an ongoing long-term extension study (NCT02004704). We compare the changes in hepatic SM levels, plasma lyso-SM, and lipoprotein profiles after 42 months of treatment. Progressive clearance of histologic SM storage was observed throughout the trial, along with similar reductions in plasma lyso-SM. Improvements in liver enzymes were observed at 6 months and remained stable at 42 months. Progressive reductions from baseline in pro-atherogenic lipid profiles (total cholesterol, LDL-C, VLDL-C, triglycerides) were observed at month 6 and 42. Conversely, there were progressive increases in anti-atherogenic markers, HDL-C and apolipoprotein A-I, with HDL-C increases up to 200% over baseline levels after 42 months of treatment. These data demonstrate that hepatic clearance of SM during olipudase alfa treatment over 42 months is associated with overall improvements in the lipid profiles of ASMD patients. The clinical relevance of these findings needs to be determined in the future, but we speculate that these improvements may reduce the risk for liver cirrhosis and cardiovascular disease. Trial registration: Clintrials.gov trial registration # NCT01722526.
MeSH term(s)	Adolescent ; Adult ; Aged ; Atherosclerosis/drug therapy ; Atherosclerosis/genetics ; Atherosclerosis/pathology ; Enzyme Replacement Therapy ; Female ; Humans ; Lipids/genetics ; Lipoproteins/biosynthesis ; Lipoproteins/metabolism ; Liver/drug effects ; Liver/metabolism ; Male ; Middle Aged ; Recombinant Proteins/administration & dosage ; Recombinant Proteins/genetics ; Sphingomyelin Phosphodiesterase/administration & dosage ; Sphingomyelin Phosphodiesterase/genetics ; Sphingomyelins/genetics ; Young Adult
Chemical Substances	Lipids ; Lipoproteins ; Recombinant Proteins ; Sphingomyelins ; SMPD1 protein, human (EC 3.1.4.12) ; Sphingomyelin Phosphodiesterase (EC 3.1.4.12) ; olipudase alfa (EC 3.1.4.12)
Language	English
Publishing date	2020-06-24
Publishing country	United States
Document type	Clinical Trial ; Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ZDB-ID	1418518-0
ISSN	1096-7206 ; 1096-7192
ISSN (online)	1096-7206
ISSN	1096-7192
DOI	10.1016/j.ymgme.2020.06.010
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Article ; Online: Continued improvement in disease manifestations of acid sphingomyelinase deficiency for adults with up to 2 years of olipudase alfa treatment: open-label extension of the ASCEND trial.

Orphanet journal of rare diseases

2023 Volume 18, Issue 1, Page(s) 378

Abstract: Background: Olipudase alfa is a recombinant human acid sphingomyelinase enzyme replacement therapy for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). The ASCEND randomized placebo-controlled trial in adults with ... ...

Abstract	Background: Olipudase alfa is a recombinant human acid sphingomyelinase enzyme replacement therapy for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). The ASCEND randomized placebo-controlled trial in adults with ASMD demonstrated reductions in sphingomyelin storage, organomegaly, interstitial lung disease and impaired diffusion capacity of the lung (DL Results: Thirty-five of 36 participants continued in the extension trial, and 33 completed year 2. Change-from-baseline results are presented as least-square mean percent change ± SEM. Improvements in the cross-over group after 1 year of treatment paralleled those of the olipudase alfa group from the primary analysis, while clinical improvement continued for those receiving olipudase alfa for 2 years. In the cross-over group, percent-predicted DL Conclusion: Treatment with olipudase alfa is well tolerated and reduces manifestations of chronic ASMD with sustained efficacy. Trial registration NCT02004691 registered 9 December 2013, https://clinicaltrials.gov/ct2/show/NCT02004691.
MeSH term(s)	Adult ; Humans ; Sphingomyelin Phosphodiesterase/therapeutic use ; Niemann-Pick Disease, Type A ; Niemann-Pick Diseases ; Recombinant Proteins/therapeutic use
Chemical Substances	olipudase alfa (EC 3.1.4.12) ; Sphingomyelin Phosphodiesterase (EC 3.1.4.12) ; Recombinant Proteins
Language	English
Publishing date	2023-12-02
Publishing country	England
Document type	Journal Article
ZDB-ID	2225857-7
ISSN	1750-1172 ; 1750-1172
ISSN (online)	1750-1172
ISSN	1750-1172
DOI	10.1186/s13023-023-02983-0
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Article ; Online: Venglustat, an orally administered glucosylceramide synthase inhibitor: Assessment over 3 years in adult males with classic Fabry disease in an open-label phase 2 study and its extension study.

Deegan, Patrick B / Goker-Alpan, Ozlem / Geberhiwot, Tarekegn / Hopkin, Robert J / Lukina, Elena / Tylki-Szymanska, Anna / Zaher, Atef / Sensinger, Charlotte / Gaemers, Sebastiaan J M / Modur, Vijay / Thurberg, Beth L / Sharma, Jyoti / Najafian, Behzad / Mauer, Michael / DasMahapatra, Pronabesh / Wilcox, William R / Germain, Dominique P

Molecular genetics and metabolism

2022 Volume 138, Issue 2, Page(s) 106963

Abstract: Venglustat inhibits the enzymatic conversion of ceramide to glucosylceramide, reducing available substrate for the synthesis of more complex glycosphingolipids. It offers a potential new approach to the treatment of patients with Fabry disease (α-Gal A ... ...

Abstract	Venglustat inhibits the enzymatic conversion of ceramide to glucosylceramide, reducing available substrate for the synthesis of more complex glycosphingolipids. It offers a potential new approach to the treatment of patients with Fabry disease (α-Gal A deficiency), in whom progressive accumulation of such glycosphingolipids, including globotriaosylceramide (GL-3), in the lysosomes of a wide range of cell types often leads to vital organ complications in adulthood. An international, open-label, single-arm, Phase 2a uncontrolled 26-week clinical study (NCT02228460) and a 130-week extension study (NCT02489344) were conducted to assess the safety, pharmacodynamics, pharmacokinetics, and exploratory efficacy of 15 mg once daily oral venglustat in treatment-naïve adult male patients with classic Fabry disease. Of 11 patients (18-37 years old) who initially enrolled, nine completed the 26-week study and seven completed the extension study. A total of 169 treatment-emergent adverse events (TEAEs) were reported by nine patients, the majority being mild (73%) and unrelated to the study drug (70%). Nine serious TEAEs (serious adverse events) and 11 severe TEAEs, including a self-harm event, were reported. No deaths or treatment-related life-threatening adverse events were reported. Skin GL-3 scores in superficial skin capillary endothelium (SSCE), estimated by light microscopy, were unchanged from baseline at Week 26 in five patients, decreased in three patients, and increased in one patient. There was no significant change in GL-3 scores or significant shift in grouped GL-3 scores. Five of six patients had reductions from baseline in GL-3 score at the end of the extension study. At Weeks 26 and 156 the mean (standard deviation) changes from baseline in the fraction of the volume of SSCE cytoplasm occupied by GL-3 inclusions, measured by electron microscopy unbiased stereology, were - 0.06 (0.03) (p = 0.0010) and - 0.12 (0.04) (p = 0.0008), respectively. Venglustat treatment reduced markers in the synthetic and degradative pathway of major glycosphingolipids; proximal markers reduced rapidly and more distal markers (plasma GL-3 and globotriaosylsphingosine) reduced progressively. There were no biochemical or histological indications of progression of Fabry disease over 3 years of follow-up. These findings confirm target engagement and the pharmacodynamic effects of venglustat in adult males with classic Fabry disease. However, further clinical evaluation in larger studies is needed to determine efficacy and safety.
MeSH term(s)	Humans ; Male ; Adult ; Adolescent ; Young Adult ; Fabry Disease/pathology ; alpha-Galactosidase/therapeutic use ; Glucosyltransferases
Chemical Substances	ceramide glucosyltransferase (EC 2.4.1.80) ; venglustat (BLP1XA3FZA) ; alpha-Galactosidase (EC 3.2.1.22) ; Glucosyltransferases (EC 2.4.1.-)
Language	English
Publishing date	2022-11-09
Publishing country	United States
Document type	Clinical Trial, Phase II ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1418518-0
ISSN	1096-7206 ; 1096-7192
ISSN (online)	1096-7206
ISSN	1096-7192
DOI	10.1016/j.ymgme.2022.11.002
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Article: Fabry disease: Four case reports of meningioma and a review of the literature on other malignancies.

Thurberg, Beth L / Germain, Dominique P / Perretta, Fernando / Jurca-Simina, Iulia E / Politei, Juan M

Molecular genetics and metabolism reports

2016 Volume 11, Page(s) 75–80

Abstract: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by loss of function mutations in ... ...

Abstract	Fabry disease (FD) is an X-linked lysosomal storage disorder caused by loss of function mutations in the
Language	English
Publishing date	2016-10-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2821908-9
ISSN	2214-4269
ISSN	2214-4269
DOI	10.1016/j.ymgmr.2016.09.005
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Article ; Online: Continued improvement in disease manifestations of acid sphingomyelinase deficiency for adults with up to 2 years of olipudase alfa treatment

Orphanet Journal of Rare Diseases, Vol 18, Iss 1, Pp 1-

open-label extension of the ASCEND trial

2023 Volume 12

Abstract: Abstract Background Olipudase alfa is a recombinant human acid sphingomyelinase enzyme replacement therapy for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). The ASCEND randomized placebo-controlled trial in adults ... ...

Abstract	Abstract Background Olipudase alfa is a recombinant human acid sphingomyelinase enzyme replacement therapy for non-central-nervous-system manifestations of acid sphingomyelinase deficiency (ASMD). The ASCEND randomized placebo-controlled trial in adults with ASMD demonstrated reductions in sphingomyelin storage, organomegaly, interstitial lung disease and impaired diffusion capacity of the lung (DLCO), during the first year of olipudase alfa treatment. In an ongoing open-label extension of the ASCEND trial, individuals in the placebo group crossed over to olipudase alfa, and those in the olipudase alfa group continued treatment. Results Thirty-five of 36 participants continued in the extension trial, and 33 completed year 2. Change-from-baseline results are presented as least-square mean percent change ± SEM. Improvements in the cross-over group after 1 year of treatment paralleled those of the olipudase alfa group from the primary analysis, while clinical improvement continued for those receiving olipudase alfa for 2 years. In the cross-over group, percent-predicted DLCO increased by 28.0 ± 6.2%, spleen volume decreased by 36.0 ± 3.0% and liver volume decreased by 30.7 ± 2.5%. For those with 2 years of olipudase alfa treatment, the percent predicted DLCO increased by 28.5 ± 6.2%, spleen volume decreased by 47.0 ± 2.7%, and liver volume decreased by 33.4 ± 2.2%. Lipid profiles and elevated liver transaminase levels improved or normalized by 1 year and remained stable through 2 years of treatment. Overall, 99% of treatment-emergent adverse events were mild or moderate, with one treatment-related serious adverse event (extrasystoles; previously documented cardiomyopathy). No individual discontinued due to an adverse event. Conclusion Treatment with olipudase alfa is well tolerated and reduces manifestations of chronic ASMD with sustained efficacy. Trial registration NCT02004691 registered 9 December 2013, https://clinicaltrials.gov/ct2/show/NCT02004691
Keywords	Recombinant human acid sphingomyelinase ; Dose escalation ; Organomegaly ; Lung diffusing capacity ; Acid sphingomyelinase deficiency ; Niemann–Pick type B ; Medicine ; R
Subject code	669 ; 610
Language	English
Publishing date	2023-12-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
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