scholarly journals Painting the Clinical Picture of Congenital Plasminogen Deficiency (C-PLGD) through a Comprehensive Case Study Review

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 21-22
Author(s):  
Karen Thibaudeau ◽  
Martin Robitaille ◽  
Victoria Ledsham ◽  
Per Morten Sandset
Keyword(s):  
Natural History ◽  
Key Words ◽  
Clinical Manifestations ◽  
Activity Level ◽  
Publicly Traded ◽  
Ligneous Conjunctivitis ◽  
Depth Analysis ◽  
Natural History Studies ◽  
Plasminogen Deficiency

C-PLGD is a rare autosomal recessive multisystem disorder of the fibrinolytic system with a diverse spectrum of clinical manifestations, and is underdiagnosed and difficult to treat. Caused by mutations in thePLGgene, C-PLGD is characterized by extravascular fibrinous deposits on mucous membranes such as the conjunctiva, gingiva, linings of airways and genitourinary tract. The abnormal accumulation or growth of fibrin-rich pseudomembranous lesions have been termed ligneous for their "woody" appearance, and often result in tissue injury and/or organ dysfunction in C-PLGD patients. We present here the results of an exhaustive MEDLINE literature database review undertaken with the PubMed search engine using the key words; 'plasminogen deficiency,' 'hypoplasminogenemia' and 'ligneous conjunctivitis'. Objective:The goal of this review was 1) to achieve a better understanding of the type and prevalence of clinical manifestations of C-PLGD and their outcomes, and 2) to evaluate whether a relationship exists between endogenous plasminogen activity levels and disease manifestations in C-PLGD patients. Methodology: A MEDLINE literature search was conducted by three independent investigators. Publications containing the key words 'plasminogen deficiency,' 'hypoplasminogenemia' and/or 'ligneous conjunctivitis' and reporting human clinical information were selected. Patients' age, sex, endogenous plasminogen levels, and clinical manifestations were tabulated. Results: The search retrieved 414 total citations, and 130 papers with relevant human clinical data were identified for full-length text review. From these, 301 unique C-PLGD patients (237 pediatric and 64 adults) were found to be reported over an 80-year period (from 1957 to 2017) and presented the following outcomes and most common and/or serious clinical manifestations: ligneous conjunctivitis (255 cases), ligneous periodontitis (71 cases), tracheobronchial obstructions (53 cases), hydrocephalus (42 cases), other corneal lesion (15 cases), ligneous vaginitis (24 cases), blindness (6 cases), and death (10 cases). Differences in disease seriousness and prevalence were observed between pediatric and adult patient populations (Table1). Of note, death or hydrocephalus were reported only in pediatric patients. Historical information indicated that 62% of the 301 reported patients were females and 36% males, while 2% of them did not have their gender disclosed. The median age of reported onset of symptoms (and/or diagnosis) was 1 year old for the 176 patients with available data. Of the 130 papers retained and analyzed, 2 studies (Klammt et. al. Thromb Haemost 2011; Tefs et. al. Blood 2006) were selected for additional in-depth analysis. These studies included a subset of 58 C-PLGD patients whose clinical, molecular and plasminogen activity data were available and reliably reported. These patients had a spectrum of plasminogen activity level ranging from 2% to 59% and presented the main following clinical manifestations: ligneous conjunctivitis (52/58), ligneous periodontitis (16/58), tracheobronchial involvement (14/58), ligneous vaginitis (6/58), and hydrocephalus (4/58) (Table 2). Out of this 58-patient cohort, 26 reported a single lesion and had an average plasminogen activity level of 22% while the 32 remaining had 2 or more lesions and an average activity level of 20%, indicating that the level of plasminogen activity may not correlate with the clinical manifestations burden/seriousness. Conclusion:This comprehensive review confirmed that the heterogeneity challenges in clinical evaluation and the overall rarity of C-PLGD can contribute to delayed diagnosis, treatment variability and less than optimal outcomes. With lack of natural history studies or reports of C-PLGD, the data described here can be used to highlight the seriousness of long-term morbidity, promote early and effective management of C-PLGD, and support the ongoing development of novel plasminogen replacement therapy to address the primary underlying drivers of morbidity in C-PLGD. The implementation of natural history studies may play an important role in addressing the knowledge gap in phenotypic expression and long-term impact of C-PLGD on the quality of life of impacted patients. Disclosures Thibaudeau: Liminal BioSciences:Current Employment, Current equity holder in publicly-traded company.Robitaille:Liminal BioSciences:Consultancy, Current equity holder in publicly-traded company, Ended employment in the past 24 months.Ledsham:Liminal BioSciences:Current Employment.Sandset:Liminal BioSciences:Other: Investigator Clinical Trial.

scholarly journals Spontaneous improvement of carbohydrate-deficient transferrin in PMM2-CDG without mannose observed in CDG natural history study

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Peter Witters ◽  
Andrew C. Edmondson ◽  
Christina Lam ◽  
Christin Johnsen ◽  
Marc C. Patterson ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Natural History ◽  
Randomized Study ◽  
Short Term ◽  
Double Blind ◽  
Natural History Study ◽  
Natural History Studies ◽  
Carbohydrate Deficient Transferrin ◽  
Spontaneous Improvement

AbstractA recent report on long-term dietary mannose supplementation in phosphomannomutase 2 deficiency (PMM2-CDG) claimed improved glycosylation and called for double-blind randomized study of the dietary supplement in PMM2-CDG patients. A lack of efficacy of short-term mannose supplementation in multiple prior reports challenge this study’s conclusions. Additionally, some CDG types have previously been reported to demonstrate spontaneous improvement in glycosylated biomarkers, including transferrin. We have likewise observed improvements in transferrin glycosylation without mannose supplementation. This observation questions the reliability of transferrin as a therapeutic outcome measure in clinical trials for PMM2-CDG. We are concerned that renewed focus on mannose therapy in PMM2-CDG will detract from clinical trials of more promising therapies. Approaches to increase efficiency of clinical trials and ultimately improve patients’ lives requires prospective natural history studies and identification of reliable biomarkers linked to clinical outcomes in CDG. Collaborations with patients and families are essential to identifying meaningful study outcomes.

scholarly journals The SPARKLE registry: protocol for an international prospective cohort study in patients with alpha-mannosidosis

2020 ◽  
Author(s):  
Julia Hennermann ◽  
Nathalie Guffon ◽  
Federica Cattaneo ◽  
Ferdinando Ceravolo ◽  
Line Borgwardt ◽  
...  
Keyword(s):  
Cohort Study ◽  
Natural History ◽  
Prospective Cohort Study ◽  
Prospective Cohort ◽  
Clinical Care ◽  
Clinical Manifestations ◽  
Routine Clinical Care ◽  
Safety Outcomes ◽  
History Of

Abstract Background: Alpha-mannosidosis is a lysosomal storage disorder caused by reduced enzymatic activity of alpha-mannosidase. SPARKLE is an alpha-mannosidosis registry intended to obtain long-term safety and effectiveness data on the use of velmanase alfa during routine clinical care in patients with alpha-mannosidosis. It is a post-approval commitment to European marketing authorization for Velmanase alfa (Lamzede®), the first enzyme replacement therapy for the treatment of non-neurologic manifestations in patients with mild to moderate alpha-mannosidosis. In addition, SPARKLE will expand the current understanding of alpha-mannosidosis by collecting data on the clinical manifestations, progression, and natural history of the disease in treated and untreated patients, respectively.Results: The SPARKLE registry is designed as a multicenter, multinational, noninterventional, prospective cohort study of patients with alpha-mannosidosis, starting patient enrollment in 2020. Patients will be followed for up to 15 years. Safety and effectiveness as post-authorization outcomes under routine clinical care in patients with treatment will be evaluated. The primary safety outcomes are the rate of adverse events (anti-velmanase alfa-immunoglobulin G antibody development, infusion-related reactions, and hypersensitivity). Secondary safety outcomes include the evaluation of medical events, change in vital signs, laboratory tests, physical examination, and electrocardiogram results. The primary effectiveness outcome is a global treatment response rate, evaluated as the individual aggregate of single endpoints from pharmacodynamic, functional, and quality of life effectiveness outcomes; secondary effectiveness outcomes are to characterize the population of patients with alpha-mannosidosis with regard to clinical manifestation, progression, and natural history of the disease. Any patient in the European Union with a diagnosis of alpha-mannosidosis who is willing to participate will likely be eligible for inclusion in the registry. Publications to disseminate scientific insights from the registry are planned. Conclusion: This study will provide real-world data on the long-term safety and effectiveness of velmanase alfa in patients with alpha-mannosidosis during routine clinical care and increase the understanding of the natural course, clinical manifestations, and progression of this ultra-rare disease.

scholarly journals The SPARKLE registry: protocol for an international prospective cohort study in patients with alpha-mannosidosis

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Julia B. Hennermann ◽  
Nathalie Guffon ◽  
Federica Cattaneo ◽  
Ferdinando Ceravolo ◽  
Line Borgwardt ◽  
...  
Keyword(s):  
Cohort Study ◽  
Natural History ◽  
Prospective Cohort Study ◽  
Prospective Cohort ◽  
Clinical Care ◽  
Clinical Manifestations ◽  
Routine Clinical Care ◽  
Safety Outcomes ◽  
History Of

Abstract Background Alpha-mannosidosis is a lysosomal storage disorder caused by reduced enzymatic activity of alpha-mannosidase. SPARKLE is an alpha-mannosidosis registry intended to obtain long-term safety and effectiveness data on the use of velmanase alfa during routine clinical care in patients with alpha-mannosidosis. It is a post-approval commitment to European marketing authorization for Velmanase alfa (Lamzede®), the first enzyme replacement therapy for the treatment of non-neurologic manifestations in patients with mild to moderate alpha-mannosidosis. In addition, SPARKLE will expand the current understanding of alpha-mannosidosis by collecting data on the clinical manifestations, progression, and natural history of the disease in treated and untreated patients, respectively. Results The SPARKLE registry is designed as a multicenter, multinational, noninterventional, prospective cohort study of patients with alpha-mannosidosis, starting patient enrollment in 2020. Patients will be followed for up to 15 years. Safety and effectiveness as post-authorization outcomes under routine clinical care in patients with treatment will be evaluated. The primary safety outcomes are the rate of adverse events (anti-velmanase alfa-immunoglobulin G antibody development, infusion-related reactions, and hypersensitivity). Secondary safety outcomes include the evaluation of medical events, change in vital signs, laboratory tests, physical examination, and electrocardiogram results. The primary effectiveness outcome is a global treatment response rate, evaluated as the individual aggregate of single endpoints from pharmacodynamic, functional, and quality-of-life effectiveness outcomes; secondary effectiveness outcomes are to characterize the population of patients with alpha-mannosidosis with regard to clinical manifestation, progression, and natural history of the disease. Any patient in the European Union with a diagnosis of alpha-mannosidosis who is willing to participate will likely be eligible for inclusion in the registry. Publications to disseminate scientific insights from the registry are planned. Conclusion This study will provide real-world data on the long-term safety and effectiveness of velmanase alfa in patients with alpha-mannosidosis during routine clinical care and increase the understanding of the natural course, clinical manifestations, and progression of this ultra-rare disease.

scholarly journals The SPARKLE registry: a multicenter, multinational, noninterventional, prospective cohort registry study in patients with alpha-mannosidosis

2019 ◽  
Author(s):  
Julia Hennermann ◽  
Nathalie Guffon ◽  
Federica Cattaneo ◽  
Ferdinando Ceravolo ◽  
Line Borgwardt ◽  
...  
Keyword(s):  
Natural History ◽  
Prospective Cohort ◽  
Clinical Care ◽  
Clinical Manifestations ◽  
Registry Study ◽  
Enzyme Replacement ◽  
Routine Clinical Care ◽  
Safety Outcomes ◽  
History Of

Abstract Background Alpha-mannosidosis is a lysosomal storage disorder caused by reduced enzymatic activity of alpha-mannosidase. Intracellular accumulation of mannose-rich oligosaccharides leads to a continuum of various heterogeneous clinical symptoms. Velmanase alfa (Lamzede®) is a human recombinant alpha-mannosidase approved in Europe in 2018 as the first enzyme replacement therapy for the treatment of non-neurologic manifestations in patients with mild-to-moderate alpha-mannosidosis. SPARKLE is an alpha-mannosidosis registry study intended to obtain long-term safety and effectiveness data on the use of velmanase alfa during routine clinical care in patients with alpha-mannosidosis and is a post-approval commitment to European marketing authorization. In addition, SPARKLE will expand the current understanding of alpha-mannosidosis by collecting data on the clinical manifestations, progression, and natural history of the disease in treated and untreated patients, respectively. Results SPARKLE is a post-authorization safety and efficacy registry designed as a multicenter, multinational, noninterventional, prospective cohort study of patients with alpha-mannosidosis, starting in 2020. Patients will be followed for up to 15 years. Safety and effectiveness outcomes under routine clinical care will be evaluated. The primary safety outcomes are the rate of adverse events (anti-velmanase alfa-immunoglobulin G antibody development, infusion-related reactions, and hypersensitivity). Secondary safety outcomes include the evaluation of medical events, change in vital signs, laboratory tests, physical examination, and electrocardiogram results. The primary effectiveness outcome is a global treatment response rate, evaluated as the individual aggregate of single endpoints from pharmacodynamic, functional, and quality of life effectiveness outcomes; secondary effectiveness outcomes are to characterize the population of patients with alpha-mannosidosis with regard to clinical manifestation, progression, and natural history of the disease. Any patient in the European Union with a diagnosis of alpha-mannosidosis who is willing to participate will likely be eligible for inclusion in the registry. Publications to disseminate scientific insights from the registry are planned. Conclusion This study will provide real-world data on the long-term safety and effectiveness of velmanase alfa in patients with alpha-mannosidosis during routine clinical care and increase the understanding of the natural course, clinical manifestations, and progression of this ultra-rare disease.

scholarly journals Successful Pregnancy in a Patient with Infertility Due to Congenital Plasminogen Deficiency Treated with Intravenous Plasminogen (Human) Replacement Therapy

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 5-6
Author(s):  
Anne Flem Jacobsen ◽  
Joseph M Parker ◽  
Diane Trybul ◽  
Per Morten Sandset
Keyword(s):  
Clinical Trial ◽  
Replacement Therapy ◽  
Healthy Child ◽  
Tissue Injury ◽  
Recovery Period ◽  
Case Series ◽  
Publicly Traded ◽  
Ligneous Conjunctivitis ◽  
Plasminogen Deficiency ◽  
Eye Lesions

Congenital plasminogen deficiency (C-PLGD) is a rare autosomal recessive multisystem disorder of the fibrinolytic system that is often underdiagnosed. It is caused by mutations in the PLG gene and is characterized by extravascular fibrinous deposits on mucus membranes resulting in tissue injury or organ dysfunction. The abnormal accumulation or growth of fibrin-rich pseudomembranous lesions on mucous membranes, such as the conjunctiva, gingiva, linings of airways and genitourinary tract have been termed ligneous for their "woody" appearance. Ligneous conjunctivitis is the most common manifestation of C-PLGD occurring in greater than 80% of affected patients. Ligneous lesions affecting the female reproductive system have been reported in one large case series in 9% of patients (Shuster et. al. JTH 2007). An extensive review of the literature (Baithun et. al. Haemophilia 2018) identified 30 cases of C-PLGD patients with gynecologic involvement. A diagnosis of infertility, when performed, was reported in 8 (26.7%) of these females of child-bearing age. Due to the rarity of the disease, infertility may be under diagnosed and under reported in the literature as no natural history studies of this disease have been conducted. We report a case of a patient with C-PLGD with a documented diagnosis of infertility who received intravenous plasminogen therapy. Although the protocol stated that adequate contraceptive measures be taken to avoid becoming pregnant during the study, she became pregnant, went to term and had a successful delivery of a healthy child. She was a 33-year-old woman with a diagnosis of C-PLGD in childhood, after developing ligneous conjunctivitis before the age of 1, developed uterine ligneous lesions and dysmenorrhea as a teenager. At age 27, a hysteroscopy was attempted and laparoscopy was performed which revealed fibrosis and web-like fibrin-rich adhesions in the uterus and fallopian tubes. She was referred to the Oslo University Hospital, Norway, for evaluation and management of her infertility and eye lesions at the age of 28. She was treated with fresh frozen plasma (FFP) infusions with improvement in eye symptoms and dysmenorrhea. At the age of 29, a vaginoscopy and hysteroscopy were performed which again demonstrated fibrin membranes in the uterus. A repeat evaluation at the age of 30 revealed fibrin membranes in the cervix, fibrin accumulation in the uterus, and tube ostia obstructed. At age 33 she was enrolled in a clinical trial, an open-label phase 2/3 study of human Glu-plasminogen administered intravenously at 6.6 mg/kg every 2-4 days in 15 patients with plasminogen deficiency, registered at www.clinicaltrials.gov as #NCT02690714. She received intravenous plasminogen replacement therapy, starting in October 2016. At baseline, she had ligneous conjunctivitis and gynecologic lesions with regular, but atypical menstrual bleeding, discharging very small amounts of thick, mucus-like material over 1-2 days. Her eye lesions had resolved by week 12 of treatment. At the end of the first menstrual cycle on plasminogen treatment, she discharged a large mucus-like plug from the vagina, and had regular and normal menstrual bleeds after that. Approximately 20 weeks into treatment, she reported being pregnant to the investigator. After discussion with the clinical study sponsor, regulatory agencies and the regional ethical committee, the patient and her physician, it was agreed to continue plasminogen replacement therapy through the pregnancy, delivery and recovery period. After approximately 55 weeks into the study treatment, the patient had an uncomplicated pregnancy and delivered a healthy child with APGAR score of 9. The patient remained on PLG treatment post-partum, and her PLG activity trough levels were maintained until she came off the study when her levels went back to baseline. (Figure 1) This is the first reported case of intravenous plasminogen used in a patient with C-PLGD and documented infertility who subsequently became pregnant and delivered a healthy child. Figure Disclosures Parker: Liminal BioSciences: Current Employment, Current equity holder in publicly-traded company. Trybul:Liminal BioSciences: Current Employment, Current equity holder in publicly-traded company. Sandset:Liminal BioSciences: Other: Investigator Clinical Trial.

scholarly journals Natural history: an approach whose time has come, passed, and needs to be resurrected†

2016 ◽  
Vol 73 (9) ◽  
pp. 2150-2155 ◽  
Author(s):  
Kenneth W. Able
Keyword(s):  
Natural History ◽  
Habitat Restoration ◽  
Natural Environments ◽  
Marine Fauna ◽  
Natural History Studies ◽  
History Of ◽  
Complex Life History ◽  
Management And Conservation ◽  
Term Monitoring

AbstractThe development of our understanding of fish and other marine fauna, including my own over several decades, has proceeded from basic natural history to ecology and evolution, but we often need to return to natural history to address deficiencies in our attempts to manage fisheries, conserve habitats, and model ecosystems. This resurrection of natural history is still needed because of the complex life history of fish, and many other marine fauna, and the lack of appreciation of shifting baselines in marine environments. These inadequacies are especially evident when we try to address the effects of human influences, e.g. fishing, urbanization, and climate change relative to fisheries management and conservation. A solution lies in the rebirth of natural history studies, especially at “places” such as marine field stations. Long-term monitoring, especially, continues to provide critical insights. All of these approaches are limited by inadequate appreciation and, as a result, funding. The solutions are largely site and investigation specific but would be enhanced by a greater appreciation of the advantages of comprehensive, long-term studies in natural environments, especially with regard to the increasing worldwide emphasis on conservation and habitat restoration.

Reduction of major amputations in the diabetic ischaemic foot: A strategy to "take control" with conservative care as well as revascularisation

VASA ◽  
2001 ◽  
Vol 30 (Supplement 58) ◽  
pp. 6-14 ◽  
Author(s):  
Edmonds ◽  
Foster
Keyword(s):  
Natural History ◽  
Treatment Plan ◽  
Staging System ◽  
Vascular Control ◽  
New Approach ◽  
Conservative Care ◽  
Arterial Bypass ◽  
Therapeutic Footwear ◽  
Frequent Problem

The diabetic ischaemic foot has become an increasingly frequent problem over the last decade. However, we report a new approach consisting of a basic classification, a simple staging system of the natural history and a treatment plan for each stage, within a multi-disciplinary framework. This approach of "taking control" consists of two parts: 1. long-term conservative care including debridement of ulcers (to obtain wound control), eradication of sepsis (micribiological control), and provision of therapeutic footwear (mechanical control), and 2. revascularisation by angioplasty and arterial bypass (vascular control). This approach has led to a 50% reduction in the rate of major amputations in patients attending with ischaemic ulceration and absent foot pulses from 1989 to 1999 (from 4.6% to 2.3% per year). Patients who underwent angioplasty increased from 6% to 13%. Arterial bypass similarly increased from 3% to 7% of cases. However, even with an increased rate of revascularisation, 80% of patients responded to conservative care alone. This,we conclude, is an essential part of the management of all patients with ischaemic feet.

The natural history of pituitary apoplexy: long term follow-up study

2019 ◽  
Author(s):  
Ayesha Shaikh ◽  
Natasha Shrikrishnapalasuriyar ◽  
Giselle Sharaf ◽  
David Price ◽  
Maneesh Udiawar ◽  
...  
Keyword(s):  
Natural History ◽  
Pituitary Apoplexy ◽  
Follow Up Study ◽  
Long Term Follow Up ◽  
History Of

Planning a system of permanent sample plots for integrated long-term studies of community-based forest management

1970 ◽  
Vol 16 (2) ◽  
pp. 3-11 ◽  
Author(s):  
H Meilby ◽  
L Puri ◽  
M Christensen ◽  
S Rayamajhi
Keyword(s):  
Forest Management ◽  
Key Words ◽  
Research Note ◽  
Managed Forests ◽  
Community Based ◽  
Permanent Sample Plots ◽  
Long Term Studies

To monitor the development of four community-managed forests, networks of permanent sample plots were established in 2005 at sites in Chitwan, Kaski and Mustang Districts, Nepal. This research note documents the procedures used when preparing for establishment of the plot networks, evaluates the applied stratification of the forest on the basis of data gathered in pilot surveys conducted in the early 2005, and provides a discussion on the implications of the choices made. Key words: Community-managed forests; permanent sample plots; stratification; allocation; estimates Banko Janakari Vol.16(2) 2006 pp.3-11

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