The RETRIEVE Study: A natural history study of type 2 Gaucher disease, and GM1 and GM2 gangliosidoses with early onset, in preparation of a clinical trial

2021 ◽  
Vol 132 (2) ◽  
pp. S48-S49
Author(s):  
Benedicte Heron-Longe ◽  
Spyros Batzios ◽  
Eugen Mengel ◽  
Roberto Giugliani ◽  
Marc Patterson ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Natural History ◽  
Early Onset ◽  
Gaucher Disease ◽  
Natural History Study ◽  
Gm2 Gangliosidoses

scholarly journals International retrospective natural history study of LMNA-related congenital muscular dystrophy

2021 ◽  
Author(s):  
Rabah Ben Yaou ◽  
Pomi Yun ◽  
Ivana Dabaj ◽  
Gina Norato ◽  
Sandra Donkervoort ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Muscular Dystrophy ◽  
Natural History ◽  
Early Onset ◽  
Age Of Onset ◽  
Clinical Care ◽  
Common Mutation ◽  
Natural History Study ◽  
Cardiac Symptoms ◽  
Independent Ambulation

Abstract Muscular dystrophies due to heterozygous pathogenic variants in LMNA gene cover a broad spectrum of clinical presentations and severity with an age of onset ranging from the neonatal period to adulthood. The natural history of these conditions is not well defined, particularly in patients with congenital or early onset who arguably present with the highest disease burden. Thus the definition of natural history endpoints along with clinically revelant outcome measures is essential to establishing both clinical care planning and clinical trial readiness for this patient group. We designed a large international cross-sectional retrospective natural history study of patients with genetically proven muscle laminopathy who presented with symptoms before two years of age intending to identify and characterize an optimal clinical trial cohort with pertinent motor, cardiac and respiratory endpoints. Quantitative statistics were used to evaluate associations between LMNA variants and distinct clinical events. The study included 151 patients (Median age at symptom onset 0.9 years, range: 0.0-2.0). Age of onset and age of death were significantly lower in patients who never aquired independent ambulation compared to patients who achieved independent ambulation. Most of the patients acquired independent ambulation (n = 101, 66.9%), and subsequently lost this ability (n = 86; 85%). The age of ambulation acquisition (Median: 1.2 years, range: 0.8-4.0) and age of ambulation loss (Median: 7 years, range 1.2-38.0) were significantly associated with the age of the first respiratory interventions and the first cardiac symptoms. Respiratory and gastrointestinal interventions occurred during first decade while cardiac interventions occurred later. Genotype-phenotype analysis showed that the most common mutation, p.Arg249Trp (20%), was significantly associated with a more severe disease course. This retrospective natural history study of early onset LMNA-related muscular dystrophy confirms the progressive nature of the disorder, initially involving motor symptoms prior to onset of other symptoms (respiratory, orthopedic, cardiac, and gastrointestinal). The study also identifies subgroups of patients with a range of long-term outcomes. Ambulatory status was an important mean of stratification along with the presence or absence of the p.Arg249Trp mutation. These categorizations will be important for future clinical trial cohorts. Finally, this study furthers our understanding of the progression of early onset LMNA-related muscular dystrophy and provides important insights into the anticipatory care needs of LMNA-related respiratory and cardiac manifestations.

Design and rational of the natural history study in preparation for the pivotal clinical trial for the treatment of Sanfilippo syndrome type A

2017 ◽  
Vol 120 (1-2) ◽  
pp. S25-S26
Author(s):  
Soraya Bekkali ◽  
Samantha Parker ◽  
Anupam Chakrapani ◽  
Roberto Giugliani ◽  
Benedicte Heron ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Natural History ◽  
Type A ◽  
Syndrome Type ◽  
Sanfilippo Syndrome ◽  
Natural History Study ◽  
Pivotal Clinical Trial

From birth to the sixth decade - A natural history study of 42 patients with neuronopathic Gaucher disease

2019 ◽  
Vol 126 (2) ◽  
pp. S49-S50
Author(s):  
Aimee Donald ◽  
Simon A. Jones ◽  
Ashok Vellodi ◽  
Gaucherite Consortium ◽  
Timothy Cox
Keyword(s):  
Natural History ◽  
Gaucher Disease ◽  
Natural History Study ◽  
Sixth Decade

scholarly journals Prader–Willi syndrome and early‐onset morbid obesity NIH rare disease consortium: A review of natural history study

2017 ◽  
Vol 176 (2) ◽  
pp. 368-375 ◽  
Author(s):  
Merlin G. Butler ◽  
Virginia Kimonis ◽  
Elisabeth Dykens ◽  
June A. Gold ◽  
Jennifer Miller ◽  
...  
Keyword(s):  
Morbid Obesity ◽  
Natural History ◽  
Rare Disease ◽  
Early Onset ◽  
Prader Willi Syndrome ◽  
Natural History Study

scholarly journals Prospective and longitudinal natural history study of patients with Type 2 and 3 spinal muscular atrophy: Baseline data NatHis-SMA study

PLoS ONE ◽  
2018 ◽  
Vol 13 (7) ◽  
pp. e0201004 ◽  
Author(s):  
Aurélie Chabanon ◽  
Andreea Mihaela Seferian ◽  
Aurore Daron ◽  
Yann Péréon ◽  
Claude Cances ◽  
...  
Keyword(s):  
Natural History ◽  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Baseline Data ◽  
Natural History Study

Longitudinal data of the European prospective natural history study of patients with type 2 and 3 spinal muscular atrophy

2017 ◽  
Vol 27 ◽  
pp. S134
Author(s):  
A. Chabanon ◽  
M. Annoussamy ◽  
A. Daron ◽  
Y. Pereon ◽  
C. Cances ◽  
...  
Keyword(s):  
Natural History ◽  
Longitudinal Data ◽  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Natural History Study

A prospective one-year natural history study of mucopolysaccharidosis types IIIA and IIIB: Implications for clinical trial design

2016 ◽  
Vol 119 (3) ◽  
pp. 239-248 ◽  
Author(s):  
K.V. Truxal ◽  
H. Fu ◽  
D.M. McCarty ◽  
K.A. McNally ◽  
K.L. Kunkler ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Natural History ◽  
Trial Design ◽  
Clinical Trial Design ◽  
Natural History Study ◽  
One Year

scholarly journals Natural history study of glycan accumulation in large animal models of GM2 gangliosidoses

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0243006
Author(s):  
Catlyn Cavender ◽  
Linley Mangini ◽  
Jeremy L. Van Vleet ◽  
Carley Corado ◽  
Emma McCullagh ◽  
...  
Keyword(s):  
Animal Models ◽  
Natural History ◽  
Biochemical Study ◽  
Sandhoff Disease ◽  
Large Animal ◽  
Natural History Study ◽  
Large Animal Models ◽  
Significant Difference ◽  
Feline Model ◽  
Gm2 Gangliosidoses

β-hexosaminidase is an enzyme responsible for the degradation of gangliosides, glycans, and other glycoconjugates containing β-linked hexosamines that enter the lysosome. GM2 gangliosidoses, such as Tay-Sachs and Sandhoff, are lysosomal storage disorders characterized by β-hexosaminidase deficiency and subsequent lysosomal accumulation of its substrate metabolites. These two diseases result in neurodegeneration and early mortality in children. A significant difference between these two disorders is the accumulation in Sandhoff disease of soluble oligosaccharide metabolites that derive from N- and O-linked glycans. In this paper we describe our results from a longitudinal biochemical study of a feline model of Sandhoff disease and an ovine model of Tay-Sachs disease to investigate the accumulation of GM2/GA2 gangliosides, a secondary biomarker for phospholipidosis, bis-(monoacylglycero)-phosphate, and soluble glycan metabolites in both tissue and fluid samples from both animal models. While both Sandhoff cats and Tay-Sachs sheep accumulated significant amounts of GM2 and GA2 gangliosides compared to age-matched unaffected controls, the Sandhoff cats having the more severe disease, accumulated larger amounts of gangliosides compared to Tay-Sachs sheep in their occipital lobes. For monitoring glycan metabolites, we developed a quantitative LC/MS assay for one of these free glycans in order to perform longitudinal analysis. The Sandhoff cats showed significant disease-related increases in this glycan in brain and in other matrices including urine which may provide a useful clinical tool for measuring disease severity and therapeutic efficacy. Finally, we observed age-dependent increasing accumulation for a number of analytes, especially in Sandhoff cats where glycosphingolipid, phospholipid, and glycan levels showed incremental increases at later time points without signs of peaking. This large animal natural history study for Sandhoff and Tay-Sachs is the first of its kind, providing insight into disease progression at the biochemical level. This report may help in the development and testing of new therapies to treat these disorders.

Sign in / Sign up

Export Citation Format

Share Document