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External Control Using RWE and Historical Data in Clinical Development
Published in Harry Yang, Binbing Yu, Real-World Evidence in Drug Development and Evaluation, 2021
Qing Li, Guang Chen, Jianchang Lin, Andy Chi, Simon Davies
Batten disease, which is also called neuronal ceroid lipofuscinoses (NCLs), is a family of rare, fatal, inherited disorders of the nervous system. It is estimated that 2–4 births per 100,000 in the United States are affected by Batten disease, which is considered as a rare disease. Batten disease was named after British pediatrician Frederick Batten, who first described the disease in 1903; however, there were no approved drugs until recently. In April 2017, the FDA approved Brineura® (cerliponase alfa), which was developed by BioMarin Pharmaceutical, Inc. as a treatment for a specific form of Batten disease (FDA 2017c). It is the first FDA-approved treatment to slow the loss of walking ability (ambulation) in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase-1 (TPP1) deficiency. The BLA of Brineura® received priority review and breakthrough therapy designation.
Hyperkinetic Movement Disorders
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Morales-Briceno Hugo, Victor S.C. Fung, Annu Aggarwal, Philip Thompson
Lysosomal storage diseases: GM1, GM2 gangliosidoses (GM).Neuronal ceroid lipofuscinosis (NCL).Niemann–Pick type C (NPC).
MFSD8 gene mutations; evidence for phenotypic heterogeneity
Published in Ophthalmic Genetics, 2019
Davood Zare-Abdollahi, Ata Bushehri, Afagh Alavi, Alireza Dehghani, Mohammadreza Mousavi-Mirkala, Jalil Effati, Seyed Ali Mohammad Miratashi, Mohammad Dehani, Payman Jamali, Hamid Reza Khorram Khorshid
WES approach identified a compound heterozygous (c.1361T>C; p.M454T and c.1235C>T; p.P412L) previously reported variants in family A and a homozygous variant (c.1361T>C; p.M454T) in family B identical to one of the variants in family A in MFSD8 gene, both confirmed by Sanger sequencing and co-segregated with disease status. c.1361T>C in exon 13 was variant of uncertain significance (VUS) and found in all patients of both families; however, variant c.1235C>T in exon 12, which observed in patient of family B (IV-1 and IV-2), was pathogenic and located at a highly conserved nucleotide, both absent from all databases and predicted to be deleterious in computational analysis. No other potential disease-causing variant was found in known retinal disease-associated genes. Based on perfect segregation of the mutant allele with the disease in the family as well as reporting these mutations associated with variant late-infantile neuronal ceroid lipofuscinoses (vLINCL), these variants are likely to be causative mutations in five patients with CCMD from two different families, rather than a rare polymorphism in the normal population.
Progress in gene and cell therapies for the neuronal ceroid lipofuscinoses
Published in Expert Opinion on Biological Therapy, 2018
Anthony Donsante, Nicholas M Boulis
The neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, are a collection of neurodegenerative disorders inherited in a predominantly recessive manner. Clinically, NCLs generally result in myoclonic epilepsy, loss of cognitive and motor function, degeneration of the retina leading to blindness, and death. Histologically, these disorders are united by the accumulation of autofluorescent storage material in lysosomes, both in the central nervous system (CNS) and visceral tissues. The pathogenesis of these disorders is complex and not well understood but may involve abnormalities in intracellular trafficking, autophagy, lipid metabolism, and the immune system (reviewed in Ref. [1]). Strikingly, gliosis precedes neurodegeneration, suggesting a role for neuroinflammation in disease progression.
Novel MFSD8 mutation causing non-syndromic asymmetric adult-onset macular dystrophy
Published in Ophthalmic Genetics, 2023
Aaron Z. Priluck, Mark P. Breazzano
The MFSD8 gene on chromosome 4 encodes a 518 amino acid protein located in lysosomal membranes and thought to be involved in substrate transport (3,4). Within the retina, the MFSD8 gene product has been localized to photoreceptor presynaptic terminals in the outer plexiform layer (6). Mutations in MFSD8 were first identified to cause type 7 neuronal ceroid lipofuscinosis (NCL). The NCLs are a heterogenous group of rare fatal neurodegenerative diseases caused by mutations in 13 different genes and are broadly characterized by seizures, declining cognitive and motor abilities, and visual decline (7). Pathophysiology involves the accumulation of lipopigment in lysosomes and neuronal cell death in the brain and eyes (8).