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Hereditary and Metabolic Diseases of the Central Nervous System in Adults
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Inclusion body subtypes include: Granular osmophilic deposits (GRODs). Associated genes are PPT1, CTSD, and CLN8. Autosomal dominant ANCL usually has GROD and has not been linked to a specific gene.Curvilinear profiles (CVs). Associated genes are CLN8, MFSD8 (major facilitator superfamily domain-8), CLN6, and TPP1.Fingerprint profiles (FPs). Associated genes are CLN3, CLN5, CLN6, and MFSD8.Mixed type inclusions (GROD, CV, FP).
Central nervous system: Paediatric and neurodevelopmental disorders
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Where degenerative metabolic disorders of the central nervous system are part of systemic metabolic conditions, these are considered in Chapter 26. An important group of disorders is largely confined to the nervous system (Table 14.4). Most are Mendelian, so that the recognition of a specific biochemical and/or molecular genetic diagnosis is of great importance for genetic counselling. Frozen tissue or stored cultured cells are often crucial where the only affected individuals are dead. The recognition of some genes, when the corresponding metabolic defect had been unknown until then, has proved especially fruitful both for genetic counselling (as with the recognition of mutation in CLN3 being the cause of Batten disease) and in efforts to work towards rational therapies.
Advances in the treatment of neuronal ceroid lipofuscinosis
Published in Expert Opinion on Orphan Drugs, 2019
Jonathan B. Rosenberg, Alvin Chen, Stephen M. Kaminsky, Ronald G. Crystal, Dolan Sondhi
CLN3 disease, also known as juvenile neuronal ceroid lipofuscinosis (JNCL), is the juvenile-onset form of the disease. It is caused by mutations to the CLN3 gene that encodes a lysosomal transmembrane protein, the function of which is unknown [52]. It is theorized to be involved with the modulation of vesicular trafficking and fusion, or alternatively with regulation of lysosomal pH or osmoregulation [16,53–56]. Disease onset usually occurs between 4 and 10 years of age, starting with visual failure from rapidly progressing retinal degeneration, followed by progressive cognitive decline and motor dysfunction [57–59]. Behavioral problems and seizures then develop. Life expectancy is in the early 20s [14,59]. A small-scale natural history trial is currently recruiting CLN3 patients (Table 2), with no results reported to date.
Paradoxical response to carbonic anhydrase inhibitors in patients with intraretinal cystoid spaces
Published in Ophthalmic Genetics, 2019
T. A. C. de Guimaraes, J. E. Capasso, A. V. Levin
Retinoschisin is a protein involved in cell-to-cell adhesion, which when mutated lead to splitting of the retinal layers at the level of the ganglion cell layer, resulting in the formation of IRCS (19). NR2E3 encodes a ligand-dependent transcription factor involved in the signaling pathway regulating photoreceptor cell differentiation and maintenance (20). It has been previously suggested that the hybrid rod-cone cells seen in these patients might not be able to form adequate tight junctions between the inner segments of the photoreceptor cells and Muller cells. This might compromise the integrity of the retinal architecture and lead to development of IRCS, which are characteristically large in this disease (21). CLN3 is a gene that encodes the 438–amino acid protein product Battenin. The functions of this protein are not fully understood. Disruptive autophagic activity in lysosomal compartments is observed in CLN3-deficient mice, and it is postulated that this transmembrane protein is associated with endocytic membrane trafficking (22–25). Although IRCS have been previously reported in CLN3-related retinal dystrophy, the cause is still unknown (26).
Progress in gene and cell therapies for the neuronal ceroid lipofuscinoses
Published in Expert Opinion on Biological Therapy, 2018
Anthony Donsante, Nicholas M Boulis
Two groups have tackled gene therapy for CLN3 disease. The first explored the use of an AAVrh.10 vector expressing CLN3 in a mouse model of this disorder. Neonatal mice were injected bilaterally into the striatum, hippocampus, and cerebellum. Expression of the CLN3 mRNA reached superphysiologic levels. This resulted in a 28% reduction in overall storage and a reduction in astrocyte activation. Microglial activation and neuron counts, however, were not significantly changed. Unfortunately, motor function could not be assessed since untreated CLN3-deficient mice showed no deficits on the tests used [57].