Novel likely disease-causing CLN5 variants identified in Pakistani patients with neuronal ceroid lipofuscinosis

Azad, Beenish; Efthymiou, Stéphanie; Sultan, Tipu; Scala, Marcello; Alvi, Javeria Raza; Neuray, Caroline; Dominik, Natalia; Gul, Asma; Houlden, Henry

doi:10.1016/j.jns.2020.116826

Cited by 4 publications

(2 citation statements)

References 21 publications

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“…Cerebella from human CLN6 patients may be normal or show some atrophy (Cannelli et al, 2009;Peña et al, 2001), but it has been reported that the cerebellum in human CLN5 cases can be severely atrophied, with an almost complete depletion of cerebellar granule and Purkinje cells observed in post mortem tissue (Goebel et al, 1999;Haltia, 2003;Tyynelä et al, 1997). Brain imaging of human CLN5 patients reveals the same moderate-to-severe cortical atrophy seen in CLN5 animal models, but marked atrophy of the human cerebellum is one of the most striking abnormalities (Autti et al, 1992;Azad et al, 2020;Bessa et al, 2006;Lauronen et al, 2002;Mancini et al, 2015;Simonati et al, 2017). This is not the case for most animal CLN5 and CLN6 NCLs.…”

Section: Discussionmentioning

confidence: 99%

Characterization of neuropathology in ovine CLN5 and CLN6 neuronal ceroid lipofuscinoses (Batten disease)

Mitchell

Russell

Barrell

et al. 2023

Developmental Neurobiology

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Sheep with naturally occurring CLN5 and CLN6 forms of neuronal ceroid lipofuscinoses (Batten disease) share the key clinical features of the human disease and represent an ideal model system in which the clinical efficacy of gene therapies is developed and test. However, it was first important to characterize the neuropathological changes that occur with disease progression in affected sheep. This study compared neurodegeneration, neuroinflammation, and lysosomal storage accumulation in CLN5 affected Borderdale, CLN6 affected South Hampshire, and Merino sheep brains from birth to end‐stage disease at ≤24 months of age. Despite very different gene products, mutations, and subcellular localizations, the pathogenic cascade was remarkably similar for all three disease models. Glial activation was present at birth in affected sheep and preceded neuronal loss, with both spreading from the visual and parieto‐occipital cortices most prominently associated with clinical symptoms to the entire cortical mantle by end‐stage disease. In contrast, the subcortical regions were less involved, yet lysosomal storage followed a near‐linear increase across the diseased sheep brain with age. Correlation of these neuropathological changes with published clinical data identified three potential therapeutic windows in affected sheep—presymptomatic (3 months), early symptomatic (6 months), and a later symptomatic disease stage (9 months of age)—beyond which the extensive depletion of neurons was likely to diminish any chance of therapeutic benefit. This comprehensive natural history of the neuropathological changes in ovine CLN5 and CLN6 disease will be integral in determining what impact treatment has at each of these disease stages.

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Section: Discussionmentioning

confidence: 99%

Characterization of neuropathology in ovine CLN5 and CLN6 neuronal ceroid lipofuscinoses (Batten disease)

Mitchell

Russell

Barrell

et al. 2023

Developmental Neurobiology

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“…Our patient had CLN5 variant that creates a premature stop codon causing non sense mutation 5,6 . Azad B, et al recently reported novel likely disease causing CLN5 variants in Pakistani patients with NCL 7 .…”

Section: Case Reportmentioning

confidence: 98%

A case of late infantile neuronal ceroid lipofuscinosis type 5

Vithanage

Yapa

Jasinge

et al. 2021

Sri Lanka J Child Health

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A lysosomal enigma CLN5 and its significance in understanding neuronal ceroid lipofuscinosis

Basak

Wicky

McDonald

et al. 2021

Cell. Mol. Life Sci.

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Neuronal Ceroid Lipofuscinosis (NCL), also known as Batten disease, is an incurable childhood brain disease. The thirteen forms of NCL are caused by mutations in thirteen CLN genes. Mutations in one CLN gene, CLN5, cause variant late-infantile NCL, with an age of onset between 4 and 7 years. The CLN5 protein is ubiquitously expressed in the majority of tissues studied and in the brain, CLN5 shows both neuronal and glial cell expression. Mutations in CLN5 are associated with the accumulation of autofluorescent storage material in lysosomes, the recycling units of the cell, in the brain and peripheral tissues. CLN5 resides in the lysosome and its function is still elusive. Initial studies suggested CLN5 was a transmembrane protein, which was later revealed to be processed into a soluble form. Multiple glycosylation sites have been reported, which may dictate its localisation and function. CLN5 interacts with several CLN proteins, and other lysosomal proteins, making it an important candidate to understand lysosomal biology. The existing knowledge on CLN5 biology stems from studies using several model organisms, including mice, sheep, cattle, dogs, social amoeba and cell cultures. Each model organism has its advantages and limitations, making it crucial to adopt a combinatorial approach, using both human cells and model organisms, to understand CLN5 pathologies and design drug therapies. In this comprehensive review, we have summarised and critiqued existing literature on CLN5 and have discussed the missing pieces of the puzzle that need to be addressed to develop an efficient therapy for CLN5 Batten disease.

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Novel likely disease-causing CLN5 variants identified in Pakistani patients with neuronal ceroid lipofuscinosis

Cited by 4 publications

References 21 publications

Characterization of neuropathology in ovine CLN5 and CLN6 neuronal ceroid lipofuscinoses (Batten disease)

Characterization of neuropathology in ovine CLN5 and CLN6 neuronal ceroid lipofuscinoses (Batten disease)

A case of late infantile neuronal ceroid lipofuscinosis type 5

A lysosomal enigma CLN5 and its significance in understanding neuronal ceroid lipofuscinosis

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