A2 Refereed review article in a scientific journal
The spectrum of neurodevelopmental, neuromuscular and neurodegenerative disorders due to defective autophagy
Authors: Deneubourg Celine, Ramm Mauricio, Smith Luke J, Baron Olga, Singh Kritarth, Byrne Susan C, Duchen Michael R, Gautel Mathias, Eskelinen Eeva-Liisa, Fanto Manolis, Jungbluth Heinz
Publisher: Taylor & Francis
Publication year: 2022
Journal: Autophagy
Journal name in source: Autophagy
Journal acronym: Autophagy
Volume: 18
Issue: 3
First page : 496
Last page: 517
ISSN: 1554-8627
eISSN: 1554-8635
DOI: https://doi.org/10.1080/15548627.2021.1943177
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/66417748
Primary dysfunction of autophagy due to Mendelian defects affecting core components of the autophagy machinery or closely related proteins have recently emerged as an important cause of genetic disease. This novel group of human disorders may present throughout life and comprises severe early-onset neurodevelopmental and more common adult-onset neurodegenerative disorders. Early-onset (or congenital) disorders of autophagy often share a recognizable "clinical signature," including variable combinations of neurological, neuromuscular and multisystem manifestations. Structural CNS abnormalities, cerebellar involvement, spasticity and peripheral nerve pathology are prominent neurological features, indicating a specific vulnerability of certain neuronal populations to autophagic disturbance. A typically biphasic disease course of late-onset neurodegeneration occurring on the background of a neurodevelopmental disorder further supports a role of autophagy in both neuronal development and maintenance. In addition, an associated myopathy has been characterized in several conditions. The differential diagnosis comprises a wide range of other multisystem disorders, including mitochondrial, glycogen and lysosomal storage disorders, as well as ciliopathies, glycosylation and vesicular trafficking defects. The clinical overlap between the congenital disorders of autophagy and these conditions reflects the multiple roles of the proteins and/or emerging molecular connections between the pathways implicated and suggests an exciting area for future research. Therapy development for congenital disorders of autophagy is still in its infancy but may result in the identification of molecules that target autophagy more specifically than currently available compounds. The close connection with adult-onset neurodegenerative disorders highlights the relevance of research into rare early-onset neurodevelopmental conditions for much more common, age-related human diseases.
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