TY - JOUR
T1 - The spectrum of neurodevelopmental, neuromuscular and neurodegenerative disorders due to defective autophagy
AU - Deneubourg, Celine
AU - Ramm, Mauricio
AU - Smith, Luke J.
AU - Baron, Olga
AU - Singh, Kritarth
AU - Byrne, Susan C.
AU - Duchen, Michael R.
AU - Gautel, Mathias
AU - Eskelinen, Eeva Liisa
AU - Fanto, Manolis
AU - Jungbluth, Heinz
N1 - Funding Information:
This work was supported by grants from the European Union’s Horizon 2020 Research and Innovation Programme (765912 — DRIVE — H2020-MSCA-ITN-2017) to CD, MR, ELE, MF and HJ, Action Medical Research (2446) to HJ and MF, Medical Research Council (G1002186) to MF, and the Myotubular Trust (12KCL01) to HJ and MG.
Publisher Copyright:
© 2021 Informa UK Limited, trading as Taylor & Francis Group.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021
Y1 - 2021
N2 - 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. Additionally, 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.
AB - 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. Additionally, 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.
KW - autophagy
KW - cellular trafficking; neurodegenerative disorders
KW - congenital disorders of autophagy
KW - neurodevelopmental disorders
UR - http://www.scopus.com/inward/record.url?scp=85112550779&partnerID=8YFLogxK
U2 - 10.1080/15548627.2021.1943177
DO - 10.1080/15548627.2021.1943177
M3 - Review article
C2 - 34130600
AN - SCOPUS:85112550779
SN - 1554-8627
JO - Autophagy
JF - Autophagy
ER -