title: Congenital disorders of autophagy: an emerging novel class of inborn errors of neuro-metabolism.
abstract: Single gene disorders of the autophagy pathway are an emerging, novel and diverse group of multisystem diseases in children. Clinically, these disorders prominently affect the central nervous system at various stages of development, leading to brain malformations, developmental delay, intellectual disability, epilepsy, movement disorders, and neurodegeneration, among others. Frequent early and severe involvement of the central nervous system puts the paediatric neurologist, neurogeneticist, and neurometabolic specialist at the forefront of recognizing and treating these rare conditions. On a molecular level, mutations in key autophagy genes map to different stages of this highly conserved pathway and thus lead to impairment in isolation membrane (or phagophore) and autophagosome formation, maturation, or autophagosome-lysosome fusion. Here we discuss 'congenital disorders of autophagy' as an emerging subclass of inborn errors of metabolism by using the examples of six recently identified monogenic diseases: EPG5-related Vici syndrome, beta-propeller protein-associated neurodegeneration due to mutations in WDR45, SNX14-associated autosomal-recessive cerebellar ataxia and intellectual disability syndrome, and three forms of hereditary spastic paraplegia, SPG11, SPG15 and SPG49 caused by SPG11, ZFYVE26 and TECPR2 mutations, respectively. We also highlight associations between defective autophagy and other inborn errors of metabolism such as lysosomal storage diseases and neurodevelopmental diseases associated with the mTOR pathway, which may be included in the wider spectrum of autophagy-related diseases from a pathobiological point of view. By exploring these emerging themes in disease pathogenesis and underlying pathophysiological mechanisms, we discuss how congenital disorders of autophagy inform our understanding of the importance of this fascinating cellular pathway for central nervous system biology and disease. Finally, we review the concept of modulating autophagy as a therapeutic target and argue that congenital disorders of autophagy provide a unique genetic perspective on the possibilities and challenges of pathway-specific drug development.
authors.affiliation: 1 The F.M. Kirby Neurobiology Centre, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA 2 Division of Paediatric Neurology and Inherited Metabolic Diseases, Department of Paediatrics, Heidelberg University Hospital, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany darius.ebrahimi-fakhari@childrens.harvard.edu.
authors.forename: Darius
authors.initials: D
authors.lastname: Ebrahimi-Fakhari
authors.affiliation: 2 Division of Paediatric Neurology and Inherited Metabolic Diseases, Department of Paediatrics, Heidelberg University Hospital, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
authors.forename: Afshin
authors.initials: A
authors.lastname: Saffari
authors.affiliation: 2 Division of Paediatric Neurology and Inherited Metabolic Diseases, Department of Paediatrics, Heidelberg University Hospital, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany 3 Department of Haematology and Oncology, Stem Cell Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Lara
authors.initials: L
authors.lastname: Wahlster
authors.affiliation: 1 The F.M. Kirby Neurobiology Centre, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Lu
authors.affiliation: 4 Department of Paediatric Neurology, Evelina's Children Hospital, Guy's and St. Thomas' Hospital NHS Foundation Trust, London, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Byrne
authors.affiliation: 2 Division of Paediatric Neurology and Inherited Metabolic Diseases, Department of Paediatrics, Heidelberg University Hospital, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
authors.forename: Georg F
authors.initials: GF
authors.lastname: Hoffmann
authors.affiliation: 4 Department of Paediatric Neurology, Evelina's Children Hospital, Guy's and St. Thomas' Hospital NHS Foundation Trust, London, UK 5 Randall Division for Cell and Molecular Biophysics, Muscle Signalling Section, King's College London, London, UK 6 Department of Basic and Clinical Neuroscience, IoPPN, King's College London, London, UK.
authors.forename: Heinz
authors.initials: H
authors.lastname: Jungbluth
authors.affiliation: 1 The F.M. Kirby Neurobiology Centre, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Sahin
mesh_terms: D061085:Agenesis of Corpus Callosum / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000502:physiology*; D020739:Brain Diseases, Metabolic, Inborn / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D002386:Cataract / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020140:Lysosomal Storage Diseases, Nervous System / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism; D015419:Spastic Paraplegia, Hereditary / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism
keywords: autophagy; inborn errors of metabolism; mammalian target of rapamycin (mTOR); neurodegeneration; neurodevelopment