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Congenital disorders of autophagy: an emerging novel class of inborn errors of neuro-metabolism

Darius Ebrahimi-Fakhari, Afshin Saffari, Lara Wahlster, Jenny Lu, Susan Byrne, Georg F. Hoffmann, Heinz Jungbluth, Mustafa Sahin
DOI: http://dx.doi.org/10.1093/brain/awv371 317-337 First published online: 29 December 2015


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.

  • autophagy
  • inborn errors of metabolism
  • mammalian target of rapamycin (mTOR)
  • neurodevelopment
  • neurodegeneration
  • Abbreviations
    AMP-activated protein kinase
    autophagy-related gene/protein
    beta-propeller protein-associated neurodegeneration
    hereditary spastic paraplegia
    induced pluripotent stem cell
    mammalian target of rapamycin
    mammalian target of rapamycin complex 1
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