Clinical and biochemical footprints of inherited disorders of autophagy.
Clinical and biochemical footprints of inherited disorders of autophagy.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
London, GB · Author affiliation
Department of Paediatric Neurology, Neuromuscular Service, Evelina London Children's Hospital, Guy's and Thomas' NHS Foundation Trust, London, UK; Randall Division of Cell and Molecular Biophysics, Muscle Signaling Section, King's College, London, UK.Location evidence
DE · Author affiliation · country only
Department of Paediatric Neurology, Neuromuscular Service, Evelina London Children's Hospital, Guy's and Thomas' NHS Foundation Trust, London, UK; Department of Pediatrics and Center for Rare Diseases, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Max Planck Institute for Biology of Aging and Cologne Excellence Cluster for Ageing-associated Diseases, Cologne, Germany.Location evidence
Bethesda, US · Author affiliation
Unit on Skeletal Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.Location evidence
Zürich, CH · Author affiliation
Division of Metabolism, University Children's Hospital, Zürich, Switzerland. Electronic address: nenad.blau@kispi.uzh.ch.Location evidence
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Original abstract
Autophagy is an evolutionarily conserved lysosomal recycling system that integrates nutrient sensing, organelle quality control, proteostasis, cellular stress responses and metabolic adaptation. Autophagy is particularly relevant for post-mitotic tissue such as neurons, skin, and immune cells. Monogenic disorders disrupting autophagy or closely coupled endolysosomal trafficking pathways have recently emerged as a recognizable group of inherited metabolic diseases. These conditions are individually rare inborn errors of metabolism and collectively important because they bridge neurodevelopmental, neuromuscular and neurodegenerative disorders, including hereditary forms of Parkinson's disease, spastic paraplegias and neurodegeneration with brain iron accumulation. Multisystem involvement is common but variable. The prototypic disorder is EPG5-related Vici syndrome, in which defective autophagosome-lysosome fusion causes severe neurodevelopmental and multisystem disease. Other disorders may affect any step of the pathway, from phosphatidylinositol 3-phosphate effector biology and ATG conjugation/lipidation to autophagosome maturation, ATG9 trafficking, HOPS/CORVET-related vesicle trafficking (including VPS16 and VPS33A), autophagosome-lysosome fusion, autolysosome reformation and lysosome-mTOR signaling. Clinically, affected individuals commonly present with global developmental delay and/or intellectual disability, epilepsy, movement disorders including dystonia, parkinsonism, ataxia and spasticity, and both neuropathic and myopathic neuromuscular manifestations. A biphasic course with progressive neurodegeneration and variable multisystem (including ocular, cardiac, immunological, cutaneous and growth) involvement are important clinical clues. Diagnosis relies on careful phenotyping, brain MRI, targeted metabolic exclusion of mimics, genomic sequencing and functional assays in patient-derived cells as required. Supportive multidisciplinary management is essential. No disease-modifying therapy is currently established in humans, but pathway-based cellular assays, model systems and small-molecule or gene-replacement strategies are creating a rational therapeutic pipeline. Importantly, IEMbase dyadic nomenclature with system-level clinical annotations provides a standardized framework for quantifying shared phenotypic signatures across these ultra-rare conditions. This review summarizes pathobiochemistry, genetics, clinical presentation, diagnosis and treatment prospects for inherited disorders of autophagy.