Congenital disorders of autophagy and intracellular trafficking – a novel class of neurometabolic disorders linking aberrant neurodevelopment and neurodegeneration


This is a hybrid seminar. Attendees are welcome to sign up for lunch with the speaker, which will occur immediately following the talk.

Autophagy is an essential intracellular degradative pathway conserved throughout evolution with fundamental roles in metabolic adaptation, defence against infection and the quality control of defective proteins and organelles. 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 comprises several early-onset neurodevelopmental disorders, including Vici syndrome due to recessive mutations in EPG5, as well as various forms of hereditary spastic paraparesis, ataxia and neurodegeneration with brain iron accumulation (NBIA). Early-onset (or congenital) disorders of autophagy often share a recognizable “clinical signature”, including distinct but 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. The clinical overlap between the congenital disorders of autophagy and these conditions reflects the multiple roles of the defective proteins and/or emerging molecular connections between the pathways implicated, suggesting 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.