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.

Heinz Jungbluth is Professor of Paediatric Neurology at King’s College London and Consultant Paediatric Neurologist at the Evelina Children’s Hospital, Guy’s & St Thomas’ NHS Foundation Trust, London, UK, with more than 25 years clinical experience in Paediatric Neurology.
His main research interest is in early-onset neuromuscular and neurodevelopmental disorders.  He has been leading the genetic and phenotypic characterization of congenital myopathies, in particular those affecting excitation-contraction coupling due to mutations in the skeletal muscle ryanodine receptor (RYR1) gene, and related episodic disorders such as malignant hyperthermia (MH) and (exertional) rhabdomyolysis (ERM). He and his team have also introduced the concept of congenital disorders of autophagy, a novel class of inborn neuromuscular and neurometabolic conditions linking aberrant neurodevelopment with common adult-onset neurodegenerative disorders such as dementia, PD and ALS.
He has published more than 230 peer-reviewed papers and chapters in key textbooks. He is a member of national and international expert consortia concerned with improving the care and developing therapies for early-onset neuromuscular and neurological disease.
Date: 25 April 2024, 10:30 (Thursday, 1st week, Trinity 2024)
Venue: John Radcliffe Hospital - Main Building, Headington OX3 9DU
Venue Details: George Pickering Education Centre, Seminar Room 4B
Speaker: Prof Heinz Jungbluth (King's College London)
Organising department: Department of Paediatrics
Organiser: MDUK Oxford Neuromuscular Centre (University of Oxford)
Organiser contact email address:
Part of: MDUK Oxford Neuromuscular Centre Seminars
Booking required?: Not required
Audience: Members of the University only
Editor: Chelsea Larabee