Abstract
Autophagy is a fundamental and conserved intracellular pathway that mediates the degradation
of macromolecules and organelles in lysosomes. Proper autophagy function is important
for central nervous system development and neuronal function. Over the last 5 years,
several single gene disorders of the autophagy pathway have emerged: EPG5-associated Vici syndrome, WDR45-associated β-propeller protein-associated neurodegeneration, SNX14-associated autosomal-recessive spinocerebellar ataxia 20, ATG5-associated autosomal-recessive ataxia syndrome, SQSTM1/p62-associated childhood-onset neurodegeneration, and several forms of the hereditary
spastic paraplegias. This novel and evolving group of disorders is characterized by
prominent central nervous system involvement leading to brain malformations, developmental
delay, intellectual disability, epilepsy, movement disorders, and neurodegeneration.
Predominant involvement of the long white matter tracts and the cerebellum are anatomic
and imaging hallmarks, with common findings that include a thinning of the corpus
callosum and cerebellar hypoplasia or atrophy. A storage disease phenotype by clinical
or imaging criteria is present in some diseases. Most congenital disorders of autophagy
are progressive and over time involve pathology in multiple brain regions. This review
provides a detailed clinical, imaging and genetic characterization of congenital disorders
of autophagy and highlights the importance of this pathway for childhood-onset neurological
diseases.
Keywords
autophagy - inborn errors of metabolism - mammalian target of rapamycin - lysosome
- neurodevelopment - neurodegeneration
