Autosomal dominant neuronal ceroid lipofuscinosis: Clinical features and molecular basis

Clin Genet. 2021 Jan;99(1):111-118. doi: 10.1111/cge.13829. Epub 2020 Aug 26.


The neuronal ceroid lipofuscinoses (NCLs) are at least 13 distinct progressive neurodegenerative disorders unified by the accumulation of lysosomal auto-fluorescent material called lipofuscin. The only form that occurs via autosomal-dominant inheritance exhibits adult onset and is sometimes referred to as Parry type NCL. The manifestations may include behavioral symptoms followed by seizures, ataxia, dementia, and early death. Mutations in the gene DNAJC5 that codes for the presynaptic co-chaperone cysteine string protein-α (CSPα) were recently reported in sporadic adult-onset cases and in families with dominant inheritance. The mutant CSPα protein may lead to disease progression by both loss and gain of function mechanisms. Iron chelation therapy may be considered as a possible pharmaceutical intervention based on our recent mechanism-based proposal of CSPα oligomerization via ectopic Fe-S cluster-binding, summarized in this review.

Keywords: CSPα; DNAJC5; Kufs disease; Parry type NCL; autosomal dominant neuronal ceroid lipofuscinosis; deferiprone.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Genes, Dominant / genetics
  • HSP40 Heat-Shock Proteins / genetics*
  • Humans
  • Iron / metabolism
  • Iron Chelating Agents / therapeutic use
  • Membrane Proteins / genetics*
  • Mutation / genetics
  • Neuronal Ceroid-Lipofuscinoses / genetics*
  • Neuronal Ceroid-Lipofuscinoses / physiopathology
  • Neuronal Ceroid-Lipofuscinoses / therapy*
  • Neurons / metabolism*
  • Neurons / pathology
  • Pedigree


  • HSP40 Heat-Shock Proteins
  • Iron Chelating Agents
  • Membrane Proteins
  • cysteine string protein
  • Iron