Bi-allelic ADPRHL2 Mutations Cause Neurodegeneration with Developmental Delay, Ataxia, and Axonal Neuropathy

Am J Hum Genet. 2018 Nov 1;103(5):817-825. doi: 10.1016/j.ajhg.2018.10.005. Epub 2018 Oct 25.


ADP-ribosylation is a reversible posttranslational modification used to regulate protein function. ADP-ribosyltransferases transfer ADP-ribose from NAD+ to the target protein, and ADP-ribosylhydrolases, such as ADPRHL2, reverse the reaction. We used exome sequencing to identify five different bi-allelic pathogenic ADPRHL2 variants in 12 individuals from 8 families affected by a neurodegenerative disorder manifesting in childhood or adolescence with key clinical features including developmental delay or regression, seizures, ataxia, and axonal (sensori-)motor neuropathy. ADPRHL2 was virtually absent in available affected individuals' fibroblasts, and cell viability was reduced upon hydrogen peroxide exposure, although it was rescued by expression of wild-type ADPRHL2 mRNA as well as treatment with a PARP1 inhibitor. Our findings suggest impaired protein ribosylation as another pathway that, if disturbed, causes neurodegenerative diseases.

Keywords: ADPRHL2; ARH3; PARP; ataxia; cerebellar atrophy; neurodegeneration; neuropathy; posttranslational modification; ribosylation; seizure.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-Ribosylation / genetics
  • Adenosine Diphosphate Ribose / genetics
  • Adolescent
  • Alleles
  • Cerebellar Ataxia / genetics*
  • Child
  • Child, Preschool
  • Developmental Disabilities / genetics*
  • Exome / genetics
  • Female
  • Glycoside Hydrolases / genetics*
  • Humans
  • Infant
  • Male
  • Mutation / genetics*
  • Nervous System Malformations / genetics
  • Neurodegenerative Diseases / genetics*
  • Protein Processing, Post-Translational / genetics


  • Adenosine Diphosphate Ribose
  • Glycoside Hydrolases
  • ADPRS protein, human