A novel pathogenic variant in the 3' end of the AGTPBP1 gene gives rise to neurodegeneration without cerebellar atrophy: an expansion of the disease phenotype?

Neurogenetics. 2021 May;22(2):127-132. doi: 10.1007/s10048-021-00643-8. Epub 2021 Apr 28.


Childhood-onset neurodegeneration with cerebellar atrophy (CONDCA) is a recently described form of the large group of infantile hereditary lower motor neuron diseases (Teoh et al. 2017), resulting from biallelic damaging variants in the AGTPBP1 gene, first described by Shashi et al. in EMBO J 37(23):e100540, 2018. AGTPBP-related neurodegeneration is a severe neurodevelopmental disorder that progresses with global developmental delay and intellectual disability, often accompanied with peripheral nerve damage and lower motor degeneration and a fatal course in the early years of life. The encoded protein is ATP/GTP-Binding Protein1, also known as cytosolic carboxypeptidase 1 (CCP1) or nervous system nuclear protein induced by axotomy (NNA1). Here we report a consanguineous family with four offspring, two of whom are affected. The index patient is a 21-month-old male with global developmental delay and hypotonia. The proband's 17-year-old sister, diagnosed with cerebral palsy, had severe hypotonia accompanied by motor and cognitive retardation. WES analysis revealed a novel homozygous c.3293G > A variant in the AGTPBP1 gene with high pathogenicity scores. Targeted Sanger sequencing confirmed the variant in both affected children and in heterozygous form in the parents. The affected siblings present with hypotonia and motor and cognitive retardation, in line with the studies previously reported. However, in our patients, no signs of cerebellar atrophy in cranial MRI were present, so the acronym CONDCA is not applicable; lower motor neuron findings were also absent. The matching and distinguishing aspects of our patients will add to the present literature and expand our understanding of this rare genetic neurodegenerative disease of early childhood.

Keywords: AGTPBP1 gene; AGTPBP1-related neurodegeneration; Hypotonia; Motor and cognitive retardation.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • 3' Untranslated Regions / genetics*
  • Adolescent
  • Animals
  • Cerebral Palsy / genetics*
  • Consanguinity
  • Developmental Disabilities / genetics*
  • Female
  • GTP-Binding Proteins / genetics*
  • Homozygote
  • Humans
  • Infant
  • Magnetic Resonance Imaging
  • Male
  • Muscle Hypotonia / genetics*
  • Mutation, Missense*
  • Neurodegenerative Diseases / genetics*
  • Neurodegenerative Diseases / veterinary
  • Neuroimaging
  • Pedigree
  • Phenotype
  • Point Mutation*
  • Serine-Type D-Ala-D-Ala Carboxypeptidase / genetics*
  • Sheep
  • Sheep Diseases / genetics
  • Sheep, Domestic
  • Turkey


  • 3' Untranslated Regions
  • AGTPBP1 protein, human
  • Serine-Type D-Ala-D-Ala Carboxypeptidase
  • GTP-Binding Proteins