A novel missense HNRNPA1 variant in the PY-NLS domain in a patient with late-onset distal myopathy

Pitcha Chompoopong, Margherita Milone, Zhiyv Niu, Gaofeng Cui, Georges Mer, Teerin Liewluck

Research output: Contribution to journalArticlepeer-review


Pathogenic HNRNPA1 variants underlying myopathy have been reported only in the prion-like domain of the heterogenous nuclear ribonucleoproteins A1, while two variants in the nuclear localization (PY-NLS) domain were described in ALS. Here we report a 61-year-old man who presented with 1-year history of bilateral foot drop without Paget disease or dementia. Examination revealed severe asymmetric distal weakness, predominantly affecting tibialis anterior and toe extensors. Creatine kinase was 1,013 U/L (normal <308). Alkaline phosphatase was normal. EMG demonstrated small polyphasic motor unit potentials and fibrillation potentials. Muscle biopsy showed numerous fibers containing rimmed vacuoles and occasional fibers harboring congophilic inclusions, or p62/TDP-43/hnRNPA1-immunoreacted aggregates. Next generation sequencing identified a novel heterozygous (c.959A>T, p. Asn320Ile) variant in HNRNPA1, affecting a highly conserved amino acid in PY-NLS domain. Muscle MRI showed abnormalities, consistent with HNRNPA1-myopathy. This patient expands the phenotypic spectrum of hnRNPA1-opathy due to a PY-NLS domain variant to include isolated distal myopathy.

Original languageEnglish (US)
Pages (from-to)521-526
Number of pages6
JournalNeuromuscular Disorders
Issue number6
StatePublished - Jun 2022


  • Distal myopathy
  • Hnrnpa1
  • Inclusion body myopathy
  • Multisystem proteinopathy
  • Nuclear localization sequence

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Neurology
  • Clinical Neurology
  • Genetics(clinical)


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