Triple A syndrome presenting as complicated hereditary spastic paraplegia

Mol Genet Genomic Med. 2018 Nov;6(6):1134-1139. doi: 10.1002/mgg3.492. Epub 2018 Oct 31.


Background: Hereditary spastic paraplegia (HSP) is a group of rare disorders characterized by spastic paraparesis and other symptoms. Often, other diseases can mimic HSP, which may delay diagnosis and treatment.

Methods: Whole exome sequencing was performed in families with clinically suspected HSP without a genetic diagnosis.

Results: We report three patients from two families who presented with lower limb spasticity, muscular atrophy, and other neurological symptoms, who were clinically diagnosed with complicated HSP. Whole exome sequencing revealed bi-allelic AAAS nonsense mutations; one individual was homozygous for the p.(Arg478*) mutation, and two siblings were homozygous for the p.(Arg286*) mutation, leading to the diagnosis of triple A syndrome. This rare syndrome is typically characterized by a triad of symptoms: achalasia, adrenal insufficiency, and alacrima, and is often accompanied by other neurological abnormalities.

Conclusions: Our findings suggest that triple A syndrome should be suspected in complicated HSP patients without a known genetic cause, especially if at least one of the main triad of triple A syndrome symptoms is present.

Keywords: AAAS; hereditary spastic paraplegia; triple A syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Female
  • Humans
  • Male
  • Mutation
  • Nerve Tissue Proteins / genetics*
  • Nuclear Pore Complex Proteins / genetics*
  • Pedigree
  • Phenotype*
  • Spastic Paraplegia, Hereditary / genetics*
  • Spastic Paraplegia, Hereditary / pathology


  • AAAS protein, human
  • Nerve Tissue Proteins
  • Nuclear Pore Complex Proteins

Associated data

  • GENBANK/NM_015665.5