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203,203 studies31 sourcesUpdated 54 min ago
Peer-reviewedCC BYNeurogenetics

Pseudodominant inheritance in paraplegin (SPG7)-associated CPEO-ataxia syndrome.

  • Weber Liu1,2,3,4
  • Serge Geara5,6,7
  • Simon Rowe5,6,7
  • Carolyn Mary Sue5,6,7,8
8 affiliations
  1. 1Neuroscience Research Australia, Randwick, NSW, 2031, Australia. [email protected].
  2. 2Faculty of Medicine and Health, University of New South Wales, Sydney, Australia. [email protected].
  3. 3Department of Neurology, Prince of Wales Hospital, Sydney, NSW, Australia. [email protected].
  4. 4Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia. [email protected].
  5. 5Neuroscience Research Australia, Randwick, NSW, 2031, Australia.
  6. 6Faculty of Medicine and Health, University of New South Wales, Sydney, Australia.
  7. 7Department of Neurology, Prince of Wales Hospital, Sydney, NSW, Australia.
  8. 8Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
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Abstract

SPG7 encodes paraplegin, a mitochondrial AAA-metalloprotease critical for inner mitochondrial membrane protein quality control. Pathogenic variants most commonly cause autosomal recessive hereditary spastic paraplegia (HSP) but its phenotypic spectrum includes cerebellar ataxia, progressive external ophthalmoplegia, myopathy and parkinsonism.We report a 47 year old man presenting with a progressive external ophthalmoplegia, ptosis, progressive gait disturbance, and spasticity. Ten-year follow-up of this individual showed slowly progressive spastic ataxia with ocular motor involvement and neurogenic bladder. His mother and maternal aunt both had marked spasticity, ataxia, ptosis and external ophthalmoplegia. Genetic testing demonstrated compound heterozygous pathogenic variants in paraplegin in this individual. Genetic testing in his mother and aunt revealed homozygous canonical splice-site variants (c.2182-2 A > G). Cascade testing of his asymptomatic father showed a common pathogenic missense variant p.(Ala510Val) in the same gene.This family demonstrates a pseudodominant inheritance pattern, instead of the expected autosomal recessive trait that applies to paraplegin. We highlight diagnostic pitfalls in relying on family history and assumed inheritance traits. We emphasise the importance of segregation analysis and comprehensive genomic testing. Recognition of pseudodominance inheritance has important implications for genetic counselling, family planning and cascade testing.

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Cite

BibTeXRIS
BibTeX
@article{liu2026pseudodominant,
  title = {{Pseudodominant inheritance in paraplegin (SPG7)-associated CPEO-ataxia syndrome.}},
  author = {Weber Liu and Serge Geara and Simon Rowe and Carolyn Mary Sue},
  journal = {Neurogenetics},
  year = {2026},
  month = oct,
  doi = {10.1007/s10048-026-00955-7},
  url = {https://europepmc.org/article/MED/42955112},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Pseudodominant inheritance in paraplegin (SPG7)-associated CPEO-ataxia syndrome.
AU  - Weber Liu
AU  - Serge Geara
AU  - Simon Rowe
AU  - Carolyn Mary Sue
PY  - 2026
DA  - 2026/10/28
JO  - Neurogenetics
DO  - 10.1007/s10048-026-00955-7
UR  - https://europepmc.org/article/MED/42955112
AB  - SPG7 encodes paraplegin, a mitochondrial AAA-metalloprotease critical for inner mitochondrial membrane protein quality control. Pathogenic variants most commonly cause autosomal recessive hereditary spastic paraplegia (HSP) but its phenotypic spectrum includes cerebellar ataxia, progressive external ophthalmoplegia, myopathy and parkinsonism.We report a 47 year old man presenting with a progressive external ophthalmoplegia, ptosis, progressive gait disturbance, and spasticity. Ten-year follow-up of this individual showed slowly progressive spastic ataxia with ocular motor involvement and neurogenic bladder. His mother and maternal aunt both had marked spasticity, ataxia, ptosis and external ophthalmoplegia. Genetic testing demonstrated compound heterozygous pathogenic variants in paraplegin in this individual. Genetic testing in his mother and aunt revealed homozygous canonical splice-site variants (c.2182-2 A > G). Cascade testing of his asymptomatic father showed a common pathogenic missense variant p.(Ala510Val) in the same gene.This family demonstrates a pseudodominant inheritance pattern, instead of the expected autosomal recessive trait that applies to paraplegin. We highlight diagnostic pitfalls in relying on family history and assumed inheritance traits. We emphasise the importance of segregation analysis and comprehensive genomic testing. Recognition of pseudodominance inheritance has important implications for genetic counselling, family planning and cascade testing.
SN  - 1364-6745
SN  - 1364-6753
ER  -