Pseudodominant inheritance in paraplegin (SPG7)-associated CPEO-ataxia syndrome.
Weber Liu, Serge Geara, Simon Rowe et al.
✦ AI-curated · Sources linked
Case in brief
A 47-year-old man presented with progressive external ophthalmoplegia, ptosis, gait disturbance and spasticity. Over ten years, he developed slowly progressive spastic ataxia with ocular motor involvement and neurogenic bladder. His mother and maternal aunt had similar features, including spasticity, ataxia, ptosis and external ophthalmoplegia. Testing found compound heterozygous pathogenic SPG7 variants in the man; his mother and aunt were homozygous for the canonical splice-site variant c.2182-2 A > G. His asymptomatic father carried the pathogenic p.(Ala510Val) missense variant, explaining the family’s pseudodominant pattern.
What made this case unusual
The family history appeared dominant despite SPG7-associated disease usually being autosomal recessive: affected relatives were homozygous for one variant, while the proband’s asymptomatic father carried another pathogenic variant.
Diagnostic / clinical pearl
A vertical pattern of affected relatives does not exclude an autosomal recessive disorder. Segregation analysis and comprehensive genomic testing can clarify apparent pseudodominance in SPG7-associated disease.
Why it matters
Recognising pseudodominant inheritance has implications for genetic counselling, family planning and cascade testing.