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

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.