Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation

Tahir Naeem Khan, Joakim Klar, Muhammad Tariq, Shehla Anjum Baig, Naveed Altaf Malik, Raja Yousaf, Shahid Mahmood Baig, Niklas Dahl

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)


Hereditary spastic paraplegias (HSPs) comprise a heterogeneous group of disorders characterized by progressive spasticity and weakness of the lower limbs. Autosomal dominant and 'pure' forms of HSP account for ∼80% of cases in Western societies of whom 10% carry atlastin-1 (ATL1) gene mutations. We report on a large consanguineous family segregating six members with early onset HSP. The pedigree was compatible with both autosomal dominant and autosomal recessive inheritance. Whole-exome sequencing and segregation analysis revealed a homozygous novel missense variant c.353G>A, p.(Arg118Gln) in ATL1 in all six affected family members. Seven heterozygous carriers, five females and two males, showed no clinical signs of HSP with the exception of sub-clinically reduced vibration sensation in one adult female. Our combined findings show that homozygosity for the ATL1 missense variant remains the only plausible cause of HSP, whereas heterozygous carriers are asymptomatic. This apparent autosomal recessive inheritance adds to the clinical complexity of spastic paraplegia 3A and calls for caution using directed genetic screening in HSP.

Original languageEnglish
Pages (from-to)1180-1184
Number of pages5
JournalEuropean Journal of Human Genetics
Issue number10
Publication statusPublished - 11 Oct 2014
Externally publishedYes


  • ATL1 gene
  • SPG3A
  • autosomal recessive


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