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Novel Homozygous Missense Mutation in SPG20 Gene Results in Troyer Syndrome Associated with Mitochondrial Cytochrome c Oxidase Deficiency

  • Ronen Spiegel
  • Devorah Soiferman
  • Avraham Shaag
  • Stavit Shalev
  • Orly Elpeleg
  • Ann Saada
Case Report
Part of the JIMD Reports book series (JIMD, volume 33)

Abstract

Troyer syndrome is an autosomal recessive form of hereditary spastic paraplegia (HSP) caused by deleterious mutations in the SPG20 gene. Although the disease is associated with a loss of function mechanism of spartin, the protein encoded by SPG20, the precise pathogenesis is yet to be elucidated. Recent data indicated an important role for spartin in both mitochondrial maintenance and function. Here we report a child presenting with progressive spastic paraparesis, generalized muscle weakness, dysarthria, impaired growth, and severe isolated decrease in muscle cytochrome c oxidase (COX) activity. Whole exome sequencing identified the homozygous c.988A>G variant in SPG20 gene (p.Met330Val) resulting in almost complete loss of spartin in skeletal muscle. Further analyses demonstrated significant tissue specific reduction of COX 4, a nuclear encoded subunit of COX, in muscle suggesting a role for spartin in proper mitochondrial respiratory chain function mediated by COX activity. Our findings need to be verified in other Troyer syndrome patients in order to classify it as a form of HSP caused by mitochondrial dysfunction.

Keywords

Cytochrome c oxidase Hereditary spastic paraplegia Mitochondria Oxidative phosphorylation SPG20 Troyer syndrome 

Notes

Acknowledgements

Corinne Alban is acknowledged for technical assistance. This research was in part funded by the Hadassah Compensatory fund.

Supplementary material

978-3-662-55012-0_580_MOESM1_ESM.docx (30 kb)
Table S1 Suspected variants identified by WES (DOCX 29 kb)
978-3-662-55012-0_580_MOESM2_ESM.tif (1.2 mb)
Fig. S1 A. Light microscopy showing normal structure of skeletal muscle. H&E stain X200. B. Skeletal muscle immune-histochemistry showing normal COX staining (TIFF 1,200 kb)
978-3-662-55012-0_580_MOESM3_ESM.tif (256 kb)
Fig. S2 High evolutionary conservation of Met residue at position 330 is illustrated (the mutated residue is marked by black box) (TIFF 256 kb)

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Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Ronen Spiegel
    • 1
    • 2
    • 3
  • Devorah Soiferman
    • 4
    • 5
  • Avraham Shaag
    • 4
  • Stavit Shalev
    • 2
    • 3
  • Orly Elpeleg
    • 4
  • Ann Saada
    • 4
    • 5
  1. 1.Department of Pediatrics BEmek Medical CenterAfulaIsrael
  2. 2.Genetic Institute, Emek Medical CenterAfulaIsrael
  3. 3.Rappaport School of MedicineTechnionHaifaIsrael
  4. 4.Monique and Jacques Roboh Department of Genetic ResearchHadassah-Hebrew University Medical CenterJerusalemIsrael
  5. 5.Department of Genetic and Metabolic DiseasesHadassah-Hebrew University Medical CenterJerusalemIsrael

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