neurogenetics

, Volume 11, Issue 4, pp 441–448

A new locus (SPG46) maps to 9p21.2-q21.12 in a Tunisian family with a complicated autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum

  • Amir Boukhris
  • Imed Feki
  • Nizar Elleuch
  • Mohamed Imed Miladi
  • Anne Boland-Augé
  • Jérémy Truchetto
  • Emeline Mundwiller
  • Nadia Jezequel
  • Diana Zelenika
  • Chokri Mhiri
  • Alexis Brice
  • Giovanni Stevanin
Original Article

Abstract

Hereditary spastic paraplegia (HSP) with thin corpus callosum (TCC) and mental impairment is a frequent subtype of complicated HSP, often inherited as an autosomal recessive (AR) trait. It is clear from molecular genetic analyses that there are several underlying causes of this syndrome, with at least six genetic loci identified to date. However, SPG11 and SPG15 are the two major genes for this entity. To map the responsible gene in a large AR-HSP-TCC family of Tunisian origin, we investigated a consanguineous family with a diagnosis of AR-HSP-TCC excluded for linkage to the SPG7, SPG11, SPG15, SPG18, SPG21, and SPG32 loci. A genome-wide scan was undertaken using 6,090 SNP markers covering all chromosomes. The phenotypic presentation in five patients was suggestive of a complex HSP that associated an early-onset spastic paraplegia with mild handicap, mental deterioration, congenital cataract, cerebellar signs, and TCC. The genome-wide search identified a single candidate region on chromosome 9, exceeding the LOD score threshold of +3. Fine mapping using additional markers narrowed the candidate region to a 45.1-Mb interval (15.4 cM). Mutations in three candidate genes were excluded. The mapping of a novel AR-HSP-TCC locus further demonstrates the extensive genetic heterogeneity of this condition. We propose that testing for this locus should be performed, after exclusion of mutations in SPG11 and SPG15 genes, in AR-HSP-TCC families, especially when cerebellar ataxia and cataract are present.

Keywords

Hereditary spastic paraplegia Autosomal recessive Thin corpus callosum Linkage SPG46 

References

  1. 1.
    Behan WM, Maia M (1974) Strumpell’s familial spastic paraplegia: genetics and neuropathology. J Neurol Neurosurg Psychiatry 37:8–20CrossRefPubMedGoogle Scholar
  2. 2.
    Harding AE (1983) Classification of the hereditary ataxias and paraplegias. Lancet 1:1151–1155CrossRefPubMedGoogle Scholar
  3. 3.
    McDermott C, White K, Bushby K, Shaw P (2000) Hereditary spastic paraparesis: a review of new developments. J Neurol Neurosurg Psychiatry 69:150–160CrossRefPubMedGoogle Scholar
  4. 4.
    Fink JK (2006) Hereditary spastic paraplegia. Curr Neurol Neurosci Rep 6:65–76CrossRefPubMedGoogle Scholar
  5. 5.
    Reid E (2003) Many pathways lead to hereditary spastic paraplegia. Lancet Neurol 2:210CrossRefPubMedGoogle Scholar
  6. 6.
    Stevanin G, Ruberg M, Brice A (2008) Recent advances in the genetics of spastic paraplegias. Curr Neurol Neurosci Rep 8:198–210CrossRefPubMedGoogle Scholar
  7. 7.
    Boukhris A, Stevanin G, Feki I et al (2008) Hereditary spastic paraplegia with mental impairment and thin corpus callosum in Tunisia: SPG11, SPG15, and further genetic heterogeneity. Arch Neurol 65:393–402CrossRefPubMedGoogle Scholar
  8. 8.
    Boukhris A, Feki I, Denis E et al (2008) Spastic paraplegia 15: linkage and clinical description of three Tunisian families. Mov Disord 23:429–433CrossRefPubMedGoogle Scholar
  9. 9.
    Boukhris A, Stevanin G, Feki I et al (2009) Tunisian hereditary spastic paraplegias: clinical variability supported by genetic heterogeneity. Clin Genet 75:527–536CrossRefPubMedGoogle Scholar
  10. 10.
    Folstein MF, Folstein SE, McHugh PR (1975) Mini-mental state. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198CrossRefPubMedGoogle Scholar
  11. 11.
    Stevanin G, Santorelli FM, Azzedine H et al (2007) Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. Nat Genet 39:366–372CrossRefPubMedGoogle Scholar
  12. 12.
    Hanein S, Martin E, Boukhris A et al (2008) Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome. Am J Hum Genet 82:992–1002CrossRefPubMedGoogle Scholar
  13. 13.
    Abecasis GR, Cherny SS, Cookson WO, Cardon LR (2002) MERLIN—rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30:97–101CrossRefPubMedGoogle Scholar
  14. 14.
    Cottingham RW Jr, Idury RM, Schaffer AA (1993) Faster sequential genetic linkage computations. Am J Hum Genet 53:252–263PubMedGoogle Scholar
  15. 15.
    Nakamura A, Izumi K, Umehara F et al (1995) Familial spastic paraplegia with mental impairment and thin corpus callosum. J Neurol Sci 131:35–42CrossRefPubMedGoogle Scholar
  16. 16.
    Ohnishi J, Tomoda Y, Yokoyama K (2001) Neuroradiological findings in hereditary spastic paraplegia with a thin corpus callosum. Acta Neurol Scand 104:191–192CrossRefPubMedGoogle Scholar
  17. 17.
    Franca MC Jr, D'Abreu A, Maurer-Morelli CV et al (2007) Prospective neuroimaging study in hereditary spastic paraplegia with thin corpus callosum. Mov Disord 22:1556–1562CrossRefPubMedGoogle Scholar
  18. 18.
    Stevanin G, Azzedine H, Denora P et al (2008) Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration. Brain 131:772–784CrossRefPubMedGoogle Scholar
  19. 19.
    Casali C, Valente EM, Bertini E et al (2004) Clinical and genetic studies in hereditary spastic paraplegia with thin corpus callosum. Neurology 62:262–268PubMedGoogle Scholar
  20. 20.
    Winner B, Uyanik G, Gross C et al (2004) Clinical progression and genetic analysis in hereditary spastic paraplegia with thin corpus callosum in spastic gait gene 11 (SPG11). Arch Neurol 61:117–121CrossRefPubMedGoogle Scholar
  21. 21.
    Tang BS, Chen X, Zhao GH et al (2004) Clinical features of hereditary spastic paraplegia with thin corpus callosum: report of 5 Chinese cases. Chin Med J 117:1002–1005PubMedGoogle Scholar
  22. 22.
    Lossos A, Stevanin G, Meiner V et al (2006) Hereditary spastic paraplegia with thin corpus callosum: reduction of the SPG11 interval and evidence for further genetic heterogeneity. Arch Neurol 63:756–760CrossRefPubMedGoogle Scholar
  23. 23.
    Hehr U, Bauer P, Winner B et al (2007) Long-term course and mutational spectrum of spatacsin-linked spastic paraplegia. Ann Neurol 62:656–665CrossRefPubMedGoogle Scholar
  24. 24.
    Paisan-Ruiz C, Nath P, Wood NW, Singleton A, Houlden H (2008) Clinical heterogeneity and genotype–phenotype correlations in hereditary spastic paraplegia because of spatacsin mutations (SPG11). Eur J Neurol 15:1065–1070CrossRefPubMedGoogle Scholar
  25. 25.
    Orlén H, Melberg A, Raininko R et al (2009) SPG11 mutations cause Kjellin syndrome, a hereditary spastic paraplegia with thin corpus callosum and central retinal degeneration. Am J Med Genet B Neuropsychiatr Genet 150B:984–992CrossRefPubMedGoogle Scholar
  26. 26.
    Kim SM, Lee JS, Kim S et al (2009) Novel compound heterozygous mutations of the SPG11 gene in Korean families with hereditary spastic paraplegia with thin corpus callosum. J Neurol 256:1714–1718CrossRefPubMedGoogle Scholar
  27. 27.
    Ueda M, Katayama Y, Kamiya T et al (1998) Hereditary spastic paraplegia with a thin corpus callosum and thalamic involvement in Japan. Neurology 51:1751–1754PubMedGoogle Scholar
  28. 28.
    Shibasaki Y, Tanaka H, Iwabuchi K et al (2000) Linkage of autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum to chromosome 15A13–15. Ann Neurol 48:108–112CrossRefPubMedGoogle Scholar
  29. 29.
    Brockmann K, Simpson MA, Faber A, Bönnemann C, Crosby AH, Gärtner J (2005) Complicated hereditary spastic paraplegia with thin corpus callosum (HSP-TCC) and childhood onset. Neuropediatrics 36:274–278CrossRefPubMedGoogle Scholar
  30. 30.
    Goizet C, Boukhris A, Maltete D et al (2009) SPG15 is the second most common cause of hereditary spastic paraplegia with thin corpus callosum. Neurology 73:1111–1119CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Amir Boukhris
    • 1
    • 2
    • 3
    • 4
    • 6
    • 8
  • Imed Feki
    • 1
    • 2
  • Nizar Elleuch
    • 1
    • 2
  • Mohamed Imed Miladi
    • 1
    • 2
  • Anne Boland-Augé
    • 5
  • Jérémy Truchetto
    • 3
    • 4
  • Emeline Mundwiller
    • 3
    • 4
  • Nadia Jezequel
    • 3
    • 4
  • Diana Zelenika
    • 5
  • Chokri Mhiri
    • 1
    • 2
  • Alexis Brice
    • 3
    • 4
    • 6
  • Giovanni Stevanin
    • 3
    • 4
    • 6
    • 7
  1. 1.Department of NeurologyHabib Bourguiba University HospitalSfaxTunisia
  2. 2.Faculté de Médecine de SfaxSfaxTunisia
  3. 3.INSERM, U975 (formerly U679)ParisFrance
  4. 4.Université Pierre et Marie Curie-Paris 6, Unité Mixte de Recherche S975, CNRS 7225, Centre de Recherche de l’Institut du Cerveau et de la Moelle EpinièreGroupe Hospitalier Universitaire Pitié-SalpêtrièreParisFrance
  5. 5.Centre National de GénotypageEvryFrance
  6. 6.AP-HP, Pitié-Salpêtrière HospitalDepartment of Genetics and CytogeneticsParisFrance
  7. 7.Ecole Pratique des Hautes EtudesParisFrance
  8. 8.Service de NeurologieHôpital Habib BourguibaSfaxTunisia

Personalised recommendations