Skip to main content

TFG associated hereditary spastic paraplegia: an addition to the phenotypic spectrum

neurogenetics volume 18, pages 105–109 (2017)Cite this article

Abstract

Hereditary spastic paraplegias (HSPs) constitute movement disorders with extreme lower limb spasticity caused by axonopathies of the upper motor neurons. We describe two siblings affected with a recessive form of movement disorder. Whole-exome sequencing revealed a homozygous missense mutation c.64 C>T (p.Arg22Trp) in TFG as cause of the disorder. Comparison of the phenotype of the patients of this study, with that reported previously, revealed differences in the severity of the disorder as well as new clinical findings. These include presence of clonus, undeveloped speech, and sleep disturbances. Our findings extend the phenotypic spectrum associated with the TFG mutations in HSP.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1

References

  1. Jarman PR, Wood NW (2002) Genetics of movement disorders and ataxia. J Neurol Neurosurg Psychiatry 73(Suppl 2):II22–II26

    PubMed  PubMed Central  Google Scholar 

  2. Dietz V (2000) Spastic movement disorder. Spinal Cord 38(7):389–393

    CAS  Article  PubMed  Google Scholar 

  3. Harlalka GV, McEntagart ME, Gupta N, Skrzypiec AE, Mucha MW, Chioza BA, Simpson MA, Sreekantan-Nair A, Pereira A, Gunther S, Jahic A, Modarres H, Moore-Barton H, Trembath RC, Kabra M, Baple EL, Thakur S, Patton MA, Beetz C, Pawlak R, Crosby AH (2016) Novel genetic, clinical, and pathomechanistic insights into TFG-associated hereditary spastic paraplegia. Hum Mutat. doi:10.1002/humu.23060

    PubMed  Google Scholar 

  4. Blackstone C (2012) Cellular pathways of hereditary spastic paraplegia. Annu Rev Neurosci 35:25–47. doi:10.1146/annurev-neuro-062111-150400

    CAS  Article  PubMed  Google Scholar 

  5. Beetz C, Johnson A, Schuh AL, Thakur S, Varga RE, Fothergill T, Hertel N, Bomba-Warczak E, Thiele H, Nurnberg G, Altmuller J, Saxena R, Chapman ER, Dent EW, Nurnberg P, Audhya A (2013) Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum structure. Proc Natl Acad Sci U S A 110(13):5091–5096. doi:10.1073/pnas.1217197110

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Soderblom C, Blackstone C (2006) Traffic accidents: molecular genetic insights into the pathogenesis of the hereditary spastic paraplegias. Pharmacol Ther 109(1–2):42–56. doi:10.1016/j.pharmthera.2005.06.001

    CAS  Article  PubMed  Google Scholar 

  7. Yagi T, Ito D, Suzuki N (2016) TFG-related neurologic disorders: new insights into relationships between endoplasmic reticulum and neurodegeneration. J Neuropathol Exp Neurol 75(4):299–305. doi:10.1093/jnen/nlw009

    Article  PubMed  Google Scholar 

  8. Arif B, Kumar KR, Seibler P, Vulinovic F, Fatima A, Winkler S, Nurnberg G, Thiele H, Nurnberg P, Jamil AZ, Bruggemann A, Abbas G, Klein C, Naz S, Lohmann K (2013) A novel OPA3 mutation revealed by exome sequencing: an example of reverse phenotyping. JAMA Neurology 70(6):783–787. doi:10.1001/jamaneurol.2013.1174

    Article  PubMed  Google Scholar 

  9. Carr IM, Bhaskar S, O’Sullivan J, Aldahmesh MA, Shamseldin HE, Markham AF, Bonthron DT, Black G, Alkuraya FS (2013) Autozygosity mapping with exome sequence data. Hum Mutat 34(1):50–56. doi:10.1002/humu.22220

    CAS  Article  PubMed  Google Scholar 

  10. Kelly AM, Shaw NJ, Thomas AM, Pynsent PB, Baker DJ (1997) Growth of Pakistani children in relation to the 1990 growth standards. Arch Dis Child 77(5):401–405

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Elsayed LE, Mohammed IN, Hamed AA, Elseed MA, Johnson A, Mairey M, Mohamed HE, Idris MN, Salih MA, El-Sadig SM, Koko ME, Mohamed AY, Raymond L, Coutelier M, Darios F, Siddig RA, Ahmed AK, Babai AM, Malik HM, Omer ZM, Mohamed EO, Eltahir HB, Magboul NA, Bushara EE, Elnour A, Rahim SM, Alattaya A, Elbashir MI, Ibrahim ME, Durr A, Audhya A, Brice A, Ahmed AE, Stevanin G (2016) Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan. Eur J Hum Genet. doi:10.1038/ejhg.2016.108

    PubMed  Google Scholar 

  12. Witte K, Schuh AL, Hegermann J, Sarkeshik A, Mayers JR, Schwarze K, Yates JR 3rd, Eimer S, Audhya A (2011) TFG-1 function in protein secretion and oncogenesis. Nat Cell Biol 13(5):550–558. doi:10.1038/ncb2225

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Alavi A, Shamshiri H, Nafissi S, Khani M, Klotzle B, Fan JB, Steemers F, Elahi E (2015) HMSN-P caused by p.Pro285Leu mutation in TFG is not confined to patients with Far East ancestry. Neurobiol Aging 36(3):1606 e1601–1606 e1607. doi:10.1016/j.neurobiolaging.2014.11.021

    Article  Google Scholar 

  14. Ishiura H, Sako W, Yoshida M, Kawarai T, Tanabe O, Goto J, Takahashi Y, Date H, Mitsui J, Ahsan B, Ichikawa Y, Iwata A, Yoshino H, Izumi Y, Fujita K, Maeda K, Goto S, Koizumi H, Morigaki R, Ikemura M, Yamauchi N, Murayama S, Nicholson GA, Ito H, Sobue G, Nakagawa M, Kaji R, Tsuji S (2012) The TRK-fused gene is mutated in hereditary motor and sensory neuropathy with proximal dominant involvement. Am J Hum Genet 91(2):320–329. doi:10.1016/j.ajhg.2012.07.014

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. Ishiura H, Tsuji S (2013) Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is caused by a mutation in TFG. Rinsho Shinkeigaku 23(11):1203–1205

    Article  PubMed  Google Scholar 

  16. Tsai PC, Huang YH, Guo YC, Wu HT, Lin KP, Tsai YS, Liao YC, Liu YT, Liu TT, Kao LS, Yet SF, Fann MJ, Soong BW, Lee YC (2014) A novel TFG mutation causes Charcot-Marie-Tooth disease type 2 and impairs TFG function. Neurology 83(10):903–912. doi:10.1212/WNL.0000000000000758

    CAS  Article  PubMed  Google Scholar 

  17. Khani M, Shamshiri H, Alavi A, Nafissi S, Elahi E (2016) Identification of novel TFG mutation in HMSN-P pedigree: emphasis on variable clinical presentations. J Neurol Sci 369:318–323. doi:10.1016/j.jns.2016.08.035

    CAS  Article  PubMed  Google Scholar 

  18. Macedo-Souza LI, Kok F, Santos S, Amorim SC, Starling A, Nishimura A, Lezirovitz K, Lino AM, Zatz M (2005) Spastic paraplegia, optic atrophy, and neuropathy is linked to chromosome 11q13. Ann Neurol 57(5):730–737. doi:10.1002/ana.20478

    CAS  Article  PubMed  Google Scholar 

  19. Melo US, Macedo-Souza LI, Figueiredo T, Muotri AR, Gleeson JG, Coux G, Armas P, Calcaterra NB, Kitajima JP, Amorim S, Olavio TR, Griesi-Oliveira K, Coatti GC, Rocha CR, Martins-Pinheiro M, Menck CF, Zaki MS, Kok F, Zatz M, Santos S (2015) Overexpression of KLC2 due to a homozygous deletion in the non-coding region causes SPOAN syndrome. Hum Mol Genet 24(24):6877–6885. doi:10.1093/hmg/ddv388

    CAS  PubMed  Google Scholar 

  20. Amorim S, Heise CO, Santos S, Macedo-Souza LI, Zatz M, Kok F (2014) Nerve conduction studies in spastic paraplegia, optic atrophy, and neuropathy (SPOAN) syndrome. Muscle Nerve 49(1):131–133. doi:10.1002/mus.24087

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This study was funded by family RDHT04 and grant #2877 by the Higher Education Commission, Islamabad, Pakistan to SN.

Author information

Affiliations

  1. School of Biological Sciences, University of the Punjab, Quaid-i-Azam Campus, Lahore, 54590, Pakistan

    Huma Tariq & Sadaf Naz

Authors
  1. Huma Tariq
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sadaf Naz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sadaf Naz.

Ethics declarations

The study was approved by the Institutional Review Board at the School of Biological Sciences, University of the Punjab, Lahore, Pakistan. Written informed consent was obtained from all participants and from the parents for their minor children.

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tariq, H., Naz, S. TFG associated hereditary spastic paraplegia: an addition to the phenotypic spectrum. Neurogenetics 18, 105–109 (2017). https://doi.org/10.1007/s10048-017-0508-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10048-017-0508-6

Keywords

  • Spastic paraplegia
  • SPG57
  • Pakistan
  • TFG
  • Reverse phenotyping