Skip to main content

Advertisement

SpringerLink
Log in

Non-motor symptoms are relevant and possibly treatable in hereditary spastic paraplegia type 4 (SPG4)

  • Original Communication
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

Hereditary spastic paraplegias (HSP) share as cardinal feature progressive spastic gait disorder. SPG4 accounts for about 25% of cases and is caused by mutations in the SPAST gene. Although HSP is an upper motor neuron disease, the relevance of non-motor symptoms is increasingly recognized because of the potential response to treatment. Our study sets out to evaluate non-motor symptoms and their relevance with regard to health-related quality of life. In 118 genetically confirmed SPG4 cases and age- and gender-matched controls, validated questionnaires were used to evaluate fatigue, depression, pain, and restless legs syndrome. In addition, self-reported medical information was collected concerning comorbidities and bladder, bowel, and sexual dysfunction. In a sub-study, cognition was evaluated using the CANTAB® test-battery and the Montreal Cognitive Assessment in 26 SPG4 patients. We found depression and pain to be significantly increased. The frequency of restless legs syndrome varied largely depending on defining criteria. There were no significant deficits in cognition as examined by CANTAB® despite a significant increase in self-reported memory impairment in SPG4 patients. Bladder, sexual, and defecation problems were frequent and seemed to be underrecognized in current treatment strategies. All identified non-motor symptoms correlated with health-related quality of life, which was reduced in SPG4 compared to controls. We recommend that clinicians regularly screen for depression, pain, and fatigue and ask for bladder, sexual, and defecation problems to recognize and treat non-motor symptoms accordingly to improve quality of life in patients with SPG4.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Notes

  1. Information retrieved from the CANTAB® website on 03.07.2019. https://www.cambridgecognition.com/cantab/cognitive-tests

References

  1. Bis-Brewer DM, Zuchner S (2018) Perspectives on the genomics of HSP beyond Mendelian inheritance. Front Neurol 9:958

    Article  Google Scholar 

  2. Schule R, Wiethoff S, Martus P, Karle KN, Otto S, Klebe S, Klimpe S, Gallenmuller C, Kurzwelly D, Henkel D, Rimmele F, Stolze H, Kohl Z, Kassubek J, Klockgether T, Vielhaber S, Kamm C, Klopstock T, Bauer P, Zuchner S, Liepelt-Scarfone I, Schols L (2016) Hereditary spastic paraplegia: clinicogenetic lessons from 608 patients. Ann Neurol 79:646–658

    Article  Google Scholar 

  3. Bellofatto M, De Michele G, Iovino A, Filla A, Santorelli FM (2019) Management of hereditary spastic paraplegia: a systematic review of the literature. Front Neurol 10:3

    Article  Google Scholar 

  4. Vahter L, Braschinsky M, Haldre S, Gross-Paju K (2009) The prevalence of depression in hereditary spastic paraplegia. Clin Rehabil 23:857–861

    Article  CAS  Google Scholar 

  5. Sperfeld AD, Unrath A, Kassubek J (2007) Restless legs syndrome in hereditary spastic paraparesis. Eur Neurol 57:31–35

    Article  Google Scholar 

  6. Servelhere K, Faber I, Saute J, Moscovich M, D'Abreu A, Jardim L, Teive H, Lopes-Cendes I, Franca M (2016) Non-motor symptoms in patients with hereditary spastic paraplegia caused by SPG4 mutations. Eur J Neurol 23:408–411

    Article  CAS  Google Scholar 

  7. Chelban V, Tucci A, Lynch DS, Polke JM, Santos L, Jonvik H, Groppa S, Wood NW, Houlden HJJNNP (2017) Truncating mutations in SPAST patients are associated with a high rate of psychiatric comorbidities in hereditary spastic paraplegia. J Neurol Neurosurg Psychiatry 88:681–687

    Article  Google Scholar 

  8. Murphy S, Gorman G, Beetz C, Byrne P, Dytko M, McMonagle P, Kinsella K, Farrell M, Hutchinson M (2009) Dementia in SPG4 hereditary spastic paraplegia clinical, genetic, and neuropathologic evidence. Neurology 73:378–384

    Article  CAS  Google Scholar 

  9. McMonagle P, Byrne P, Hutchinson M (2004) Further evidence of dementia in SPG4-linked autosomal dominant hereditary spastic paraplegia. Neurology 62:407–410

    Article  Google Scholar 

  10. Tallaksen CE, Guichart-Gomez E, Verpillat P et al (2003) Subtle cognitive impairment but no dementia in patients with spastin mutations. Arch Neurol 60:1113–1118

    Article  Google Scholar 

  11. Chamard L, Ferreira S, Pijoff A, Silvestre M, Berger E, Magnin E (2016) Cognitive impairment involving social cognition in SPG4 hereditary spastic paraplegia. Behav Neurol. https://doi.org/10.1155/2016/6423461

    Article  PubMed  PubMed Central  Google Scholar 

  12. Lindig T, Bender B, Hauser T-K, Mang S, Schweikardt D, Klose U, Karle KN, Schüle R, Schöls L, Rattay TW (2015) Gray and white matter alterations in hereditary spastic paraplegia type SPG4 and clinical correlations. J Neurol 261:1961–1971

    Article  Google Scholar 

  13. Schule R, Holland-Letz T, Klimpe S, Kassubek J, Klopstock T, Mall V, Otto S, Winner B, Schols L (2006) The spastic paraplegia rating scale (SPRS): a reliable and valid measure of disease severity. Neurology 67:430–434

    Article  CAS  Google Scholar 

  14. Béreau M, Anheim M, Chanson J-B, Tio G, Echaniz-Laguna A, Depienne C, Collongues N, de Sèze J (2015) Dalfampridine in hereditary spastic paraplegia: a prospective, open study. J Neurol 262:1285–1288

    Article  Google Scholar 

  15. Hinz A, Klaiberg A, Brahler E, Konig HH (2006) The quality of life questionnaire EQ-5D: Modelling and norm values for the general population. Psychother Psychosom Med Psychol 56:42–48

    Article  Google Scholar 

  16. EuroQol-Group (1990) EuroQol-a new facility for the measurement of health-related quality of life. J Health policy 16:199–208

    Article  Google Scholar 

  17. Allen RP, Picchietti DL, Garcia-Borreguero D, Ondo WG, Walters AS, Winkelman JW, Zucconi M, Ferri R, Trenkwalder C, Lee HB (2014) Restless legs syndrome/Willis–Ekbom disease diagnostic criteria: updated international restless legs syndrome Study Group (IRLSSG) consensus criteria—history, rationale, description, and significance. Sleep Med 15:860–873

    Article  Google Scholar 

  18. Schmitt M, Altstötter-Gleich C, Hinz A, Maes J, Brähler EJD (2006) Normwerte für das vereinfachte Beck-Depressions-Inventar (BDI-V) in der Allgemeinbevölkerung. 52:51–59

    Article  Google Scholar 

  19. Smets E, Garssen B, Bonke Bd, De Haes J (1995) The multidimensional fatigue inventory (MFI) psychometric qualities of an instrument to assess fatigue. J Psychosom Res 39:315–325

    Article  CAS  Google Scholar 

  20. Radbruch L, Loick G, Kiencke P, Lindena G, Sabatowski R, Grond S, Lehmann KA, Cleeland CS (1999) Validation of the German version of the brief pain inventory. J Pain Symptom Manag 18:180–187

    Article  CAS  Google Scholar 

  21. Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow HJ (2005) The montreal cognitive assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 53:695–699

    Article  Google Scholar 

  22. Harding AE (1983) Classification of the hereditary ataxias and paraplegias. Lancet 1:1151–1155

    Article  CAS  Google Scholar 

  23. Parodi L, Fenu S, Barbier M, Banneau G, Duyckaerts C, Tezenas du Montcel S, Monin M-L, Ait Said S, Guegan J, Tallaksen CME, Sablonniere B, Brice A, Stevanin G, Depienne C, Dur Network AS (2018) Spastic paraplegia due to SPAST mutations is modified by the underlying mutation and sex. Brain 141:3331–3342

    Article  Google Scholar 

  24. Karle KN, Schule R, Klebe S, Otto S, Frischholz C, Liepelt-Scarfone I, Schols L (2013) Electrophysiological characterisation of motor and sensory tracts in patients with hereditary spastic paraplegia (HSP). Orphanet J Rare Dis 8:158

    Article  Google Scholar 

  25. Fink JK (2003) Advances in the hereditary spastic paraplegias. Exp Neurol 184:106–110

    Article  Google Scholar 

  26. Guthrie G, Pfeffer G, Bailie M, Bradshaw K, Browning AC, Horvath R, Chinnery PF (2013) The neurological and ophthalmological manifestations of SPG4-related hereditary spastic paraplegia. J Neurol 260:906

    Article  Google Scholar 

  27. Wiethoff, S., Zhour, A., Schols, L., et al., Retinal nerve fibre layer loss in hereditary spastic paraplegias is restricted to complex phenotypes. BMC Neurol, 2012. 12: p. 143

    Article  Google Scholar 

  28. Klimpe S, Schüle R, Kassubek J, Otto S, Kohl Z, Klebe S, Klopstock T, Ratzka S, Karle K, Schöls L (2012) Disease severity affects quality of life of hereditary spastic paraplegia patients. Eur J Neurol 19:168–171

    Article  CAS  Google Scholar 

  29. Braschinsky M, Rannikmäe K, Krikmann Ü, Lüüs S, Raidvee A, Gross-Paju K, Haldre S (2011) Health-related quality of life in patients with hereditary spastic paraplegia in Estonia. Spinal Cord 49:175

    Article  CAS  Google Scholar 

  30. Wald A, Bharucha AE, Cosman BC, Whitehead WE (2014) ACG clinical guideline: management of benign anorectal disorders. Am J Gastroenterol 109:1141

    Article  Google Scholar 

  31. Rao SSC (2004) Pathophysiology of adult fecal incontinence. Gastroenterology 126:S14–S22

    Article  Google Scholar 

  32. Wiesel PH, Norton C, Glickman S, Kamm MA (2001) Pathophysiology and management of bowel dysfunction in multiple sclerosis. Eur J Gastroenterol Hepatol 13:441–448

    Article  CAS  Google Scholar 

  33. Menting J, Tack CJ, Bleijenberg G, Donders R, Droogleever Fortuyn HA, Fransen J, Goedendorp MM, Kalkman JS, Strik-Albers R, van Alfen N, van der Werf SP, Voermans NC, van Engelen BG, Knoop H (2018) Is fatigue a disease-specific or generic symptom in chronic medical conditions? Health Psychol 37:530–543

    Article  Google Scholar 

  34. Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi J (2003) Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology: a report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med 4:101–119

    Article  Google Scholar 

  35. Bhimani R, Anderson L (2014) Clinical understanding of spasticity: implications for practice. Rehabil Res Pract 2014:279175

    PubMed  PubMed Central  Google Scholar 

  36. Rattay TW, Lindig T, Baets J, Smets K, Deconinck T, Söhn AS, Hörtnagel K, Eckstein KN, Wiethoff S, Reichbauer J, Döbler-Neumann M, Krägeloh-Mann I, Auer-Grumbach M, Plecko B, Münchau A, Wilken B, Janauschek M, Giese A-K, De Bleecker JL, Ortibus E, Debyser M, Lopez de Munain A, Pujol A, Bassi MT, D’Angelo MG, De Jonghe P, Züchner S, Bauer P, Schöls L, Schüle R (2019) FAHN/SPG35: a narrow phenotypic spectrum across disease classifications. Brain 142:1561–1572

    Article  Google Scholar 

  37. Moussavi S, Chatterji S, Verdes E, Tandon A, Patel V, Ustun B (2007) Depression, chronic diseases, and decrements in health: results from the World health surveys. Lancet 370:851–858

    Article  Google Scholar 

Download references

Acknowledgments

We thank our patients and their families as well as all healthy controls for participating in this study. We would also like to thank our study nurses Katrin Dillmann-Jehn and Elke Feil for their support in recruiting patients. Finally, we thank Thilo Rattay for assistance in proofreading and language editing.

Funding

This study was  partially funded by the HSP Selbsthilfegruppe Deutschland e.V. (Grant to TWR, RS, and LS). TWR receives funding from the University of Tübingen, medical faculty, for the Clinician Scientist Program Grant: #386-0-0. SW is supported by the Ministry of Science, Research and the Arts of Baden-Württemberg and the European Social Fund (ESF) of Baden-Württemberg (31-7635 41/67/1). TWR, HH, RS and LS are members of the European Reference Network for Rare Neurological Diseases (Project ID No 739510). 

Author information

Authors and Affiliations

  1. Department of Neurodegenerative Disease, Hertie-Institute for Clinical Brain Research, and Center for Neurology, University of Tübingen, Hoppe-Seyler-Straße 3, 72076, Tübingen, Germany

    Tim W. Rattay, Andreas Boldt, Maximilian Völker, Sarah Wiethoff, Holger Hengel, Rebecca Schüle & Ludger Schöls

  2. German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany

    Tim W. Rattay, Sarah Wiethoff, Holger Hengel, Rebecca Schüle & Ludger Schöls

Authors
  1. Tim W. Rattay
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andreas Boldt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maximilian Völker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sarah Wiethoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Holger Hengel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rebecca Schüle
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ludger Schöls
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LS and TWR designed the experiments. TWR, AB, MV, HH, SW, RS, and LS recruited the patients. TWR and AB analyzed the data. TWR wrote the first draft of the manuscript, with important contributions from HH, SW, RS, and LS. All authors provided input for the final manuscript and approved the final submitted version.

Corresponding author

Correspondence to Tim W. Rattay.

Ethics declarations

Conflicts of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Data availability statement

The data sets for this manuscript are not publicly available, because raw data regarding human subjects (e.g., genetic raw data, personal data) are not shared freely to protect the privacy of the human subjects involved in this study; no consent for open sharing has been obtained. Requests to access the data sets should be directed to Dr. Tim W. Rattay.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 14 kb)

Supplementary file2 (DOCX 18 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rattay, T.W., Boldt, A., Völker, M. et al. Non-motor symptoms are relevant and possibly treatable in hereditary spastic paraplegia type 4 (SPG4). J Neurol 267, 369–379 (2020). https://doi.org/10.1007/s00415-019-09573-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-019-09573-w

Keywords

Search

Navigation