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Human Genetics

, Volume 137, Issue 11–12, pp 911–919 | Cite as

SACS variants are a relevant cause of autosomal recessive hereditary motor and sensory neuropathy

  • Katharina Vill
  • Wolfgang Müller-Felber
  • Dieter Gläser
  • Marius Kuhn
  • Veronika Teusch
  • Herbert Schreiber
  • Joachim Weis
  • Jörg Klepper
  • Anja Schirmacher
  • Astrid Blaschek
  • Manuela Wiessner
  • Tim M. Strom
  • Bianca Dräger
  • Kristina Hofmeister-Kiltz
  • Moritz Tacke
  • Lucia Gerstl
  • Peter Young
  • Rita Horvath
  • Jan Senderek
Original Investigation
  • 200 Downloads

Abstract

Mutations in the SACS gene have been initially reported in a rare autosomal recessive cerebellar ataxia syndrome featuring prominent cerebellar atrophy, spasticity and peripheral neuropathy as well as retinal abnormalities in some cases (autosomal recessive spastic ataxia of Charlevoix–Saguenay, ARSACS). In the past few years, the phenotypic spectrum has broadened, mainly owing to the availability and application of high-throughput genetic testing methods. We identified nine patients (three sib pairs, three singleton cases) with isolated, non-syndromic hereditary motor and sensory neuropathy (HMSN) who carried pathogenic SACS mutations, either in the homozygous or compound heterozygous state. None of the patients displayed spasticity or pyramidal signs. Ataxia, which was noted in only three patients, was consistent with a sensory ataxia. Nerve conduction and nerve biopsy studies showed mixed demyelinating and axonal neuropathy. Brain MRI scans were either normal or revealed isolated upper vermis atrophy of the cerebellum. Our findings confirm the broad clinical spectrum associated with SACS mutations, including pure polyneuropathy without characteristic clinical and brain imaging manifestations of ARSACS.

Notes

Funding

This work was supported by the German Federal Ministry of Education and Research (BMBF) through the German Network for Charcot-Marie-Tooth Neuropathies (CMT-Net) (01GM1511B, 01GM1511D, 01GM1511E; to Katharina Vill, Joachim Weis, Peter Young, Wolfgang Müller-Felber and Jan Senderek) and the Fritz-Thyssen-Stiftung (Az10.15.1.021MN; to Jan Senderek).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

439_2018_1952_MOESM1_ESM.docx (15 kb)
Supplementary material 1 (DOCX 15 KB)
439_2018_1952_MOESM2_ESM.docx (13 kb)
Supplementary material 2 (DOCX 12 KB)

Supplementary material 3: Supplemental Video File: Patient A-II:2, showing pes cavus (A), foot drop and impaired heel walking (B), difficulty walking on a line (C) and reduced ability to hop on one foot (D). (WMV 9038 KB)

References

  1. Baets J, Deconinck T, Smets K, Goossens D, Van den Bergh P, Dahan K et al (2010) Mutations in SACS cause atypical and late-onset forms of ARSACS. Neurology 75(13):1181–1188CrossRefGoogle Scholar
  2. Baumann M, Schreiber H, Schlotter-Weigel B, Loscher WN, Stucka R, Karall D et al (2018) MPV17 mutations in juvenile- and adult-onset axonal sensorimotor polyneuropathy. Clin Genet.  https://doi.org/10.1111/cge.13462 CrossRefPubMedGoogle Scholar
  3. Bergmann C, Zerres K, Senderek J, Rudnik-Schoneborn S, Eggermann T, Hausler M et al (2003) Oligophrenin 1 (OPHN1) gene mutation causes syndromic X-linked mental retardation with epilepsy, rostral ventricular enlargement and cerebellar hypoplasia. Brain: J Neurol 126(Pt 7):1537–1544CrossRefGoogle Scholar
  4. Bouchard JP, Richter A, Mathieu J, Brunet D, Hudson TJ, Morgan K et al (1998) Autosomal recessive spastic ataxia of Charlevoix-Saguenay. Neuromuscul Disord: NMD 8(7):474–479CrossRefGoogle Scholar
  5. Bradshaw TY, Romano LE, Duncan EJ, Nethisinghe S, Abeti R, Michael GJ et al (2016) A reduction in Drp1-mediated fission compromises mitochondrial health in autosomal recessive spastic ataxia of Charlevoix Saguenay. Hum Mol Genet 25(15):3232–3244CrossRefGoogle Scholar
  6. Chen YC, Auer-Grumbach M, Matsukawa S, Zitzelsberger M, Themistocleous AC, Strom TM et al (2015) Transcriptional regulator PRDM12 is essential for human pain perception. Nat Genet 47(7):803–808CrossRefGoogle Scholar
  7. Choi YR, Hong YB, Jung SC, Lee JH, Kim YJ, Park HJ et al (2015) A novel homozygous MPV17 mutation in two families with axonal sensorimotor polyneuropathy. BMC Neurol 15:179CrossRefGoogle Scholar
  8. Criscuolo C, Procaccini C, Meschini MC, Cianflone A, Carbone R, Doccini S et al (2015) Powerhouse failure and oxidative damage in autosomal recessive spastic ataxia of Charlevoix-Saguenay. J Neurol 262(12):2755–2763CrossRefGoogle Scholar
  9. De Braekeleer M, Giasson F, Mathieu J, Roy M, Bouchard JP, Morgan K (1993) Genetic epidemiology of autosomal recessive spastic ataxia of Charlevoix-Saguenay in northeastern Quebec. Genet Epidemiol 10(1):17–25CrossRefGoogle Scholar
  10. Duquette A, Brais B, Bouchard JP, Mathieu J (2013) Clinical presentation and early evolution of spastic ataxia of Charlevoix-Saguenay. Mov Disord 28(14):2011–2014CrossRefGoogle Scholar
  11. El Euch-Fayache G, Lalani I, Amouri R, Turki I, Ouahchi K, Hung WY et al (2003) Phenotypic features and genetic findings in sacsin-related autosomal recessive ataxia in Tunisia. Arch Neurol 60(7):982–988CrossRefGoogle Scholar
  12. Engert JC, Berube P, Mercier J, Dore C, Lepage P, Ge B et al (2000) ARSACS, a spastic ataxia common in northeastern Quebec, is caused by mutations in a new gene encoding an 11.5-kb ORF. Nat Genet 24(2):120–125CrossRefGoogle Scholar
  13. Fischer C, Trajanoski S, Papic L, Windpassinger C, Bernert G, Freilinger M et al (2012) SNP array-based whole genome homozygosity mapping as the first step to a molecular diagnosis in patients with Charcot-Marie-Tooth disease. J Neurol 259(3):515–523CrossRefGoogle Scholar
  14. Girard M, Lariviere R, Parfitt DA, Deane EC, Gaudet R, Nossova N et al (2012) Mitochondrial dysfunction and Purkinje cell loss in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). Proc Natl Acad Sci USA 109(5):1661–1666CrossRefGoogle Scholar
  15. Hong YB, Lee JH, Park JM, Choi YR, Hyun YS, Yoon BR et al (2013) A compound heterozygous mutation in HADHB gene causes an axonal Charcot-Marie-tooth disease. BMC Med Genet 14:125CrossRefGoogle Scholar
  16. Kamionka M, Feigon J (2004) Structure of the XPC binding domain of hHR23A reveals hydrophobic patches for protein interaction. Protein Sci 13(9):2370–2377CrossRefGoogle Scholar
  17. Lariviere R, Gaudet R, Gentil BJ, Girard M, Conte TC, Minotti S et al (2015) Sacs knockout mice present pathophysiological defects underlying autosomal recessive spastic ataxia of Charlevoix-Saguenay. Hum Mol Genet 24(3):727–739CrossRefGoogle Scholar
  18. Liu L, Li XB, Zi XH, Shen L, Hu Zh M, Huang Sh X et al (2016) A novel hemizygous SACS mutation identified by whole exome sequencing and SNP array analysis in a Chinese ARSACS patient. J Neurol Sci 362:111–114CrossRefGoogle Scholar
  19. Miyatake S, Miyake N, Doi H, Saitsu H, Ogata K, Kawai M et al. (2012) A novel SACS mutation in an atypical case with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). Intern Med (Tokyo, Japan) 51(16):2221–2226CrossRefGoogle Scholar
  20. Palmio J, Karppa M, Baumann P, Penttila S, Moilanen J, Udd B (2016) Novel compound heterozygous mutation in SACS gene leads to a milder autosomal recessive spastic ataxia of Charlevoix-Saguenay, ARSACS, in a Finnish family. Clin Case Rep 4(12):1151–1156CrossRefGoogle Scholar
  21. Parfitt DA, Michael GJ, Vermeulen EG, Prodromou NV, Webb TR, Gallo JM et al (2009) The ataxia protein sacsin is a functional co-chaperone that protects against polyglutamine-expanded ataxin-1. Hum Mol Genet 18(9):1556–1565CrossRefGoogle Scholar
  22. Peyronnard JM, Charron L, Barbeau A (1979) The neuropathy of Charlevoix-Saguenay ataxia: an electrophysiological and pathological study. Can J Neurol Sci 6(2):199–203CrossRefGoogle Scholar
  23. Pilliod J, Moutton S, Lavie J, Maurat E, Hubert C, Bellance N et al (2015) New practical definitions for the diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay. Ann Neurol 78(6):871–886CrossRefGoogle Scholar
  24. Prodi E, Grisoli M, Panzeri M, Minati L, Fattori F, Erbetta A et al (2013) Supratentorial and pontine MRI abnormalities characterize recessive spastic ataxia of Charlevoix-Saguenay. A comprehensive study of an Italian series. Eur J Neurol 20(1):138–146CrossRefGoogle Scholar
  25. Pyle A, Griffin H, Yu-Wai-Man P, Duff J, Eglon G, Pickering-Brown S et al (2012) Prominent sensorimotor neuropathy due to SACS mutations revealed by whole-exome sequencing. Arch Neurol 69(10):1351–1354CrossRefGoogle Scholar
  26. Rudnik-Schoneborn S, Tolle D, Senderek J, Eggermann K, Elbracht M, Kornak U et al (2016) Diagnostic algorithms in Charcot-Marie-Tooth neuropathies: experiences from a German genetic laboratory on the basis of 1206 index patients. Clin Genet 89(1):34–43CrossRefGoogle Scholar
  27. Rudnik-Schoneborn S, Auer-Grumbach M, Senderek J (2017) Hereditary Neuropathies update 2017. Neuropediatrics 48(4):282–293CrossRefGoogle Scholar
  28. Schroder JM, Mayer M, Weis J (1996) Mitochondrial abnormalities and intrafamilial variability of sural nerve biopsy findings in adrenomyeloneuropathy. Acta Neuropathol 92(1):64–69CrossRefGoogle Scholar
  29. Senderek J, Bergmann C, Weber S, Ketelsen UP, Schorle H, Rudnik-Schoneborn S et al (2003) Mutation of the SBF2 gene, encoding a novel member of the myotubularin family, in Charcot-Marie-Tooth neuropathy type 4B2/11p15. Hum Mol Genet 12(3):349–356CrossRefGoogle Scholar
  30. Shimazaki H, Takiyama Y, Honda J, Sakoe K, Namekawa M, Tsugawa J et al (2013) Middle cerebellar peduncles and Pontine T2 hypointensities in ARSACS. J Neuroimaging 23(1):82–85CrossRefGoogle Scholar
  31. Souza PVS, Bortholin T, Naylor FGM, Pinto W, Oliveira ASB (2018) Early-onset axonal Charcot-Marie-Tooth disease due to SACS mutation. Neuromuscul Disord: NMD 28(2):169–172CrossRefGoogle Scholar
  32. Spinazzola A, Viscomi C, Fernandez-Vizarra E, Carrara F, D’Adamo P, Calvo S et al (2006) MPV17 encodes an inner mitochondrial membrane protein and is mutated in infantile hepatic mitochondrial DNA depletion. Nat Genet 38(5):570–575CrossRefGoogle Scholar
  33. Synofzik M, Soehn AS, Gburek-Augustat J, Schicks J, Karle KN, Schule R et al (2013) Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS): expanding the genetic, clinical and imaging spectrum. Orphanet J Rare Dis 8:41CrossRefGoogle Scholar
  34. Tzoulis C, Johansson S, Haukanes BI, Boman H, Knappskog PM, Bindoff LA (2013) Novel SACS mutations identified by whole exome sequencing in a norwegian family with autosomal recessive spastic ataxia of Charlevoix-Saguenay. PLoS One 8(6):e66145CrossRefGoogle Scholar
  35. Van Damme P, Demaerel P, Spileers W, Robberecht W (2009) Autosomal recessive spastic ataxia of Charlevoix-Saguenay. Neurology 72(20):1790CrossRefGoogle Scholar
  36. Vermeer S, van de Warrenburg BP, Kamsteeg EJ (1993) ARSACS. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A (eds) GeneReviews®. University of Washington, Seattle (WA)Google Scholar
  37. Vermeer S, Meijer RP, Pijl BJ, Timmermans J, Cruysberg JR, Bos MM et al (2008) ARSACS in the Dutch population: a frequent cause of early-onset cerebellar ataxia. Neurogenetics 9(3):207–214CrossRefGoogle Scholar
  38. Wanders RJ, IJlst L, Poggi F, Bonnefont JP, Munnich A, Brivet M et al.(1992) Human trifunctional protein deficiency: a new disorder of mitochondrial fatty acid beta-oxidation. Biochem Biophys Res Commun 188(3):1139–1145CrossRefGoogle Scholar
  39. Weis J, Claeys KG, Roos A, Azzedine H, Katona I, Schroder JM et al (2017) Towards a functional pathology of hereditary neuropathies. Acta Neuropathol 133(4):493–515CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Katharina Vill
    • 1
  • Wolfgang Müller-Felber
    • 1
  • Dieter Gläser
    • 2
  • Marius Kuhn
    • 2
  • Veronika Teusch
    • 3
    • 4
  • Herbert Schreiber
    • 5
  • Joachim Weis
    • 6
  • Jörg Klepper
    • 7
  • Anja Schirmacher
    • 8
  • Astrid Blaschek
    • 1
  • Manuela Wiessner
    • 9
  • Tim M. Strom
    • 10
  • Bianca Dräger
    • 8
  • Kristina Hofmeister-Kiltz
    • 11
  • Moritz Tacke
    • 1
  • Lucia Gerstl
    • 1
  • Peter Young
    • 8
  • Rita Horvath
    • 12
  • Jan Senderek
    • 9
  1. 1.Department of Pediatric Neurology and Developmental Medicine, Dr. v. Hauner Children’s HospitalUniversity Hospital, LMU MunichMunichGermany
  2. 2.genetikum, Center for Human GeneticsNeu-UlmGermany
  3. 3.University Clinic and Policlinic of Radiology, Martin-Luther-Universität Halle-WittenbergHalleGermany
  4. 4.Department of RadiologyKlinikum Schwabing, Städtisches Klinikum MünchenMunichGermany
  5. 5.Neurological Practice & Neuropoint Patient AcademyUlmGermany
  6. 6.Institute of NeuropathologyRWTH Aachen University HospitalAachenGermany
  7. 7.Department of Pediatrics and NeuropediatrcsKlinikum Aschaffenburg-AlzenauAschaffenburgGermany
  8. 8.Institute for Sleep Medicine and Neuromuscular DisordersMuenster University HospitalMünsterGermany
  9. 9.Friedrich Baur Institute at the Department of NeurologyUniversity Hospital, LMU MunichMunichGermany
  10. 10.Institute of Human GeneticsHelmholtz Zentrum MünchenNeuherbergGermany
  11. 11.Department of Neurology, Neurophysiology, Early Rehabilitation and Sleep MedicineKlinikum ChristophsbadGöppingenGermany
  12. 12.Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic MedicineNewcastle UniversityNewcastle upon TyneUK

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