LRSAM1 variants and founder effect in French families with ataxic form of Charcot-Marie-Tooth type 2

Article metrics


Currently only 25–30% of patients with axonal forms of Charcot-Marie-Tooth disease (CMT) receive a genetic diagnosis. We aimed to identify the causative gene of CMT type 2 in 8 non-related French families with a distinct clinical phenotype. We collected clinical, electrophysiological, and laboratory findings and performed genetic analyses in four different French laboratories. Seventy-two patients with autosomal dominant inheritance were identified. The disease usually started in the fourth decade and the clinical picture was dominated by sensory ataxia (80%), neuropathic pain (38%), and length-dependent sensory loss to all modalities. Electrophysiological studies showed a primarily axonal neuropathy, with possible isolated sensory involvement in milder phenotypes. Disease severity varied greatly but the clinical course was generally mild. We identified 2 novel variants in LRSAM1 gene: a deletion of 4 amino acids, p.(Gln698_Gln701del), was found in 7 families and a duplication of a neighboring region of 10 amino acids, p.(Pro702_Gln711dup), in the remaining family. A common haplotype of ~450 kb suggesting a founder effect was noted around LRSAM1 in 4 families carrying the first variant. LRSAM1 gene encodes for an E3 ubiquitin ligase important for neural functioning. Our results confirm the localization of variants in its catalytic C-terminal RING domain and broaden the phenotypic spectrum of LRSAM1-related neuropathies, including painful and predominantly sensory ataxic forms.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3

Data availability

Genetic data have been submitted to ClinVar (Submission ID: SUB4224652).


  1. 1.

    Skre H. Genetic and clinical aspects of Charcot-Marie-Tooth's disease. Clin Genet. 1974;6:98–118.

  2. 2.

    Pareyson D, Marchesi CDiagnosis. natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurol. 2009;8:654–67.

  3. 3.

    Harding AE, Thomas PK. The clinical features of hereditary motor and sensory neuropathy types I and II. Brain. 1980;103:259–80.

  4. 4.

    Berciano J, García A, Gallardo E, Peeters K, Pelayo-Negro AL, Álvarez-Paradelo S, et al. Intermediate Charcot-Marie-Tooth disease: an electrophysiological reappraisal and systematic review. J Neurol. 2017;264:1655–77.

  5. 5.

    Pisciotta C, Shy ME. Neuropathy. Neuromolecular Med. 2018;148:653–65.

  6. 6.

    Rossor AM, Polke JM, Houlden H, Reilly MM. Clinical implications of genetic advances in Charcot-Marie-Tooth disease. Nat Rev Neurol. 2013;9:562–71.

  7. 7.

    Hakonen JE, Sorrentino V, Avagliano Trezza R, de Wissel MB, van den Berg M, Bleijlevens B, et al. LRSAM1-mediated ubiquitylation is disrupted in axonal Charcot-Marie-Tooth disease 2P. Hum Mol Genet. 2017;26:2034–41.

  8. 8.

    Guernsey DL, Jiang H, Bedard K, Evans SC, Ferguson M, Matsuoka M, et al. Mutation in the gene encoding ubiquitin ligase LRSAM1 in patients with Charcot-Marie-Tooth disease. PLoS Genet. 2010;6:e1001081.

  9. 9.

    Weterman MA, Sorrentino V, Kasher PR, Jakobs ME, van Engelen BG, Fluiter K, et al. A frameshift mutation in LRSAM1 is responsible for a dominant hereditary polyneuropathy. Hum Mol Genet. 2012;21:358–70.

  10. 10.

    Nicolaou P, Cianchetti C, Minaidou A, Marrosu G, Zamba-Papanicolaou E, Middleton L, et al. A novel LRSAM1 mutation is associated with autosomal dominant axonal Charcot-Marie-Tooth disease. Eur J Hum Genet. 2013;21:190–4.

  11. 11.

    Engeholm M, Sekler J, Schöndorf DC, Arora V, Schittenhelm J, Biskup S, et al. A novel mutation in LRSAM1 causes axonal Charcot-Marie-Tooth disease with dominant inheritance. BMC Neurol. 2014;14:118.

  12. 12.

    Peeters K, Palaima P, Pelayo-Negro AL, García A, Gallardo E, García-Barredo R, et al. Charcot-Marie-Tooth disease type 2G redefined by a novel mutation in LRSAM1. Ann Neurol. 2016;80:823–33.

  13. 13.

    Hu B, Arpag S, Zuchner S, Li J. A novel missense mutation of CMT2P alters transcription machinery. Ann Neurol. 2016;80:834–45.

  14. 14.

    Zhao G, Song J, Yang M, Song X, Liu X. A novel mutation of LRSAM1 in a Chinese family with Charcot-Marie-Tooth disease. J Peripher Nerv Syst. 2018;23:55–9.

  15. 15.

    Sommer CL, Brandner S, Dyck PJ, Harati Y, LaCroix C, Lammens M, et al. Peripheral Nerve Society Guideline on processing and evaluation of nerve biopsies. J Peripher Nerv Syst. 2010;15:164–75.

  16. 16.

    Bacquet J, Stojkovic T, Boyer A, Martini N, Audic F, Chabrol B, et al. Molecular diagnosis of inherited peripheral neuropathies by targeted next-generation sequencing: molecular spectrum delineation. BMJ Open. 2018;8:e021632.

  17. 17.

    Masingue M, Perrot J, Carlier RY, Piguet-Lacroix G, Latour P, Stojkovic T. WES homozygosity mapping in a recessive form of Charcot-Marie-Tooth neuropathy reveals intronic GDAP1 variant leading to a premature stop codon. Neurogenetics. 2018;19:67–76.

  18. 18.

    Chahin N, Sorenson EJ. Serum creatine kinase levels in spinobulbar muscular atrophy and amyotrophic lateral sclerosis. Muscle Nerve. 2009;40:126–9.

  19. 19.

    Luigetti M, Modoni A, Renna R, Silvestri G, Ricci E, Montano N, et al. A case of CMT 1B due to Val 102/fs null mutation of the MPZ gene presenting as hyperCKemia. Clin Neurol Neurosurg. 2010;112:794–7.

  20. 20.

    Berciano J, García A, Peeters K, Gallardo E, De Vriendt E, Pelayo-Negro AL, et al. NEFL E396K mutation is associated with a novel dominant intermediate Charcot-Marie-Tooth disease phenotype. J Neurol. 2015;262:1289–300.

  21. 21.

    Aerts MB, Weterman AJ, Quadri M, Schelhaas HJ, Bloem BR, Esselink RA, et al. A LRSAM1 mutation links Charcot-Marie-Tooth type 2 to Parkinson's disease. Ann Clin Transl Neurol. 2015;3:146–9.

  22. 22.

    Tang B, Seredenina T, Coppola G, Kuhn A, Geschwind DH, Luthi-Carter R, et al. Gene expression profiling of R6/2 transgenic mice with different CAG repeat lengths reveals genes associated with disease onset and progression in Huntington's disease. Neurobiol Dis. 2011;42:459–67.

  23. 23.

    Trempe JF, Sauvé V, Grenier K, Seirafi M, Tang MY, Ménade M, et al. Structure of parkin reveals mechanisms for ubiquitin ligase activation. Science. 2013;340:1451–5.

  24. 24.

    Bogdanik LP, Sleigh JN, Tian C, Samuels ME, Bedard K, Seburn KL, et al. Loss of the E3 ubiquitin ligase LRSAM1 sensitizes peripheral axons to degeneration in a mouse model of Charcot-Marie-Tooth disease. Dis Model Mech. 2013;6:780–92.

  25. 25.

    Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem. 1998;67:425–79.

  26. 26.

    Amit I, Yakir L, Katz M, Zwang Y, Marmor MD, Citri A, et al. Tal, a Tsg101-specific E3 ubiquitin ligase, regulates receptor endocytosis and retrovirus budding. Genes Dev. 2004;18:1737–52.

Download references

Author information

Drs. AP and TS contributed equally to this study. Drs. AP and TS also had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Drs. TS and SL-L. Acquisition, analysis, or interpretation of data: Drs. AP, MP, DV, FB, KD, MM, FD, CG, RJ-M, LM, GS, SN, AN, SL-L, BF, EL, AS-L, CM, PL, and TS. Drafting of the manuscript: Drs. AP, TS, and PL. Critical revision of the manuscript for important intellectual content: Drs. AP, SL-L, PL, and TS. Administrative, technical, or material support: Drs. AP, TS, and PL. Study supervision: Drs TS and PL

Correspondence to Alessia Peretti.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark