, Volume 5, Issue 1, pp 27–34 | Cite as

New FKRP mutations causing congenital muscular dystrophy associated with mental retardation and central nervous system abnormalities. Identification of a founder mutation in Tunisian families

  • Nacim Louhichi
  • Chahnez Triki
  • Susana Quijano-Roy
  • Pascale Richard
  • Samira Makri
  • Mériem Méziou
  • Brigitte Estournet
  • Slah Mrad
  • Norma B. Romero
  • Hammadi Ayadi
  • Pascale Guicheney
  • Faiza FakhfakhEmail author
Original Article


The congenital muscular dystrophies (CMD) constitute a clinically and genetically heterogeneous group of autosomal recessive myopathies. Patients show congenital hypotonia, muscle weakness, and dystrophic changes on muscle biopsy. Mutations in four genes (FKT1, POMGnT1, POMT1, FKRP) encoding putative glycosyltransferases have been identified in a subset of patients characterized by a deficient glycosylation of α-dystroglycan on muscle biopsy. FKRP mutations account for a broad spectrum of patients with muscular dystrophy, from a severe congenital form with or without mental retardation (MDC1C) to a much milder limb-girdle muscular dystrophy (LGMD2I). We identified two novel homozygous missense FKRP mutations, one, A455D, in six unrelated Tunisian patients and the other, V405L, in an Algerian boy. The patients, between the ages of 3 and 12 years, presented with a severe form of MDC1C with calf hypertrophy and high serum creatine kinase levels. None had ever walked. Two had cardiac dysfunction and one strabismus. They all had mental retardation, microcephaly, cerebellar cysts, and hypoplasia of the vermis. White matter abnormalities were found in five, mostly when cranial magnetic resonance imaging was performed at a young age. These abnormalities were shown to regress in one patient, as has been observed in patients with Fukuyama CMD. Identification of a new microsatellite close to the FKRP gene allowed us to confirm the founder origin of the Tunisian mutation. These results strongly suggest that particular FKRP mutations in the homozygous state induce structural and clinical neurological lesions in addition to muscular dystrophy. They also relate MDC1C to other CMD with abnormal protein glycosylation and disordered brain function.


Congenital muscular dystrophy FKRP gene Founder haplotype Mental retardation Cerebellar cysts 



We thank the patients and their families for their participation. This work was supported by funds from the Secrétariat d’Etat à la Recherche Scientifique et à la Technologie (Tunisia), the Institut National de la Santé et de la Recherche Médicale (INSERM), Association Française contre les Myopathies (AFM), and the European Commission (contract no. QLG1-CT1999-00870).


  1. 1.
    Dubowitz V, Fardeau M (1995) Proceedings of the 27th ENMC sponsored workshop on congenital muscular dystrophy, 22–24 April 1994, The Netherlands. Neuromuscul Disord 5:253–258CrossRefPubMedGoogle Scholar
  2. 2.
    Tome FM, Evangelista T, Leclerc A, Sunada Y, Manole E, Estournet B, Barois A, Campbell KP, Fardeau M (1994) Congenital muscular dystrophy with merosin deficiency. CR Acad Sci [III] 317:351–357Google Scholar
  3. 3.
    Helbling-Leclerc A, Zhang X, Topaloglu H, Cruaud C, Tesson F, Weissenbach J, Tome FM, Schwartz K, Fardeau M, Tryggvason K, et al (1995) Mutations in the laminin alpha2-chain gene (LAMA2) cause merosin-deficient congenital muscular dystrophy. Nat Genet 11:216–218PubMedGoogle Scholar
  4. 4.
    Allamand V, Guicheney P (2002) Merosin-deficient congenital muscular dystrophy, autosomal recessive (MDC1A, MIM#156225, LAMA2 gene coding for alpha2 chain of laminin). Eur J Hum Genet 10:91–94CrossRefPubMedGoogle Scholar
  5. 5.
    Philpot J, Cowan F, Pennock J, Sewry C, Dubowitz V, Bydder G, Muntoni F (1999) Merosin-deficient congenital muscular dystrophy: the spectrum of brain involvement on magnetic resonance imaging. Neuromuscul Disord 9:81–85CrossRefPubMedGoogle Scholar
  6. 6.
    Pini A, Merlini L, Tome FM, Chevallay M, Gobbi G (1996) Merosin-negative congenital muscular dystrophy, occipital epilepsy with periodic spasms and focal cortical dysplasia. Report of three Italian cases in two families. Brain Dev 18:316–322CrossRefPubMedGoogle Scholar
  7. 7.
    Sunada Y, Edgar TS, Lotz BP, Rust RS, Campbell KP (1995) Merosin-negative congenital muscular dystrophy associated with extensive brain abnormalities. Neurology 45:2084–2089PubMedGoogle Scholar
  8. 8.
    Yoshida A, Kobayashi K, Manya H, Taniguchi K, Kano H, Mizuno M, Inazu T, Mitsuhashi H, Takahashi S, Takeuchi M, Herrmann R, Straub V, Talim B, Voit T, Topaloglu H, Toda T, Endo T (2001) Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1. Dev Cell 1:717–724PubMedGoogle Scholar
  9. 9.
    Beltran-Valero de Bernabe D, Currier S, Steinbrecher A, Celli J, Beusekom E van, Zwaag B van der, Kayserili H, Merlini L, Chitayat D, Dobyns WB, Cormand B, Lehesjoki AE, Cruces J, Voit T, Walsh CA, Bokhoven H van, Brunner HG (2002) Mutations in O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. Am J Hum Genet 71:1033–1043CrossRefPubMedGoogle Scholar
  10. 10.
    Kobayashi K, Nakahori Y, Miyake M, Matsumura K, Kondo-Iida E, Nomura Y, Segawa M, Yoshioka M, Saito K, Osawa M, Hamano K, Sakakihara Y, Nonaka I, Nakagome Y, Kanazawa I, Nakamura Y, Tokunaga K, Toda T (1998) An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 394:388–392PubMedGoogle Scholar
  11. 11.
    Brockington M, Blake DJ, Prandini P, Brown SC, Torelli S, Benson MA, Ponting CP, Estournet B, Romero NB, Mercuri E, Voit T, Sewry CA, Guicheney P, Muntoni F (2001) Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin alpha2 deficiency and abnormal glycosylation of alpha-dystroglycan. Am J Hum Genet 69:1198–1209CrossRefPubMedGoogle Scholar
  12. 12.
    Quijano-Roy S, Galan L, Ferreiro A, Cheliout-Heraut F, Gray F, Fardeau M, Barois A, Guicheney P, Romero NB, Estournet B (2002) Severe progressive form of congenital muscular dystrophy with calf pseudohypertrophy, macroglossia and respiratory insufficiency. Neuromuscl Disord 12:466–475CrossRefGoogle Scholar
  13. 13.
    Topaloglu H, Brockington M, Yuva Y, Talim B, Haliloglu G, Blake D, Torelli S, Brown SC, Muntoni F (2003) FKRP gene mutations cause congenital muscular dystrophy, mental retardation and cerebellar cysts. Neurology 60:988–992PubMedGoogle Scholar
  14. 14.
    Kawazaki ES (1990) Sample preparation from blood, cells, and other fluids. In: Innis M, Gelffand D, Snisky G, White T (eds) PCR protocols. A guide to methods and application. Academic Press, San Diego, pp 146–52Google Scholar
  15. 15.
    Triki C, Louhichi N, Meziou M, Choyakh F, Kechaou MS, Jlidi R, Mhiri C, Fakhfakh F, Ayadi H (2003) Merosin-deficient congenital muscular dystrophy with mental retardation and cerebellar cysts in three Tunisian patients unlinked to the LAMA2, FCMD, MEB and CMD1B. Neuromuscul Disord 13:4–12CrossRefPubMedGoogle Scholar
  16. 16.
    Brockington M, Yuva Y, Prandini P, Brown SC, Torelli S, Benson MA, Herrmann R, Anderson LV, Bashir R, Burgunder JM, Fallet S, Romero N, Fardeau M, Straub V, Storey G, Pollitt C, Richard I, Sewry CA, Bushby K, Voit T, Blake DJ, Muntoni F (2001) Mutations in the ukutin related-protein gene (FKRP) identifies limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C. Hum Mol Genet 10:2851–2859CrossRefPubMedGoogle Scholar
  17. 17.
    Mercuri E, Brockington M, Straub V, Quijano-Roy S, Yuva Y, Herrmann R, Brown SC, Torelli S, Dubowitz V, Blake DJ, Romero NB, Estournet B, Sewry CA, Guicheney P, Voit T, Muntoni F (2003) Phenotypic spectrum associated with mutations in the fukutin-related protein gene. Ann Neurol 53:537–542CrossRefPubMedGoogle Scholar
  18. 18.
    Quijano-RoyS, RomeroNB, LouhichiN, BrockingtonM, ManyH, YelizY, RichardP, EstournetB, MuntoniF, FardeauF, BaroisA, GuicheneyP (2002) FKRP (fukutin related protein) gene mutations associated with intermediate phenotype between CMD type 1C and LGMD2I (abstract). Neuromuscul Disord 12:743Google Scholar
  19. 19.
    Muntoni F, Valero de Bernabe B, Bittner R, Blake D, Bokhoven H van, Brockington M, Brown S, Bushby K Campbell KP, Fiszman M, Gruenewald S, Merlini L, Quijano-Roy S, Romero N, Sabatelli P, Sewry CA, Straub V, Talim H, Topaloglu H, Voit T, Yurchenco PD, Urtizberea JA, Wewer U, Guicheney P (2004) 114th ENMC International Workshop on Congenital Muscular Dystrophy (CMD), 17-19 January 2003, Naarden, The Netherlands (in press)Google Scholar
  20. 20.
    Osawa M, Sumida S, Suzuki N, Arai Y, Ikenaka H, Murasugi H, Shishikura K, Suzuki H, Saito K, Fukuyama Y (1997) Fukuyama type congenital progressive muscular dystrophy.In: Fukujama Y, Osawa M, Saito K (eds) Congenital muscular dystrophies. Elsevier Science, pp 31–68Google Scholar
  21. 21.
    Esapa CT, Benson MA, Schroder JE, Martin-Rendon E, Brockington M, Brown SC, Muntoni F, Kroger S, Blake DJ (2002) Functional requirements for fukutin-related protein in the Golgi apparatus. Hum Mol Genet 11:3319–3331CrossRefPubMedGoogle Scholar
  22. 22.
    Ervasti JM, Campbell KP (1993) A role for the dystrophin-glycoprotein complex as a transmenbrane linker between laminin and actin. J Cell Biol 122:809–823PubMedGoogle Scholar
  23. 23.
    Michele DE, Barresi R, Kanagawa M, Saito F, Cohn RD, Satz JS, Dollar J, Nishino I, Kelley RI, Somer H, Straub V, Mathews KD, Moore SA, Campbell KP (2002) Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies. Nature 418:417–422CrossRefPubMedGoogle Scholar
  24. 24.
    Moore SA, Saito F, Chen J, Michele DE, Henry MD, Messing A, Cohn RD, Ross-Barta SE, Westra S, Williamson RA, Hoshi T, Campbell KP (2002) Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy. Nature 418:422–425CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Nacim Louhichi
    • 1
  • Chahnez Triki
    • 2
  • Susana Quijano-Roy
    • 3
  • Pascale Richard
    • 4
  • Samira Makri
    • 5
  • Mériem Méziou
    • 2
  • Brigitte Estournet
    • 3
  • Slah Mrad
    • 3
  • Norma B. Romero
    • 6
  • Hammadi Ayadi
    • 1
  • Pascale Guicheney
    • 6
  • Faiza Fakhfakh
    • 1
    Email author
  1. 1.Laboratoire de Génétique Moléculaire HumaineFaculté de Médecine de SfaxTunisia
  2. 2.Service de NeurologieCHU Habib BourguibaSfaxTunisia
  3. 3.Service de Pédiatrie, Rééducation et Réanimation NeurorespiratoireHôpital Raymond-PoincaréFrance
  4. 4.UF Cardio-MyoGénétiqueGroupe Hospitalier Pitié-SalpêtrièreParisFrance
  5. 5.Etablissement Hospitalier Spécialisé Ali Ait IdirAlgerAlgeria
  6. 6.INSERM U582 Institut de MyologieGroupe Hospitalier Pitié-SalpêtrièreParisFrance

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