Update on McLeod Syndrome

  • H. H. Jung

McLeod syndrome is an X-linked neuroacanthocytosis syndrome caused by mutations of the XK gene. Central nervous system manifestations resemble Huntington’s disease, and include a choreatic movement disorder, dysexecutive cognitive deficits, psychiatric abnormalities, and generalized seizures. Neuromuscular manifestations include myopathy, sensory-motor axonal neuropathy, and cardiomyopathy. In the recent years, McLeod syndrome has increasingly recognized in various countries. Several studies demonstrate a high phenotypic variability. Most mutations in the XK gene predict an absent or truncated XK protein, and no clear genotype—genotype correlation has been found. Missense mutations are rare and may be associated with a milder phenotype. Imaging studies demonstrate striatal atrophy and subtle cerebral metabolic abnormalities. Neuropathological studies reveal striatal neuronal loss and gliosis without specific features. There is an ongoing search for a suitable animal model to disclose the pathogenetic mechanisms of the disorder and search for possible therapeutic targets.


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  1. 1.
    Allen FH, Krabbe SMR, Corcoran PA (1961) A new phenotype (McLeod) in the Kell blood-group system. Vox Sang 6:555–560.CrossRefPubMedGoogle Scholar
  2. 2.
    Brin MF, Hays A, Symmans WA, Marsh WL, Rowland LP (1993) Neuropathology of McLeod phenotype is like choreaacanthocytosis (CA). Can J Neurol Sci 20(Suppl):S234.CrossRefGoogle Scholar
  3. 3.
    Calenda G, Peng J, Redman CM, Sha Q, Wu X, Lee S (2006) Identification of two new members, XPLAC and XTES, of the XK family. Gene 370:6–16.CrossRefPubMedGoogle Scholar
  4. 4.
    Claperon A, Hattab C, Armand V, Trottier S, Bertrand O, Ouimet T (2007) The Kell and XK proteins of the Kell blood group are not co-expressed in the central nervous system. Brain Res. 1147:12–24.CrossRefPubMedGoogle Scholar
  5. 5.
    Danek A, Rubio JP, Rampoldi L, Ho M, Dobson-Stone C, Tison F et al (2001) McLeod neuroacanthocytosis: genotype and phenotype. Ann Neurol 50:755–764.CrossRefPubMedGoogle Scholar
  6. 6.
    Dydak U, Mueller S, Sandor PS, Meier D, Boesiger P, Jung HH (2006) Cerebral metabolic alterations in McLeod syndrome. Eur Neurol 56(1):17–23.CrossRefPubMedGoogle Scholar
  7. 7.
    Hardie RJ, Pullon HW, Harding AE, Owen JS, Pires M, Daniels GL et al (1991) Neuroacanthocytosis. A clinical, haematological and pathological study of 19 cases. Brain 114:13–49.PubMedGoogle Scholar
  8. 8.
    Ho M, Chelly J, Carter N, Danek A, Crocker P, Monaco AP (1994) Isolation of the gene for McLeod syndrome that encodes a novel membrane transport protein. Cell 77:869–880.CrossRefPubMedGoogle Scholar
  9. 9.
    Ho MF, Chalmers RM, Davis MB, Harding AE, Monaco AP (1996) A novel point mutation in the McLeod syndrome gene in euroacanthocytosis. Ann Neurol 39:672–675.CrossRefPubMedGoogle Scholar
  10. 10.
    Jung HH (2004) McLeod syndrome: a clinical review. In: Danek A (ed) Neuroacanthocytosis syndromes. Springer, Dordrecht, pp 45–53.CrossRefGoogle Scholar
  11. 11.
    Jung HH, Brandner S (2002) Malignant McLeod myopathy. Muscle Nerve 26:424–427.CrossRefPubMedGoogle Scholar
  12. 12.
    Jung HH, Hergersberg M, Kneifel S, Alkadhi H, Schiess R, Weigell-Weber M et al (2001) McLeod syndrome: a novel mutation, predominant psychiatric manifestations, and distinct striatal imaging findings. Ann Neurol 49:384–392.CrossRefPubMedGoogle Scholar
  13. 13.
    Jung HH, Russo D, Redman C, Brandner S (2001) Kell and XK immunohistochemistry in McLeod myopathy. Muscle Nerve 24:1346–1351.CrossRefPubMedGoogle Scholar
  14. 14.
    Kawakami T, Takiyama Y, Sakoe K, Ogawa T, Yoshioka T, Nishizawa M et al (1999) A case of McLeod syndrome with unusually severe myopathy. J Neurol Sci 166:36–39.CrossRefPubMedGoogle Scholar
  15. 15.
    Khamlichi S, Bailly P, Blanchard D, Goossens D, Cartron JP, Bertrand O (1995) Purification and partial characterization of the erythrocyte Kx protein deficient in McLeod patients. Eur J Biochem 228:931–934.CrossRefPubMedGoogle Scholar
  16. 16.
    Lee S (1997) Molecular basis of Kell blood group phenotypes. Vox Sang 73:1–11.CrossRefPubMedGoogle Scholar
  17. 17.
    Lee S, Lin M, Mele A, Cao Y, Farmar J, Russo D et al. (1999) Proteolytic processing of big endothelin-3 by the Kell blood group protein. Blood 94:1440–1450.PubMedGoogle Scholar
  18. 18.
    Lee S, Russo D, Redman CM (2000) Kell blood group system: Kell and XK membrane proteins. Semin Hematol 37:113–121.CrossRefPubMedGoogle Scholar
  19. 19.
    Lee S, Sha Q, Wu X, Calenda G, Peng J (2007) Expression profiles of mouse Kell, XK, and XPLAC mRNA. J Histochem Cytochem 55:365–374.CrossRefPubMedGoogle Scholar
  20. 20.
    Miranda M, Castiglioni C, Frey BM, Hergersberg M, Danek A, Jung HH (2007) Phenotypic variability of a distinct deletion in McLeod syndrome. Mov Disord. 22:1358–1361.CrossRefPubMedGoogle Scholar
  21. 21.
    Nicholl DJ, Sutton I, Dotti MT, Supple SG, Danek A, Lawden M (2004) White matter abnormalities on MRI in neuroacanthocytosis. J Neurol Neurosurg Psychiatry 75:1200–1201.CrossRefPubMedGoogle Scholar
  22. 22.
    Oechsner M, Buchert R, Beyer W, Danek A (2001) Reduction of striatal glucose metabolism in McLeod choreoacanthocytosis. J Neurol Neurosurg Psychiatry 70:517–520.CrossRefPubMedGoogle Scholar
  23. 23.
    Phelan JK, Pinto SM, Falquet L, Jung HH, Hengartner MO (2006). Characterization of ced-8 and ced-8 interacting genes. European Worm Meeting 2006, Hersonissos, Crete, Greece, April 29–May 3.Google Scholar
  24. 24.
    Phelan JK, Wong K, Jung HH, Hengartner MO (2005). Sequence analysis identifies a family of human genes related to ced-8. 15th Biennial International C. elegans Conference, University of California, Los Angeles, CA, USA, June 25–29.Google Scholar
  25. 25.
    Russo D, Lee S, Redman C (1999) Intracellular assembly of Kell and XK blood group proteins. Biochim Biophys Acta 1461:10–18.CrossRefPubMedGoogle Scholar
  26. 26.
    Russo D, Redman C, Lee S (1998) Association of XK and Kell blood group proteins. J Biol Chem 273:13950–13956.CrossRefPubMedGoogle Scholar
  27. 27.
    Russo D, Wu X, Redman CM, Lee S (2000) Expression of Kell blood group protein in nonerythroid tissues. Blood 96:340–346.PubMedGoogle Scholar
  28. 28.
    Stanfield GM, Horvitz HR (2000) The ced-8 gene controls the timing of programmed cell deaths in C. elegans. Mol Cell 5:423–433.CrossRefPubMedGoogle Scholar
  29. 29.
    Starling A, Schlesinger D, Kok F, Passos-Bueno MR, Vainzof M, Zatz M (2005) A family with McLeod syndrome and calpainopathy with clinically overlapping diseases. Neurology 65:1832–1833.CrossRefPubMedGoogle Scholar
  30. 30.
    Wada M, Kimura M, Daimon M, Kurita K, Kato T, Johmura Y et al (2003) An unusual phenotype of McLeod syndrome with late onset axonal neuropathy. J Neurol Neurosurg Psychiatry 74:1697–1698.CrossRefPubMedGoogle Scholar
  31. 31.
    Walker RH, Danek A, Uttner I, Offner R, Reid M, Lee S (2007) McLeod phenotype without the McLeod syndrome. Transfusion 47:299–305.CrossRefPubMedGoogle Scholar
  32. 32.
    Walker RH, Jung HH, Dobson-Stone C, Rampoldi L, Sano A, Tison F et al (2007) Neurologic phenotypes associated with acanthocytosis. Neurology 68:92–98.CrossRefPubMedGoogle Scholar
  33. 33.
    Walker RH, Jung HH, Tison F, Lee S, Danek A (2007) Phenotypic variation among brothers with the McLeod neuroacanthocytosis syndrome. Mov Disord 22:244–248.CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  • H. H. Jung
    • 1
  1. 1.Departments of NeurologyUniversity Hospital ZürichZürichSwitzerland

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