Neurogenetics

, Volume 8, Issue 1, pp 39–44

Frameshift mutation in GJA12 leading to nystagmus, spastic ataxia and CNS dys-/demyelination

  • Nicole I. Wolf
  • Maria Cundall
  • Paul Rutland
  • Elisabeth Rosser
  • Robert Surtees
  • Sarah Benton
  • Wui K. Chong
  • Sue Malcolm
  • Friedrich Ebinger
  • Maria Bitner-Glindzicz
  • Karen J. Woodward
Original Article

Abstract

Mutations in GJA12 have been shown to cause Pelizaeus–Merzbacher-like disease (PMLD). We present two additional patients from one family carrying a homozygous frameshift mutation in GJA12. Both presented initially with nystagmus. The older girl developed ataxia first, then progressive spastic ataxia. The younger boy suffered from severe sensory neuropathy. Magnetic resonance imaging (MRI) of both children showed progressive demyelination in addition to dysmyelination, and also characteristic brainstem abnormalities. In children with nystagmus, ataxia and dysmyelination, mutation analysis of GJA12 should be considered early, especially if inheritance is autosomal recessive.

Keywords

Ataxia Leukencephalopathy Neuropathy Nystagmus Pelizaeus–Merzbacher disease 

References

  1. 1.
    Ellis D, Malcolm S (1994) Proteolipid protein gene dosage effect in Pelizaeus–Merzbacher disease. Nat Genet 6:333–334PubMedCrossRefGoogle Scholar
  2. 2.
    Inoue K (2005) PLP1-related inherited dysmyelinating disorders: Pelizaeus–Merzbacher disease and spastic paraplegia type 2. Neurogenetics 6:1–16PubMedCrossRefGoogle Scholar
  3. 3.
    Wolf NI, Sistermans EA, Cundall M, Hobson GM, Davis-Williams AP, Palmer R, Stubbs P, Davies S, Endziniene M, Wu Y, Chong WK, Malcolm S, Surtees R, Garbern JY, Woodward KJ (2005) Three or more copies of the proteolipid protein gene PLP1 cause severe Pelizaeus–Merzbacher disease. Brain 128:743–751PubMedCrossRefGoogle Scholar
  4. 4.
    Van der Knaap MS, Valk J (1989) The reflection of histology in MR imaging of Pelizaeus–Merzbacher disease. Am J Neuroradiol 10:99–103PubMedGoogle Scholar
  5. 5.
    Uhlenberg B, Schuelke M, Rüschendorf F, Ruf N, Kaindl AM, Henneke M, Thiele H, Stoltenburg-Didinger G, Aksu F, Topaloglu H, Nurnberg P, Hübner C, Weschke B, Gärtner J (2004) Mutations in the gene encoding gap junction protein alpha 12 (connexin 46.6) cause Pelizaeus–Merzbacher-like disease. Am J Hum Genet 75:251–260PubMedCrossRefGoogle Scholar
  6. 6.
    Woodward K, Kendall E, Vetrie D, Malcolm S (1998) Pelizaeus–Merzbacher disease: identification of Xq22 proteolipid-protein duplications and characterization of breakpoints by interphase FISH. Am J Hum Genet 63:207–217PubMedCrossRefGoogle Scholar
  7. 7.
    Wolf NI, Willemsen MA, Engelke UF, van der Knaap MS, Pouwels PJ, Harting I, Zschocke J, Sistermans EA, Rating D, Wevers RA (2004) Severe hypomyelination associated with increased levels of N-acetylaspartylglutamate in CSF. Neurology 62:1503–1508PubMedGoogle Scholar
  8. 8.
    Bugiani MD, Al Shawan S, Lamantea E, Bizzi A, Bakhsh E, Moroni I, Balestrini MR, Uziel G, Zeviani M (2006) GJA12 mutations in children with recessive hypomyelinating leukoencephalopathy. Neurology 67:273–279PubMedCrossRefGoogle Scholar
  9. 9.
    Plecko B, Stockler-Ipsiroglu S, Gruber S, Mlynarik V, Moser E, Simbrunner J, Ebner F, Bernert G, Harrer G, Gal A, Prayer D (2003) Degree of hypomyelination and magnetic resonance spectroscopy findings in patients with Pelizaeus Merzbacher phenotype. Neuropediatrics 34:127–136PubMedCrossRefGoogle Scholar
  10. 10.
    Hobson GM, Huang Z, Sperle K, Stabley DL, Marks HG, Cambi F (2002) A PLP splicing abnormality is associated with an unusual presentation of PMD. Ann Neurol 52:477–488PubMedCrossRefGoogle Scholar
  11. 11.
    Nezu A, Kimura S, Takeshita S, Osaka H, Kimura K, Inoue K (1998) An MRI and MRS study of Pelizaeus–Merzbacher disease. Pediatr Neurol 18:334–337PubMedCrossRefGoogle Scholar
  12. 12.
    Odermatt B, Wellershaus K, Wallraff A, Seifert G, Degen J, Euwens C, Fuss B, Bussow H, Schilling K, Steinhauser C, Willecke K (2003) Connexin 47 (Cx47)-deficient mice with enhanced green fluorescent protein reporter gene reveal predominant oligodendrocytic expression of Cx47 and display vacuolized myelin in the CNS. J Neurosci 23:4549–4559PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Nicole I. Wolf
    • 1
    • 2
  • Maria Cundall
    • 1
  • Paul Rutland
    • 1
  • Elisabeth Rosser
    • 1
  • Robert Surtees
    • 3
    • 4
  • Sarah Benton
    • 4
  • Wui K. Chong
    • 5
  • Sue Malcolm
    • 1
  • Friedrich Ebinger
    • 2
  • Maria Bitner-Glindzicz
    • 1
  • Karen J. Woodward
    • 1
    • 6
  1. 1.Clinical and Molecular Genetics UnitInstitute of Child HealthLondonUK
  2. 2.Department of Pediatric NeurologyUniversity Children’s Hospital HeidelbergHeidelbergGermany
  3. 3.Neurosciences UnitInstitute of Child HealthLondonUK
  4. 4.Pediatric NeurologyGreat Ormond Street Hospital for ChildrenLondonUK
  5. 5.RadiologyGreat Ormond Street Hospital for ChildrenLondonUK
  6. 6.Western Diagnostic PathologyPerthAustralia

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