Acta Neuropathologica

, Volume 122, Issue 6, pp 775–781 | Cite as

An autopsy case of adult-onset hereditary spastic paraplegia type 2 with a novel mutation in exon 7 of the proteolipid protein 1 gene

  • Satoshi O. Suzuki
  • Toru Iwaki
  • Kenji Arakawa
  • Hirokazu Furuya
  • Naoki Fujii
  • Akiko Iwaki
Case Report

Abstract

We report an autopsy case of rare adult-onset spastic paraplegia type 2 (SPG2) with a novel missense mutation in exon 7 of the proteolipid protein 1 gene (PLP1). The patient was a 67-year-old man whose elder brother had died of a similar disease with onset in his 40s. Thirty-three years before death at the age of 35, he noticed difficulty in walking. He gradually became abasic over a period of 6 years. He also developed progressive dementia and eventually became bed-ridden by 28 years after onset. At autopsy, gross inspection revealed diffuse, moderate atrophy of the cerebrum with a dilated ventricular system and softening of the white matter throughout the central nervous system (CNS). Histopathologically, the CNS showed widespread myelin pallor in the white matter. By contrast, the gray matter and peripheral nerves were well preserved. Some white matter tracts, including the corticospinal tracts, were preferentially affected, and severe axonal degeneration was observed in these tracts. Genetic analysis revealed a novel mutation, p.Tyr263Cys, in exon 7 of PLP1. This case represents an adult-onset SPG2 patient with one of the oldest ages of onset reported to date. The late onset and long clinical course suggest that this novel mutation does not affect the maturation of oligodendrocytes, but is related to insufficient maintenance of myelin.

Keywords

Proteolipid protein 1 Gene mutation Hereditary spastic paraplegia SPG2 Adult onset 

Notes

Acknowledgments

This work was supported in part by a Health and Labour Sciences Research Grant from the Ministry of Health, Labour and Welfare of Japan (A.I.). The authors thank Ms. Sachiko Koyama (Dept. of Neuropathology, Kyushu University) for her excellent technical support.

References

  1. 1.
    Cailloux F, Gauthier-Barichard F, Mimault C et al (2000) Genotype-phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations. Clinical European network on brain dysmyelinating disease. Eur J Hum Genet 8:837–845PubMedCrossRefGoogle Scholar
  2. 2.
    Fink JK, Heiman-Patterson T, Bird T et al (1996) Hereditary spastic paraplegia: advances in genetic research. Hereditary Spastic Paraplegia Working group. Neurology 46:1507–1514PubMedGoogle Scholar
  3. 3.
    Garbern JY (2007) Pelizaeus-Merzbacher disease: genetic and cellular pathogenesis. Cell Mol Life Sci 64:50–65PubMedCrossRefGoogle Scholar
  4. 4.
    Garbern JY, Yool DA, Moore GJ et al (2002) Patients lacking the major CNS myelin protein, proteolipid protein 1, develop length-dependent axonal degeneration in the absence of demyelination and inflammation. Brain 125:551–561PubMedCrossRefGoogle Scholar
  5. 5.
    Gow A, Friedrich VL Jr, Lazzarini RA (1994) Many naturally occurring mutations of myelin proteolipid protein impair its intracellular transport. J Neurosci Res 37:574–583PubMedCrossRefGoogle Scholar
  6. 6.
    Gow A, Lazzarini RA (1996) A cellular mechanism governing the severity of Pelizaeus–Merzbacher disease. Nat Genet 13:422–428PubMedCrossRefGoogle Scholar
  7. 7.
    Gow A, Sharma R (2003) The unfolded protein response in protein aggregating diseases. Neuromol Med 4:73–94CrossRefGoogle Scholar
  8. 8.
    Griffiths I, Klugmann M, Anderson T et al (1998) Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science 280:1610–1613PubMedCrossRefGoogle Scholar
  9. 9.
    Grossi S, Regis S, Biancheri R et al (2011) Molecular genetic analysis of the PLP1 Gene in 38 families with PLP1-related disorders: identification and functional characterization of 11 Novel PLP1 mutations. Orphanet J Rare Dis 6:40PubMedCrossRefGoogle Scholar
  10. 10.
    Hodes ME, Blank CA, Pratt VM, Morales J, Napier J, Dlouhy SR (1997) Nonsense mutation in exon 3 of the proteolipid protein gene (PLP) in a family with an unusual form of Pelizaeus–Merzbacher disease. Am J Med Genet 69:121–125PubMedCrossRefGoogle Scholar
  11. 11.
    Hodes ME, Zimmerman AW, Aydanian A et al (1999) Different mutations in the same codon of the proteolipid protein gene, PLP, may help in correlating genotype with phenotype in Pelizaeus–Merzbacher disease/X-linked spastic paraplegia (PMD/SPG2). Am J Med Genet 82:132–139PubMedCrossRefGoogle Scholar
  12. 12.
    Hudson LD, Berndt JA, Puckett C, Kozak CA, Lazzarini RA (1987) Aberrant splicing of proteolipid protein mRNA in the dysmyelinating jimpy mutant mouse. Proc Natl Acad Sci USA 84:1454–1458PubMedCrossRefGoogle Scholar
  13. 13.
    Hudson LD, Friedrich VL Jr, Behar T, Dubois-Dalcq M, Lazzarini RA (1989) The initial events in myelin synthesis: orientation of proteolipid protein in the plasma membrane of cultured oligodendrocytes. J Cell Biol 109:717–727PubMedCrossRefGoogle Scholar
  14. 14.
    Inoue K (2005) PLP1-related inherited dysmyelinating disorders: Pelizaeus–Merzbacher disease and spastic paraplegia type 2. Neurogenetics 6:1–16PubMedCrossRefGoogle Scholar
  15. 15.
    Iwaki A, Muramoto T, Iwaki I et al (1993) A missense mutation in the proteolipid protein gene responsible for Pelizaeus–Merzbacher disease in a Japanese family. Hum Mol Genet 2:19–22PubMedCrossRefGoogle Scholar
  16. 16.
    Kobayashi H, Hoffman EP, Marks HG (1994) The rumpshaker mutation in spastic paraplegia. Nat Genet 7:351–352PubMedCrossRefGoogle Scholar
  17. 17.
    Kurosawa K, Iwaki A, Miyake S, Imaizumi K, Kuroki Y, Fukumaki Y (1993) A novel insertional mutation at exon VII of the myelin proteolipid protein gene in Pelizaeus–Merzbacher disease. Hum Mol Genet 2:2187–2189PubMedCrossRefGoogle Scholar
  18. 18.
    Lee ES, Moon HK, Park YH, Garbern J, Hobson GM (2004) A case of complicated spastic paraplegia 2 due to a point mutation in the proteolipid protein 1 gene. J Neurol Sci 224:83–87PubMedCrossRefGoogle Scholar
  19. 19.
    Osaka H, Koizume S, Aoyama H et al (2010) Mild phenotype in Pelizaeus–Merzbacher disease caused by a PLP1-specific mutation. Brain Dev 32:703–707PubMedCrossRefGoogle Scholar
  20. 20.
    Saugier-Veber P, Munnich A, Bonneau D et al (1994) X-linked spastic paraplegia and Pelizaeus–Merzbacher disease are allelic disorders at the proteolipid protein locus. Nat Genet 6:257–262PubMedCrossRefGoogle Scholar
  21. 21.
    Sima AA, Pierson CR, Woltjer RL et al (2009) Neuronal loss in Pelizaeus–Merzbacher disease differs in various mutations of the proteolipid protein 1. Acta Neuropathol 118:531–539PubMedCrossRefGoogle Scholar
  22. 22.
    Sivakumar K, Sambuughin N, Selenge B et al (1999) Novel exon 3B proteolipid protein gene mutation causing late–onset spastic paraplegia type 2 with variable penetrance in female family members. Ann Neurol 45:680–683PubMedCrossRefGoogle Scholar
  23. 23.
    Southwood CM, Garbern J, Jiang W, Gow A (2002) The unfolded protein response modulates disease severity in Pelizaeus–Merzbacher disease. Neuron 36:585–596PubMedCrossRefGoogle Scholar
  24. 24.
    Thomson CE, Montague P, Jung M, Nave KA, Griffiths IR (1997) Phenotypic severity of murine Plp mutants reflects in vivo and in vitro variations in transport of PLP isoproteins. Glia 20:322–332PubMedCrossRefGoogle Scholar
  25. 25.
    Woodward KJ (2008) The molecular and cellular defects underlying Pelizaeus–Merzbacher disease. Expert Rev Mol Med 10:e14PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Satoshi O. Suzuki
    • 1
  • Toru Iwaki
    • 1
  • Kenji Arakawa
    • 2
  • Hirokazu Furuya
    • 2
  • Naoki Fujii
    • 2
  • Akiko Iwaki
    • 3
  1. 1.Department of Neuropathology, Graduate School of Medical SciencesKyushu UniversityFukuokaJapan
  2. 2.Department of Neurology, Neuro-Muscular CenterNational Ohmuta HospitalFukuokaJapan
  3. 3.Division of Human Molecular Genetics, Research Center for Genetic Information, Medical Institute of BioregulationKyushu UniversityFukuokaJapan

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