Hereditary diffuse leukoencephalopathy with axonal spheroids: three patients with stroke-like presentation carrying new mutations in the CSF1R gene

Abstract

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is an autosomal dominant disorder characterized by white matter neurodegeneration, progressive cognitive decline, and motor symptoms. Histologically, it is characterized by axonal swellings (“spheroids”). To date, over 20 different mutations affecting the tyrosine kinase domain of the protein have been identified in the colony stimulating factor 1 receptor (CSF1R) gene. Our goal is to describe three unrelated Italian patients affected by HDLS and carrying new CSF1R mutations, thus expanding the mutational spectrum and phenotypic presentation. CSF1R gene analysis was performed in 15 patients (age range 25–83 years) with undefined leukoencephalopathy and progressive cognitive decline. In three patients (two males and one female, aged 58, 37, and 48 years, respectively), new heterozygous missense mutations affecting the protein tyrosine kinase domain of the CSF1R gene were detected. In all of these patients, behavioural and cognitive changes were preceded by an ischemic stroke-like episode. A positive family history was present in only one case.

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References

  1. 1.

    Axelsson R, Röyttä M, Sourander P et al (1984) Hereditary diffuse leucoencephalopathy with spheroids. Acta Psychiatr Scand Suppl 314:1–65

    CAS  PubMed  Google Scholar 

  2. 2.

    Freeman SH, Hyman BT, Sims KB et al (2009) Adult onset leukodystrophy with neuroaxonal spheroids: clinical, neuroimaging and neuropathologic observations. Brain Pathol 19(1):39–47

    PubMed Central  Article  PubMed  Google Scholar 

  3. 3.

    Itoh K, Shiga K, Shimizu K et al (2006) Autosomal dominant leukodystrophy with axonal spheroids and pigmented glia: clinical and neuropathological characteristics. Acta Neuropathol 111(1):39–45

    Article  PubMed  Google Scholar 

  4. 4.

    Rademakers R, Baker M, Nicholson AM et al (2011) Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat Genet 44:200–205

    PubMed Central  Article  PubMed  Google Scholar 

  5. 5.

    Kinoshita M, Yoshida K, Oyanagi K et al (2012) Hereditary diffuse leukoencephalopathy with axonal spheroids caused by R782H mutation in CSF1R: case report. J Neurol Sci 318:115–118

    Article  PubMed  Google Scholar 

  6. 6.

    Kleinfeld K, Mobley B, Hedera P et al (2013) Adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia: report of five cases and a new mutation. J Neurol 260:558–571

    Article  PubMed  Google Scholar 

  7. 7.

    Mitsui J, Matsukawa T, Ishiura H et al (2012) CSF1R mutations identified in three families with autosomal dominantly inherited leukoencephalopathy. Am J Med Genet B Neuropsychiatr Genet 159B(8):951–957

    Article  PubMed  Google Scholar 

  8. 8.

    Guerreiro R, Kara E, Le Ber I et al (2013) Genetic analysis of inherited leukodystrophies: genotype-phenotype correlations in the CSF1R gene. JAMA Neurol 70(7):875–882

    PubMed Central  Article  PubMed  Google Scholar 

  9. 9.

    Keegan BM, Giannini C, Parisi JE et al (2008) Sporadic adult-onset leukoencephalopathy with neuroaxonal spheroids mimicking cerebral MS. Neurology 70 (13 Part 2):1128–1133

    Article  Google Scholar 

  10. 10.

    Mendes A, Pinto M, Vieira S et al (2010) Adult-onset leukodystrophy with axonal spheroids. J Neurol Sci 297(1–2):40–45

    Article  PubMed  Google Scholar 

  11. 11.

    Moritani T, Smoker WRK, Sato Y et al (2005) Diffusion-weighted imaging of acute excitotoxic brain injury. Am J Neuroradiol 26:216–228

    PubMed  Google Scholar 

  12. 12.

    Kimura T, Ishizawa K, Mitsufuji T et al (2013) A clinicopathological and genetic study of sporadic diffuse leukoencephalopathy with spheroids: a report of two cases. Neuropathol Appl Neurobiol (Epub ahead of print)

  13. 13.

    Spillantini MG, Goedert M (2013) Tau pathology and neurodegeneration. Lancet Neurol 12(6):609–622

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Delacourte A, Buée L (2000) Tau pathology: a marker of neurodegenerative disorders. Curr Opin Neurol;13(4):371–376 (Review)

    Google Scholar 

  15. 15.

    Levin N, Soffer D, Biran I et al (2008) Leukoencephalopathy with neuroaxonal spheroids presenting as frontotemporal dementia. Isr Med Assoc J 10(5):386–387

    PubMed  Google Scholar 

  16. 16.

    Saitoh BY, Yamasaki R, Hayashi S et al (2013) A case of hereditary diffuse leukoencephalopathy with axonal spheroids caused by a de novo mutation in CSF1R masquerading as primary progressive multiple sclerosis. Mult Scler 19(10):1367–1370

    Article  PubMed  Google Scholar 

  17. 17.

    Sundal C, Lash J, Aasly J et al (2012) Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS): a misdiagnosed disease entity. J Neurol Sci 314(1–2):130–137

    PubMed Central  Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by a grant from MIUR (Ministero dell’Istruzione, dell’Università e della Ricerca), programmi di ricerca cofinanziati-2009 (MIUR 2009-prot. 20095JPSNA) to MTD.

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The authors declare that they have no conflict of interest.

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Correspondence to Antonio Federico.

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C. Battisti and I. Di Donato have contributed equally.

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Battisti, C., Di Donato, I., Bianchi, S. et al. Hereditary diffuse leukoencephalopathy with axonal spheroids: three patients with stroke-like presentation carrying new mutations in the CSF1R gene. J Neurol 261, 768–772 (2014). https://doi.org/10.1007/s00415-014-7257-3

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Keywords

  • HDLS
  • CSF1R
  • Presenile dementia
  • Axonal spheroids
  • Leukoencephalopathy