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
Axelsson R, Röyttä M, Sourander P et al (1984) Hereditary diffuse leucoencephalopathy with spheroids. Acta Psychiatr Scand Suppl 314:1–65
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
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
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
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
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
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
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
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
Mendes A, Pinto M, Vieira S et al (2010) Adult-onset leukodystrophy with axonal spheroids. J Neurol Sci 297(1–2):40–45
Moritani T, Smoker WRK, Sato Y et al (2005) Diffusion-weighted imaging of acute excitotoxic brain injury. Am J Neuroradiol 26:216–228
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)
Spillantini MG, Goedert M (2013) Tau pathology and neurodegeneration. Lancet Neurol 12(6):609–622
Delacourte A, Buée L (2000) Tau pathology: a marker of neurodegenerative disorders. Curr Opin Neurol;13(4):371–376 (Review)
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
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
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
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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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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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DOI: https://doi.org/10.1007/s00415-014-7257-3