Advertisement

Biopsy histopathology in the diagnosis of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP)

  • Chenhui Mao
  • Liangrui Zhou
  • Lixin Zhou
  • Yingmai Yang
  • Jingwen Niu
  • Jie Li
  • Xinying Huang
  • Haitao Ren
  • Yanhuan Zhao
  • Bin Peng
  • Jing GaoEmail author
Original Article
  • 4 Downloads

Abstract

Aim

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is an inherited rare disease affecting young adults. We present the clinical, imaging, and neuropathological results of our case series, emphasizing biopsy histology combined with clinical information will increase the accuracy of early diagnosis.

Methods

In total, 4 females and 2 male ALSP patients with onset at ages 24–45 years were enrolled. Clinical manifestations, neuroimaging, and histopathology as well as gene mutation were analyzed and compared with literature.

Results

Clinical manifestations include cognitive decline with/without psycho-behavior problems and movement disorders including paralysis, hemiplegia, parkinsonism, and pyramidal tract injury, as well as dysarthria, dysphagia, and sensory disturbances. MRI showed multiple periventricular and subcortical white matter lesions, involving the corpus callosum, with no enhancement, but with persistent hyperintensity on diffuse-weighted imaging. Histology showed widespread white matter damage and pale stain, especially destroyed axons with spheroids and funicular axons which were stained with neurofilament and ubiquitin. Foamy and pigmented macrophages were another typical change. CSF1R mutation was found in 4 of them. All of the patients were misdiagnosed and treated for a long time for multiple sclerosis, cerebral infarction, normal pressure hydrocephalus, etc.

Conclusion

ALSP will cause rapidly progressing dementia with/without movement disorders in young adults. The definite diagnosis should be based on a comprehensive analysis of clinical manifestations, and neuroimaging, histology, and genetic results. Early biopsy will add to the accuracy of the diagnosis.

Keywords

ALSP Biopsy White matter disease Axon spheroids Funicular axons 

Notes

Funding information

This work was supported by Chinese Academy of Medical Sciences Innovation fund for medical sciences (2016-I2M-1-004), National Natural Science Foundation of China (81550021), 13th Five year National Key Research and Development Program of China (2016YFC1306300), and the strategic priority research program (Pilot study) “Biological Basis of Aging and Therapeutic Strategies” of the Chinese Academy of Sciences (grant XDPB10).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (PUMC ethics committee 2017006) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Nicholson AM, Baker AM, Finch NA, Rutherford NJ, Wider C, Graff-Radford NR et al (2013) CSF1R mutations link POLD and HDLS as a single disease entity. Neurology 80:1033–1040CrossRefGoogle Scholar
  2. 2.
    Marotti JD, Tobias S, Fratkin JD, Powers JM, Rhodes CH (2004) Adult onset leukodystrophy with neuroaxonal spheroids and pigmented glia: report of a family, historical perspective, and review of the literature. Acta Neuropathol 107:481–488CrossRefGoogle Scholar
  3. 3.
    Terada S, Ishizu H, Yokota O, Ishihara T, Nakashima H, Kugo A et al (2004) An autopsy case of hereditary diffuse leukoencephalopathy with spheroids, clinically suspected of Alzheimer’s disease. Acta Neuropathol 108:538–545CrossRefGoogle Scholar
  4. 4.
    Wider C, Van Gerpen JA, DeArmond S, Shuster EA, Dickson DW, Wszolek ZK (2009) Leukoencephalopathy with spheroids (HDLS) and pigmentary leukodystrophy (POLD): a single entity? Neurology 72:1953–1959CrossRefGoogle Scholar
  5. 5.
    Wong JC, Chow TW, Hazrati LN (2011) Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia can present as frontotemporal dementia syndrome. Dement Geriatr Cogn Disord 32:150–158CrossRefGoogle Scholar
  6. 6.
    Maillart E, Rousseau A, Galanaud D, Gray F, Polivka M, Labauge P, Hauw JJ, Lyon-Caen O, Gout O, Sedel F (2009) Rapid onset frontal leukodystrophy with decreased diffusion coefficient and neuroaxonal spheroids. J Neurol 256:1649–1654CrossRefGoogle Scholar
  7. 7.
    Lynch DS, Zhang WJ, Lakshmanan R, Kinsella JA, Uzun GA, Karbay M, Tüfekçioglu Z, Hanagasi H, Burke G, Foulds N, Hammans SR, Bhattacharjee A, Wilson H, Adams M, Walker M, Nicoll JA, Chataway J, Fox N, Davagnanam I, Phadke R, Houlden H (2016) Analysis of mutations in AARS2 in a series of CSF1R-negative patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. JAMA Neurol 73:1433–1439CrossRefGoogle Scholar
  8. 8.
    Freeman SH, Hyman BT, Sims KB, Hedley-Whyte ET, Vossough A, Frosch MP et al (2009) Adult onset leukodystrophy with neuroaxonal spheroids: clinical, neuroimaging and neuropathologic observations. Brain Pathol 19:39–47CrossRefGoogle Scholar
  9. 9.
    Mendes A, Pinto M, Vieira S et al (2010) Adult-onset leukodystrophy with axonal spheroids. J Neurol Sci 297:40–45CrossRefGoogle Scholar
  10. 10.
    Kleinfeld K, Mobley B, Hedera P, Wegner A, Sriram S, Pawate S (2013) Adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia: report of five cases and a new mutation. J Neurol 260:558–571CrossRefGoogle Scholar
  11. 11.
    Kim E-J, Shin J-H, Lee JH et al (2015) Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia linked CSF1R mutation: report of four Korean cases. J Neurol Sci 349:232–238CrossRefGoogle Scholar
  12. 12.
    Konno T, Yoshida K, Mizuta I, Mizuno T, Kawarai T, Tada M, Nozaki H, Ikeda SI, Onodera O, Wszolek ZK, Ikeuchi T (2018) Diagnostic criteria for adult-onset leukoencephalopathy with axonal spheroids and pigmented glia due to CSF1R mutation. Eur J Neurol 25:142–147CrossRefGoogle Scholar
  13. 13.
    Martinez-Saez E, Shah S, Costa C, Fleminger S, Connor S, Bodi I (2012) Adult onset leukodystrophy with neuroaxonal spheroids and demyelinating plaque-like lesions. Neuropathology 32:285–292CrossRefGoogle Scholar
  14. 14.
    Keegan BM, Giannini C, Parisi JE, Lucchinetti CF, Boeve BF, Josephs KA (2008) Sporadic adult-onset leukoencephalopathy with neuroaxonal spheroids mimicking cerebral MS. Neurology 70:1128–1133CrossRefGoogle Scholar
  15. 15.
    Ikeuchi T, Mezaki N, Miura T et al (2018) Cognitive dysfunction and symptoms of movement disorders in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. Parkinsonism Relat Disord 46:S39–S41CrossRefGoogle Scholar
  16. 16.
    Sundal C, Fujioka S, Van Gerpen JA et al (2013) Parkinsonian features in hereditary diffuse leukoencephalopathy with spheroids (HDLS) and CSF1R mutations. Parkinsonism Relat Disord 19:869–877CrossRefGoogle Scholar
  17. 17.
    Lynch DS, Jaunmuktane Z, Sheerin U-M et al (2016) Hereditary leukoencephalopathy with axonal spheroids: a spectrum of phenotypes from CNS vasculitis to parkinsonism in an adult onset leukodystrophy series. J Neurol Neurosurg Psychiatry 87:512–519CrossRefGoogle Scholar
  18. 18.
    Itoh K, Shiga K, Shimizu K, Muranishi M, Nakagawa M, Fushiki S (2006) Autosomal dominant leukodystrophy with axonal spheroids and pigmented glia: clinical and neuropathological characteristics. Acta Neuropathol 111:39–45CrossRefGoogle Scholar
  19. 19.
    Hoffmann S, Murrell J, Harms L, Miller K, Meisel A, Brosch T, Scheel M, Ghetti B, Goebel HH, Stenzel W (2014) Enlarging the nosological spectrum of hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS). Brain Pathol 24:452–458CrossRefGoogle Scholar
  20. 20.
    Riku Y, Ando T, Goto Y, Mano K, Iwasaki Y, Sobue G, Yoshida M (2014) Early pathologic changes in hereditary diffuse leukoencephalopathy with spheroids. J Neuropathol Exp Neurol 73:1183–1190CrossRefGoogle Scholar
  21. 21.
    Oyanagi K, Kinoshita M, Suzuki-Kouyamal E et al (2017) Adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and Nasu–Hakola disease: lesion staging and dynamic changes of axons and microglial subsets. Brain Pathol 27:748–769CrossRefGoogle Scholar
  22. 22.
    Konno T, Yoshida K, Mizuno T, Kawarai T, Tada M, Nozaki H, Ikeda SI, Nishizawa M, Onodera O, Wszolek ZK, Ikeuchi T (2017) Clinical and genetic characterization of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia associated with CSF1R mutation. Eur J Neurol 24:37–45CrossRefGoogle Scholar
  23. 23.
    Lakshmanan R, Adams ME, Lynch DS et al (2017) Redefining the phenotype of ALSP and AARS2 mutation–related leukodystrophy. Neurol Genet 3:e135CrossRefGoogle Scholar
  24. 24.
    Wang D, Yu M, Zhang W et al (2018) AARS2 compound heterozygous variants in a case of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. J Neuropathol Exp Neurol 77:997–1000CrossRefGoogle Scholar

Copyright information

© Fondazione Società Italiana di Neurologia 2019

Authors and Affiliations

  1. 1.Department of Neurology, Peking Union Medical College HospitalChinese Academy of Medical Science/Peking Union Medical CollegeBeijingChina
  2. 2.Department of Pathology, Peking Union Medical College HospitalChinese Academy of Medical Science/Peking Union Medical CollegeBeijingChina

Personalised recommendations