Acta Neuropathologica

, Volume 111, Issue 4, pp 300–311

Hereditary diffuse leukoencephalopathy with spheroids: clinical, pathologic and genetic studies of a new kindred

  • Yasuhiko Baba
  • Bernardino Ghetti
  • Matthew C. Baker
  • Ryan J. Uitti
  • Michael L. Hutton
  • Keiji Yamaguchi
  • Thomas Bird
  • Wenlang Lin
  • Michael W. DeLucia
  • Dennis W. Dickson
  • Zbigniew K. Wszolek
Original Paper


Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare autosomal dominant disorder characterized by cerebral white matter degeneration with axonal spheroids leading to progressive cognitive and motor dysfunction. We report clinical and pathological features, as well as molecular genetic analysis, of a family with HDLS. A pedigree consisting of 27 persons in 5 generations contained 6 affected individuals. Dementia and depression were common; two individuals presented with a syndrome resembling corticobasal degeneration (CBD). Postmortem neuropathologic evaluation of three affected individuals revealed enlargement of the lateral ventricles and marked attenuation of cerebral white matter, but preservation of white matter in brainstem and cerebellum, except for the corticospinal tract. Histopathologic studies showed a loss of myelinated fibers, lipid-laden macrophages and bizarre astrocytes, as well as abundant axonal spheroids that were immunoreactive for phosphorylated neurofilament protein and amyloid precursor protein (APP), but not αB-crystallin and variably with ubiquitin. By electron microscopy, axonal spheroids contained aggregates of intermediate filaments or of organelles that were predominantly vesicular and lamellar. The cerebral cortex had focal neuronal degeneration with αB-crystallin-immunoreactive ballooned neurons. In summary, the present report describes a previously unreported kindred with HDLS with individuals presenting as CBD. Immunohistochemistry for APP and αB-crystallin demonstrates distinctive neurodegeneration in cerebral axons and perikarya.


Hereditary diffuse leukoencephalopathy with spheroids (HDLS) Parkinsonism Corticobasal degeneration Neurofilament Amyloid precursor protein 



Hereditary diffuse leukoencephalopathy with spheroids


Eukaryotic translation initiation factor 2B


Mini-Mental Status Examination


Hematoxylin and eosin


Luxol fast blue–periodic acid Schiff


Amyloid precursor protein


Glial fibrillary acidic protein


Polymerase chain reaction


Microtubule associated protein tau


Frontotemporal dementia and parkinsonism linked to chromosome


Corticobasal degeneration


Magnetic resonance imaging




Computed tomogram


  1. 1.
    Adolfsson R, Forsell A, Johansson G (1978) Hereditary polycystic osteodysplasia with progressive dementia in Sweden. Lancet 1:1209–1210CrossRefPubMedGoogle Scholar
  2. 2.
    Axelsson R, Roytta M, Sourander P, Akesson HO, Andersen O (1984) Hereditary diffuse leucoencephalopathy with spheroids. Acta Psychiatr Scand Suppl 314:1–65PubMedGoogle Scholar
  3. 3.
    Browne L, Sweeney BJ, Farrell MA (2003) Late-onset neuroaxonal leucoencephalopathy with spheroids and vascular amyloid. Eur Neurol 50:85–90CrossRefPubMedGoogle Scholar
  4. 4.
    Dickson DW, Bergeron C, Chin SS, Duyckaerts C, Horoupian D, Ikeda K, Jellinger K, Lantos PL, Lippa CF, Mirra SS, Tabaton M, Vonsattel JP, Wakabayashi K, Litvan I (2002) Office of rare diseases neuropathologic criteria for corticobasal degeneration. J Neuropathol Exp Neurol 61:935–946PubMedGoogle Scholar
  5. 5.
    Eldridge R, Anayiotos CP, Schlesinger S, Cowen D, Bever C, Patronas N, McFarland H (1984) Hereditary adult-onset leukodystrophy simulating chronic progressive multiple sclerosis. N Engl J Med 311:948–953PubMedGoogle Scholar
  6. 6.
    Goodman LE, Dickson DW (1995) Nonhereditary diffuse leukoencephalopathy with spheroids presenting as early-onset, rapidly progressive dementia [abstract]. J Neuropathol Exp Neurol 54:471CrossRefGoogle Scholar
  7. 7.
    Gwinn-Hardy K, Mehta ND, Farrer M, Maraganore D, Muenter M, Yen SH, Hardy J, Dickson DW (2000) Distinctive neuropathology revealed by α-synuclein antibodies in hereditary parkinsonism and dementia linked to chromosome 4p. Acta Neuropathol (Berl) 99:663–672CrossRefGoogle Scholar
  8. 8.
    Hancock N, Poon M, Taylor B, McLean C (2003) Hereditary diffuse leucoencephalopathy with spheroids. J Neurol Neurosurg Psychiatry 74:1345–1347PubMedCrossRefGoogle Scholar
  9. 9.
    Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, de Graaff E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Che LK, Norton J, Morris JC, Reed LA, Trojanowski J, Basun H, Lannfelt L, Neystat M, Fahn S, Dark F, Tannenberg T, Dodd PR, Hayward N, Kwok JB, Schofield PR, Andreadis A, Snowden J, Craufurd D, Neary D, Owen F, Oostra BA, Hardy J, Goate A, van Swieten J, Mann D, Lynch T, Heutink P (1998) Association of missense and 5’-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393:702–705PubMedCrossRefGoogle Scholar
  10. 10.
    Jellinger KA, Duda J (2003) Neuroaxonal dystrophies. In: Dickson DW (eds) Neurodegeneration: the molecular pathology of dementia and movement disorders. ISN Neuropath Press, Basel, pp 386–389Google Scholar
  11. 11.
    Kondo T, Takahashi K, Kohara N, Takahashi Y, Hayashi S, Takahashi H, Matsuo H, Yamazaki M, Inoue K, Miyamoto K, Yamamura T (2002) Heterogeneity of presenile dementia with bone cysts (Nasu–Hakola disease): three genetic forms. Neurology 59:1105–1107PubMedGoogle Scholar
  12. 12.
    Leegwater PA, Vermeulen G, Konst AA, Naidu S, Mulders J, Visser A, Kersbergen P, Mobach D, Fonds D, van Berkel CG, Lemmers RJ, Frants RR, Oudejans CB, Schutgens RB, Pronk JC, van der Knaap MS (2001) Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter. Nat Genet 29:383–388CrossRefPubMedGoogle Scholar
  13. 13.
    Litvan I, Bhatia KP, Burn DJ, Goetz CG, Lang AE, McKeith I, Quinn N, Sethi KD, Shults C, Wenning GK (2003) Movement disorders society scientific issues committee report: SIC task force appraisal of clinical diagnostic criteria for parkinsonian disorders. Mov Disord 18:467–486CrossRefPubMedGoogle Scholar
  14. 14.
    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 (Berl) 107:481–488CrossRefGoogle Scholar
  15. 15.
    Miyazu K, Kobayashi K, Fukutani Y, Nakamura I, Hasegawa H, Yamaguchi N, Saitoh T (1991) Membranous lipodystrophy (Nasu–Hakola disease) with thalamic degeneration: report of an autopsied case. Acta Neuropathol (Berl) 82:414–419CrossRefGoogle Scholar
  16. 16.
    Moser HW, Loes DJ, Melhem ER, Raymond GV, Bezman L, Cox CS, Lu SE (2000) X-linked adrenoleukodystrophy: overview and prognosis as a function of age and brain magnetic resonance imaging abnormality. A study involving 372 patients. Neuropediatrics 31:227–239CrossRefPubMedGoogle Scholar
  17. 17.
    Paloneva J, Autti T, Raininko R, Partanen J, Salonen O, Puranen M, Hakola P, Haltia M (2001) CNS manifestations of Nasu–Hakola disease: a frontal dementia with bone cysts. Neurology 56:1552–1558PubMedGoogle Scholar
  18. 18.
    Paloneva J, Kestila M, Wu J, Salminen A, Bohling T, Ruotsalainen V, Hakola P, Bakker AB, Phillips JH, Pekkarinen P, Lanier LL, Timonen T, Peltonen L (2000) Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts. Nat Genet 25:357–361CrossRefPubMedGoogle Scholar
  19. 19.
    Prass K, Bruck W, Schroder NW, Bender A, Prass M, Wolf T, Van der Knaap MS, Zschenderlein R (2001) Adult-onset leukoencephalopathy with vanishing white matter presenting with dementia. Ann Neurol 50:665–668CrossRefPubMedGoogle Scholar
  20. 20.
    Racette BA, Perry A, D’Avossa G, Perlmutter JS (2001) Late-onset neurodegeneration with brain iron accumulation type 1: expanding the clinical spectrum. Mov Disord 16:1148–1152CrossRefPubMedGoogle Scholar
  21. 21.
    Sabbadini G, Francia A, Calandriello L, Di Biasi C, Trasimeni G, Gualdi GF, Palladini G, Manfredi M, Frontali M (1995) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). Clinical, neuroimaging, pathological and genetic study of a large Italian family. Brain 118:207–215PubMedCrossRefGoogle Scholar
  22. 22.
    Terada S, Ishizu H, Yokota O, Ishihara T, Nakashima H, Kugo A, Tanaka Y, Nakashima T, Nakashima Y, Kuroda S (2004) An autopsy case of hereditary diffuse leukoencephalopathy with spheroids, clinically suspected of Alzheimer’s disease. Acta Neuropathol (Berl) 108:538–545CrossRefGoogle Scholar
  23. 23.
    van der Knaap MS, Kamphorst W, Barth PG, Kraaijeveld CL, Gut E, Valk J (1998) Phenotypic variation in leukoencephalopathy with vanishing white matter. Neurology 51:540–547PubMedGoogle Scholar
  24. 24.
    van der Knaap MS, Leegwater PA, Konst AA, Visser A, Naidu S, Oudejans CB, Schutgens RB, Pronk JC (2002) Mutations in each of the five subunits of translation initiation factor eIF2B can cause leukoencephalopathy with vanishing white matter. Ann Neurol 51:264–270CrossRefPubMedGoogle Scholar
  25. 25.
    van der Knaap MS, Naidu S, Kleinschmidt-Demasters BK, Kamphorst W, Weinstein HC (2000) Autosomal dominant diffuse leukoencephalopathy with neuroaxonal spheroids. Neurology 54:463–468PubMedGoogle Scholar
  26. 26.
    Waltz G, Harik SI, Kaufman B (1987) Adult metachromatic leukodystrophy. Value of computed tomographic scanning and magnetic resonance imaging of the brain. Arch Neurol 44:225–227PubMedGoogle Scholar
  27. 27.
    Wszolek ZK, Tsuboi Y, Farrer M, Uitti RJ, Hutton ML (2003) Hereditary tauopathies and parkinsonism. Adv Neurol 91:153–163PubMedGoogle Scholar
  28. 28.
    Yamashita M, Yamamoto T (2002) Neuroaxonal leukoencephalopathy with axonal spheroids. Eur Neurol 48:20–25CrossRefPubMedGoogle Scholar
  29. 29.
    Yazawa I, Nakano I, Yamada H, Oda M (1997) Long tract degeneration in familial sudanophilic leukodystrophy with prominent spheroids. J Neurol Sci 147:185–191CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Yasuhiko Baba
    • 1
  • Bernardino Ghetti
    • 4
  • Matthew C. Baker
    • 2
  • Ryan J. Uitti
    • 1
  • Michael L. Hutton
    • 2
  • Keiji Yamaguchi
    • 4
  • Thomas Bird
    • 5
    • 6
  • Wenlang Lin
    • 3
  • Michael W. DeLucia
    • 3
  • Dennis W. Dickson
    • 3
  • Zbigniew K. Wszolek
    • 1
  1. 1.Department of NeurologyMayo Clinic College of MedicineJacksonvilleUSA
  2. 2.Department of NeuroscienceMayo Clinic College of MedicineJacksonvilleUSA
  3. 3.Department of Pathology (Neuroscience)Mayo Clinic College of MedicineJacksonvilleUSA
  4. 4.Department of Pathology and Laboratory MedicineIndiana University School of MedicineIndianapolisUSA
  5. 5.Department of NeurologyUniversity of Washington School of MedicineSeattleUSA
  6. 6.Geriatric Research ServiceVeterans Affairs Medical CenterSeattleUSA

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