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

Department of Neurology, Mayo Clinic College of Medicine, Jacksonville, FL, USA.
Acta Neuropathologica (Impact Factor: 10.76). 05/2006; 111(4):300-11. DOI: 10.1007/s00401-006-0046-z
Source: PubMed


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 alphaB-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 alphaB-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 alphaB-crystallin demonstrates distinctive neurodegeneration in cerebral axons and perikarya.

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    • "For instance, hereditary diffuse leukoencephalopathy with spheroids (HDLS) is associated with variable behavioral, cognitive, and motor dysfunction (Rademakers et al., 2011). Clinically, it is difficult to diagnose because it often presents with intra-familial heterogeneity and a firm diagnosis often occurs post-mortem (Baba et al., 2006). Pelizaeus–Merzbacher disease (PMD) is an X-linked hypomyelinating leukodystrophy, manifested as impaired motor development followed by ataxia, dystonia, dysarthria, and progressive spasticity (Vaurs-Barriere et al., 2009). "
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