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. 2017 Aug 29;26(22):4506–4518. doi: 10.1093/hmg/ddx338

Figure 2.

Figure 2.

Neuropathology of TUBB4A-related diseases. Images in the top left box are D249N mutation pathology figures and images in the top right box are N414K mutation pathology figures. (A) In classical H-ABC (D249N mutation), the cerebellar cortex is severely atrophic with massive loss of granular neurons; stain against neurofilaments (NF) (B) shows swelling of Purkinje cell dendrites and axons (asterix). (C) In early onset encephalopathy (N414K mutation), the cerebellum also shows severe cortical atrophy with enlargement of the sulci and thinning of the granular layer; stain against NF (D) shows swellings of Purkinje cell axons and dendrites (asterix). (E) On macroscopic examination of a classical H-ABC brain, the putamen and, to a lesser degree, the caudate nucleus is not recognizable (arrows) on this coronal brain slice cut at the level of the anterior hippocampus. (F) This corresponds microscopically with loss of striatal neurons. Note also the small perivascular calcification (arrow). (G) In the individual with the severe combined phenotype, the putamen and caudate nucleus are preserved (arrows), and (H) there is no loss of striatal neurons. (I–L) Microscopic examination of the cerebral white matter reveals lack of oligodendrocytes (dark round nuclei) (I) and presence of axonal swelling and spheroids (I, J; arrow in J) in classical H-ABC, whereas the number of oligodendrocytes is increased in the severe combined phenotype (K) and no spheroids are present (L). Note the white matter neuron normally expressing NF. (M–P) In both H-ABC (M,N) and the severe combined phenotype (R,S), the white matter also shows strong activation of rod-shaped microglia (O,P) with accruing of some plump macrophages in the perivascular spaces (bv) (P) and moderate isomorphic reactive astrogliosis with scattered hypertrophic cells in the parenchyma and around blood vessels (N,P). The bottom box has immunohistochemical stain against the major myelin protein proteolipid protein (PLP) from D249N (Q), control (R), and N414K (S) brain slices. (R) PLP staining in frontal lobe of normal brain. (Q,S) Images show severe lack of myelin in the frontal lobe in classical H-ABC (Q) and an even more profound lack in the severe combined phenotype (S).