PMC10436302_01
Clinical timeline depicting the disease progression of the patient from disease onset to mortality.
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F1
Then, rapid deterioration occurred, with increased spasticity and intense pain in the lower extremities, dysphagia, loss of ambulation, dystonic-like seizures, dysautonomia and encephalopathy, from which the patient succumbed within 2 months (Figure 1). This is predicted to cause a frameshift resulting in a truncated protein product (p.Glu121Valfs*4) (Supplementary Figure 1).
Brain MRIs at age 3 years and 10 months (A-D) and 3 years and 11 months (E-H) show a cavitating leukodystrophy with white matter abnormalities predominantly involving the posterior cerebral white matter and the splenium of the corpus callosum. Axial images show hypointense T1 (A,B,E,F) and hyperintense T2 (C,G) and FLAIR (D,H) parieto-occipital white matter. Numerous well-demarcated cysts are seen in the posterior white matter. Contrast imaging shows enhancement of the rim of cysts on the first MRI (B). FLAIR images show the white matter involvement, together with the numerous well-demarcated cysts (D,H). The follow-up MRI (E-H) shows mild improvement of the white matter abnormalities, less contrast enhancement and mild cerebral atrophy.
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F2
The brain MRI at presentation (Figures 2A-D) revealed a distinctive pattern of a bilateral symmetric cavitating leukodystrophy, predominantly involving the posterior cerebral white matter and splenium of the corpus callosum. MRI 2 weeks later (Figures 2E-H) showed improvement of the white matter lesions, as well as decreased contrast enhancement and diffusion restriction. Mild atrophy was noted.
Immunohistochemical investigations of the patient following autopsy. Macroscopic images depict prominent lesions in coronal sections at the level of the splenium (A) and left occipital lobe (B), including a magnified image of cavitations in the occipital white matter (arrow, B). Luxol staining of the occipital lobe (C-E) displays cavitation of the white matter (arrow, D) with surrounding well-circumscribed myelin loss (double-lined arrow, D). Diffuse myelin pallor is evident (arrowhead, D) as well as sparing of the ependyma (dashed arrow, D) and subcortical U-fibers (double-lined dashed arrow, D). Luxol PAS staining (F) and Luxol H&E staining (G) and magnified at 20x (H) in the frontal lobe reveal well-demarcated loss of myelin with rarefaction (arrow, F) and mild spongiosis (dashed arrow, F). Macrophages are evident within the rarefied region (arrow, G). H&E staining in the parietal lobe and splenium show cavitation in demyelinated areas (arrow, I), seen magnified at 10x (J). Immunohistochemical staining of the temporal lobe and hippocampus with GFAP (K), seen magnified at 20x (L) demonstrates reactive astrocytes near the demyelinated section. Staining of the frontal lobe with CD68 reveals macrophage invasion at the edge of the zones of more recent myelin loss (M), and seen magnified at 20x (N).
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F3
Neuropathological examination revealed prominent white matter abnormalities in the parietal and occipital lobes, including cystic lesions in the deep white matter (Figures 3A, B). Histological examination revealed widespread loss of myelin in the deep white matter of the cerebral hemispheres extending beyond the cystic changes noted on macroscopic examination (Figures 3C-J). Well demarcated lesions with cavitation were found in a serpiginous pattern throughout the parietal and occipital lobes, corresponding to the lesions noted on macroscopic examination (Figures 3C-E, I, J). Specifically, occipital sections showed clear cavitation of the white matter and diffuse myelin pallor with sparing of the ependyma (Figures 3C-E). White matter rarefaction was evident in the temporal lobe and hippocampus as well as in the frontal lobe, accompanied with mild spongiosis (Figures 3F-H). Immunostaining for CD68 revealed infiltration of macrophages at the edge of the zones of more recent demyelination (Figures 3M, N). GFAP staining of the temporal lobe showed preservation of astrocytes around blood vessels and reactive astrocytes at the edge of the demyelinated rarefied zone (Figures 3K, L).