Article Figures & Data
Figures
- Figure 1 Pedigree Drawing of the Family
Sex has been masked, and the number and order of siblings altered to protect participants' confidentiality. Black diamonds represent affected individuals, gray diamonds individuals not examined, and white diamonds clinically unaffected individuals. Diamonds with round circle denote uncertain status. A dot at the left inferior edge of a diamond means the individual was genetically analyzed. A diagonal line indicates that the individual is deceased. A total of 20 individuals were studied (II.1–3; III.3–7, 11, 17–20, 22–24; IV.1–3). Eight affected (II.3, III.4, 11, 17–20, 22), 2 unaffected (III.23 and 24), and 5 relatives with undetermined clinical status (III.6,7; IV.1, IV.3) were studied in person. Medical records were also retrieved from (II.1,2; III.3,16; and IV.2). DNA was obtained for 14 individuals and for 12 of them (III.4–7, 11, 17–20, 22–24) was analyzed in this study, whereas individuals IV.1 and IV.3 were not analyzed genetically because of their young age. Skin biopsies from 5 affected (III.11, 18–20, 22) and 1 unaffected individual (III.24) were examined. Sg = Sanger sequencing of the MAP3K6 c.322G>A p.(Asp108Asn) variant; Mut = the mutated variant is present; WES = whole-exome sequencing; WGS = whole-genome sequencing; Wt = wild type.
- Figure 2 Neuroimaging of 9 Affected Family Members
(A) WMHs in the deep and periventricular white matter and in the brain stem (mesencephalon or pons). Images are ordered according to age at examination. Individual III.18 was examined twice with an interval of 7 years; a clear increase in the number and size of lesions is visible. Planes that showed the most prominent changes are shown for each individual. On these images, lacunar infarcts are visible for individuals III.17 and III.20. Additional images are shown in table e1. (B) Mild calcifications in the globi pallidi were visible on MRI or CT of these 3 affected individuals. WMH = white matter hyperintensity.
- Figure 3 Pathology in Brain and Skin Vessels
(A–F) Photomicrographs of specimens from the neuropathologic examination of individual III.17. (A and B) Large arteries showed pronounced arteriosclerotic-like pathology with irregular multinodular intimal/subintimal proliferation. (C–F) Small vessels (approximately 0.2 mm diameter and below) showed moderate concentric thickening of the vessel wall with degenerative loosening and extravasation. (B and C) The elastica (dark violet) is irregular in thickness, at parts consisting of 2 layers. (D) Extravasated homogeneous fluid accumulation (non-filled arrowheads). (E) Concentric thickening of the walls of parenchymal arterioles, sometimes with double layers, and uneven intimal fibrosis. (F) Electron microscopy revealed increased vessel wall thickness, of both muscular and intimal layers. (G–I) Skin biopsies from affected members showed nodular subepidermal deposits (solid arrowheads) that in some fields were located immediately adjacent to arterioles (non-filled arrowheads). (I) Electron microscopy of a nodular deposit showing debris of degenerated elastica constituents (dark fragments).
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