Article Figures & Data
Figures
- Figure 1 Diagnostic Process Diagram and Diagnostic Yield
(A) Number of cases included in the study and diagnostic process. (B) Global, whole-exome sequencing (WES), and whole-genome sequencing (WGS) diagnostic yield. (C) Percentage of diagnosis in the first WES analysis, obtained by WES reanalysis and by WGS. (D) Diagnostic percentage according to age.
- Figure 2 MRI Findings in Patients With New/Atypical and Blended Phenotypes
(A) LNF-48, 5 years. PARS2; p.Arg186Gly/p.Lys187Arg (COMP HTZ). Periatrial white matter (WM) hyperintensity (red arrows) with frontal-parietal atrophy, ventriculomegaly, and thin corpus callosum (arrowheads) (axial T2 fluid-attenuated inversion recovery [FLAIR], sagittal T1-weighted images). (B) LNF-29, 10 months. PNPT1; p.Ala507Ser (HMZ). Bilateral periatrial and temporal anterior subcortical WM hyperintensities (red arrows) with temporal cystic lesions (arrowheads) (axial T2 and coronal T2 FLAIR-weighted images). (C) LNF-47, 2 years. POLR3A; c.1771-7C > G/p.Leu1129 (COMP HTZ). Optic radiation mild WM hyperintensity (red arrows), striatal atrophy and hyperintensity (arrowheads), and superior cerebellar peduncles hyperintense signal (asterisks) (axial T2 images). (D) LNF-85, 48 years. PSEN1; p.Thr350Ile (HTZ). MRI showed diffuse WM hyperintensities (red arrows) with corpus callosum and cortical atrophy (arrowheads) (axial T2 and sagittal T1 FLAIR images). (E) LNF-88, 13 years. GFPT1; p.Asp296Val (HMZ). Axial T2 hyperintensities involving deep cerebral WM (red arrows), cerebellar peduncles (white arrows), and middle blade of corpus callosum (arrowheads), sparing subcortical WM (axial T2 and sagittal T1-weighted images). (F) LNF-114, 5 months. SCN8A; p.Val409Met (HTZ). Important myelination delay, thin corpus callosum and signs of cerebral and cerebellar atrophy (axial and sagittal T1-weighted images). (G) SPG-25, 44 years. SOX10; p.Tyr83Asp (HTZ). Periventricular WM signal abnormality, sparing U fibers (red arrows), and thin isthmus of the corpus callosum (arrowhead) (axial T2-FLAIR and sagittal T1 weighted images). (H) LNF-40.0, 13 years. CYP2U1; p.Arg178Thr (HMZ) and LNF-40.4, 15 years. PAH; p.Thr380Met (HMZ). Periventricular WM hyperintensities (red arrows) (axial T2 weighted images). (I) LNF-56, 15 years. POLR3A; p.Cys724Tyr/p.Pro705Ala (COMP HTZ) and CACNA1A; p.Tyr546Ter (HTZ). Periventricular symmetric heterogeneous WM hyperintensities (red arrows) and hypointensity in globus pallidus (arrowheads), thalamic anterolateral nuclei (asterisks), optic radiations, and pyramidal tracts, with mild atrophy of the cerebellar superior vermis (white arrow) (axial T2 and sagittal T1-weighted images). (J) LNF-89.3, 15 years. CP; p.Gly868GlufsTer26 (HMZ)/NDUFS1; p.Ser701Asn (HTZ). Periventricular symmetric T2 hyperintensity with cystic degeneration and pyramidal tract involvement (red arrows) and corpus callosum atrophy. Accumulation of paramagnetic material in the substantia nigra (asterisks) (axial T2-FLAIR and axial susceptibility-weighted imaging).
- Figure 3 MRI of Selected Cases With Variants in Hereditary Spastic Paraparesis Genes and White Matter Involvement
T2 hyperintensity in the bilateral periventricular white matter. (A, D) Axial T2 images. (B, C) Axial T2 fluid-attenuated inversion recovery images.
- Figure 4 GWMD Expanded Interactome
(A) The genetic white matter disorder (GWMD) seeds + expanded network was generated by the network prioritization tool, resulting in 1,530 proteins. The seed genes known to be mutated in GWMD are shown in yellow circles, disease genes not previously associated with GWMD are shown in green, and new GWMD candidates are shown in blue. Comparison of statistical connectivity strength of the GWMD expanded network with 1,000 permutations of randomly selected proteins from the global human network. Red dots denote the value of the metric on the GWMD expanded network constituted by 1,530 proteins. Box and whisker plots denote matched null distributions (i.e., 1,000 permutations). (D, left) Within-group edge count (i.e., number of edges between members of the query set). (D, right) distance is the average path length in the network obtained by calculating the shortest paths between all pairs of proteins. (B–E) Zoom in the network for specific putative candidates as illustrative example of the GWMD expanded network potentiality. (B) Delta 4-desaturase, sphingolipid 1 (DEGS1); (C) phosphatidylinositol 4-kinase alpha (PI4KA); (D) mitochondrial ribosome-associated GTPase 1 (MTG1); and (E) potassium voltage-gated channel subfamily A regulatory beta subunit 2 (KCNAB2) protein. *Recently associated with leukodystrophy. White matter expanded network available in NDEx repository at public.ndexbio.org/#/network/fd5fc166-9ecc-11eb-9e72-0ac135e8bacf?accesskey=a75ac048b59aca2c9310c04a6f1d96ea34052231d9204f284c5e1d420fc2ca26
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