PMC9978770_01
Magnetic resonance imaging. (A) T1-weighted image 2 months after the onset of the disease shows extensive cortical atrophy. (B) T1-weighted image 12 months after the onset of the disease reveals severe cortical atrophy, and the degree of atrophy gradually increased compared to A. (C) T1-weighted image 4 months after the onset of the disease demonstrates that the midbrain volume was comparatively well preserved compared with cortical atrophy.
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F1
Babinski signs bilaterally. Brain magnetic resonance imaging showed extensive cortical atrophy (Figure 1). Table 1. As shown in Supplementary Figure S1, they came from China (32.35%, 22/68), Brazil (19.12%, 13/68), Korea (19.12%, 13/68), multicenter (including the United States, the UK, Italy, Spain, Germany, Ireland, Canada, the Netherlands, Belgium, and New Zealand, 17.65%, 12/68), and France (11.76%, 8/68). According to the previously reported cases, most (80.88%, 55/68) of the ANXA11 variants presented with typical ALS phenotype, and one (1.47%, 1/68) showed ALS with co-morbid FTD (ALS-FTD), while our patient (1.47%, 1/68) showed ALS with co-morbid PSP-like symptoms (ALS-PSP), which has not been reported. The phenotypes of ANXA11 mutations are summarized in Supplementary Figure S2.
The missense variant of ANXA11 identified in our patient. Sequence chromatograms of polymerase chain reaction (PCR) show the heterozygous c.119A > G (p.D40G) variant (upper lane) compared with healthy control (lower lane).
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F2
A missense mutation c.119A > G (p.D40G) of the ANXA11 gene was identified using whole-exome sequencing and verified by Sanger sequencing (Figure 2). Table 1. As shown in Supplementary Figure S1, they came from China (32.35%, 22/68), Brazil (19.12%, 13/68), Korea (19.12%, 13/68), multicenter (including the United States, the UK, Italy, Spain, Germany, Ireland, Canada, the Netherlands, Belgium, and New Zealand, 17.65%, 12/68), and France (11.76%, 8/68). According to the previously reported cases, most (80.88%, 55/68) of the ANXA11 variants presented with typical ALS phenotype, and one (1.47%, 1/68) showed ALS with co-morbid FTD (ALS-FTD), while our patient (1.47%, 1/68) showed ALS with co-morbid PSP-like symptoms (ALS-PSP), which has not been reported. The phenotypes of ANXA11 mutations are summarized in Supplementary Figure S2.
In total, 29 ANXA11 variants identified. In total, four variants considered to be pathogenic or likely pathogenic are marked in purple. Variants considered to be benign or likely benign are marked in orange. Variants of uncertain significance are marked in blue.
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F3
We identified 29 ANXA11 variants marked in Figure 3, and four variants (13.79%, 4/29) are considered to be pathogenic or likely pathogenic, including p.D40Y, p.D40G, p.G38R, and p.A58_Q187del.