PMC9846158_01
(A) Disease course of case 1. The graph shows ALSFRS-R total score (left) and FVC % (right) decline from disease onset. The bold vertical line represents the time when NIV was initiated, while the dashed vertical line represents the beginning of intrathecal Tofersen administration. (B) Family pedigree of case 1. Filled circle/square, affected individuals; open circle/square, unaffected individuals; arrow, proband; diagonal line, deceased individuals. The proband's mother died at 79 years of age from HCV infection complications and chronic COPD; the father died at 94 years of age after a hip fracture. A paternal uncle died at an advanced age because of Parkinson's disease. (C,D) Brain MRI images of case 1. MRI T2-weighted images revealing the hypointensity along the bilateral motor cortex (red arrows).
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F1
He reported a family history of ALS (Figure 1B): his brother died at 59 years of age because of ALS, characterized by progressive weakness in the lower limbs with respiratory impairment leading to non-invasive ventilation (NIV) 5 years after onset. Interestingly, MRI revealed UMN involvement as hypointensity along the bilateral motor cortex on T2-weighted images (Figures 1C, D), with a reduction in the fractional anisotropy (FA) values of the pyramidal bundle in tractography acquisitions. One year later, the weakness had spread to the upper limbs, and NIV was initiated to support respiratory function (Figure 1A).
PMC9846158_02
(A) Disease course of case 2. The graph shows ALSFRS-R total score (left) and FVC % (right) decline from the onset of symptoms. The bold vertical line represents the time when NIV was initiated, while the dashed vertical line represents the beginning of intrathecal Tofersen administration. (B) Family pedigree of case 2. Filled circle/square, affected individuals; open circle/square, unaffected individuals; arrow, proband; diagonal line, deceased individuals. The proband's father died at 56 years of age of colon cancer; the mother is still alive; a 51-year-old brother is alive and in good health and is currently undergoing psychological counseling to evaluate genetic testing. Maternal grandfather had dementia which started at an advanced age; a paternal aunt had Alzheimer's disease with onset at 75 years. (C) MRI coronal acquisition showing FLAIR hyperintensity of left cortico-spinal bundle; the red arrow indicates the peculiar involvement of the internal capsule segment. (D)
18FDG-PET images Glass brain rendering of the comparison between subject 2 and 40 healthy controls (HC). The cluster showing a statistically significant relative hypermetabolism in subject 2 compared to HC is projected on the brain surface (height threshold p < 0.001; p < 0.05 FWE-corrected at cluster level). For 18F-FDG-PET acquisition and elaboration details please refer to Canosa et al. and Supplementary material.
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F2
No family history of ALS was reported (Figure 2B). MRI T2-weighted images showed hypointensity of the bilateral motor cortex and FLAIR hyperintensity of the left cortico-spinal bundle (Figure 2C). MRI tractography revealed reduced FA values in the cortico-spinal tract acquisitions. 18FDG-PET showed areas of hypermetabolism affecting both cerebellar hemispheres, with a prevalence in the right lobe (Figure 2D). The progression rate measured by ALSFRS-R revealed that monthly decline at diagnosis was slow (0.25 points/month); however, a subsequent acceleration (1.27 points/month) was present due to respiratory function decline (Figure 2A).