PMC6146370_01
(A-E) Computed tomography images obtained following hospitalization show high-density signals in the great cerebral vein (arrow in A), sagittal sinus (arrow in B,D), torcular herophili (arrow in C), transverse sinus (arrow in E) (thrombus formation was not excluded). High-density signals were also observed in the cerebral falx (hollow arrow in C), leading us to consider subarachnoid hemorrhage.
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F1
High-density computed tomography (CT) signals were observed in the great cerebral vein (arrow in Figure 1A), sagittal sinus (arrow in Figures 1B,D), torcular herophili (arrow in Figure 1C), and transverse sinus (arrow in Figure 1E). High-density CT signals were also observed in the cerebral falx (hollow arrow in Figure 1C), which was suggestive of subarachnoid hemorrhage.
(A-D) Axial, T2-weighted MRI at 1 month following hospitalization revealed high signal intensity in the lateral ventricle, periaqueductal gray matter (bilateral hypothalamus and midbrain tegmentum, arrow in A,B), and medullary tegmentum (arrow in D). There were no evident lesions in the tegmentum of pons at this stage (small arrow in C).
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T2-weighted magnetic resonance imaging (MRI) (Figure 2) revealed areas of high signal intensity in the lateral ventricle, periaqueductal gray matter (bilateral hypothalamus and midbrain tegmentum, arrow in Figures 2A,B), and medullary tegmentum (arrow in Figure 2D). There were no evident lesions in the tegmentum of pons at this stage (small arrow in Figure 2C).
(A-E) Axial, T2-weighted MRI at 2 months following hospitalization revealed hyperintensities in the bilateral thalamus (arrow and hollow arrow in A), tegmental area of the midbrain (arrow in B), pons (hollow arrow in C), and medulla (arrow in D). The thalamic lesions had increased in size, and new lesions had emerged (hollow arrow in A,C). There were no evident lesions in the cervical and thoracic spinal cord at this stage (small arrows in E).
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After 2 months, T2-weighted MRI (Figure 3) revealed hyperintensities in the bilateral thalamus (arrow and hollow arrow in Figure 3A), tegmental area of the midbrain (arrow in Figure 3B), pons (hollow arrow in Figure 3C), and medulla (arrow in Figure 3D). As shown in Figure 3, the thalamic lesions had increased in size and new lesions had emerged (hollow arrow in Figures 3A,C). There were no evident lesions in the cervical and thoracic spinal cord at this stage (small arrows in Figure 3E).
(A-E) Axial and sagittal T2-weighted MRI at 7 months following hospitalization revealed hyperintensities in the bilateral thalamus (arrow in A), tegmental area of the midbrain (arrow in B), pons (arrow in C), medulla (arrow in D), and the cervical and thoracic spinal cord (new lesions, hollow arrow in E). The previously identified lesions had decreased in size because of atrophy.
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After 7 months, T2-weighted MRI (Figure 4) revealed hyperintensities in the bilateral thalamus (arrow in Figure 4A), tegmental area of the midbrain (arrow in Figure 4B), pons (arrow in Figure 4C), medulla (arrow in Figure 4D), and the cervical and thoracic spinal cord (new lesions, hollow arrow in Figure 4E). As shown in Figure 4, the previously identified lesions had decreased in size because of atrophy.
(A-E) T2-weighted MRI results at 8 months following hospitalization were similar to those obtained 1 month earlier (arrow in A-E).
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After 8 months, T2-weighted MRI (Figure 5) revealed no new developments (arrow in Figures 5A-E).
(A-C) After 4 months of hospitalization, muscle biopsy results revealed no remarkable mitochondrial abnormalities (including RRF) following histochemical analysis. However, 6 months after disease onset, modified Gomori trichrome staining of muscle biopsy specimens revealed the presence of scattered ragged red fibers (RRF, arrow in A), while succinate dehydrogenase staining revealed the presence of ragged blue fibers (arrow in B). Cytochrome C oxidase histochemical analyses revealed a diffuse reduction in the number of fibers (arrow in C). Bar represents 50 mum.
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However, 6 months after hospitalization, MGT staining of muscle biopsy specimens revealed the presence of scattered RRF (arrow in Figure 6A), while SDH staining revealed the presence of ragged blue fibers (arrow in Figure 6B). Histochemical analyses after COX staining revealed a diffuse reduction in the number of fibers (arrow in Figure 6C).
Proband's family pedigree.   = non-carrier, woman;   = non-carrier, man; / = deceased;   = carrier;    = symptomatic members. The arrow indicates the proband. The patient's mother (III:7 in this figure) developed seizures at the age of 30. One of the patient's cousins (IV:1 in this figure) developed seizures at the age of 8. The point mutation level of these two relatives (from blood) were 77% (III:7 in this figure) and 87% (IV:1 in this figure), respectively, which are relatively high. Most of the other maternal relatives carrying the same mutation showed no evident symptoms.
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Quantitative pyrosequencing confirmed the presence of the m.8344A>G mutation at very high levels in the patient's blood (95%, IV:4 in Figure 7) and muscle (96%). The point mutation levels of these two relatives (from blood) were 77% (III:7 in Figure 7) and 87% (IV:1 in Figure 7), respectively, which were relatively high.