PMC6125373_01
Pedigree of the family. Circles are women and squares are men. A shaded symbol indicates the proposita, half-shaded symbols indicate asymptomatic carriers of the homoplasmic m.8393C>T/p.Pro10Ser variant in MT-ATP8.
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F1
A 65-year old Caucasian woman with mild diabetes since 4 years, migraine and family history negative for neuromuscular diseases (Figure 1), had a few episodes of loss of consciousness and fall, sometimes associated with urinary incontinence. The p.Pro10Ser variant, of uncertain pathogenic significance (www.mitomap.org/foswiki/bin/view/Main/SearchAllele) but already associated with VPA-induced toxic encephalopathy (1), was also homoplasmic in blood from six healthy relatives (Figure 1). Western blot analyses in muscle homogenate from the patient did not reveal any reduction in the expression of respiratory chain complex subunits compared to controls (Supplementary Figure 1) whereas ATP levels determined in cultured skin fibroblasts showed reduced mitochondrial ATP synthesis and increased glycolytic ATP in the proposita, but not in her healthy daughter (III-02), compared to controls (Supplementary Figure 2), suggesting an impaired ATP production machinery.
(A) EEG showing a slow alpha with theta and delta activity (blue arrow); (B,C) MRI scan showing cortical and subcortical atrophy with confluent areas of white matter hyperintensity (red arrows) in T1 and T2-weighted images.
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F2
The EEG showed slow activity in the lower alpha range (7.5-9/sec), mixed to theta and delta activity over the left fronto-temporal and occipital regions (Figure 2A). There were large confluent areas of white matter (WM) hyperintensity in T1 and T2-weighted images at level of the semioval centers and the periventricular region bilaterally, with extension in the capsula externa and sparing of the juxtacortical "U" fibers (Figures 2B,C). Western blot analyses in muscle homogenate from the patient did not reveal any reduction in the expression of respiratory chain complex subunits compared to controls (Supplementary Figure 1) whereas ATP levels determined in cultured skin fibroblasts showed reduced mitochondrial ATP synthesis and increased glycolytic ATP in the proposita, but not in her healthy daughter (III-02), compared to controls (Supplementary Figure 2), suggesting an impaired ATP production machinery.
Hematoxylin and eosin stain (A) and Gomori trichrome stain (B, 20X) showed variability of muscle morphology with some atrophic fibers. In (B) asterisks denote some ragged-red fibers. Double cytochrome c-oxidase/succinate dehydrogenase (COX/SDH) stain (40X) is depicted in panel (C); a single COX-deficient blue fiber is indicated (arrow). In (D) SDH staining (10X) showed globally reduced activity.
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F3
In particular, 20% of the fibers were ragged-red at the Gomori trichrome stain with few cytochrome c oxidase negative (COX) fibers and slightly reduced activity of succinate dehydrogenase (SDH) (Figure 3).