Figure 1. ECG in patient with WPW syndrome
NT-pro-brain natiuretic peptide (NT-pro-BNP) level was 5887 ng/ml (>125 ng/ml) with normal renal function, without lactic acidosis.
TTE (iE 33, Philips Medical System, Best
, the Netherlands) showed eccentric, moderate left ventricular walls hypertrophy (parasternal long axis: LVDD/S-38/20mm, IVSD/S–17/24mm, PWD/S-25/28mm), preserved left ventricular systolic function (LV ejection fraction: 60% according to Simpson’s method), without any significant valvular insufficiency, moderate diastolic dysfunction and max. 10mm pericardial effusion (Figure2). Patient was referred for CMR.Figure 2. Moderate LV hypertrophy A) in echocardiography B) in CMR – late gadolinium enhancement.
CMR findings were: cine CMR (gradient echo showed preserved left ventricular function, EF 59% and large, eccentric, left ventricular walls hypertrophy: antero–lateral wall diastolic 30mm, IVS diastolic 15mm, LV mass 220g), on T1 inversion recovery sequences diffuse, patchy, late gadolinium enhancement was noted in the midwall and sub-epicardial area of the IVS and anterolateral wall constituted 24% of LV mass. Coronary angiography did not reveal any significant stenosis.
Brain MRI revealed: features of cerebellum atrophy, mostly in the areas of the cerebellum hemispheres with cerebellum fissure and IV chamber dilation. There were no cortical or cortico-subcortical scars.
Evaluation in the Audiology Clinic of Institute of Physiology and Pathology of Hearing revealed normal otoscopy, bilateral, symmetrical, pantonal sensorineural hearing loss of moderate degree with average hearing threshold level of 60 dB HL (in tonal audiometry). Speech audiometry showed speech understanding level at 85 dB HL for both ears and maximal discrimination level at 90% for 100 dB HL. Tympanometry was type A bilaterally; stapedial reflex was absent after ipsilateral and contralateral stimulation. Signal of evoked otoacoustic emissions was absent bilaterally. Auditory evoked brainstem responses confirmed cochlear origin of the hearing loss. Patient was fitted with hearing aids and achieved great auditory benefit. Figure 3. Audiogram of a patient affected by bilateral sensorineural hearing loss.
Clinical symptoms like hearing loss, cardiomyopathy, short stature, biopsy findings and weakness together with family history raised a suspicion of mitochondrial disorder. Endomyocardial biopsies were performed to exclude localized cardiac amyloidosis or other secondary forms of hypertrophic cardiomyopathy. Endomyocardial biopsy showed microscopic features of cardiomyocyte hypertrophy (diameter up to 50 – 60 mirometers) with moderate archiectural disarray. Biopsy revealed no noticeable fibrosis, necrosis, vasculopathy or inflammatory infiltrates. Histochemical assessment of myocardium demonstrated no cytochrome c oxidase (COX) deficiency, normal SDH activity, with only mild degree of lipid accumulation in cardiomyocytes. Biopsy findings were reported as non-specific, with multiorgan involvement suggesing mitochondrial disorder. Cardiomyocytes with increased number of variably shaped mitochondria were observed in TEM. (Figure 4).
Figure 4. Endomyocardial biopsy with high mitochondria density in electron microscopy.
Skeletal muscle biopsy was performed after the results of endomyocardial biopsy (due to suspicion of mitochondrial disease). Skeletal muscle biopsy showed typical pattern of mitochondrial disease/myopathy with ragged red fibers (RRF), ragged blue fibers (RBF) and mosaic COX deficit. Ragged red fibers, rather sparse in number were COX positive what corresponded with a pattern characteristic for MELAS syndrome. Biopsy demonstrated no other essential myopathic or neuropathic involvement. Semi-thin epon sections showed darkly staining subsarcolemmal accumulation of mitochondria in individual fibers corresponding to RRF’s. TEM examination confirmed mitochondrial accumulation and their structural variability.
Figure 5. An image of skeletal muscle fibers. A) RRF fibers - Modified trichrome stain of frozen section. Original magnification 600X. B) Cytochrome C oxidase mosaic deficit_RRF fibers are COX positive. Original magnification 600X
Molecular tests confirmed 3243 A>G mutation in mtDNA. Detection of 3243 A>G mutation was performed by RealTime allelic discrimination technique with TaqMan probes (Custom TaqMan® SNP Genotyping Assays Applied Biosystems). Analysis of a heteroplasmy level revealed presence of the mutation in each of the examined tissues: in blood leukocytes at the level of 24,1 %, in hair follicles of 43,4 %, in nails of 38,3 %, in buccal mucosa of 35,2 % and in urinary sediment of 91,8 %. The heteroplasmy level was estimated as a ratio between digested and sum of digested and undigested peak area. The level of the mutation in each tissue was relatively high.
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