In order to bring you the best possible user experience, this site uses Javascript. If you are seeing this message, it is likely that the Javascript option in your browser is disabled. For optimal viewing of this site, please ensure that Javascript is enabled for your browser.
Did you know that your browser is out of date? To get the best experience using our website we recommend that you upgrade to a newer version. Learn more.

We use cookies to optimise the design of this website and make continuous improvement. By continuing your visit, you consent to the use of cookies. Learn more

Unusual case with WPW syndrome, LV hypertrophy and hearing impairment

A 28 year old man was referred to our hospital for the diagnosis of Wolff-Parkinson-White syndrome because of several episodes of syncope and suspicious ECG findings. The patient has complained exercise intolerance, nausea, intensive vomiting 2-3 hours after meal, 2-3 times a week for 2 years.   Additionally, he reported hearing impairment and difficulties in speech understanding. He noticed progressive, rapid hearing deterioration five years earlier, after a stressful event (his mother suddenly died presenting with neurological symptoms). He reported no tinnitus or vertigo. Family history revealed hearing problems in all maternal relatives: sister, mother, and sister of mother and grandmother. We observed also short stature (weight: 40 kg, BMI = 16,4 kg/m2). 
On admission, no signs of heart failure were detected. Electrocardiogram revealed (Figure 1) sinus rhythm 60/min with short PR interval, normal QRS complex (110ms in length) with slurred upstroke of the QRS complex and secondary repolarization changes reflected in ST segment-T wave changes.
Myocardial Disease


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.

Questions:

  • Would you consider endocardial biopsy helpful in the diagnostic process (in order to rule out storage disease)?
  • Would you consider skeletal muscle biopsy?
  • Would you consider genetic tests helpful in the diagnostic process?
  • Which diagnosis do you consider?
  • Would you recommend an ICD implantation on the basis of significant hypertrophy?

 

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.

Conclusion:

During 3 years of the follow up we have not observed the appearance of further essential neurological symptoms despite the fact that the presence of cardiomyopathy in MELAS syndrome worsens the prognosis. Acidosis as, a typical feature of MELAS, was observed only one time during infection. In our opinion, clinical presentation and examination strongly suggest that this case represents another form of MELAS phenotype resulting from the mutation at position 3243 of human mitochondrial DNA.
Patient had cardioverter–defibrilator implanted due to heart wall hypertrophy (>30mm in diastole) and ventricular heart rhythm disturbances . He was referred for rehabilitation and he had coenzyme Q analogues, L-arginine and vitamin from antioxidative group prescribed.

Notes to editor


Presented by: Agnieszka Pawlak1, Maciej Pronicki2, Katarzyna Iwanicka-Pronicka3,4, Olga Możeńska1, Rafał Płoski5, Robert J. Gil6.

1.   Department of Invasive Cardiology, Central Clinical Hospital of Ministry of Internal Affairs
      Warsaw, Poland,
2.   Department of Pathology, The Children’s Memorial Health Institute, Warsaw, Poland, 
3.    Phoniatrica-Audiolological Outpatient, The Children’s Memorial Health Institute, Warsaw, Poland,  
4.   Departament of Rehabilitation, Institute of Physiology and Pathology of Hearing, Warsaw, Poland
5.   Departament of Medical Genetics, Medical University of Warsaw, Warsaw, Poland
6.   Department  of Surgical Researchand Transplantology, Mossakowski Medical Research Centre,    Academy of Science, Warsaw, Poland.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.