The patient was primarily referred to her local hospital for cardiac evaluation because of an abnormal ECG (Fig. 1.). She was diagnosed with hypertrophic cardiomyopathy (Fig. 2.). At that stage she did not have specific cardiac symptoms but over the years she gradually developed dyspnoea and increased fatigue. She was put on relevant anti-congestive medication but her symptoms worsened and she had to give up her work as cleaner. A few months ago the patient experienced increasing difficulties with her short-term memory and also had frequent “black-outs” lasting for minutes in which it was not possible to get in contact with her.
In addition to her cardiac condition the patient had type one diabetes diagnosed at the age of 43 and had previously been treated successfully with cochlea implants because of deafness developed in her twenties. There was no family history of obvious cardiac disease.
Figure 1. ECG in sinus-rhythm, prominent p-waves, short PQ-interval and left axis
Figure 2. Echocardiogram with septal hypertrophy of 2.1 cm, normal cavity dimensions, and an ejection fraction of 30%
Question 1: What could be the explanation of the disease presentation?
As described above echocardiography of the patient revealed LVH and impaired systolic function. Her ECG was also abnormal. In addition the patient was short of stature and had remarkable high number of disease manifestations from other organs: (a) sensorineural hearing loss necessitating cochlear implants at a young age, (b) diabetes, (c) neurological deficits, and, (d) impaired exercise capacity.
The involvement of multiple organ systems in a patient with unexplained cardiomyopathy should lead to a suspected diagnosis of mitochondrial disease (1-3).
Mitochondria are small organelles and part of most cells in which they generate energy in the form of ATP. They are unique in that they carry their own circular genome in multiple copies within each mitochondrion. Mutations in mitochondrial DNA cause defects in energy production and usually manifest in organs with high energy consumption such as pancreas, cochlea, heart, retina, muscle, kidney and brain. There is a continuum of the disease expression from isolated diabetes or hearing loss to mitochondrial encephalomyopathy, lactate acidosis, and stroke-like episodes (MELAS-syndrome). One of the reasons for the heterogeneous disease expression is that only a proportion of the mitochondrial DNA is mutated in each cell. The mixture of normal and mutant mitochondrial DNA is called heteroplasmy and the grade of heteroplasmy is proportional with the severity of disease manifestations and number of organ systems involved within each affected individual (4). Since mitochondria are present in oocytes and not in spermatozoa’s the disease can only be transmitted by maternal inheritance. The implication is that offspring of affected mothers will become obligate carriers of the mutation while affected fathers cannot pass the disease on.
Question 2: Would it be relevant to perform further investigations and blood tests?
Endomyocardial biopsies were taken on a routine basis and light microscopy of a hematoxyline-eosine-stained biopsy showed pronounced myocytic variation and hypertrophy with coarse cytoplasmic vacuolization. A supplemental glycogen staining (PAS reaction) showed increased reactivity in these areas. There was slight interstitial fibrosis without inflammation (figure 1. Electron microscopy showed increased numbers of mitochondria (mitochondriosis) with size variation and increased glycogen content (figure 2). Lactate acid was measured in multiple blood samples and was elevated above normal range. A skeletal muscle biopsy underwent metabolic investigations abnormal function of respiratory-chain enzymes consistent with mitochondrial disease. Subsequent mutation analysis of mitochondria from skeletal muscle tissue identified a frequent mitochondrial point mutation (3243A>G), which is commonly associated with the maternally inherited diabetes and deafness syndrome (MIDD) (1).
Mutation analysis was undertaken in mitochondria of skeletal muscle tissue since the content of mutated mitochondrial DNA decreases in blood leucocytes with age and therefore in some cases may be undetectable in a blood sample. The degree of heteroplasmy was determined in blood leucocytes (39%), in mouth-epithelia (53%) and urine-sediment (64%) consistent with severe symptoms of mitochondrial disease.
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