Primary mitochondrial disease as a rare cause of unclear breathlessness and distinctive performance degradation – a case report

Abstract

Background

Primary muscular disorders (metabolic myopathies, including mitochondrial disorders) are a rare cause of dyspnea. We report a case of dyspnea caused by a mitochondrial disorder with a pattern of clinical findings that can be classified in the known pathologies of mitochondrial deletion syndrome.

Case presentation

The patient presented to us at 29 years of age, having had tachycardia, dyspnea, and functional impairment since childhood. She had been diagnosed with bronchial asthma and mild left ventricular hypertrophy and treated accordingly, but her symptoms had worsened. After more than 20 years of progressive physical and social limitations was a mitochondrial disease suspected in the exercise testing. We performed cardiopulmonary exercise testing (CPET) with right heart catheterization showed typical signs of mitochondrial myopathy. Genetic testing confirmed the presence of a ~ 13 kb deletion in mitochondrial DNA from the muscle. The patient was treated with dietary supplements for 1 year. In the course of time, the patient gave birth to a healthy child, which is developing normally.

Conclusion

CPET and lung function data over 5 years demonstrated stable disease. We conclude that CPET and lung function analysis should be used consistently to evaluate the cause of dyspnea and for long-term observation.

Background

Dyspnea can be caused by cardiac, pulmonary, and/or muscular disorders [1]. Muscular disorders in the context of cardiac or pulmonary disease are usually a secondary phenomenon; primary muscular disorders (metabolic myopathies, comprising disorders of glycogenolysis and glycolysis, mitochondrial function, and lipid metabolism [2]) are less common. Metabolic myopathy subtypes are associated with different findings in cardiopulmonary exercise testing (CPET) [3]. In particular, patients with mitochondrial disorders show an early and continuous increase in lactate under stress, leading to exaggerated circulatory and ventilatory responses [4]. Typical but not specific to any pattern is reduced anaerobic capacity (low VO₂ @AT so-called ventilatory threshold VT₁ and VO₂peak) and increased ventilatory equivalents for O₂ (VE/VO₂) and CO₂ (VE/VCO₂).

If one considers primarily the muscular disorders as the cause of unclear shortness of breath and reduced performance, it becomes clear, that such changes in cardiac or pulmonary diseases often represent a secondary phenomenon. The clinical spectrum ranges from severe multisystem disorders in early childhood to isolated muscle spasms in adults. It is therefore easy to understand that the CPET parameters also show different patterns [6], whereby the “mitochondriopathies” are particularly characterized by an early and continuous increase in lactate under stress. In summary, patients are unable to adequately utilize oxygen for oxidative phosphorylation; and as consequence lactic acid accumulates early in exercise, which leads to exaggerated circulatory and ventilatory responses.

We report a case of dyspnea caused by a mitochondrial disorder (detected by CPET and confirmed by genetic testing) with a pattern of clinical findings that cannot be classified in the known pathologies of mitochondrial deletion syndrome [2, 5, 6].

Case presentation

A 29-year-old woman was referred to our department for evaluation of unclear exertional dyspnea with extreme functional limitation.

She had experienced breathing difficulties and performance limitations since early childhood. A medical examination at 6 years of age had shown tachycardia, low blood pressure, and a normal electrocardiogram. Subsequently, her symptoms had worsened and she had developed severe pain and increasing weakness in her leg muscles. At 15 years of age, she was diagnosed with exercise-induced asthma. At 16 years of age, she underwent low-stress ergometry, which caused a sharp increase in heart rate there (a sharp increase in already at 20 watts from 100 to 160/min and at 60 watts to 200/min) with extreme shortness of breath. In CPET (bicycle, 3 min at 25 watts followed by 3 min at 50 watts), the respiratory quotient at rest was 1.02 and oxygen uptake (VO₂) increased from 1.76 ml/min/kg to a maximum of 13.8 ml/kg/min. Echocardiography showed mild to moderate left ventricular hypertrophy, which declined after 3 years of beta-blocker therapy. She was not under beta-blocker therapy when referred to our department.

The patient was admitted to our department with pathological findings in ergometry (ramp protocol, increase of 15 watts/min up to 80 watts, reduced peak oxygen consumption with 8.5 ml/kg/min (29% predicted) with severe lactic acidosis (pH: 7.17; lactate: 25.8 mmol/L) and leading symptom of exercise dyspnea and inability to move her legs after physical exertion (walking 500 m). The clinical examination, laboratory analysis, and pulmonary function test showed no abnormalities. Inspiratory muscle strength was clearly impaired (maximal inspiratory pressure: 5.83 kPa [53% of normal], P0.1 0.10 (normal value 0.19), P0.1/Pi max 0.02 (normal value 0.02)). In CPET (3 min rest, 1 min unloaded cycling, then 16 watts/min intensification), a maximum load of 84 watts was achieved (60% of normal). Peak VO₂ was 10.1 mL/kg/min (29% predicted), while the minute ventilation VE/VO₂ ratio increased from 31 at rest to a maximum of 95 (Table 1). The leading reason for exercise termination was dyspnea followed by muscle weakness, sometimes dizziness and thoracic tightness without ECG-changes.

Table 1 Description of parameters in lung function analysis and exercise testing

Echocardiography showed mild hypertrophic left cardiomyopathy, without signs of pulmonary hypertension.

Invasive CPET (combined with right heart catheterization in semi-supine position, Fig. 1) showed a normal pulmonary pressure at rest (PAPmean 15 mmHg) and at 25 W (PAPmean 24 mmHg and with normal pulmonary vascular resistance (PVR < 1,5 WU at all measurements, Table 2). The mixed venous oxygen saturation was constant over the whole exercise time. The lactate concentration was 15.0 mmol/L at 25 watts (Fig. 2) and fell to 7.0 mmol/L at rest over 15 min.

Fig. 1

Invasive cardiopulmonary exercise testing combined with right heart catheterization in semi-supine position.

Fig. 2

Cardiopulmonary exercise testing combined with right heart catheterization shows a rapid increase in lactate level, hyperdynamic circulatory adaptation, and low arteriovenous oxygen difference, consistent with the presence of a mitochondrial disorder. Δ = change; CO = cardiac output; VO₂ = oxygen uptake

Table 2 Invasive cardiopulmonary exercise testing

Histological analysis of a muscle biopsy showed no abnormalities or mitochondrial disorders (no ragged red fibers in Gomori trichrome stain). Histochemical analysis showed significantly increased citrate synthase activity, reduced activity of complex I and IV, and normal activity of complex II and III. Mitochondrial DNA from the muscle showed a deletion of bases 3,261 to 16,068 with 36% heteroplasmy.

After the diagnosis, the patient, at her own request, received dietary supplements (including coenzyme Q10/ubiquinol, vitamin B1/B6 complex, alpha-lipoic acid, L-taurine, magnesium, and potassium) for a year.

The patient’s symptoms persisted and lung function and CPET data remained unchanged over 5 years (Table 1). After thorough genetic counseling, the patient had an uncomplicated pregnancy resulting in the birth of a healthy boy (c-Sect. 05/2019, male, 55 cm, 4150 g). who is developing normally.

Discussion

In this case of dyspnea, the suspicion of mitochondrial disease was raised only after ~ 20 years of progressively worsening functional limitation. Although the clinical pattern of mild hypertrophic left cardiomyopathy and muscle weakness did not match the known pathologies of mitochondrial deletion syndrome [2, 5, 6], CPET findings were consistent with mitochondrial myopathy. Small case series [7,8,9] have previously shown significantly reduced maximum VO₂ and increased VE/VO₂ in patients with mitochondrial disorders compared with control individuals. Hyperdynamic circulatory adaptation and reduced arteriovenous oxygen difference were previously identified in a study of 40 patients with mitochondrial myopathy compared with healthy sedentary individuals [7] and allow differentiation of mitochondrial myopathy from muscular deconditioning due to cardiac and pulmonary diseases [10]. Further, as shown in this case elevated lactate concentrations in blood may be a clue to impaired aerobic energy metabolism [11].

Treatment options for primary mitochondrial disease are limited and may include physiotherapy and dietary supplements [5, 6, 12]. Although the latter did not produce any clinical improvement in our patient, such therapy should be evaluated cautiously. We clearly emphasize that exercise therapy may be a therapeutic solution in these patients, in particular, aerobic endurance training can increase mitochondrial mass, by stimulating mitochondrial biogenesis, and increase muscle mitochondrial enzyme activities and muscle strength [12, 13].

Although the pregnancy and subsequent development of the child were uneventful in our case, it should be noted that the offspring of women with mitochondrial DNA deletion disorders have a ~ 4% risk of inheriting the deletion [14]. Patients with mitochondrial diseases have been reported to have worsening of symptoms and an increased rate of complications during pregnancy, and their children tend to have more congenital anomalies than expected [14]. Our patient had no complications during pregnancy and delivery. The now almost four-year-old child also shows no abnormalities. In a retrospective analysis of pregnancies of patients with mitochondrial diseases (38% with myopathies) worsening of symptoms and findings during pregnancy and an increased rate of complications (gestational diabetes, preeclampsia) were found. The newborns were born on their expectation date but tended to have more congenital anomalies than expected [15].

Conclusion

In summary, this case demonstrates the importance of CPET in evaluating unclear dyspnea, both for diagnosis and long-term monitoring.