<abstract xmlns="http://www.w3.org/1999/xhtml">

<sec>
<h3>Introduction</h3>
<p>MELAS is a systemic hereditary condition that can present as hypertrophic or mixed hypertrophic and dilated phenotype cardiomyopathy in young individuals, although a late-onset form is also described in the literature. Genetic testing is essential for correct diagnosis and appropriate management.</p>
</sec>
<sec>
<h3>Case presentation</h3>
<p>We present the case of a 22-year-old male who was referred to our center after being diagnosed with NYHA class III heart failure with a mixed hypertrophic and dilated cardiomyopathy. His medical history included stroke episodes, seizures, progressive hypoacusis, neurocognitive impairment, and muscle atrophy. Lactic acidosis and elevated CK levels were also noted. The ECG revealed short PR interval and delta wave in lateral leads. TTE showed mildly dilated and hypertrophied LV and RV with severe biventricular systolic impairment. The CMR study was relevant for ring-like subepicardial fibrosis, predominantly in the medium and apical segments. Brain MRI showed multifocal supratentorial subcortical stroke-like lesions in both cerebral hemispheres, involving multiple vascular territories and following a migratory pattern. Genetic testing confirmed a pathogenic MT-TL1 mutation (m.324A>G) and the patient was diagnosed with MELAS. Further management included specific lifestyle recommendations and cascade genetic screening, as well as starting GDMT for HFrEF. Three months after discharge, his clinical status improved. However, the LVEF remained reduced. After careful consideration, an ICD was implanted for primary prevention.</p>
</sec>
<sec>
<h3>Conclusion</h3>
<p>A red-flag approach in this young patient, which took into consideration the stroke-like episodes, lactic acidosis, seizures, hypoacusis, myopathy, as well as the short PR interval, led to the correct diagnosis, further confirmed by using the appropriate genetic test. Failure to diagnose affects the patient’s prognosis, as their prognosis and clinical status are influenced by enforcing specific recommendations.</p>
</sec>
</abstract>

Introduction
MELAS is a systemic hereditary condition that can present as hypertrophic or mixed hypertrophic and dilated phenotype cardiomyopathy in young individuals, although a late-onset form is also described in the literature. Genetic testing is essential for correct diagnosis and appropriate management.


Case presentation
We present the case of a 22-year-old male who was referred to our center after being diagnosed with NYHA class III heart failure with a mixed hypertrophic and dilated cardiomyopathy. His medical history included stroke episodes, seizures, progressive hypoacusis, neurocognitive impairment, and muscle atrophy. Lactic acidosis and elevated CK levels were also noted. The ECG revealed short PR interval and delta wave in lateral leads. TTE showed mildly dilated and hypertrophied LV and RV with severe biventricular systolic impairment. The CMR study was relevant for ring-like subepicardial fibrosis, predominantly in the medium and apical segments. Brain MRI showed multifocal supratentorial subcortical stroke-like lesions in both cerebral hemispheres, involving multiple vascular territories and following a migratory pattern. Genetic testing confirmed a pathogenic MT-TL1 mutation (m.324A>G) and the patient was diagnosed with MELAS. Further management included specific lifestyle recommendations and cascade genetic screening, as well as starting GDMT for HFrEF. Three months after discharge, his clinical status improved. However, the LVEF remained reduced. After careful consideration, an ICD was implanted for primary prevention.


Conclusion
A red-flag approach in this young patient, which took into consideration the stroke-like episodes, lactic acidosis, seizures, hypoacusis, myopathy, as well as the short PR interval, led to the correct diagnosis, further confirmed by using the appropriate genetic test. Failure to diagnose affects the patient’s prognosis, as their prognosis and clinical status are influenced by enforcing specific recommendations.


<div xmlns="http://www.w3.org/1999/xhtml">
<sec id="j_rjc-2023-0020_s_007">
<div>Introduction</div>
<p>Syndromic disorders caused by mitochondrial mutations are a spectrum of rare diseases which usually become clinically manifest before the age of 40, with later onsets being described.<sup>[<a ref-type="bibr" href="#j_rjc-2023-0020_ref_001">1</a>, <a ref-type="bibr" href="#j_rjc-2023-0020_ref_002">2</a>]</sup> MELAS is a rare and life-threatening mitochondrial disorder due to the severe metabolic impairment, predominantly affecting organs with the highest metabolic activity: heart, muscles, and brain. The metabolic impairment translates into lactic acidosis, severe hypoglycemia and hyperglycemia, which can lead to diabetes mellitus.<sup>[<a ref-type="bibr" href="#j_rjc-2023-0020_ref_003">3</a>]</sup> The clinical presentation consists of hypertrophic or mixed phenotype (HCM and DCM) with certain systemic features, such as stroke-like episodes, seizures, hypoacusis and cognitive impairment. Nevertheless, the phenotype is highly variable, partly explainable by the mithocondrial heteroplasmy phenomenon.<sup>[<a ref-type="bibr" href="#j_rjc-2023-0020_ref_004">4</a>]</sup> Diagnosis is confirmed by finding a pathogenic mutation in one of the mitochondrial genes: MT-TL1 (the most common) and MT-ND5.<sup>[<a ref-type="bibr" href="#j_rjc-2023-0020_ref_005">5</a>]</sup> However, these genes are not included in most HCM or DCM panels. Treatment options include general considerations, such as GDMT, but also specific recommendations, namely, avoiding mitochondrion toxic drugs and situations which further aggravate the metabolic impairment to such an extent that they can become lethal. These specific considerations are essential in the management of patients, as they greatly impact the long-term prognosis and life expectancy.</p>
</sec>
<sec id="j_rjc-2023-0020_s_008">
<div>Case presentation</div>
<p>A 22-year-old male patient was referred to our center after being recently diagnosed with DCM, with symptoms of fatigue and exertional dyspnea corresponding to a NYHA class III. His medical history included hypoacusis, recurrent seizures, depression, and weight-loss, all of which developed progressively in the past 2 years. A prior TTE performed at 19 years showed mild LVH with preserved EF and HCM was considered. Genetic testing was performed for sarcomeric HCM, yielding no results. Two months prior to referral, he presented two transitory stroke episodes, which were believed to be cardioembolic, as the initial TTE and subsequent CMR performed at the time revealed a reduced LVEF complicated by LV apical thrombus. He was started on treatment with sacubitril/ valsartan, bisoprolol, diuretics, rivaroxaban, and valproic acid. A physical examination revealed short stature, hypertelorism, and lower and upper limbs muscle wasting, with moderate lower limb edema. Family history was unremarkable regarding cardiovascular diseases, with first degree relatives being asymptomatic and not exhibiting any syndromic features. In the blood workup, elevated CK levels (416U/L), lactic acidosis (ph. 7.29, lactic acid – 3.5mmol/L), hyponatremia, elevated NTproBNP (2767pg/ml) and hs-troponin (107ng/ml) were noted. The ECG revealed sinus rhythm with short PR interval and delta wave in lateral leads, with left axis deviation and wide QRS (<a ref-type="fig" href="#j_rjc-2023-0020_fig_001">Figure 1</a>), while ECG Holter monitoring was unremarkable for significant arrhythmias. TTE showed a mildly dilated hypertrophied LV (MWT 14mm), with a severely reduced EF (28%) and longitudinal function (GLS -5.6%) (<a ref-type="fig" href="#j_rjc-2023-0020_fig_002">Figure 2</a>). Resolution of LV apical thrombus was noted. The RV was mildly dilated and hypertrophied (FW MWT 5mm), with impaired longitudinal function. The CMR performed prior to referral was consistent with severely impaired biventricular function (LVEF 14%, RVEF 18%), mild LVH, and ring-like subepicardial fibrosis, predominantly in the medium and apical segments (<a ref-type="fig" href="#j_rjc-2023-0020_fig_003">Figure 3</a>). T2 mapping was unremarkable. EGE detected 3 non-enhancing masses within the LV apex, suggestive of LV thrombi (<a ref-type="fig" href="#j_rjc-2023-0020_fig_003">Figure 3D</a>). The neurologist was consulted and a brain MRI was performed, revealing multifocal supratentorial subcortical stroke-like lesions in both cerebral hemispheres, involving multiple vascular territories and following a migratory pattern. Considering the mixed cardiac phenotype, the short PR interval, and the associated systemic features consisting of stroke-like episodes, particular brain MRI pattern, seizures, hypoacusis, lactic acidosis and myopathy, a mitochondrial disease was suspected. The patient was tested specifically for MELAS-related genes and a pathogenic MT-TL1 mutation was confirmed (m.324A>G). Arginine (3g/day), co-enzyme Q10 (200mg/day), and L-carnitine (2g/day) were initiated. Regarding the HFrEF GDMT, sacubitril/valsartan, bisoprolol, and rivaroxaban were continued, with spironolactone and dapaglifozin being added. The patient was re-assessed three months after discharge. His clinical status improved, as he was in NYHA class II, without any signs of congestion. Furthermore, no seizures or stroke-like episodes are reported, and the burden of myopathy related symptoms is reduced. The LVEF was re-assessed, showing a similar value (28%), without apical thrombi. Given that the LVEF was stationary, the DOAC was continued to prevent the recurrence of apical thrombosis, and an ICD was implanted for primary prevention after careful consideration. At the 6 months ICD control, one episode of anti-tachycardia pacing for sustained ventricular tachycardia was detected.</p>
<figure id="j_rjc-2023-0020_fig_001" position="float" fig-type="figure">
<h2>Figure 1</h2>
<figCaption>
<p>ECG findings showing a short PR interval and the positive delta wave in the lateral leads.</p>
</figCaption>
<img xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="graphic/j_rjc-2023-0020_fig_001.jpg" src="https://sciendo-parsed.s3.eu-central-1.amazonaws.com/651bb80603b7e54136081e20/j_rjc-2023-0020_fig_001.jpg?X-Amz-Algorithm=AWS4-HMAC-SHA256&amp;X-Amz-Date=20240716T110925Z&amp;X-Amz-SignedHeaders=host&amp;X-Amz-Expires=18000&amp;X-Amz-Credential=AKIA6AP2G7AKP25APDM2%2F20240716%2Feu-central-1%2Fs3%2Faws4_request&amp;X-Amz-Signature=fd765e817ec800acc230e1d449ce8568a2f6208ab7f930291fc337f76aedc5d2" class="mw-100"/>
</figure>
<figure id="j_rjc-2023-0020_fig_002" position="float" fig-type="figure">
<h2>Figure 2</h2>
<figCaption>
<p>2D Echocardiography findings. A: Parasternal long axis with mild LVH (interventricular septum of 14 mm, posterior wall of 13mm). B: Apical 4 chamber view shows dilatation of all 4 chambers. C: Myocardial deformation bull’s eye showing severely reduced GLS of 05.6% with non-specific pattern.</p>
</figCaption>
<img xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="graphic/j_rjc-2023-0020_fig_002.jpg" src="https://sciendo-parsed.s3.eu-central-1.amazonaws.com/651bb80603b7e54136081e20/j_rjc-2023-0020_fig_002.jpg?X-Amz-Algorithm=AWS4-HMAC-SHA256&amp;X-Amz-Date=20240716T110925Z&amp;X-Amz-SignedHeaders=host&amp;X-Amz-Expires=18000&amp;X-Amz-Credential=AKIA6AP2G7AKP25APDM2%2F20240716%2Feu-central-1%2Fs3%2Faws4_request&amp;X-Amz-Signature=640c846a74ce952ad6d332ed4b6fef1060d6a9ee346ecca3fe50cad9d1d18e23" class="mw-100"/>
</figure>
<figure id="j_rjc-2023-0020_fig_003" position="float" fig-type="figure">
<h2>Figure 3</h2>
<figCaption>
<p>Contrast enhanced cardiovascular magnetic resonance findings. A, B, and C: Diastolic frames of cine images in 2, 4 and 3 chamber views showing a severely dilated left ventricle (LV) with interventricular septum hypertrophy. Large right pleural effusion and small circumferential pericardial effusion are also seen. D: Early Gadolinium enhancement showing multiple thrombi in the LV apex. E, F, G, and I: Late Gadolinium Enhancement (LGE) in 2, 4, 3 chambers and short axis views respectively showing extensive subepicardial LGE with a ring-like pattern.</p>
</figCaption>
<img xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="graphic/j_rjc-2023-0020_fig_003.jpg" src="https://sciendo-parsed.s3.eu-central-1.amazonaws.com/651bb80603b7e54136081e20/j_rjc-2023-0020_fig_003.jpg?X-Amz-Algorithm=AWS4-HMAC-SHA256&amp;X-Amz-Date=20240716T110925Z&amp;X-Amz-SignedHeaders=host&amp;X-Amz-Expires=18000&amp;X-Amz-Credential=AKIA6AP2G7AKP25APDM2%2F20240716%2Feu-central-1%2Fs3%2Faws4_request&amp;X-Amz-Signature=236c34f492052ed1e0c7a740925ad4fce6d3662c83e4c8274b9a7d58836ad6e7" class="mw-100"/>
</figure>
</sec>
<sec id="j_rjc-2023-0020_s_009">
<div>Discussion</div>
<p>The case illustrates the many particular and challenging aspects of diagnosing and treating patients with rare inherited diseases, which can be overcome if a patient-centered team is enforced. Electrical abnormalities, such as short PR interval and delta wave, were previously reported in MELAS.<sup>[<a ref-type="bibr" href="#j_rjc-2023-0020_ref_006">6</a>]</sup> The CMR was not highly suggestive for a particular cardiomyopathy. Ring-like fibrosis has been reported in left-dominant variants of ACM with desmoplakine mutations.<sup>[<a ref-type="bibr" href="#j_rjc-2023-0020_ref_007">7</a>]</sup> However, in the DSP cardiomyopathy, the LV walls would have been thin, not hypertrophied. CMR findings in patients with mitochondrial myopathies are heterogenous and highly variable, with MELAS patients showing more frequently overt concentric hypertrophy and a rather unique, focally accentuated and diffusely distributed LGE. <sup>[<a ref-type="bibr" href="#j_rjc-2023-0020_ref_008">8</a>]</sup> Diagnosis was delayed in our patient. As his initial genetic test yielded no mutation for sacomeric HCM, an alternative diagnosis should have been sought. Nevertheless, as the specific signs and symptoms can develop progressively with age, it is possible that they were not clinically overt at the time. This highlights the importance of carefully monitoring patients with cardiomyopathies for the development of systemic features, which could be in relation to the cardiac abnormalities. Our patient’s evolution was complicated by two stroke-like episodes in the absence of the specific treatment and prevention. Arginine is essential in preventing and treating stroke-like episodes in patients with MELAS, while coQ10 and L-carnitine have a favorable effect on cellular metabolism, including on cardiomyocytes.<sup>[<a ref-type="bibr" href="#j_rjc-2023-0020_ref_009">9</a>]</sup> Being a mitochondrial disease, certain drugs and situations, such as general anesthesia or hypoglycemia, can interfere with the cellular metabolism, leading to lactic acidosis, coma, and even death.<sup>[<a ref-type="bibr" href="#j_rjc-2023-0020_ref_010">10</a>]</sup> Furthermore, it can precipitate stroke-like episodes and seizures and aggravate the pre-existing myopathy, as well as the decline of the myocardial function. Valproic acid was stopped, as it impairs mitochondrial function, aggravating epilepsy in patients with MELAS (10). Thus, the patient was started on levetiracetam. After these changes were made, our patient’s neurological status improved, without recurrence of seizures or stroke-like episodes. Regarding cardiac treatment, no specific options are available and the use of GDMT is preferred (11). However, data regarding their beneficial effect on the prognosis of patients with MELAS is limited. Of note, the most specific pattern of cardiac involvement is a hypertrophic phenotype, with dilated cardiomyopathy being less prevalent, but reported in the literature (12). The decision to implant an ICD in primary prevention is difficult as there are no known specific considerations regarding the primary prevention of sudden cardiac death in patients with MELAS, relying on current guidelines (IIa indication) (11). Furthermore, the patient’s clinical status and life expectancy should be considered. The life expectancy of patients with MELAS cannot be accurately predicted, as different organs can be affected with various degrees of severity. In our case, we decided to refer the patient to ICD implantation as we estimated a survival longer than 1 year, considering that the onset of the disease was not during childhood and that with proper treatment the patient achieved a good clinical status. Data regarding heart transplantation are limited in this instance.<sup>[<a ref-type="bibr" href="#j_rjc-2023-0020_ref_013">13</a>]</sup> It is possible as a long-term option in our patient, given his young age and rapidly progressive LVEF decline, which was not reversible with GDMT. However, the indication is controversial, considering that, unlike with other cardiomyopathies, multiorgan failure develops with disease progression. Mitochondrial diseases are maternally inherited, but can also occur as a result of a de-novo mutation (i.e., other relatives are not affected). Cascade genetic testing is to be performed in 1<sup>st</sup> degree relatives, except in the father of the patient.</p>
</sec>
<sec id="j_rjc-2023-0020_s_010">
<div>Conclusion</div>
<p>MELAS is a rare, systemic, and potentially life-threatening disorder which can present as a mixed HCM/DCM phenotype. A red-flag approach in this young patient took into consideration the strokelike episodes, lactic acidosis, seizures, deafness, and myopathy, as well as the short PR interval and delta wave. Diagnosis relied on genetic testing and finding a pathogenic mutation in the MT-TL1 gene. Clinicians should be aware of the systemic features associated with MELAS when considering genetic testing in patients with HCM or mixed HCM and DCM phenotype, as mitochondrial DNA genes may not be included in all panels. Failure to diagnose affects the patients, as their prognosis and clinical status is influenced by enforcing specific recommendations, such as avoiding certain mitochondriontoxic drugs or using arginine, carnitine, and coQ10 supplements.</p>
</sec>
</div>

A rare cause of mixed hypertrophic and dilated phenotype cardiomyopathy – the MELAS syndrome

Romanian Journal of Cardiology

This work is licensed under the Creative Commons Attribution 4.0 International License.

Introduction
MELAS is a systemic hereditary condition that can present as hypertrophic or mixed hypertrophic and dilated phenotype cardiomyopathy in young...

A rare cause of mixed hypertrophic and dilated phenotype cardiomyopathy – the MELAS syndrome

Article Category: Case Presentation

Published Online: Sep 30, 2023

Page range: 118 - 122

DOI: https://doi.org/10.2478/rjc-2023-0020

Keywords
MELAS, mitochondrial disease, hereditary cardiomyopathy, genetic test

© 2023 Mihnea Casian et al., published by Sciendo

This work is licensed under the Creative Commons Attribution 4.0 International License.

A rare cause of mixed hypertrophic and dilated phenotype cardiomyopathy – the MELAS syndrome

Article Category: Case Presentation

Published Online: Sep 30, 2023

Page range: 118 - 122

DOI: https://doi.org/10.2478/rjc-2023-0020

KeywordsMELAS, mitochondrial disease, hereditary cardiomyopathy, genetic test

© 2023 Mihnea Casian et al., published by Sciendo

This work is licensed under the Creative Commons Attribution 4.0 International License.

Keywords
MELAS, mitochondrial disease, hereditary cardiomyopathy, genetic test