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MELAS or more

Georg Thieme Verlag KG
Arquivos de Neuro-Psiquiatria
Authors:
Josef Finsterer at Danube University Krems
Josef Finsterer
Marlies Frank
Marlies Frank
Marlies Frank
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259
DOI: 10.1590/0004-282X20160022
OPINION
MELAS or more
Melas
With interest we read the review by Lorenzoni et al. about
the diagnostic criteria of mitochondrial encephalopathy lac-
tic acidosis and stroke-like episodes (MELAS) syndrome
1
.
We have the following comments, and concerns.
Concerning the cardiac involvement it is essential to
be more specic with the variable manifestations, since dif-
ferent manifestations require dierent treatment and have a
variable outcome. e m.3243A > G mutation has been re-
ported in association with dilated cardiomyopathy
2
and hy-
pertrophic cardiomyopathy. e MELAS phenotype has
been reported in association with dilated cardiomyopathy
3
and hypertrophic cardiomyopathy
4,5
. e MELAS pheno-
type or the m.3243A > G mutation have not been described
in association with restrictive cardiomyopathy, noncompac-
tion, or Takotsubo-syndrome. Arrhythmias have been hard-
ly described in MELAS syndrome but conduction defects
such as pre-excitation (Wol-Parkinson-White syndrome)
6
,
AV-conduction defects
7
, or intra-ventricular conduction de-
fects
8
were reported. e most frequent of the conduction de-
fects in MELAS is Wol-Parkinson-White syndrome. In a sin-
gle patient sudden cardiac death has been described
9
.
Concerning the pathogenesis of stroke-like-episodes it has
been also hypothesized that an initial seizure may cause stress in
aected neurons resulting in secondary metabolic break-down
clinically manifesting as stroke-like-episode
10
. An argument for
the seizure hypothesis is that stroke-like episodes are frequent-
ly associated with seizures and that appropriate antiepileptic
treatment may be benecial also for stroke-like-episodes.
ough the authors mention that epilepsy as an “absolute
criterion” for diagnosing MELAS they do not mention the anti-
epileptic treatment, which is critical in patients with mitochon-
drial disorders (MIDs) since mitochondrion-toxic antiepileptic
drugs should be avoided. Particularly mitochondrion-toxic are
valproic acid, carbamazepine, phenobarbital, and phenytoin.
Less mitochondrion-toxic are ethosuximide, oxcarbazepine,
topiramate, felbamate, zonisamide, lamotrigine, levetirazetam,
and gabapentine. However, mitochondrion-toxicity of antiep-
ileptic drugs may depend on the mutation load within a tis-
sue, which means that the toxicity increases with the amount
of heteroplasmy. If liver or kidneys are additionally involved in
MELAS, metabolisation of antiepileptic drugs may be further
impaired and may contribute to the toxicity of these agents to-
wards mitochondria.
e review lacks description of lactate-stress-tests as
appropriate tools for suspecting a MID. Particularly, the
lactate-stress-test on a cycle ergometer can be helpful to
direct the further diagnostic work-up in these patients
11
.
e principle of the test relies on the nding that patients
with a MID may show a signicant increase of serum lactate
already at a minimal constant work-load below the lactate
threshold
12
. ough the test can produce false positive and
false negative results, it can help to decide if further invasive
diagnostic steps should be initiated.
Overall, this excellent review could widen the spectrum of
discussion by inclusion of issues addressed above. Since MELAS
is a multisystem disease it requires a multi-professional thera-
peutic approach. Since particularly brain and heart functions
determine the outcome of these patients it is important that
neurologists closely work together with cardiologists. Some of
the clinical cerebral or cardiac manifestations are particularly
accessible to treatment why it is essential that patients receive
appropriate treatment in due time.
Josef Finsterer
1
, Marlies Frank
2
1
Krankenanstalt Rudolfstiftung, Vienna, Austria
2
First Medical Department, Krankenanstalt Rudolfstiftung, Vienna, Austria.
Correspondence: Josef Finsterer; Postfach 20, 1180 Vienna, Austria, Europe; E-mail: fifigs1@yahoo.de
Conflict of interest: There are no conflicts of interest to declare.
Received 14 November 2015; Accepted 25 November 2015.
1. Lorenzoni PJ, Werneck LC, Kay CS, Silvado CE, Scola RH. When should
MELAS (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis,
and Stroke-like episodes) be the diagnosis? Arq Neuropsiquiatr.
2015;73(11):959-67. doi:10.1590/0004-282X20150154
2. Stalder N, Yarol N, Tozzi P, Rotman S, Morris M, Fellmann F
et al. Mitochondrial A3243G mutation with manifestation of
acute dilated cardiomyopathy. Circ Heart Fail. 2012;5(1):e1-3.
doi:10.1161/CIRCHEARTFAILURE.111.963900
References
260
DOI: 10.1590/0004-282X20160022
OPINION
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dilated-hypertrophic cardiomyopathy: a case report. G Ital Cardiol.
1995;25(1):69-76. Italian.
4. Wortmann SB, Champion MP, Heuvel L, Barth H, Trutnau B,
Craig K et al.. Mitochondrial DNA m.3242G > A mutation, an
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renal tubular dysfunction? Eur J Med Genet. 2012;55(10):552-6.
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B, Messner R et al.. Lactate stress test in the diagnosis of
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ResearchGate has not been able to resolve any citations for this publication.
When should MELAS (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes) be the diagnosis?
Article
Full-text available
Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) is a rare mitochondrial disorder. Diagnostic criteria for MELAS include typical manifestations of the disease: stroke-like episodes, encephalopathy, evidence of mitochondrial dysfunction (laboratorial or histological) and known mitochondrial DNA gene mutations. Clinical features of MELAS are not necessarily uniform in the early stages of the disease, and correlations between clinical manifestations and physiopathology have not been fully elucidated. It is estimated that point mutations in the tRNALeu(UUR) gene of the DNAmt, mainly A3243G, are responsible for more of 80% of MELAS cases. Morphological changes seen upon muscle biopsy in MELAS include a substantive proportion of ragged red fibers (RRF) and the presence of vessels with a strong reaction for succinate dehydrogenase. In this review, we discuss mainly diagnostic criterion, clinical and laboratory manifestations, brain images, histology and molecular findings as well as some differential diagnoses and current treatments. © 2015, Associacao Arquivos de Neuro-Psiquiatria. All rights reserved.
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Wolff-Parkinson-White syndrome in a child with recurrent seizures
Article
Full-text available
  • Feb 2010
  • CARDIOL YOUNG
short PR interval on monitoring duringanaesthesia for tonsillectomy. Subsequenttwelve-lead electrocardiograms (Fig 1) showedWolff-Parkinson-White syndrome with delta wavesseen best in leads I, II, and V3–V5, and a broadQRS complex. This was confirmed by electrophy-siologic study, during which a left lateral accessorypathway with rapid antegrade conduction, down toa cycle length of 170milliseconds, was successfullycatheter ablated (arrow).At the age of 12 years, the patient experiencedthe onset of headache, vomiting, impaired visualacuity, and recurrent focal seizures. Blood and cere-brospinal fluid lactate were increased at 5.6millimolesper litres with a reference unit of 1.0–2.6millimolesper litres and 3.7millimoles per litres with a referenceunit of 0.9–2.2millimoles per litres, respectively.Electroencephalogram showed epileptic discharges onthe left occipital region, while magnetic resonanceimaging of the brain revealed localised T2-hyper-intensity of the left occipital cortex and cerebellaratrophy. The echocardiogram (Fig 2) in the parasternallong (a) and short (b) axis views demonstrated, for thefirst time, concentric left ventricular hypertrophy(arrows). The left ventricular posterior wall measured11 millimetres – the upper limit of normal was 8millimetres – and the ventricular function was normal,without outflow obstruction. MELAS syndrome(mitochondrial myopathy, encephalopathy, lacticacidosis, and stroke-like episodes) was suspected, andthe diagnostic A3243G mutation in mitochondrial
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Mitochondrial DNA m.3242G > A mutation, an under diagnosed cause of hypertrophic cardiomyopathy and renal tubular dysfunction?
Article
  • Jul 2012
We present two new patients with the recently described mitochondrial m.3242G > A mutation. Although the mutation is situated next to the well known m.3243A > G mutation, the most common alteration associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, the clinical presentation is quite different, but characteristic. All three m.3242G > A patients presented in the neonatal period with hypertrophic and dilated cardiomyopathy, generalized muscle hypotonia and lactic acidosis. Two additionally had creatine kinase elevation, renal tubular acidosis/dysfunction and showed a mild clinical course with a favourable psychomotor development. The third patient had more neurological involvement and died in infancy. The mutation occurred de novo in the two patients where maternal investigations were performed. The combination of hypertrophic cardiomyopathy and renal tubular acidosis/renal tubular dysfunction is clinically distinctive and may represent a separate entity.
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Mitochondrial A3243G Mutation With Manifestation of Acute Dilated Cardiomyopathy
Article
  • Jan 2012
  • CIRC-HEART FAIL
A 35-year-old woman (body mass index, 16 kg/m2; height, 140 cm) presented to the emergency ward with severe dyspnea of acute onset. The medical history was noteworthy for bilateral hypacusis treated with a hearing aid. On admission, the laboratory results revealed an N-terminal prohormone of brain natriuretic peptide level of 10 219 ng/L (normal <200 ng/L). Thoracic CT scan excluded pulmonary embolism but showed cardiomegaly with pericardial and bilateral pleural effusion suggesting the presence of acute heart failure. Cardiac MRI (CMR) demonstrated a severely reduced left ventricular ejection fraction (LVEF, 13%) and severe right ventricular dysfunction (Figure 1A and 1B, baseline); LV mass index was normal. Late gadolinium enhancement images demonstrated extensive subepicardial lesions in inferior and lateral LV segments (Figure 1C, baseline). The angiogram excluded a coronary pathology, and myocardial histology …
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Intraventricular conduction disturbances and paroxysmal atrioventricular block in a young patient with MELAS
Article
  • Nov 2010
  • J CARDIOVASC MED
We present the case of a 36-year-old male patient with MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) who developed intraventricular conduction disturbances and syncopal episodes due to a paroxysmal atrioventricular block. This case suggests that in MELAS, as well as in other mithochondriopathies, intraventricular conduction disturbances and atrioventricular block can be features of the disease. In our case, progression toward atrioventricular block was rapid, suggesting that in MELAS patients presenting with worsening conduction system anomalies, pacemaker implantation has to be considered without delay, irrespective of age.
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[The MELAS syndrome and dilated-hypertrophic cardiomyopathy: a case report]
Article
  • Feb 1995
  • Giorn Ital Cardiol
We describe a case of a 34-year-old male patient first hospitalized in February '93 for stroke (concomitant dilated-hypertrophic cardiomyopathy was noted), and then in April '93 for congestive heart failure. The presence of myopathy, encephalopathy, lactic acidosis and stroke episode allows for the diagnosis of MELAS syndrome, proven by a specific point mutation in mitochondrial DNA. In this case we were able to observe not only the electrocardiographic and echocardiographic features of hypertrophic cardiomyopathy, previously described in mitochondrial encephalomyopathies, but we were also able to monitor the rapid evolution of this cardiomyopathy towards the hypokinetic dilated form with severe impairment of systolic function; this transition was due to changes in the heart anatomy and structure with reduction in the left ventricular (LV) wall thickness and dilatation of all chambers. The remodeling of LV geometry seems to be not definite and capable of dynamic evolution, as suggested by clinical and echocardiographic findings evaluated six months after the hospitalization. In this patient, we obtained a mid-term favourable clinical outcome using inotropic drugs and Ubiquinone (coenzyme Q), an intermediate substrate of the energetic metabolism, which seems to be poorly synthetized because of the early enzymatic defects in the mitochondrial respiratory chain.
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Lactate stress test in the diagnosis of mitochondrial myopathy
Article
  • Sep 1998
  • J NEUROL SCI
The aim of the study was to determine the sensitivity and specificity of the lactate stress test in the detection of mitochondrial myopathies. Thirty one healthy subjects, 10 patients with non-mitochondrial myopathy and 26 patients with mitochondrial myopathy underwent lactate stress testing at a standardized workload of 30 W during 15 min on a bicycle ergometer. Lactate was determined before the exercise (R1), 5, 10, 15 min after starting the exercise (S5, S10, S15) and 15 min after finishing the exercise (R2). A result was interpreted as pathologic if more than two of the five lactate values were above the corresponding upper reference limits. The upper reference limits for the venous lactate at R1, S5, S10, S15 and R2 were 1.9, 2.0, 2.1, 2.0 and 1.7 mmol/l respectively. The lactate stress test was pathologic in 1/10 of the non-mitochondrial myopathies and in 18/26 of the mitochondrial myopathies. The sensitivity of the lactate stress test was 69%. The specificity of the test was 90%. In conclusion, the lactate stress test proved to be helpful for evaluating the integrity of the oxidative metabolism in the majority of patients with mitochondrial myopathy.
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Lactate Stress Testing in 155 Patients with Mitochondriopathy
Article
  • Mar 2002
Few data are available about the diagnostic yield of the lactate stress test (LST) in a large group of patients with mitochondriopathy (MCP). Serum lactate was determined once before, three times during, and once after a 15-minute, constant 30W workload on a bicycle in 62 controls, aged 17 to 84 years, 155 patients with MCP, aged 17 to 87 years, and 31 patients with neurological disorders other than MCP. Lactate's upper reference limits at rest, 5, 10, 15 minutes after starting, and 15 minutes after finishing the exercise were 2.0, 2.1, 2.1, 2.1 and 1.8 mmol/l respectively. The test was regarded abnormal if more than two of the five lactate values exceeded the cut-off levels. Among the 103 patients with abnormal LST, 64 (62 %) had normal resting lactate. The sensitivity of the test was 67% and the specificity 94%. The LST proved to have a high sensitivity and specificity in the detection of patients with MCP, being thus a simple but powerful tool to assess the impaired oxidative metabolism in MCP patients.
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[A case of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), showing temporary improvement during the treatment with eicosapentaenoic acid ethyl ester]
Article
  • Oct 2001
We report a 67-year-old man with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), successfully treated with eicosapentaenoic acid ethyl ester (EPA-E) for about eight months. He showed bilateral auditory disturbance and slowly progressive gait ataxia at age 50 during treatment of diabetes mellitus (DM) with subcutaneous injection of insulin since age 29. At age 58 he manifested an acute hemiparesis of right extremities for one week with no abnormal findings on neuroradiological examinations. A permanent pacemaker was implanted at age 61 to treat frequent syncopal attacks due to complete atrioventricular block. On admission to our hospital, neurological examinations revealed dementia, auditory disturbance, severe cerebellar ataxia and mild atrophy of proximal muscles with systemic hyporeflexia. Based on a point mutation in position 3243 of mitochondrial DNA, he was diagnosed as having MELAS with severe DM, auditory disturbance and cardiac conduction block. After initiation of treatment with EPA-E at a dose of 2,700 mg/day he showed temporarily an improvement in auditory disturbance, blood glucose control and cerebellar ataxia. In objective evaluations for cerebellar ataxia, we could find significant decreases in times for 20 m walking and heel-knee patting in the ninth month, and in time for tracing of a whirl from the third to the ninth month, compared with those before treatment of EPA-E (p < 0.0001). Because EPA-E is taken into mitochondrial membranes and activates electron transmission enzyme complexes, it might be a candidate for therapy of mitochondrial encephalomyopathy, including MELAS.
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