Heteroplasmic pathogenic m.12315G>A variant in MT-TL2 presenting with MELAS syndrome and depletion of nitric oxide donors.

The MT-TL2 m.12315G>A pathogenic variant has previously been reported in five individuals with mild clinical phenotypes. Herein we report the case of a 5-year-old child with heteroplasmy for this variant who developed neurological regression and stroke-like episodes similar to those observed in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Biochemical evaluation revealed depletion of arginine on plasma amino acid analysis and low z-scores for citrulline on untargeted plasma metabolomics analysis. These findings suggested that decreased availability of nitric oxide may have contributed to the stroke-like episodes. The use of intravenous arginine during stroke-like episodes and daily enteral L-citrulline supplementation normalized her biochemical values of arginine and citrulline. Untargeted plasma metabolomics showed the absence of nicotinamide and 1-methylnicotinamide, and plasma total glutathione levels were low; thus, nicotinamide riboside and N-acetylcysteine therapies were initiated. This report expands the phenotype associated with the rare mitochondrial variant MT-TL2 m.12315G>A to include neurological regression and a MELAS-like phenotype. Individuals with this variant should undergo in-depth biochemical analysis to include untargeted plasma metabolomics, plasma amino acids, and glutathione levels to help guide a targeted approach to treatment.

[Therapeutics for Mitochondrial Encephalomyopathy].

In MELAS, taurine modification defect in the anticodon of mitochondrial leucine tRNA causes codon translation failure. An investigator-started clinical trials of high-dose taurine therapy, that showed its efficacy in preventing stroke-like episodes, and improving the taurine modification rate. The drug was found to be safe. Taurine has been approved as a drug covered by public insurance for prevention of stroke-like episodes since 2019. Recently, L-arginine hydrochloride has also been approved for off-label use as a treatment for both acute and intermittent stages of stroke-like episodes.

Thalamic aphasia associated with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes: A case report.

BACKGROUND: Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) with aphasia is a rare disorder, with the associated aphasia reported as either Wernicke's or Broca's. Herein, we report a patient with MELAS complicated by thalamic aphasia. CASE: A 15-year-old right-handed girl presented with headache, nausea, right homonymous hemianopsia, and aphasia. She could repeat words said by others, but had word-finding difficulty, paraphasia, and dysgraphia. Brain MRI revealed abnormal signals from the left occipital lobe to the temporal lobe and left thalamus, but Wernicke's area and Broca's area were not involved. Additionally, she had short stature, lactic acidosis, bilateral sensorineural hearing loss, and a maternal family history of diabetes and mild deafness. Based on clinical findings and the presence of a mitochondrial A3243G mutation, she was diagnosed with MELAS. With treatment, the brain MRI lesions disappeared and her symptoms improved. Her aphasia was classified as amnesic aphasia because she could repeat words, despite having word-finding difficulty, paraphasia, and dysgraphia. Based on MRI findings of a left thalamic lesion, we diagnosed her with thalamic aphasia. CONCLUSION: Thalamic aphasia may be caused by MELAS. Assessment of whether repetition is preserved is important for classifying aphasia.

Taurine supplementation for prevention of stroke-like episodes in MELAS: a multicentre, open-label, 52-week phase III trial.

OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of high-dose taurine supplementation for prevention of stroke-like episodes of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes), a rare genetic disorder caused by point mutations in the mitochondrial DNA that lead to a taurine modification defect at the first anticodon nucleotide of mitochondrial tRNALeu(UUR), resulting in failure to decode codons accurately. METHODS: After the nationwide survey of MELAS, we conducted a multicentre, open-label, phase III trial in which 10 patients with recurrent stroke-like episodes received high-dose taurine (9 g or 12 g per day) for 52 weeks. The primary endpoint was the complete prevention of stroke-like episodes during the evaluation period. The taurine modification rate of mitochondrial tRNALeu(UUR) was measured before and after the trial. RESULTS: The proportion of patients who reached the primary endpoint (100% responder rate) was 60% (95% CI 26.2% to 87.8%). The 50% responder rate, that is, the number of patients achieving a 50% or greater reduction in frequency of stroke-like episodes, was 80% (95% CI 44.4% to 97.5%). Taurine reduced the annual relapse rate of stroke-like episodes from 2.22 to 0.72 (P=0.001). Five patients showed a significant increase in the taurine modification of mitochondrial tRNALeu(UUR) from peripheral blood leukocytes (P<0.05). No severe adverse events were associated with taurine. CONCLUSIONS: The current study demonstrates that oral taurine supplementation can effectively reduce the recurrence of stroke-like episodes and increase taurine modification in mitochondrial tRNALeu(UUR) in MELAS. TRIAL REGISTRATION NUMBER: UMIN000011908.

Taurine ameliorates impaired the mitochondrial function and prevents stroke-like episodes in patients with MELAS.

OBJECTIVE: Post-transcriptional taurine modification at the first anticodon ("wobble") nucleotide is deficient in A3243G-mutant mitochondrial (mt) tRNA(Leu(UUR)) of patients with myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Wobble nucleotide modifications in tRNAs have recently been identified to be important in the accurate and efficient deciphering of codons. We herein examined whether taurine can alleviate mitochondrial dysfunction in patient-derived pathogenic cells and prevent clinical symptoms in MELAS patients. METHODS AND RESULTS: The addition of taurine to the culture media ameliorated the reduced oxygen consumption, decreased the mitochondrial membrane potential, and increased the oxidative stress in MELAS patient-derived cells. Moreover, high dose oral administration of taurine (0.25 g/kg/day) completely prevented stroke-like episodes in two MELAS patients for more than nine years. CONCLUSION: Taurine supplementation may be a novel potential treatment option for preventing the stroke-like episodes associated with MELAS.

L-arginine is effective in stroke-like episodes of MELAS associated with the G13513A mutation.

We report a case involving a 15-year-old boy with MELAS (G13513A mutation) who developed several stroke-like episodes in a short period of time. Intravenous administration of l-arginine during the acute phase of the stroke-like episodes reduced symptoms immediately, and oral supplementation of l-arginine successfully prevented further stroke-like episodes. This is the first report on effective l-arginine therapy in MELAS associated with the G13513A mutation.

[Characteristics of status epilepticus in MELAS. Analysis of four cases]. / Características del estado del mal epiléptico en MELAS. Análisis de cuatro casos.

INTRODUCTION: Clinical characteristics of status epilepticus (SE) as a first manifestation in patients with MELAS who had not previously epileptic episode has been studied little in the literature. OBJECTIVES: Our aim was to analyse precipitating factors, clinical characteristics, EEG and difficulties in the treatment of SE in MELAS. PATIENTS AND METHODS: We studied four cases with ages between 27 an 41 years who began with SE and they had been diagnosed with MELAS during the episode. Case 3 was confirmed by autopsy. Cases 1, 2 and 4 showed a 3243 mtDNA mutation in the lymphocytes. Epileptic seizures had not been present in any previous status case. The precipitating factor in cases 1 and 3 was fever and in case 2 and 4 stress by headache. Moreover in case 2 second status was caused by stress in hyperglycaemic ketoacidosis. All cases were studied with EEG and a brain CT or MRI. RESULTS: All patients started with epilepsia partialis continua that began with partial motor simple seizures, but sometimes progressed to partial complex seizures or secondary tonic clonic seizures. In two cases the initial symptom was migraine with aura, in two cases fever with cephalalgia and in one case diabetes mellitus decompensation. The EEG during a seizure presented a complex pseudoperiodic complex in the temporal-occipital contralateral region that spread to all hemisphere when myoclonus was increased. CONCLUSIONS: SE in MELAS appears in cell stress situation precipitated by hypermetabolic conditions and it provokes claudication in ill mitochondria. In fact, events such as fever, glycemic alterations, hypoxemia or headache that could change the normal mechanism of sequester mitochondrial calcium in the neuron are able to trigger SE. Optimal evolution depends on an improvement of basal metabolic conditions that could precipitate the status. Supplementary folic acid, riboflavin and coenzyme Q 10 can be useful.

Características del estado del mal epiléptico en MELAS. Análisis de cuatro casos / Characteristics of status epilepticus in MELAS. Analysis of four cases

Introducción. El estado de mal epiléptico (EE) como primera manifestación en pacientes con MELAS que previamente no habían tenido crisis epilépticas ha sido escasamente analizado en la literatura.Objetivos. Nuestro propósito ha sido analizar los factores precipitantes, las características electroclínicas y las dificultades en el tratamiento del EE en el MELAS.Pacientes y métodos. Analizamos cuatro casos diagnosticados de MELAS, con edades comprendidas entre 27 y 41 años, que se inician con un EE y son diagnosticados de MELAS durante el episodio. El diagnóstico se realizó en los casos 1, 2 Y 4 analizando en una muestra de sangre periférica el ADN mitocondrial, obteniéndose en todos ellos la mutación 3243 en el ADN linfocitario. El caso 3 se confirmó por necropsia. Ninguno de los pacientes había presentado crisis epilépticas previamente. El factor desencadenante en los casos 1 y 3 fue la fiebre, mientras que los casos 2 y 4 se asociaron a migraña con aura. El estrés provocado por la hiperglucemia cetoacidótica desencadenó el segundo episodio en el caso 2. Todos los casos fueron estudiados con EEG, TC o RM craneal.Resultados. Clínica mente todos los pacientes empezaron con una epilepsia parcial continua que comenzó con crisis parciales motoras simples, pudiendo progresar a crisis parciales complejas o a crisis tonicoclónicas secundariamente generalizadas. En dos ocasiones se asoció a migraña con aura, en dos casos a fiebre con cefalea y en uno a descompensación diabética. El EEG durante las crisis mostraba complejos seudoperiódicos en la región temporo-occipital que se difundían a todo el hemisferio o contra lateralmente cuando se incrementaban las mioclonías.Conclusiones. El EE en el MELAS aparece en situaciones de estrés celular, desencadenado por situaciones hipermetabólicas que hacen claudicar a las mitocondrias enfermas. De esta manera efectos como fiebre, alteraciones de la glucemia o crisis migrañosas que puedan modificar el mecanismo habitual de secuestro del calcio mitocondrial en la neurona son capaces de desencadenarlo. El pronóstico dependerá en parte de la mejoría de las condiciones metabólicas basa les que lo han precipitado

Introduction. Clinical characteristics of status epilepticus (SE) as a first manifestation in patients with MELAS who had not previously epileptic episode has been studied little in the literature.Objectives. Our aim was to analyse precipitating factors, clinical characteristics, EEG and difficulties in the treatment of SE in MELAS.Patients and methods. We studied four cases with ages between 27 an 41 years who began with SE and they had been diagnosed with MELAS during the episode. Case 3 was confirmed by autopsy. Cases 1, 2 and 4 showed a 3243 mtDNA mutation in the lymphocytes. Epileptic seizures had not been present in any previous status case. The precipitating factor in cases 1 and 3 was fever and in case 2 and 4 stress by headache. Moreover in case 2 second status was caused by stress in hyperglycaemic ketoacidosis. AlI cases were studied with EEG and a brain CT or MRI.Results. All patients started with epilepsia partialis continua that began with partial motor simple seizures, but sometimes progressed to partial complex seizures or secondary tonic clonic seizures. In two cases the initial symptom was migraine with aura, in two cases fever with cephalalgia and in one case diabetes mellitus decompensation. The EEG during a seizure presented a complex pseudoperiodic complex in the temporal-occipital contralateral region that spread to all hemisphere when myoclonus was increased.Conclusions. SE in MELAS appears in cell stress situation precipitated by hypermetabolic conditions and it provokes claudication in ill mitochondria. In fact, events such as fever, glycemic alterations, hypoxemia or headache that could change the normal mechanism of sequester mitochondrial calcium in the neuron are able to trigger SE. Optimal evolution depends on an improvement of basal metabolic conditions that could precipitate the status. Supplementary folic acid, riboflavin and coenzyme Q 10 can be useful

Effects of oral creatine supplementation in a patient with MELAS phenotype and associated nephropathy.

An 18-year-old male patient with MELAS phenotype and 2 previous episodes of cerebral stroke, recurrent seizures and nephropathy, was treated with creatine monohydrate after the acute onset of psychomental regression and changing states of somnolence and aggressive and agitated behaviour. These symptoms disappeared completely after 4 weeks of treatment with creatine after which the patient regained all his previous mental abilites. Brain (white matter) proton magnetic resonance spectroscopy (chemical shift imaging) performed at 6 and 12 months of treatment showed lactic acid (Lac) accumulation and high creatine (Cr) levels in relation to choline-containing compounds (Cho). Urinary creatinine excretion as an indicator of the muscle and brain creatine pool increased upon short-term (12 days) high-dosage creatine supplementation (20 g per day) while plasma creatinine concentrations as possible indicators both of increasing creatine pool and of renal insufficiency increased during the course (28 months) of low-dosage creatine supplementation (5 g per day). Deterioration of renal function was finally indicated by urea retention and by impairment of renal creatinine clearance. These observations suggest that creatine supplementation may have a neuroprotective effect in patients with MELAS and episodes of acute mental deterioration. Adverse effects of creatine supplementation on renal function must be considered especially in patients with preexisting nephropathy.

Cerebral blood flow and oxygen metabolism before and after a stroke-like episode in patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS).

Cerebral blood flow and oxygen metabolism were examined in two patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) using positron emission tomography (PET). Regional cerebral blood flow (rCBF), regional cerebral oxygen metabolic rate (rCMRO2) and regional oxygen extraction fraction (rOEF) were determined with the steady-state technique using oxygen-15-labeled tracers (15O2, C15O2 and C15O). Case 1, a 45-year-old woman, presented with abrupt onset of fluent aphasia. T2-weighted magnetic resonance imaging (MRI) showed a high signal intensity lesion in the left temporoparietal region. The first PET study on day 16 showed increased rCBF and decreased rCMRO2 in the temporal region. In the second PET study, on day 35, rCBF in the temporal region had decreased. Case 2 was a 19-year-old male; the second son of Case 1. He complained of transient blurring of vision, and then generalized tonic-clonic convulsion occurred. A PET study six days before this stroke-like episode demonstrated increased rCBF in both frontal lobes and putamen, where MRI showed lesions after the episode. Focal hyperemia of the lesion antedated and lasted for at least sixteen days after the stroke-like episode in these MELAS patients. These stroke-like episodes appear to be the result of metabolic dysfunction in neural tissue, although the role of an ischemic vascular event cannot be ruled out.