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TARS2 encodes human mitochondrial threonyl tRNA-synthetase that is responsible for generating mitochondrial Thr-tRNAThr and clearing mischarged Ser-tRNAThr during mitochondrial translation. Pathogenic variants in TARS2 have hitherto been reported in a pair of siblings and an unrelated patient with an early onset mitochondrial encephalomyopathy and a combined respiratory chain enzyme deficiency in muscle. We here report five additional unrelated patients with TARS2-related mitochondrial diseases, expanding the clinical phenotype to also include epilepsy, dystonia, hyperhidrosis and severe hearing impairment. In addition, we document seven novel TARS2 variants—one nonsense variant and six missense variants—that we demonstrate are pathogenic and causal of the disease presentation based on population frequency, homology modeling and functional studies that show the effects of the pathogenic variants on TARS2 stability and/or function.

Purpose Magnetic resonance spectroscopy (MRS) is a diagnostic tool used to detect abnormal accumulation of lactate in the brain parenchyma in various metabolic diseases. This study evaluated the clinical roles of brain MRS in the initial assessment of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) caused by impairment of the mitochondrial respiratory chain. Methods Twenty-five patients with the A3243G mutation among 34 MELAS patients referred to the pediatric neurology clinic of Gangnam Severance Hospital between January 2006 and December 2020 were included. In this retrospective study, demographic, clinical, laboratory (serum lactate and lactate-to-pyruvate ratio), magnetic resonance imaging (MRI), and initial MRS (presence of lactate peak and abnormal N-acetylaspartate [NAA]) data were reviewed. Results Brain MRI showed cortical lesions in 24 of 25 genetically confirmed A3243G MELAS patients with neurologic symptoms in this study. On MRS, 18 patients (72%) had increased lactate peaks, depicting anaerobic energy metabolism, and 17 patients (68%) had decreased NAA levels, indicating neuronal integrity. Ten patients underwent MRS in the acute stage (within 2 weeks of symptoms). Unlike patients who underwent MRS more than 2 weeks after symptom onset, a lactate peak on MRS was observed in all patients in the acute stage (P=0.011). Conclusion Elevated lactate peaks in acute cerebral infarctions are highly suggestive of mitochondrial encephalopathy. MRS alone is insufficient to diagnose MELAS, but it is valuable as a noninvasive supplemental diagnostic tool in combination with genetic testing.

Introduction Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, is a multisystemic entity of mitochondrial inheritance. To date, there is no epidemiological information on MELAS syndrome in Mexico. Case series A retrospective, cross-sectional design was employed to collect and analyze the data. The clinical records of patients with mitochondrial cytopathies in the period ranging from January 2018 to March 2020 were reviewed. Patients who met definitive Yatsuga diagnostic criteria for MELAS syndrome were included to describe frequency, clinical, imaging, histopathologic, and molecular studies. Of 56 patients diagnosed with mitochondrial cytopathy, 6 patients met definitive Yatsuga criterion for MELAS (10.7%). The median age at diagnosis was 34 years (30 to 34 y), 2 females and the median time from onset of symptoms at diagnosis 3.5 years (1 to 10 y). The median of the number of stroke-like episodes before the diagnosis was 3 (range, 2 to 3). The main findings in computed tomography were basal ganglia calcifications (33%), whereas in magnetic resonance imaging were a lactate peak in the spectroscopy sequence in 2 patients. Five patients (84%) had red-ragged fibers and phantom fibers in the Cox stain in the muscle biopsy. Four patients (67%) had presence of 3243A>G mutation in the mitochondrial MT-TL1 gene. One patient died because of status epilepticus. Conclusions MELAS syndrome represents a common diagnostic challenge for clinicians, often delaying definitive diagnosis. It should be suspected in young patients with stroke of undetermined etiology associated with other systemic and neurological features.

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a disease that should be considered as a differential diagnosis to acute ischemic stroke taking into account its onset pattern and neurological symptoms, which are similar to those of an ischemic stroke. Technological advancements in neuroimaging modalities have greatly facilitated differential diagnosis between stroke and MELAS on diagnostic imaging. Stroke-like episodes in MELAS have the following features: (1) symptoms are neurolocalized according to lesion site; (2) epileptic seizures are often present; (3) lesion distribution is inconsistent with vascular territory; (4) lesions are common in the posterior brain regions; (5) lesions continuously develop in adjacent sites over several weeks or months; (6) neurological symptoms and stroke-like lesions tend to be reversible, as presented on magnetic resonance imaging; (7) the rate of recurrence is high; and; (8) brain dysfunction and atrophy are slowly progressive. The m.3243ANG mutation in the MT-TL1 gene encoding the mitochondrial tRNALeu(UUR) is most commonly associated with MELAS. Although the precise pathophysiology is still unclear, one possible hypothesis for these episodes is a neuronal hyperexcitability theory, including neuron–astrocyte uncoupling. Supplementation, such as with L-arginine or taurine, has been proposed as preventive treatments for stroke-like episodes. As this disease is still untreatable and devastating, numerous drugs are being tested, and new gene therapies hold great promise for the future. This article contributes to the understanding of MELAS and its implications for clinical practice, by deepening their insight into the latest pathophysiological hypotheses and therapeutic developments.

Objective The purpose of this study was to investigate correlations between brain proton magnetic resonance spectroscopy (1H‐MRS) findings with serum biomarkers and heteroplasmy of mitochondrial DNA (mtDNA) mutations. This study enrolled patients carrying mtDNA mutations associated with Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke‐like episodes (MELAS), and MELAS‐Spectrum Syndrome (MSS). Methods Consecutive patients carrying mtDNA mutations associated with MELAS and MSS were recruited and their serum concentrations of lactate, alanine, and heteroplasmic mtDNA mutant load were evaluated. The brain protocol included single‐voxel 1H‐MRS (1.5T) in the medial parieto‐occipital cortex (MPOC), left cerebellar hemisphere, parieto‐occipital white matter (POWM), and lateral ventricles. Relative metabolite concentrations of N‐acetyl‐aspartate (NAA), choline (Cho), and myo‐inositol (mI) were estimated relative to creatine (Cr), using LCModel 6.3. Results Six patients with MELAS (age 28 ± 13 years, 3 [50%] female) and 17 with MSS (age 45 ± 11 years, 7 [41%] female) and 39 sex‐ and age‐matched healthy controls (HC) were enrolled. These patients demonstrated a lower NAA/Cr ratio in MPOC compared to HC (p = 0.006), which inversely correlated with serum lactate (p = 0.021, rho = −0.68) and muscle mtDNA heteroplasmy (p

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is one of the most common maternally inherited mitochondrial disorders, with no specific treatment available. We report a case of a 34-year-old female in whom symptoms of MELAS were initially misdiagnosed as herpes simplex encephalitis (HSE). Her clinical course was marked by an acute episode of consciousness disturbance with newly developed lesions on brain MRI five years after disease onset and followed by progressive sensorineural hearing loss. Brain imaging sequences throughout the seven years of her illness are presented. The final diagnosis of MELAS syndrome was confirmed by m.3243A>G mitochondrial mutation. In conclusion, understanding the overlapping imaging features between MELAS syndrome and other mimickers, such as HSE or ischemic stroke, is crucial to help establish early diagnosis and initiate appropriate treatment.

There have been considerations since the beginning of the Coronavirus pandemic that COVID-19 infection, like any other viral illness, can trigger neurological and metabolic decompensation in patients with mitochondrial diseases. At the time of writing, there were no published reports reviewing experiences and guidelines about management of COVID-19 infection in this patient population. We present a challenging case of an adult patient with a known diagnosis of Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like Episodes (MELAS) complicated by COVID-19 infection. She initially presented with altered mental status and vomiting and went on to develop a stroke-like episode, pancreatitis, and pneumatosis intestinalis. We review salient features of her hospitalization, including initiation of thromboprophylaxis in relation to intravenous arginine therapy, caution regarding medications such as remdesivir, and the incidence of gastrointestinal complications.

Mutations in the mitochondrial DNA polymerase gamma catalytic subunit (POLγA) compromise the stability of mitochondrial DNA (mtDNA) by leading to mutations, deletions and depletions in mtDNA. Patients with mutations in POLγA often differ remarkably in disease severity and age of onset. In this work we have studied the functional consequence of POLγA mutations in a patient with an uncommon and a very severe disease phenotype characterized by prenatal onset with intrauterine growth restriction, lactic acidosis from birth, encephalopathy, hepatopathy, myopathy, and early death. Muscle biopsy identified scattered COX-deficient muscle fibers, respiratory chain dysfunction and mtDNA depletion. We identified a novel POLγA mutation (p.His1134Tyr) in trans with the previously identified p.Thr251Ile/Pro587Leu double mutant. Biochemical characterization of the purified recombinant POLγA variants showed that the p.His1134Tyr mutation caused severe polymerase dysfunction. The p.Thr251Ile/Pro587Leu mutation caused reduced polymerase function in conditions of low dNTP concentration that mimic postmitotic tissues. Critically, when p.His1134Tyr and p.Thr251Ile/Pro587Leu were combined under these conditions, mtDNA replication was severely diminished and featured prominent stalling. Our data provide a molecular explanation for the patient´s mtDNA depletion and clinical features, particularly in tissues such as brain and muscle that have low dNTP concentration.

To report a Chinese family with combined m.14459G>A mutation and m.6064A>T mutation of which the female proband presenting unique Leber hereditary optic neuropathy and dystonia (LDYT) overlapping mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) phenotype. Clinical information of the pedigree was collected. We performed muscle biopsy and whole-length mitochondrial DNA (mtDNA) sequencing on the proband. The activity of respiratory chain complexes in immortalized lymphoblasts was determined. The current 23-year-old proband suffered from vision decline at age 15 and developed seizures and dystonia with bilateral lesions in precentral gyri at age 18. When she was 21, the lesions in bilateral putamen were found with elevated cerebrospinal fluid lactate. Her mother had optic atrophy; one of her brother died at age 4 with respiratory distress; and the other 8-year-old brother was asymptomatic. Muscle biopsy of the proband was unremarkable. The mtDNA sequencing revealed a heteroplasmic m.14459G>A mutation and a previously unreported m.6064A>T mutation. The respiratory chain complex I activity in the proband’s immortalized lymphoblasts was 50% less than the normal control; while there was no statistical difference between the proband and the normal control in the activity of complex IV. We presented the first case exhibiting LDYT and MELAS phenotype with m.14459G>A mutation, and the decreased complex I activity contributed to the pathogenicity. Our study expanded the clinical spectrum of m.14459G>A mutation.

Posttransplant diabetes mellitus, presenile deafness, and myopathy are not commonly accompanied symptoms after kidney transplant. We report the case of a 48-year-old woman with diabetes mellitus, sensorineural hearing loss, and severe myopathy without neuropathy after deceased donor kidney transplant. ShehadamitochondrialDNApointmutation at position 3243 (A>G), and mitochondrial diseases such as maternally inherited diabetes deafness or mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodeswere suspected.Diabetes andother symptoms following kidney transplant can often be overlooked as complications of immunosuppressants taken after kidney transplant. However, in patients without a known cause of their symptoms, appropriate examinations and consultation for other diseases, including genetic diseases, should be considered.

Background and Objective: Mitochondrial encephalomyopathies represent a clinically heterogeneous group of disorders resulting from abnormal mitochondrial function. This study investigates the clinical and genetic characteristics of families with mitochondrial encephalomyopathy. Methods: The clinical manifestations, biopsy and gene detection were retrospectively analyzed for four probands with definitively diagnosed mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) from three families with MELAS and/or maternally inherited diabetes and deafness (MIDD). Results: The initial symptoms of probands were convulsive headache and/or epilepsy. The members of the three families also had diabetes, deafness, muscle weakness and short statures. Typical characteristics were indicated by muscle biopsy and gene detection in all. Conclusion: We reveal that the same family can have MIDD and MELAS cases, which clearly show that the unique mutation may cause different syndromes in one family. Neurologists should take into account more possibilities and phenotypes in screening and genetic counselling for the families of probands. How to Cite This: Xia H, Niu FN, Jin B, Zhao KR, Ma R, Yu M. Different phenotypes caused by the unique mutation in the same family with mitochondrial encephalomyopathy. Biomedica; 36 (4): 388-93.Doi: https://doi.org/10.51441/BioMedica/5-85.

BackgroundMitochondrial encephalomyopathy with lactic acidosis and stroke-like episode (MELAS) is a group of genetic diseases caused by mutations in mitochondrial DNA and nuclear DNA. The causative mutations of MELAS have drawn much attention, among them, mutations in mitochondrial tRNA genes possessing prominent status. However, the detailed molecular pathogenesis of these tRNA gene mutations remains unclear and there are very few effective therapies available to date.MethodsWe performed muscle histochemistry, genetic analysis, molecular dynamic stimulation and measurement of oxygen consumption rate and respiratory chain complex activities to demonstrate the molecular pathomechanisms of m.5541C>T mutation. Moreover, we use cybrid cells to investigate the potential of taurine to rescue mitochondrial dysfunction caused by this mutation.ResultsWe found a pathogenic m.5541C>T mutation in the tRNATrp gene in a large MELAS family. This mutation first affected the maturation and stability of tRNATrp and impaired mitochondrial respiratory chain complex activities, followed by remarkable mitochondrial dysfunction. Surprisingly, we identified that the supplementation of taurine almost completely restored mitochondrial tRNATrp levels and mitochondrial respiration deficiency at the in vitro cell level.ConclusionThe m.5541C>T mutation disturbed the translation machinery of mitochondrial tRNATrp and taurine supplementation may be a potential treatment for patients with m.5541C>T mutation. Further studies are needed to explore the full potential of taurine supplementation as therapy for patients with this mutation.

Many mitochondrial diseases are caused by mutations in mitochondrial DNA (mtDNA). Patients' cells contain a mixture of mutant and nonmutant mtDNA (a phenomenon called heteroplasmy). The proportion of mutant mtDNA varies across patients and among tissues within a patient. We simultaneously assayed single-cell heteroplasmy and cell state in thousands of blood cells obtained from three unrelated patients who had A3243G-associated mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes. We observed a broad range of heteroplasmy across all cell types but also found markedly reduced heteroplasmy in T cells, a finding consistent with purifying selection within this lineage. We observed this pattern in six additional patients who had heteroplasmic A3243G without strokelike episodes. (Funded by the Marriott Foundation and others.).

Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) may cause whole-brain functional changes due to mitochondrial dysfunction. Our purpose is to comprehensively evaluate the alterations of spontaneous brain activity in MELAS patients at stroke-like episodes (SLE) attack and remission stages using resting-state functional magnetic resonance imaging. Forty MELAS patients at attack stage (n = 20) and remission stage (n = 20) and 22 healthy controls were enrolled in this study. We suggested that MELAS patients presented decreased spontaneous brain activities beyond the areas of stroke-like lesions (SLLs), with a downward trend from SLE attack stage to remission stage. In addition, the regional spontaneous activity of SLL, an inherent change in MELAS, was less than that in unaffected areas. Furthermore, the fractional amplitude of low frequency fluctuations value in left precuneus may be used as a promising neuroimaging biomarker for monitoring the disease status of MELAS.

BACKGROUND Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a rare maternally inherited genetic disease; however, little is known about its underlying brain basis. Furthermore, the dynamic functional connectivity (dFC) of brain networks in MELAS has not been explored. PURPOSE To investigate the abnormalities of dFC in patients with MELAS at the acute and chronic stages, and to determine the possible relations between dynamic connectivity alterations and volumes of stroke-like lesions (SLLs). STUDY TYPE Prospective. SUBJECTS Twenty-two MELAS patients at the acute stage, 23 MELAS patients at the chronic stage, and 22 healthy controls. FIELD STRENGTH/SEQUENCE Single-shot gradient-recalled echo planar imaging (EPI) sequence at 3T. ASSESSMENT Dynamic FC states were estimated using the sliding window approach and k-means clustering analyses. Combined with graph theory, the topological properties of the dFC network were also accessed. STATISTICAL TESTS Permutation test, Pearson correlation coefficient, and false discovery rate correction. RESULTS We identified four dFC states and found that MELAS patients (especially at the acute stage) spent more time in a state with weaker connectivity (state 1) and less time in states with stronger connectivity. In addition, volumes of acute SLLs were positively correlated with mean dwell time in state 1 (r = 0.539, P

Abstract Mitochondrial diseases are highly heterogeneous metabolic disorders caused by genetic alterations in the mitochondrial DNA (mtDNA) or in the nuclear genome. In this study, we investigated a panel of blood biomarkers in a cohort of 123 mitochondrial patients, with prominent neurological and muscular manifestations. These biomarkers included creatine, fibroblast growth factor 21 (FGF21) and growth/differentiation factor 15 (GDF-15), and the novel cell free circulating-mtDNA (ccf-mtDNA). All biomarkers were significantly increased in the patient group. After stratification by the specific phenotypes, ccf-mtDNA was significantly increased in the Mitochondrial Encephalomyopathy Lactic Acidosis Stroke-like episodes syndrome (MELAS) group, and FGF21 and GDF-15 were significantly elevated in patients with MELAS and Myoclonic Epilepsy Ragged Red Fibers syndrome. On the contrary, in our cohort, creatine was not associated to a specific clinical phenotype. Longitudinal assessment in four MELAS patients showed increased levels of ccf-mtDNA in relation to acute events (stroke-like episodes/status epilepticus) or progression of neurodegeneration. Our results confirm the association of FGF21 and GDF-15 with mitochondrial translation defects due to tRNA mutations. Most notably, the novel ccf-mtDNA was strongly associated with MELAS and may be used for monitoring the disease course or to evaluate the efficacy of therapies, especially in the acute phase. Key messages • FGF21/GDF15 efficiently identifies mitochondrial diseases due to mutations in tRNA genes. • The novel ccf-mtDNA is associated with MELAS and increases during acute events. • Creatine only discriminates severe mitochondrial patients. • FGF21, GDF-15, and ccf-mtDNA are possibly useful for monitoring therapy efficacy.

Epitranscriptomic systems enable post-transcriptional modifications of cellular RNA that are essential for regulating gene expression. Of the ~ 170 known RNA chemical modifications, methylation is among the most common. Loss of function mutations in NSUN3, encoding the 5-methylcytosine (m5C) methyltransferase NSun3, have been linked to multisystem mitochondrial disease associated with combined oxidative phosphorylation deficiency. Here, we report a patient with early-onset mitochondrial encephalomyopathy and seizures in whom the novel biallelic NSUN3 missense variants c.421G>C (p.A141P) and c.454T>A (p.C152S) were detected. Segregation studies and in silico functional analysis confirmed the likely pathogenic effects of both variants. These findings expand the molecular and phenotypic spectrum of NSUN3-related mitochondrial disease.

Mitochondrial dysfunction underlies several human chronic pathologies, including cardiovascular disorders, cancers and neurodegenerative diseases. Impaired mitochondrial function associated with oxidative stress can be a result of both nuclear and mitochondrial DNA (mtDNA) mutations. Neurological disorders associated with mtDNA mutations include mitochondrial encephalomyopathy, chronic progressive external ophthalmoplegia, neurogenic weakness, and Leigh syndrome. Moreover, mtDNA mutations were shown to play a role in the development of Parkinson and Alzheimer’s diseases. In this review, current knowledge on the distribution and possible roles of mtDNA mutations in the onset and development of various neurodegenerative diseases, with special focus on Parkinson’s and Alzheimer’s diseases has been discussed.

Objective: To investigate the clinical features and imaging characteristics of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS).Methods: Seventeen patients wi...

Case report : A 30-year-old woman with a history of bilateral sensorineural deafness since the age of 14 years, a right occipital ischemic stroke with left hemianopia and epilepsy was admitted to the neurology department with speech disorders and a new epileptic insult. MRI revealed extensive cytotoxic edema of the left temporo–parieto–occipital cortex and mirrored right-sided sequelae (Fig. 1a, b). MR-angiography and MR-venography (not shown) were normal. [...]

AIM Mitochondrial encephalomyopathy, lactic acidosis, and recurrent stroke-like episodes (MELAS) syndrome is a rare but one of the most common maternally inherited multisystem disorder. Although patients with MELAS present a variable clinical profile, stroke-like lesions have been detected in 90% of cases, with stroke being the first presenting symptom in 25% of cases. However, cases of local brain edema requiring decompressive craniectomy has not been reported. CASE DESCRIPTION A 12-year-old male patient was admitted to our pediatric intensive care unit with altered mental status, seizures, and vision loss. The patient was stuporous and presented neck stiffness. Complete blood count, serum electrolytes, biochemistry (including lactate level), acute phase reactants, and repeated blood gas analysis were unremarkable. Brain magnetic resonance imaging (MRI) revealed an edematous stroke-like lesion in the right occipital lobe accompanied by brain swelling. Intravenous ceftriaxone, acyclovir, intravenous immunoglobulin (IVIG), and pulse steroid therapy were started for possible diagnosis of viral/bacterial/autoimmune encephalitis; levetiracetam, phenytoin, and an infusion of sodium thiopental were started for refractory status epilepticus; and a 3% NaCl infusion was started for local brain edema. The results of serum autoimmune encephalitis panel were negative. Further investigations for rheumatic, vascular, and metabolic disorders were unremarkable. Despite these supportive treatments, the patient was clinically decompensated due to brain swelling that progressed to the left midline shift, and he underwent decompressive craniectomy. Histologic examination of brain biopsy specimen revealed non-specific encephalitis findings. A pathogenic variant of the MT-TL1 gene (m.3243A T), responsible for MELAS, was detected. The patient's condition dramatically improved after specific treatment for MELAS. CONCLUSION If the diagnosis and treatment are delayed, MELAS syndrome can cause serious brain edema, which may ultimately require decompressive craniectomy.

Mitochondrial stroke-like episodes (SLEs) are a hallmark of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). They should be suspected in anyone with an acute/subacute onset of focal neurological symptoms at any age and are usually driven by seizures. Suggestive features of an underlying mitochondrial pathology include evolving MRI lesions, often originating within the posterior brain regions, the presence of multisystemic involvement, including diabetes, deafness, or cardiomyopathy, and a positive family history. The diagnosis of MELAS has important implications for those affected and their relatives, given it enables early initiation of appropriate treatment and genetic counselling. However, the diagnosis is frequently challenging, particularly during the acute phase of an event. We describe four cases of mitochondrial strokes to highlight the considerable overlap that exists with other neurological disorders, including viral and autoimmune encephalitis, ischemic stroke, and central nervous system (CNS) vasculitis, and discuss the clinical, laboratory, and imaging features that can help distinguish MELAS from these differential diagnoses.

Pathogenic mitochondrial (mt)DNA molecules can exhibit heteroplasmy in single cells and cause a range of clinical phenotypes, although their contribution to immunity is poorly understood. Here, in mice carrying heteroplasmic C5024T in mt-tRNAAla– that impairs oxidative phosphorylation – we found a reduced mutation burden in peripheral T and B memory lymphocyte subsets, compared to their naïve counterparts. Furthermore, selection diluting the mutation was inducedin vitroby triggering T and B cell antigen receptors. While C5024T dysregulated naïve CD8+T cell respiration and metabolic remodeling post-activation, these phenotypes were partially ameliorated by selection. Analogous to mice, peripheral blood memory T and B lymphocyte subsets from human MELAS (Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like episodes) patients – carrying heteroplasmic A3243G in mt-tRNALeu– displayed a reduced mutation burden, compared to naïve cells. In both humans and mice, mtDNA selection was observed in IgG+antigen-specific B cells after SARS-CoV-2 Spike vaccination, illustrating an on-going processin vivo. Taken together, these data illustrate purifying selection of pathogenic mtDNA variants during the oxidative phosphorylation checkpoints of the naïve-memory lymphocyte transition.HighlightsIn human MELAS patients (A3243G in mt-tRNALeu) and a related mouse model (C5024T in mt-tRNAAla), T and B memory subsets displayed a reduced mtDNA mutation burden compared to their naïve counterparts.Selection was observed in antigen-specific IgG+B cells after SARS-CoV-2 Spike protein vaccination.T and B cell antigen receptor stimulation triggered purifying selectionin vitro, facilitating mechanistic studies of mtDNA selection.Heteroplasmic pathogenic mutations in mtDNA dysregulated metabolic remodeling after lymphocyte activation and reduced macrophage OXPHOS capacity.

MELAS syndrome (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) is a genetically determined disease caused by mutations in mitochondrial DNA. We present a girl who was suspected of MELAS syndrome during the diagnostic evaluation of short stature. The patient suffered from symptoms potentially indicating mitochondrial disease, such as muscular weakness, cranial nerve VI palsy, headaches, retinitis pigmentosa, sensory-neural hearing loss, and elevated lactic acid. T2-weighted brain MRI showed hyperintense lesions in the white matter. Muscular biopsy revealed ragged red fibres. Genetic evaluation did not detect the most common mutations in the MT-TL1 gene and MT-ND5 gene. Endocrine tests led to the confirmation of growth hormone deficiency, and so replacement treatment was started. After 1 year of recombinant growth hormone therapy the patient was diagnosed with diabetes. At the age of 14 years the LH-RH test showed prepubertal values. Endocrine disorders may be one of the first manifestations of MELAS syndrome. In differential diagnosis of short stature, less common causes, such as mitochondrial diseases, should be taken into consideration.Zespół MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) jest chorobą uwarunkowaną genetycznie, związaną z mutacją w mitochondrialnym DNA. Przedstawiamy przypadek pacjentki, u której w trakcie diagnostyki niedoboru wzrostu wysunięto podejrzenie zespołu MELAS. U dziewczynki oprócz niedoboru wzrostu obserwowano inne objawy sugerujące chorobę mitochondrialną, takie jak m.in. hipotonia mięśniowa, bóle głowy, niedowład nerwu VI lewego, zwyrodnienie barwnikowe siatkówki, niedosłuch zmysłowo-nerwowy, zwiększone stężenie kwasu mlekowego. W rezonansie magnetycznym mózgu zobrazowano hiperdensyjne zmiany w istocie białej w obrazach T2- zależnych. Biopsja mięśnia wykazała obraz poszarpanych włókien czerwonych charakterystyczny dla zespołu MELAS. W wykonanych badaniach genetycznych nie wykryto najczęstszych mutacji w genie MT-TL1 i MT-ND5. W toku diagnostyki endokrynologicznej rozpoznano somatotropinową niedoczynność przysadki, rozpoczęto leczenie preparatem hormonu wzrostu (rhGH). Po roku leczenia rhGH na podstawie doustnego testu obciążenia glukozą zdiagnozowano cukrzycę. Ponadto u obecnie 14-letniej dziewczynki obserwuje się opóźnione dojrzewanie płciowe. Test z LH–RH wykazał wartości przedpokwitaniowe. Zaburzenia endokrynologiczne mogą być jedną z pierwszych manifestacji zespołu MELAS. W diagnostyce niedoboru wzrostu należy uwzględniać jego rzadsze przyczyny jak np. choroby mitochondrialne.