Cytosolic phosphoenoylpyruvate carboxykinase (PEPCK-C) is an essential, rate-limiting enzyme in the gluconeogenesis pathway. PEPCK-C deficiency presents with hypoglycaemia, hyperlactataemia and hepatopathy, and was first reported in association with bi-allelic PCK1 variants in 2014. A Finnish cohort with a common homozygous variant (c.925G>A, p.(Gly309Arg)) is well-described, but few other genotypes are reported. Five non-Finnish probands with PEPCK-C deficiency with novel genotypes are presented. All five presented with hypoglycaemia (hypoketotic in three), lactic acidosis, and elevated transaminases. Age at presentation was newborn to 3 years. Two presented with hypoglycaemic seizures after overnight fasting during intercurrent infection. Prominent renal manifestations were noted in two, including proximal tubulopathy with bicarbonate wasting, and acute renal failure, respectively, with markedly elevated plasma glutamine in both. Urine organic acid analysis identified elevated lactate, dicarboxylic aciduria, and tricarboxylic acid cycle metabolites, especially fumarate which was detected in 3/5. PCK1 genotypes included homozygous missense variants c.1211C>T, p.(Ser404Leu) and c.265G>A, p.(Glu89Lys), or compound heterozygous variants including c.824del, p.(Gly275Valfs21); c.496G>A, p.(Val166Met); c.961 + 2 T>C; c.204del, p.(Leu69), and c.728A>G p.(Lys243Arg). A severe phenotype with failure to thrive, short fasting tolerance, liver dysfunction, and tubulopathy was noted in one individual harboring compound heterozygous splicing and nonsense variants. Evidence from in silico analyses and the specific phenotype supported the pathogenicity of novel missense variants. These patients reinforce the recognizable presentation of PEPCK-C deficiency while highlighting renal manifestations and expanding the genotypic spectrum.

We report on an 8-week-old infant who presented as an outpatient due to abnormal skin color a few hours after surgical achillotomy under local anesthesia. The infant showed a dirty brownish, cyanotic skin color with reduced general condition and hypoxemia at SaO2 84% without improvement by oxygen supplementation. The blood gas analysis showed lactic acidosis and a significantly elevated methemoglobin level of 38% (reference value≤1.5%). Due to the temporal correlation, this is most likely due to the infiltration anesthesia with mepivacaine, which was performed for the achillotomy. Treatment with methylene blue was administered, resulting in a restitutio ad integrum.Methemoglobin is formed by the oxidation of iron contained in hemoglobin, which prevents oxygen from binding. Significant cyanosis can occur when the methemoglobin level exceeds 10%. The reduction of methemoglobin to oxyhemoglobin by the enzyme NADH cytochrome b5 reductase is physiologically not fully developed in young infants. Furthermore, the hemoglobin of young infants is more easily oxidized, which makes these children susceptible to methemoglobinaemia. As the methemoglobin content increases, the blood turns brown with increasing levels of methemoglobin, which is visible clinically and in blood samples.Local anesthetics applied cutaneously, subcutaneously or mucous membranes can cause clinically relevant methemoglobinemia, which can result in potentially severe hypoxemia. The risk is increased in young infants. It is important to recognize methemoglobinemia as the cause of cyanosis in time, as it is easily treatable.

Myopathy, Lactic Acidosis, and Sideroblastic Anemia type 2 (MLASA2) is a rare mitochondrial disorder caused by pathogenic variants (PVs) in the YARS2 gene (which encodes the Mt-TyrRS protein. We performed a comprehensive clinical–molecular synthesis by integrating a systematic review and meta-analysis of all published MLASA2 cases with survival modeling and three-dimensional structural mapping. Across the aggregated cohort, anemia (88.6%), sideroblastic phenotype (85.7%), and lactic acidosis (82.9%) were the most prevalent phenotypes. Fifteen PVs were identified, dominated by p.(Phe52Leu) (29.4%). Survival estimates were 94.1% at 10 years, 70.7% at 30 years, and 42.4% at 50 years; cardiomyopathy and diagnosis before age 10 were associated with decreased survival. We generated the first 3D structural map of all reported Mt-TyrRS PVs, identifying nine spatial hotspots across catalytic, anticodon-binding, and tRNA-binding domains. An integrated framework combining structural density, clinical severity, in silico predictions, and ΔΔG destabilization classified three clusters as High-risk, three as Medium-risk, and three as Low-risk. Among them, cluster 3, a large catalytic hotspot encompassing 44 residues and including nearly half of all MLASA2 cases, showed the strongest pathogenic convergence. This clinical–structural integration provides new insights for a better comprehension of MLASA2, enhancing variant interpretation and improving diagnostic and prognostic precision.

Background Sodium-glucose cotransporter-2 (SGLT2) inhibitors are increasingly prescribed for heart failure and chronic kidney disease, irrespective of diabetic status. While their cardiovascular and renal benefits are well established, euglycemic ketoacidosis (EKA) remains a rare but potentially life-threatening complication that can occur even in non-diabetic individuals. Case presentation We report a 58-year-old man with ischemic cardiomyopathy (LVEF 35%) and stage 2 chronic kidney disease who developed nausea, vomiting, and fatigue two weeks after initiating dapagliflozin. Laboratory evaluation revealed high-anion-gap metabolic acidosis (pH 7.21 [reference: 7.35–7.45], HCO 3 - 12 mmol/L [reference: 22–28 mmol/L], anion gap 23 mmol/L [reference: 8–16 mmol/L])with markedly elevated β-hydroxybutyrate (5.4 mmol/L) and normal plasma glucose (108 mg/dL). Diabetes, infection, lactic acidosis, and hepatic dysfunction were excluded. Management & outcome The SGLT2 inhibitor was discontinued, and the patient was treated with intravenous saline, insulin infusion, and dextrose. Metabolic parameters normalized within 48 hours, and he was discharged in stable condition. No recurrence was noted at three-month follow-up. Conclusion This case highlights that SGLT2 inhibitors can precipitate euglycemic ketoacidosis even in non-diabetic patients. Because normal glucose levels may obscure recognition, clinicians should maintain a high index of suspicion and perform ketone testing in patients on SGLT2 therapy who present with unexplained gastrointestinal or constitutional symptoms.

Introduction Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a rare mitochondrial disorder primarily presenting with neurological manifestations, but it may also lead to gastrointestinal complications such as intestinal pseudo-obstruction, which can significantly complicate clinical management. Case presentation We report a 24-year-old woman with genetically confirmed MELAS (mtDNA A3243G mutation and TRPM3 c.2878G > T heterozygous variant) who was admitted with acute confusion and generalized convulsive seizures. Neuroimaging revealed multiple low-density lesions on CT and abnormal signals in the bilateral occipital lobes and basal ganglia on MRI. Although her neurological symptoms stabilized after emergency treatment, she subsequently developed recurrent episodes of intestinal obstruction characterized by vomiting and decreased bowel sounds. Conservative measures were unsuccessful, and jejunal decompression was performed, resulting in significant improvement in bowel function and successful transition to normal oral intake. Conclusion This case illustrates delayed acute intestinal pseudo-obstruction (AIPO) as an uncommon but clinically important complication of MELAS, and shows that timely jejunal decompression can be an effective therapeutic intervention in selected patients.

Two cases of mitochondrial encephalomyopathy with lactic acidosis and stroke like episodes complicated by Henoch-Schönlein purpura nephritis

This study aimed to determine whether urinary pH can be used to predict metabolic acidosis in sheep with acute rumen lactic acidosis (ALRA). ALRA was induced by administering sucrose intraruminally to 40 apparently healthy sheep. Venous blood and urine samples were collected before induction (‒18h) and prior to treatment (0h) to measure blood pH, base excess (BE), and urinary pH. Associations between urinary and blood pH, and between urinary pH and BE, were examined using Pearson correlation and linear regression. Blood and urinary pH were positively correlated (r = 0.633; P < 0.001), as were BE and urinary pH (r = 0.602; P < 0.001). The regression coefficients were r2 = 0.401 and r2 = 0.362, respectively, and the relationships were described by the following equations: pH = (urinary pH × 0.063) + 6.909; BE = (urinary pH × 3.66) ‒ 30.512. Calculated values of blood pH and BE did not differ from measured values ​​(7.346 ± 0.072 vs. 7.346 ± 0.114; P = 0.979; and ‒5.11 ± 4.21 mmol/L vs. ‒5.11 ± 6.99 mmol/L; P = 0.998, respectively). When used as a diagnostic criterion for metabolic acidosis, the BE calculated from urinary pH demonstrated a sensitivity of 81.8%, specificity of 82.5%, negative predictive value of 84.6%, positive predictive value of 79.4%, and accuracy of 82.2%. These findings indicate that urinary pH can be used as a practical predictor of metabolic acidosis in sheep with ALRA.

A bstract Metformin is the first-line therapy for the patients with type 2 diabetes, which is a time-tested drug for its safety. While metformin therapy is commonly reported to have gastrointestinal side effects, lactic acidosis is a rare complication of metformin use. Here, we present a case of 65-year-old women with known type 2 diabetes mellitus continued to take her usual medications, including metformin, while suffering from urinary tract infection. On presentation, she was found to have high blood glucose, severe acidosis without ketonuria, and acute kidney injury. Supportive treatment resulted in rapid improvement in her metabolic and hemodynamic parameters. Metformin-associated lactic acidosis, a rare complication, is reported in patients mostly among those with other risk factors for lactic acidosis. Patient education and awareness among physicians are essential for prevention and treatment of this potentially fatal condition.

IntroductionMultiple symmetric lipomatosis (MSL) is a rare disorder characterized by symmetrical, unencapsulated lipomatous masses, most commonly involving the neck and upper trunk. Beyond cosmetic disfigurement, MSL can be associated with systemic complications such as insulin resistance, type 2 diabetes, peripheral neuropathy, and hepatosplenomegaly. In this report, we present a genetically confirmed syndromic MSL case carrying a homozygous pathogenic variant in the Mitofusin-2 (MFN2) gene, consistent with MSL and axonal sensorimotor neuropathy, together with a homozygous variant in the Gonadotropin-Releasing Hormone Receptor (GNRHR) gene, consistent with hypogonadotropic hypogonadism type 7.Clinical CaseA 52-year-old male patient with type 2 diabetes diagnosed in 2022 (HbA1c: 7.2%) and treated with oral antidiabetics (linagliptin and pioglitazone) presented with bilateral limb weakness, glove-and-stocking paresthesia, cervical swelling, and inadequately controlled diabetes. His medical history included hepatic steatosis and two prior spinal surgeries for benign lipomatous tumors. Family history revealed paternal consanguinity and a sibling with similar neuromuscular symptoms resulting in immobility.Physical examination showed cervical lipomatosis, parotid gland enlargement, scoliosis, and lower extremity motor deficits and a BMI of 23.9 kg/m². Laboratory results demonstrated insulin resistance (C-peptide: 10.1 μg/L), hypertriglyceridemia (229 mg/dL), hypoalbuminemia, and pancytopenia consistent with hypersplenism. Imaging confirmed hepatosplenomegaly, marked cervical subcutaneous lipomatous infiltration, and peripheral neuropathy. Neck MRI revealed bilateral parathyroid region masses, more prominent on the right side, consistent with lipomatous lesions (right: 45×45 mm; left: 40×35 mm).Genetic testing identified a homozygous pathogenic variant in the MFN2 gene (c.2119C>T, p.Arg707Trp), consistent with MSL and axonal sensorimotor neuropathy. Additionally, a homozygous GNRHR variant (c.317A>G, p.Gln106Arg) was detected, consistent with hypogonadotropic hypogonadism type 7. Despite normal testosterone levels, the patient had a history of infertility, and relatives reported delayed puberty.The patient is currently treated with linagliptin and pioglitazone for glycemic control, nutritional support, and symptomatic therapy for neuropathy. Metformin was avoided due to the risk of lactic acidosis in mitochondrial dysfunction, and SGLT-2 inhibitors were contraindicated due to prior SGLT-2–induced urticaria.ConclusionThis genetically confirmed syndromic form of MSL was associated with insulin resistance, hepatic steatosis, and axonal neuropathy. Early diagnosis, genetic counseling, and multidisciplinary management are essential for the recognition of rare familial lipomatosis disorders. As one of the few reported cases with concurrent MFN2 and GNRHR mutations, this case further expands the genotype–phenotype spectrum of MSL.Figure 1:Neck MRI demonstrating extensive bilateral subcutaneous lipomatous infiltration, more prominent on the right side, with masses in the parathyroid regions (right: 45×45 mm; left: 40×35 mm), consistent with multiple symmetric lipomatosis.

Refractory status epilepticus (RSE) is a medical emergency defined as "status epilepticus persisting despite administration of at least 2 appropriately selected and dosed parenteral medications including a benzodiazepine." Control of RSE is critical to avoid irreversible neuronal damage, with midazolam and propofol as the most commonly used agents. This study evaluates the effectiveness of midazolam versus propofol in preventing mortality and complications of RSE. Patients from the TriNetX Research Network who received either midazolam or propofol monotherapy on the day of RSE onset were included. Outcomes were assessed at 30 days and maximal follow-up (≤20 years) using Cox proportional hazard models. Propensity score matching (1:1) controlled for demographics and 93 comorbidities from the Charlson Comorbidity Index. Among 117 736 patients with RSE, 5310 received midazolam and 2136 received propofol. Midazolam was associated with significantly decreased hazards of mortality at 30 days (HR = 0.509 [95% CI: 0.397, 0.653]) but not at maximal follow-up (HR = 0.922 [0.797, 1.067]). Midazolam was also associated with significantly reduced hazards of lactic acidosis (HR = 0.537 [0.427, 0.674]), rhabdomyolysis (HR = 0.295 [0.150, 0.578]), hypertriglyceridemia (HR = 0.316 [0.135, 0.740]), tracheostomy (HR = 0.633 [0.438, 0.916]), PEG placement (HR = 0.519 [0.371, 0.725]), and mechanical ventilation (HR = 0.313 [0.265, 0.370]). Among patients with a traumatic brain injury in the week prior to RSE, midazolam was associated with a significantly lower hazard of 30-day mortality (HR = 0.381 [0.136, 0.993]), while the hazards were not significantly changed in patients with CNS infections (HR = 1.150 [0.351, 3.768]) or cerebrovascular disease (HR = 0.656 [0.421, 1.025]) in the week prior to RSE onset. Midazolam monotherapy for RSE was associated with decreased mortality and adverse effects compared to propofol monotherapy in the short term, but relatively equivalent in the long term. Prospective comparative trials are needed to ascertain superiority of either intervention in reducing morbidity and mortality in patients with RSE.

Adrenaline (epinephrine) is an endogenous catecholamine with potent β₁-adrenergic, moderate β₂-, and α₁-adrenergic activity, widely used in resuscitation and critical care. At lower infusion rates, it increases cardiac output and decreases systemic vascular resistance. While at higher doses it will result in greater inotropy and peripheral vasoconstriction, with potential adverse effects such as arrhythmias, lactic acidosis, and ischemia. This review synthesises contemporary evidence surrounding adrenaline's physiological and pharmacological profile, highlighting its role in cardiac arrest, perioperative medicine, sepsis, toxidromes, and specific contraindicated states. Clinical trials, including PARAMEDIC-2 and various observational registries, support adrenaline's effectiveness in achieving return of spontaneous circulation but raise concerns regarding neurological outcomes. The timing and dosing of adrenaline administration, particularly in non-shockable rhythms and in-hospital cardiac arrests, appear critical to optimising survival. Specific scenarios, such as post-cardiac surgery, neurosurgery, tamponade, and paediatric sepsis, demand tailored approaches due to distinct haemodynamic and pharmacological considerations. Conversely, adrenaline use may be contraindicated or require modification in patients with hypertrophic cardiomyopathies, carcinoid syndrome, or catecholamine-sensitive conditions. Despite its ubiquitous role in acute care, ongoing research is needed to define optimal dosing strategies and identify patient subgroups most likely to benefit from its use. Thoughtful, context-specific administration of adrenaline is essential to balancing efficacy with risk across the spectrum of emergency and perioperative medicine.

Patients in the intensive care unit often develop anion gap metabolic acidosis most commonly from lactic acidosis. Clinicians routinely measure serum lactate levels, but it is not clear if one is able to use the measured serum lactate level to determine if there is a second cause for anion gap metabolic acidosis in these critically ill patients. In this report, 503 episodes of lactic acidosis with serum lactate levels greater than 5 mmol/L at a single institution over two years were analyzed. The average serum anion gap minus serum lactate level in these patients was 6.9 ± 0.21 mEq/L, the average corrected anion gap was -1.3 ± 0.23 mEq/L and the average strong ion gap was 5.1 ± 0.3 mEq/L. The majority of the episodes with anion gap-serum lactate concentration >8.0 mEq/L were explained by elevated serum albumin concentration, elevated serum phosphorus concentration, presence of ketones in the urine or high β-hydroxybutyrate concentrations. The above data suggest that one can use the measured serum lactate concentration and subtract from the serum anion gap to determine if there is a second reason for anion gap metabolic acidosis.

Corticosteroids are commonly used to manage a multitude of conditions, ranging from autoimmune to neurological diseases, including central nervous system vasculitis and vasogenic edema from large strokes. Type A lactic acidosis and type B lactic acidosis are the two forms of lactic acidosis. Medications are the most common cause of type B lactic acidosis. An elevated lactate confers a higher mortality rate in patients. Corticosteroids are not commonly known to cause elevated lactate. The relationship between corticosteroids and lactic acidosis has only been described in critically ill patients in the intensive care unit and animal studies. There have not been any reports of this association in stable patients in the general ward setting. We describe a case of an elderly Chinese woman in her 70s, clinically stable, who was diagnosed with an acute stroke and who was undergoing inpatient rehabilitation in the general ward setting. She was started on a course of a tapering dose of dexamethasone for an incidental finding of a likely large meningioma with surrounding vasogenic edema. Shortly after starting dexamethasone, lactic acidosis was discovered on the basis of low bicarbonate. After a thorough workup, it was discovered that she had type B lactic acidosis, and dexamethasone was the likely cause of the elevated lactate. She remained asymptomatic and clinically well throughout this period. The lactic acidosis resolved within 72h of completion of dexamethasone. Early identification and addressing the underlying cause of lactic acidosis is important to reduce morbidity and mortality associated with lactic acidosis, this often requires a thorough medication review for type B lactic acidosis. This case report aims to increase awareness in clinicians regarding the association between dexamethasone and lactic acidosis.

Safety of metformin in chronic kidney disease and type 2 diabetes mellitus: a systematic review and meta-analysis.

Ethanol and lactate: Is there a direct association?

Whether metformin causes lactic acidosis in m.3243A&gt;G carriers depends on several factors

Synergistic therapeutic potential of curcumin and metformin: a multi-pathway approach to disease management.

Cooling-Seeking Behavior and Hot Sensation as Hallmark Toxidromes in Chlorfenapyr Intoxication: A Case Report.

Maternally Inherited Diabetes and Deafness (MIDD) syndrome is a rare form of monogenic diabetes most often caused by the pathogenic m.3243A>G mutation in the mitochondrial tRNALeu (UUR) gene, MT-TL1. Mutations causing MIDD are also associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). This paper analyzes the data of 15 probands with mitochondrial diabetes enrolled in the University of Chicago Monogenic Diabetes Registry all of whom have confirmed pathogenic variants, primarily m.3243A>G. Three of these probands (3/15) were selected for detailed case studies and pedigree analysis. Among the total cohort, sensorineural hearing loss (80%) and muscle weakness (53%) were frequent comorbidities, and all tested individuals were negative for islet autoantibodies. Treatment regimens included insulin and sulfonylureas, with some reporting use of biguanides despite safety concerns related to mitochondrial dysfunction. Three probands noted subjective improvement with mitochondrial cocktail supplementation. Familial heteroplasmy testing revealed significant inter- and intrafamilial variability. This cohort represents one of the largest clinically characterized U.S. populations with mitochondrial diabetes and underscores the importance of urine-based heteroplasmy testing and personalized management strategies informed by mitochondrial pathophysiology.

Hierarchy is a fundamental principle of network organization in the human brain. Functional gradient introduces a new perspective in identifying hierarchy alterations by capturing major axes of functional connectivity (FC) in lowdimensional space. However, whether this gradient structure is disrupted in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) patients with stroke-like episodes (SLE) and how this disruption modulated by gene expression profiles remain unknow. Thirty-one MELAS patients at acute stage (MELAS-acute) and 31 healthy controls (HC) underwent restingstate functional magnetic resonance imaging (rs-fMRI) scan. Based on the whole-brain voxel-wise FC patterns, functional gradient values were generated and group-averaged gradient values were further extracted and compared from global to voxel level. Combined with the Allen Human Brain Atlas, we then assessed the spatial correlations between MELAS-related gradient alterations and gene expression profiles. Relative to the HC, MELAS-acute patients exhibited global alterations in the principal gradient, including reduced gradient range and gradient variation. In addition, patients showed lower gradient values in the default mode network (DMN) but higher values in the ventral attention network (VAN) and sensorimotor network (SMN) at network and voxel level. Furthermore, we established a link between MELAS-acute related principal gradient and gene expression profiles, with two gene sets mainly enriched in mitochondrion, neuron, glutamatergic synapse, and ATPase activity. These results highlight the connectome gradient alterations in MELAS patients at acute stage and its linkage with gene expression profiles, providing insight into the neurobiological basis of functional alterations during the acute SLE stage in MELAS. AHBA = Allen Human Brain Atlas; DMN = default mode network; FPN = frontoparietal network; GO = Gene ontology; HC = healthy controls; MELAS = mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; MELAS-acute = MELAS patients at acute stage; MNI = Montreal Neurological Institute; SLE = stroke-like episodes; SMN = sensorimotor network; VAN = ventral attention network; VN = visual network.