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American Journal of Ophthalmology Case... Jun 2024To describe a case with Leber's hereditary optic neuropathy (LHON) like optic atrophy in the presence of gene variant m.8969G > A.
PURPOSE
To describe a case with Leber's hereditary optic neuropathy (LHON) like optic atrophy in the presence of gene variant m.8969G > A.
OBSERVATIONS
A 20-year-old patient with a history of mild developmental delay, mild cognitive impairment, and positional tremor presented with subacute painless visual loss over a few weeks. Mitochondrial genome sequencing revealed a variant in , m.8969G > A (p.Ser148Asn). This variant was previously reported in association with mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA) and with nephropathy, followed by brain atrophy, muscle weakness and arrhythmias, but not with optic atrophy.
CONCLUSIONS AND IMPORTANCE
Rare variants in can also cause LHON like optic atrophy. It is important to perform further genetic analysis of mitochondrial DNA in genetically unsolved cases suspected of Leber's hereditary optic neuropathy to confirm the clinical diagnosis.
PubMed: 38756953
DOI: 10.1016/j.ajoc.2024.102070 -
Journal of the American College of... Jun 2024Propylene glycol (PG) is a diol (a double alcohol) that is commonly used as a food additive to preserve shelf life and enhance flavors, texture, and appearance. Although...
Propylene glycol (PG) is a diol (a double alcohol) that is commonly used as a food additive to preserve shelf life and enhance flavors, texture, and appearance. Although PG makes up only a small percentage of cornstarch, ingestion of large doses can cause lactic acidosis leading to hyperosmolarity, high anion gap metabolic acidosis (HAGMA), and a sepsis-like syndrome. A 17-year-old female presented to our emergency department (ED) with chronic chest pain, dyspnea, nausea, and vomiting. Laboratory testing showed an elevated anion gap of 18 mEq/L with no osmolar gap. Toxicology screening was negative. Twelve hours after ED arrival, she admitted to consuming one box of cornstarch daily for the past 6 months. She was admitted to the intensive care unit (ICU) with multisystem organ failure due to propylene glycol toxicity. After empiric treatment with fomepizole and continuous renal replacement therapy, her clinical status gradually improved. This case highlights the importance of obtaining a thorough dietary history in patients with suspected toxicities, especially when laboratory values demonstrate an unexplained HAGMA and/or lactic acidosis. Prompt recognition and therapeutic intervention with fomepizole, a potent inhibitor of alcohol dehydrogenase, is essential in reducing life-threatening sequelae following toxic alcohol ingestions.
PubMed: 38756767
DOI: 10.1002/emp2.13188 -
Scientific Reports May 2024This pilot study focusing on Sickle Cell Anemia (SCA) patients offers a comprehensive and integrative evaluation of respiratory, cardiovascular, hemodynamic, and...
This pilot study focusing on Sickle Cell Anemia (SCA) patients offers a comprehensive and integrative evaluation of respiratory, cardiovascular, hemodynamic, and metabolic variables during exercise. Knowing that diastolic dysfunction is frequent in this population, we hypothesize that a lack of cardiac adaptation through exercise might lead to premature increase in blood lactate concentrations in SCA patients, a potential trigger for acute disease complication. SCA patients were prospectively included in PHYSIO-EXDRE study and underwent a comprehensive stress test with a standardized incremental exercise protocol up to 4 mmol L blood lactate concentration (BL4). Gas exchange, capillary lactate concentration and echocardiography were performed at baseline, during stress test (at ∼ 2 mmol L) and BL4. The population was divided into two groups and compared according to the median value of percentage of theoretical peak oxygen uptake (% ) at BL4. Twenty-nine patients were included (42 ± 12 years old, 48% of women). Most patients reached BL4 at low-intensity exercise [median value of predicted power output (W) was 37%], which corresponds to daily life activities. The median value of % at BL4 was 39%. Interestingly, diastolic maladaptation using echocardiography during stress test along with hemoglobin concentration were independently associated to early occurrence of BL4. As BL4 occurs for low-intensity exercises, SCA patients may be subject to acidosis-related complications even during their daily life activities. Beyond assessing physical capacities, our study underlines that diastolic maladaptation during exercise is associated with an early increase in blood lactate concentration.
Topics: Humans; Anemia, Sickle Cell; Male; Female; Adult; Diastole; Middle Aged; Exercise Tolerance; Exercise Test; Pilot Projects; Echocardiography; Adaptation, Physiological; Lactic Acid; Prospective Studies; Oxygen Consumption; Exercise
PubMed: 38750085
DOI: 10.1038/s41598-024-61689-w -
Research Square Apr 2024Septic patients who develop acute respiratory failure (ARF) requiring mechanical ventilation represent a heterogenous subgroup of critically ill patients with widely...
Septic patients who develop acute respiratory failure (ARF) requiring mechanical ventilation represent a heterogenous subgroup of critically ill patients with widely variable clinical characteristics. Identifying distinct phenotypes of these patients may reveal insights about the broader heterogeneity in the clinical course of sepsis. We aimed to derive novel phenotypes of sepsis-induced ARF using observational clinical data and investigate their generalizability across multi-ICU specialties, considering multi-organ dynamics. We performed a multi-center retrospective study of ICU patients with sepsis who required mechanical ventilation for ≥24 hours. Data from two different high-volume academic hospital systems were used as a derivation set with N=3,225 medical ICU (MICU) patients and a validation set with N=848 MICU patients. For the multi-ICU validation, we utilized retrospective data from two surgical ICUs at the same hospitals (N=1,577). Clinical data from 24 hours preceding intubation was used to derive distinct phenotypes using an explainable machine learning-based clustering model interpreted by clinical experts. Four distinct ARF phenotypes were identified: A (severe multi-organ dysfunction (MOD) with a high likelihood of kidney injury and heart failure), B (severe hypoxemic respiratory failure [median P/F=123]), C (mild hypoxia [median P/F=240]), and D (severe MOD with a high likelihood of hepatic injury, coagulopathy, and lactic acidosis). Patients in each phenotype showed differences in clinical course and mortality rates despite similarities in demographics and admission co-morbidities. The phenotypes were reproduced in external validation utilizing an external MICU from second hospital and SICUs from both centers. Kaplan-Meier analysis showed significant difference in 28-day mortality across the phenotypes ( <0.01) and consistent across both centers. The phenotypes demonstrated differences in treatment effects associated with high positive end-expiratory pressure (PEEP) strategy. The phenotypes demonstrated unique patterns of organ injury and differences in clinical outcomes, which may help inform future research and clinical trial design for tailored management strategies.
PubMed: 38746442
DOI: 10.21203/rs.3.rs-4307475/v1 -
Journal of Translational Medicine May 2024Inherited deficiency of thymidine phosphorylase (TP), encoded by TYMP, leads to a rare disease with multiple mitochondrial DNA (mtDNA) abnormalities, mitochondrial...
Inherited deficiency of thymidine phosphorylase (TP), encoded by TYMP, leads to a rare disease with multiple mitochondrial DNA (mtDNA) abnormalities, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). However, the impact of TP deficiency on lysosomes remains unclear, which are important for mitochondrial quality control and nucleic acid metabolism. Muscle biopsy tissue and skin fibroblasts from MNGIE patients, patients with m.3243 A > G mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and healthy controls (HC) were collected to perform mitochondrial and lysosomal functional analyses. In addition to mtDNA abnormalities, compared to controls distinctively reduced expression of LAMP1 and increased mitochondrial content were detected in the muscle tissue of MNGIE patients. Skin fibroblasts from MNGIE patients showed decreased expression of LAMP2, lowered lysosomal acidity, reduced enzyme activity and impaired protein degradation ability. TYMP knockout or TP inhibition in cells can also induce the similar lysosomal dysfunction. Using lysosome immunoprecipitation (Lyso- IP), increased mitochondrial proteins, decreased vesicular proteins and V-ATPase enzymes, and accumulation of various nucleosides were detected in lysosomes with TP deficiency. Treatment of cells with high concentrations of dThd and dUrd also triggers lysosomal dysfunction and disruption of mitochondrial homeostasis. Therefore, the results provided evidence that TP deficiency leads to nucleoside accumulation in lysosomes and lysosomal dysfunction, revealing the widespread disruption of organelles underlying MNGIE.
Topics: Humans; Lysosomes; Thymidine Phosphorylase; Mitochondrial Encephalomyopathies; Fibroblasts; DNA, Mitochondrial; Mitochondria; Nucleosides; Intestinal Pseudo-Obstruction; Ophthalmoplegia; Muscular Dystrophy, Oculopharyngeal; Male; Female; Skin; Lysosomal-Associated Membrane Protein 2
PubMed: 38741129
DOI: 10.1186/s12967-024-05275-8 -
Frontiers in Pediatrics 2024There are few reports of infantile mitochondrial DNA depletion syndrome (MDDS) caused by variants in and the correlation between genotype and phenotype has rarely been...
BACKGROUND
There are few reports of infantile mitochondrial DNA depletion syndrome (MDDS) caused by variants in and the correlation between genotype and phenotype has rarely been analyzed in detail. This study investigated an infantile patient with MDDS, from clinical characteristics to genetic causes.
METHODS
Routine physical examinations, laboratory assays, which included gas chromatography-mass spectrometry of blood and urine, and MRI scans were performed to obtain an exact diagnosis. Whole-exome sequencing was used to pinpoint the abnormal gene and bioinformatic analyses were performed on the identified variant.
RESULTS
The case presented with progressive neurologic deterioration, failure to thrive, respiratory distress and lactic acidosis. Sequencing revealed that the patient had a homozygous novel missense variant, c.155T>C (p.Ile52Thr), in exon 2 of the gene. Multiple lines of bioinformatic evidence suggested that this was a likely detrimental variant. In addition, reported variants were compiled from the relevant literature to analyze disease etiology. We found a distinctive distribution of genotypes across disease manifestations of different severity. Pathogenic alleles of were significantly enriched in MDDS cases.
CONCLUSION
The novel variant is a likely genetic cause of MDDS. It expands our understanding of the pathogenic variant spectrum and the contribution of the gene to the disease spectrum of MDDS.
PubMed: 38737634
DOI: 10.3389/fped.2024.1363728 -
International Journal of Critical... 2024Metformin toxicity is a life-threatening condition with high morbidity and mortality. Toxicity predominantly occurs in the setting of acute renal dysfunction, as the... (Review)
Review
Metformin toxicity is a life-threatening condition with high morbidity and mortality. Toxicity predominantly occurs in the setting of acute renal dysfunction, as the drug is solely eliminated by the kidneys. While this risk is widely known to clinicians, diagnosing metformin toxicity is challenging because commercially available serum metformin levels require days to weeks to result. Therefore, the intensivist must rely on medical history, clinical presentation, and routine laboratory findings to make the preliminary diagnosis. Treatment of metformin toxicity includes supportive fluid hydration, vasopressors, and emergent hemodialysis (HD). We report three critically ill patients who had near-fatal severe metformin-induced lactic acidosis. Their metformin levels were markedly higher than the toxicity threshold reported by the Federal Drug Agency. These patients made a prompt and complete recovery after the initiation of HD. We also review the pathophysiology, clinical presentation, diagnosis, and treatment of metformin toxicity.
PubMed: 38715749
DOI: 10.4103/ijciis.ijciis_46_23 -
Reversible encephalitis-like episodes in fragile X-associated tremor/ataxia syndrome: a case report.BMC Neurology May 2024Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by CGG repeat expansion of FMR1 gene. Both FXTAS and neuronal intranuclear...
BACKGROUND
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by CGG repeat expansion of FMR1 gene. Both FXTAS and neuronal intranuclear inclusion disease (NIID) belong to polyglycine diseases and present similar clinical, radiological, and pathological features, making it difficult to distinguish these diseases. Reversible encephalitis-like attacks are often observed in NIID. It is unclear whether they are presented in FXTAS and can be used for differential diagnosis of NIID and FXTAS.
CASE PRESENTATION
A 63-year-old Chinese male with late-onset gait disturbance, cognitive decline, and reversible attacks of fever, consciousness impairment, dizziness, vomiting, and urinary incontinence underwent neurological assessment and examinations, including laboratory tests, electroencephalogram test, imaging, skin biopsy, and genetic test. Brain MRI showed T2 hyperintensities in middle cerebellar peduncle and cerebrum, in addition to cerebellar atrophy and DWI hyperintensities along the corticomedullary junction. Lesions in the brainstem were observed. Skin biopsy showed p62-positive intranuclear inclusions. The possibilities of hypoglycemia, lactic acidosis, epileptic seizures, and cerebrovascular attacks were excluded. Genetic analysis revealed CGG repeat expansion in FMR1 gene, and the number of repeats was 111. The patient was finally diagnosed as FXTAS. He received supportive treatment as well as symptomatic treatment during hospitalization. His encephalitic symptoms were completely relieved within one week.
CONCLUSIONS
This is a detailed report of a case of FXTAS with reversible encephalitis-like episodes. This report provides new information for the possible and rare features of FXTAS, highlighting that encephalitis-like episodes are common in polyglycine diseases and unable to be used for differential diagnosis.
Topics: Humans; Male; Middle Aged; Tremor; Fragile X Syndrome; Ataxia; Encephalitis; Fragile X Mental Retardation Protein; Diagnosis, Differential; Intranuclear Inclusion Bodies; Neurodegenerative Diseases
PubMed: 38714961
DOI: 10.1186/s12883-024-03641-z -
Sports Medicine and Health Science Jun 2024The purpose of this research was to use a historical method and core principles from scientific philosophy to explain why mistakes were made in the development of the... (Review)
Review
The purpose of this research was to use a historical method and core principles from scientific philosophy to explain why mistakes were made in the development of the lactic acidosis construct. On a broader scope, this research explains what science is, why some scientists despite good intention, often get it wrong, and why it takes so long (decades) to correct these errors. Science is a human behaviour that consists of the identification of a problem based on the correct application of prior knowledge, the development of a method to best resolve or test the problem, completion of these methods to acquire results, and then a correct interpretation of the results. If these steps are done correctly there is an increased probability (no guarantee) that the outcome is likely to be correct. Thomas Kuhn proposed that you can understand what science is from how it has been performed, and from his essays he revealed a very dysfunctional form of science that he called 'normal' (due the preponderance of its presence) science. Conversely, Karl Popper was adamant that the practice of 'normal' science revealed numerous flaws that deviate from fundamental principles that makes science, science. Collectively, the evidence reveals that within the sports medicine and health sciences, as with all disciplines, errors in science are more frequent than you might expect. There is an urgent need to improve how we educate and train scientists to prevent the pursuit of 'normal' science and the harm it imparts on humanity.
PubMed: 38708325
DOI: 10.1016/j.smhs.2024.03.008 -
American Journal of Ophthalmology Case... Jun 2024To describe examination and findings in a case of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) with particular focus on the ocular...
PURPOSE
To describe examination and findings in a case of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) with particular focus on the ocular sequelae from diabetes.
OBSERVATIONS
Neovascular glaucoma is not a common manifestation of MELAS.
CONCLUSIONS AND IMPORTANCE
We present a rare case of neovascular glaucoma in a patient with MELAS with a history of diabetes, hearing loss, and macular dystrophy. MELAS should be suspected in patients with this constellation of symptoms.
PubMed: 38707951
DOI: 10.1016/j.ajoc.2024.102064