Pyruvate Dehydrogenase Deficiency Research Articles

Upregulation of the AMPK-FOXO1-PDK4 pathway is a primary mechanism of pyruvate dehydrogenase activity reduction in tafazzin-deficient cells

Barth syndrome (BTHS) is a rare disorder caused by mutations in the TAFAZZIN gene. Previous studies from both patients and model systems have established metabolic dysregulation as a core component of BTHS pathology. In particular, features such as lactic acidosis, pyruvate dehydrogenase (PDH) deficiency, and aberrant fatty acid and glucose oxidation have been identified. However, the lack of a mechanistic understanding of what causes these conditions in the context of BTHS remains a significant knowledge gap, and this has hindered the development of effective therapeutic strategies for treating the associated metabolic problems. In the current study, we utilized tafazzin-knockout C2C12 mouse myoblasts (TAZ-KO) and cardiac and skeletal muscle tissue from tafazzin-knockout mice to identify an upstream mechanism underlying impaired PDH activity in BTHS. This mechanism centers around robust upregulation of pyruvate dehydrogenase kinase 4 (PDK4), resulting from hyperactivation of AMP-activated protein kinase (AMPK) and subsequent transcriptional upregulation by forkhead box protein O1 (FOXO1). Upregulation of PDK4 in tafazzin-deficient cells causes direct phospho-inhibition of PDH activity accompanied by increased glucose uptake and elevated intracellular glucose concentration. Collectively, our findings provide a novel mechanistic framework whereby impaired tafazzin function ultimately results in robust PDK4 upregulation, leading to impaired PDH activity and likely linked to dysregulated metabolic substrate utilization. This mechanism may underlie previously reported findings of BTHS-associated metabolic dysregulation.

Adult Onset of Pyruvate Dehydrogenase Deficiency Presenting with Dystonia and Chorea in Female Patient from India - A Very Rare Case

We reported a very rare case of pyruvate dehydrogenase complex E1α (PDHA1) gene deficiency presenting as cervical dystonia and chorea in an adult female patient from India. Patient was presented with a history of involuntary rhythmic repetitive movements of both hands, legs, and head, lips and stammering of speech with tilting of neck to one side along with orofacial dyskinetic movements since past 6 years and gait changes since past 4 years. Her symptoms were progressive in nature. Her physical examination and systemic examinations were normal. Neurological examinations suggestive of cervical dystonia with chorea form movements. Brain MRI investigations revealed marked atrophy of bilateral caudate nuclei and putamina. Patient had a familial history of father and second brother had mild hand tremors. Patient has been referred for whole exome sequencing. The exome data analysis identified a very rare and unusual heterozygous indel variant c.-20_-19delinsCT, (chrX:19344018_19344019delinsCT) in 5’UTR region of PDHA1 gene caused late phenotypic onset of cervical dystonia as major clinical manifestation of PDHA1 deficiency along with chorea form movement disorders at the age of 24 year. In conclusion, to the best of our literature knowledge this is the novel and unusual case of adult female patient wherein we are reporting a novel heterozygous indel variant c.-20_-19delinsCT, (chrX:19344018_19344019delinsCT) in 5’UTR region of PDHA1 gene responsible for PDHA1 deficiency presenting with cervical dystonia and chorea as major clinical manifestations. Hence, dystonia and chorea as major clinical manifestations of PDH deficiency could be considered in adult patients also rather than only in paediatric patients.

Loss of muscle PDH induces lactic acidosis and adaptive anaplerotic compensation via pyruvate-alanine cycling and glutaminolysis

Pyruvate dehydrogenase (PDH) is the rate-limiting enzyme for glucose oxidation that links glycolysis-derived pyruvate with the tricarboxylic acid (TCA) cycle. Although skeletal muscle is a significant site for glucose oxidation and is closely linked with metabolic flexibility, the importance of muscle PDH during rest and exercise has yet to be fully elucidated. Here, we demonstrate that mice with muscle-specific deletion of PDH exhibit rapid weight loss and suffer from severe lactic acidosis, ultimately leading to early mortality under low-fat diet provision. Furthermore, loss of muscle PDH induces adaptive anaplerotic compensation by increasing pyruvate-alanine cycling and glutaminolysis. Interestingly, high-fat diet supplementation effectively abolishes early mortality and rescues the overt metabolic phenotype induced by muscle PDH deficiency. Despite increased reliance on fatty acid oxidation during high-fat diet provision, loss of muscle PDH worsens exercise performance and induces lactic acidosis. These observations illustrate the importance of muscle PDH in maintaining metabolic flexibility and preventing the development of metabolic disorders.

The antianginal ranolazine fails to improve glycaemia in obese liver-specific pyruvate dehydrogenase deficient male mice.

Recent studies have demonstrated that stimulating pyruvate dehydrogenase (PDH, gene Pdha1), the rate-limiting enzyme of glucose oxidation, can reverse obesity-induced non-alcoholic fatty liver disease (NAFLD), which can be achieved via treatment with the antianginal ranolazine. Accordingly, our aim was to determine whether ranolazine's ability to mitigate obesity-induced NAFLD and hyperglycaemia requires increases in hepatic PDH activity. We generated liver-specific PDH-deficient (Pdha1Liver-/- ) mice, which were provided a high-fat diet for 12 weeks to induce obesity. Pdha1Liver-/- mice and their albumin-Cre (AlbCre ) littermates were randomized to treatment with either vehicle control or ranolazine (50 mg/kg) once daily via oral gavage during the final 5weeks, following which we assessed glucose and pyruvate tolerance. Pdha1Liver-/- mice exhibited no overt phenotypic differences (e.g. adiposity, glucose tolerance) when compared to their AlbCre littermates. Of interest, ranolazine treatment improved glucose tolerance and mildly reduced hepatic triacylglycerol content in obese AlbCre mice but not in obese Pdha1Liver-/- mice. The latter was independent of changes in hepatic mRNA expression of genes involved in regulating lipogenesis. Liver-specific PDH deficiency is insufficient to promote an NAFLD phenotype. Nonetheless, hepatic PDH activity partially contributes to how the antianginal ranolazine improves glucose tolerance and alleviates hepatic steatosis in obesity.

Machine-learning Assisted Differentiation Between Physiological Oscillation Epochs and Muscle or Epileptiform activity in EEGs (S30.005)

<h3>Objective:</h3> Machine-learning assisted separation of spontaneous cognition-relevant EEG oscillations from EEG perturbation induced by epileptiform events and muscle artifacts. <h3>Background:</h3> Transient band-limited alpha and gamma frequency oscillations in EEGs of awake subjects reflect cognitive processes and integrity of excitation-inhibition balance. These oscillations are diminished in disorders such as mitochondrial encephalopathies as we have previously shown. Automated capture of such oscillation epochs in prolonged EEGs can prove valuable for numerous clinical and research studies. However, EEG recordings can be degraded by superimposed high frequency activity inherent in movement and epileptiform discharges. <h3>Design/Methods:</h3> Forty band-limited alpha and gamma spontaneous oscillation epochs were recorded from electrode C3 in a standard 20-lead EEG configuration. The gaussian distribution of non-event wavelet scalogram allowed automated identification of outlier putative events, which were then confirmed or rejected by a human observer. An instantaneous wavelet scalogram “cross-section” of the event was used to generate a representative frequency waveform for that event and analyzed using action potential waveform sorting Wave clus (<i>Neural Computation</i> 16, 1661–1687; 2004). This protocol was applied to EEGs containing muscle (27 events) and to EEGs with epileptiform activity (36 events) due to mitochondrial pyruvate dehydrogenase deficiency. <h3>Results:</h3> Oscillation epoch waveforms exhibited distinct band-limited peaks which were absent for muscle or epileptiform activity. Muscle events uniformly displayed broad-band high-frequencies, whereas epileptiform events were more variable. Oscillation epoch wavelet coefficients were reliably differentiated from other events (MANOVA p&lt;10⁻⁴). A support vector machine-learning protocol examining the difference between epochs and muscle and epileptiform events demonstrated a misclassification rate of zero and 1.3%, respectively, and an area under the curve for a receiver operating characteristic curve of 1 for both. <h3>Conclusions:</h3> Instantaneous wavelet scalogram profiles provide high precision in differentiating oscillation epochs from muscle or epileptiform activity, allowing for automated oscillation epoch detection in subjects with epilepsy. <b>Disclosure:</b> Dr. Jakkamsetti has nothing to disclose. Miss Kathote has nothing to disclose. Mr. Avila has nothing to disclose. Sharon Primeaux has nothing to disclose. Mr. Dobariya has nothing to disclose. Dr. Malaga Dieguez has nothing to disclose. Dr. Pascual has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevir. The institution of Dr. Pascual has received research support from NIH.

Management of a patient with pyruvate dehydrogenase deficiency.

Management of a patient with pyruvate dehydrogenase deficiency.

Застосування кетогенної дієти в педіатрії: спектр можливостей

Purpose - to describe the possibilities of using a ketogenic diet (KD) in the pediatric population for therapeutic purposes in refractory seizure syndrome and congenital metabolic disorders. The historical aspects of the development of special medical nutrition to achieve stable ketosis in children for the treatment of seizures of various genesis are briefly highlighted; the development of the evidence base for the effectiveness of the KD in children is presented. A review of current data on the multifactorial mechanisms of neuroprotective effects of KD is carried out. In particular, individual ways of modulating fundamental biochemical pathways, presynaptic and postsynaptic changes in vesicular transport and release of excitotoxic and inhibitory substrates at synapses are considered. Four types of diets are described according to the distribution of proteins, fats, and carbohydrates: the classic, modified Atkins diet, medium-chain triglyceride diet, and low glycemic index diet. The indications and contraindications for the appointment of medical ketogenic dietary therapy are considered. The most appropriate age periods of childhood for the type of KD are outlined to achieve maximum effectiveness. The authors describe in detail the main objectives of the stages of preparation of the child and family for the start of dietary treatment, the principles of initiation of KD, laboratory and instrumental monitoring and discontinuation of ketogenic dietary therapy. Particular attention is paid to the issue of counseling a child before starting a KD, the main steps in calculating the proportion of macronutrients and the principles of daily nutrition. The possibilities of prescribing medical ketogenic dietary therapy outside of refractory seizures, in particular, in glucose transaminase 1 deficiency syndrome, pyruvate dehydrogenase deficiency, mitochondrial disorders, heart failure, and brain injury, are analyzed. Available special products for medical purposes (clinical nutrition) for the organization of medical ketogenic therapy in pediatric patients, especially in the first years of life, are presented. No conflict of interests was declared by the authors.

Pearls & Oy-sters: Paroxysmal Exercise-Induced Dyskinesias Due to Pyruvate Dehydrogenase Deficiency.

Paroxysmal exercise-induced movement disorders may be caused by energy metabolism disorders, such as Glut 1 deficiency, pyruvate dehydrogenase deficiency, or mitochondrial respiratory chain disorders. A 4-year-old boy with a history of febrile seizures presented with paroxysmal dystonia, triggered by exercise, or occurring at rest. Additional investigations demonstrated pallidal hyperintensities on brain MRI and low CSF glucose. Pyruvate and lactate were elevated. The clinical presentation combined with neuroimaging abnormalities and biochemical profile (the lactate/pyruvate ratio) were clues to pyruvate dehydrogenase deficiency, a treatable metabolic disorder with neurologic presentations.

Personalized medicine – parenteral ketogenic diet in pyruvate dehydrogenase deficiency in the ICU; what do we need to know about it?

Personalized medicine – parenteral ketogenic diet in pyruvate dehydrogenase deficiency in the ICU; what do we need to know about it?

Comparison Between Dichloroacetate and Phenylbutyrate Treatment for Pyruvate Dehydrogenase Deficiency.

Pyruvate dehydrogenase (PDH) deficiency is caused by a number of pathogenic variants and the most common are found in the PDHA1 gene. The PDHA1 gene encodes one of the subunits of the PDH enzyme found in a carbohydrate metabolism pathway involved in energy production. Pathogenic variants of PDHA1 gene usually impact the α-subunit of PDH causing energy reduction. It potentially leads to increased mortality in sufferers. Potential treatments for this disease include dichloroacetate and phenylbutyrate, previously used for other diseases such as cancer and maple syrup urine disease. However, not much is known about their efficacy in treating PDH deficiency. Effective treatment for PDH deficiency is crucial as carbohydrate is needed in a healthy diet and rice is the staple food for a large portion of the Asian population. This review analysed the efficacy of dichloroacetate and phenylbutyrate as potential treatments for PDH deficiency caused by PDHA1 pathogenic variants. Based on the findings of this review, dichloroacetate will have an effect on most PDHA1 pathogenic variant and can act as a temporary treatment to reduce the lactic acidosis, a common symptom of PDH deficiency. Phenylbutyrate can only be used on patients with certain pathogenic variants (p.P221L, p.R234G, p.G249R, p.R349C, p.R349H) on the PDH protein. It is hoped that the review would provide an insight into these treatments and improve the quality of lives for patients with PDH deficiency.

Pyruvate Dehydrogenase Deficiency: With More Phenotypes Than We Believe

Introduction: The pyruvate dehydrogenase complex (PDC) is a multienzyme complex responsible for catalyzing the oxidative decarboxylation of pyruvate to Acetyl-CoA. A defect in any of its components can interfere with the production of energy on a cellular level; within these disorders we find pyruvate dehydrogenase (PDH) deficiency characterized by clinical neurological and systemic signs of varying severity, highlighting lactic acidosis, neurological and progressive neuromuscular deterioration. Objective: Describe the case of a female, school aged patient with characteristic craniofacial dysmorphology, neurodevelopmental delay and episodes of metabolic decompensation due to infections, with a mutation in the PDHX gene, treated with a ketogenic diet, thiamine, lipoic acid and carnitine. Results: The findings that made it possible to focus the diagnosis were elevated plasma and CSF lactate levels associated with persistent metabolic acidosis with accentuation of hyper intensity in the cortical sulci and in the in the bilateral basal ganglia and lenticular nuclei region of the brain on magnetic resonance imaging. Magnetic resonance imaging with spectroscopy showed a negative peak of lactate. Confirming the diagnosis with an exome of 6000 genes where a homozygous pathogenic variant is found in the PDHX gene position c.1426C&gt; T. Conclusion: PDH deficiency should be considered in cases of neurodevelopmental delay associated with intermittent episodes of neurological deterioration and elevated blood lactate and as well as elevated lactate in magnetic resonance spectroscopy of the brain. Unlike those affected by other subtypes, patients with E3-binding protein deficiency often survive childhood and even adulthood due to the presence of assembly to a certain extent of some of the pyruvate dehydrogenase complex. Prompt diagnosis opens the possibility of starting early supportive management, providing genetic counseling to parents, as well as establishing prognosis.

Clinical Characteristics and Outcomes of Acute Childhood Encephalopathy in a Tertiary Pediatric Intensive Care Unit.

Childhood encephalopathy comprises a wide range of etiologies with distinctive distribution in different age groups. We reviewed the pattern of encephalopathy admitted to the pediatric intensive care unit (PICU) of a tertiary children's hospital. We reviewed the medical records and reported the etiologies, clinical features, and outcomes of children with encephalopathy. Twenty-four admissions to the PICU between April 2019 and May 2020 were reviewed. The median (interquartile range) age was 10.0 (14.7) years and 62.5% were boys. Confusion (66.7%) was the most common presentation. Adverse effects related to medications (33.3%) and metabolic disease (20.8%) were predominant causes of encephalopathies in our study cohort. Methotrexate was responsible for most of the medication-associated encephalopathy (37.5%), whereas Leigh syndrome, pyruvate dehydrogenase deficiency and Wernicke's encephalopathy accounted for those with metabolic disease. The median Glasgow Coma Scale (GCS) on admission was 12.5 (9.0). Antimicrobials (95.8%) and antiepileptic drugs (60.9%) were the most frequently given treatment. Children aged 2 years or younger were all boys (P = 0.022) and had a higher proportion of primary metabolic disease (P = 0.04). Intoxication or drug reaction only occurred in older children. The mortality was 8.3%, and over half of the survivors had residual neurological disability upon PICU discharge. Primary metabolic disease (P = 0.002), mechanical ventilation (P = 0.019), failure to regain GCS back to baseline level (P = 0.009), and abnormal cognitive function on admission (P = 0.03) were associated with cerebral function impairment on PICU discharge. Primary metabolic encephalopathy was prevalent in younger children, whereas drug-induced toxic encephalopathy was common among older oncology patients. Survivors have significant neurologic morbidity. Failure to regain baseline GCS was a poor prognostic factor for neurological outcomes.

Fumarase deficiency: a difficult diagnosis and a challenging treatment approach

Introduction: Fumarase deficiency is a rare autosomal metabolic disease that curse with hypotonia, hyperlacticaemia and seizures. Diagnosis based in laboratory test might be done carefully, as most of metabolic diseases present similar symptomatology: hypotony, convulsions, lactic and pyruvic acidemia.&#x0D; Method: The objective is to analyse the pharmacological and nutritional approach of a neonate who presented symptoms of metabolic congenital disorders.&#x0D; Results: The patient is a three-month girl with heterozygote mutation in fumarase gene, who presented clinical manifestations of the altered enzyme function. She presented hyperlacticaemia, organic aciduria and alterations of amino acid levels. First diagnosis suspected was pyruvate dehydrogenase deficiency, so nutritional treatment with ketogenic diet was initiated. After medical discharge, she was hospitalized in emergency basis with cardiac arrest and metabolic decompensation. Genetic test revealed a heterozygote mutation in fumarase. Clinical symptomatology could have worsened because of the difficult diagnosis.&#x0D; Conclusions: Nutritional and pharmacological treatment of fumarase deficiency is considered essential for the patient’s evolution, but further researchers must be carried out to profoundly understand the mechanism underlying metabolic inborn errors. Multidisciplinary teams would manage the disease from the point of view of diverse clinician experts so the correct diagnosis and treatment would be decided with precision.

A subset of synaptic transmission events is coupled to acetyl coenzyme A production.

Biological principles sustain the inference that synaptic function is coupled to neural metabolism, but the precise relationship between these two activities is not known. For example, it is unclear whether all synaptic transmission events are uniformly dependent on metabolic flux. Most synapses use glutamate, and the principal metabolic function of the brain is glucose oxidation, which starts with glycolysis. Thus, we asked how glutamatergic synaptic currents are modified by partial deficiency of the main glycolytic enzyme pyruvate dehydrogenase (PDH), which generates the intermediary metabolism product acetyl coenzyme A (acetyl-CoA). Using brain slices obtained from mice that were genetically modified to harbor a behaviorally relevant degree of PDH suppression, we also asked whether such impact is indeed metabolic via the bypassing of PDH with a glycolysis-independent acetyl-CoA substrate. We analyzed spontaneous synaptic currents under recording conditions that minimize artificial metabolic augmentation. Principal component analysis identified synaptic charge transfer as the major difference between a subset of wild-type and PDH-deficiency (PDHD) postsynaptic currents. This was due to reduced charge transfer as well as diminished current rise and decay times. The alternate acetyl-CoA source acetate rapidly restored these features but only for events of large amplitude as revealed by correlational and kernel density analyses. Application of tetrodotoxin to block large-amplitude events evoked by action potentials removed synaptic event charge transfer and decay-time differences between wild-type and PDHD neurons. These results suggest that glucose metabolic flux and excitatory transmission are intimately coupled for synaptic events characterized by large current amplitude.NEW & NOTEWORTHY In all tissues, metabolism and excitation are coupled but the details of this relationship remain elusive. Using a brain-targeted genetic approach in mice, reduction of pyruvate dehydrogenase, a major gateway in glucose metabolism, leads to changes that affect the synaptic event charge associated primarily with large excitatory (i.e., glutamate mediated) synaptic potentials. This can be modified in the direction of normal using the alternative fuel acetate, indicating that this phenomenon depends on rapid metabolic flux.

FoxO1 inhibition alleviates type 2 diabetes-related diastolic dysfunction by increasing myocardial pyruvate dehydrogenase activity

Type 2 diabetes (T2D) increases the risk for diabetic cardiomyopathy and is characterized by diastolic dysfunction. Myocardial forkhead box O1 (FoxO1) activity is enhanced in T2D and upregulates pyruvate dehydrogenase (PDH) kinase 4 expression, which inhibits PDH activity, the rate-limiting enzyme of glucose oxidation. Because low glucose oxidation promotes cardiac inefficiency, we hypothesize that FoxO1 inhibition mitigates diabetic cardiomyopathy by stimulating PDH activity. Tissue Doppler echocardiography demonstrates improved diastolic function, whereas myocardial PDH activity is increased in cardiac-specific FoxO1-deficient mice subjected to experimental T2D. Pharmacological inhibition of FoxO1 with AS1842856 increases glucose oxidation rates in isolated hearts from diabetic C57BL/6J mice while improving diastolic function. However, AS1842856 treatment fails to improve diastolic function in diabetic mice with a cardiac-specific FoxO1 or PDH deficiency. Our work defines a fundamental mechanism by which FoxO1 inhibition improves diastolic dysfunction, suggesting that it may be an approach to alleviate diabetic cardiomyopathy.

Orthopaedic Problems in 35 Patients With Organic Acid Disorders.

Organic acid disorders (OADs) are a subset of inborn errors of metabolism that result in a toxic accumulation of organic acids in the body, which can lead to metabolic derangements and encephalopathy. Patients with these disorders are managed by a team of biochemical geneticists and metabolic nutritionists. However, subspecialists such as neurologists and orthopaedic surgeons are often needed to help manage the sequelae of the metabolic derangements. The breadth of orthopaedic sequelae of these disease states is poorly understood. Herein, we describe orthopaedic problems associated with 5 types of OAD most commonly seen at our institution: maple syrup urine disease, methylmalonic aciduria, propionic aciduria, pyruvate dehydrogenase deficiency, and glutaric aciduria type 1. We retrospectively reviewed medical records of 35 patients with an OAD who were seen at our academic tertiary care center from May 1999 to May 2020. Patients were grouped into cohorts according to OAD type and analyzed for orthopaedic presentations of hip, knee, or foot disorders, presence and severity of scoliosis, history of fracture, movement disorders, and osteopenia/osteoporosis. Of the 35 patients, 13 had maple syrup urine disease, 12 had methylmalonic aciduria, 4 had propionic aciduria, 4 had pyruvate dehydrogenase deficiency, and 2 had glutaric aciduria type 1. Associated orthopaedic problems included spasticity causing neuromuscular scoliosis and/or hip subluxation or dislocation (10 patients), fractures (7 patients), and osteopenia/osteoporosis (7 patients). Overall, 22 of 35 patients had some orthopaedic condition. Most in this cohort of patients with OAD also had an orthopaedic abnormality. It is important for physicians treating these patients to understand their propensity for musculoskeletal problems. When treating patients with OAD, it is important to initiate and maintain communication with specialists in several disciplines and to develop collaborative treatments for this unique population. Level IV-prognostic study.

P0029 / #1808: CLINICAL CHARACTERISTICS AND OUTCOMES OF ACUTE CHILDHOOD ENCEPHALOPATHY IN A TERTIARY PAEDIATRIC INTENSIVE CARE UNIT (PICU)

Aims & Objectives: Childhood encephalopathy comprises a wide range of etiologies. We reviewed the pattern and outcomes of children with encephalopathy admitted to the PICU of a newly established tertiary children’s hospital Methods: We retrospective reviewed the medical records of children with encephalopathy admitted to the PICU of the Hong Kong Children’s Hospital from April 2019 to May 2020. Results: We identifeid altogether 24 admissions. The median (interquartile range) age was 10.0 (14.7) years and 62.5% were male. Confusion (66.7%) was the most common presentation. Drug adverse effect (33.3%) and metabolic disease (20.8%) were the predominant causes of encephalopathy. Methotrexate accounted for most of the medication-associated encephalopathy (37.5%), while Leigh syndrome, pyruvate dehydrogenase deficiency and Wernicke’s encephalopathy accounted for those with metabolic disease. The median Glasgow comatose scale on admission was 12.5 (9.0). Anti-microbials (95.8%) and anti-epileptic drugs (60.9%) were the most frequently given treatment. Children aged ≤2 years old were all male (p=0.022) and had a higher proportion of primary metabolic disease (p=0.04). Drug reaction only occurred in older children. The mortality was 8.3% and over half of the survivors had residual neurological disability upon PICU discharge. Primary metabolic disease (p=0.002), mechanical ventilation (p=0.019), failure to regain GCS back to baseline level (p=0.009) and abnormal cognitive function on admission (p=0.03) were associated with cerebral function impairment on PICU discharge.Conclusions: Primary metabolic encephalopathy was prevalent in younger children, whereas drug-induced encephalopathy was common among older oncology patients. Children survived PICU admission carried significant neurologic morbidity. Failure to regain baseline GCS was associated with poor neurological outcomes.

Ambiguous Presentations of Pyruvate Dehydrogenase Deficiency: Combined Case Studies

Background: The pyruvate dehydrogenase (PDH) complex is essential in the glycolytic conversion of pyruvate to acetyl-CoA. This reaction helps yield adenosine triphosphate (ATP) – a source for energy. Hence, PDH deficiency will lead to metabolic dysfunction. Case: The case report at hand unearths the perplexing presentation of two genetically predisposed Emirati siblings that were found to be thiamine responsive. Both patients complained of a variety of symptoms at the same age following an episode of gastritis. They undergo extensive laboratory tests and imaging and are initially diagnosed with non-alcoholic Wernicke encephalopathy (WE). Objective: It has come to our attention that this rapidly debilitating condition demonstrates a constellation of seemingly incongruent gastrointestinal and neuropsychiatric manifestations. It is imperative that the peculiarities of this disease be recognized. Because PDH deficiency does not conform to defined diagnostic criteria outlined in evidence-based guidelines, treatment is likely to be delayed. Method: A careful retrospective scrutiny of the patients’ initial presentation and peculiar hospital course encourages identification of our limitations in providing efficacious quality care and in hopes of devising a systematic approach for future encounters. Conclusion: Any patient presenting to the emergency department with prolonged vomiting or diarrhea, for example, should be given thiamine as it is safe, inexpensive and may be lifesaving. We herein report two patients with indistinct, yet similar, signs and symptoms.

Potential role of stress-induced gluconeogenesis in disease aggravation and mortality in pyruvate dehydrogenase deficiency: A case-based hypothesis

Pyruvate dehydrogenase (PDH) deficiency is an inherited metabolic disorder caused by a defect in any subunit of the pyruvate dehydrogenase complex (PDHC), which has an essential role in glucose metabolism. The causes of disease progression in PDH deficiency are not fully understood yet. Based on repeated observations of a patient with PDH deficiency at our center, we hypothesized that stress-induced gluconeogenesis contributes to rapid exacerbation of the disease. This link has not been established previously.

Triheptanoin in Pyruvate Dehydrogenase Deficiency

Triheptanoin in Pyruvate Dehydrogenase Deficiency