Pyruvate dehydrogenase complex (PDC) deficiency is a rare mitochondrial disorder characterized by impaired oxidative metabolism, predominantly due to pathogenic variants in the PDHA1 gene. We present the clinical, biochemical, radiologic, and molecular characterization of 4 Argentine pediatric patients with PDHA1-related PDC deficiency, including a novel missense variant, c.260T>C p.(Ile87Thr). Clinical presentations ranged from severe neonatal encephalopathy with central apneas to a more slowly progressive neurodegenerative course in childhood. All patients exhibited lactic acidosis and structural brain abnormalities, with 3 fulfilling criteria for Leigh syndrome. Molecular studies identified 4 missense variants located in conserved regions of the E1α subunit. In silico analysis of the novel p.(Ile87Thr) variant suggested impaired thiamine pyrophosphate binding. All patients received thiamine and a ketogenic diet, with favorable outcomes in seizure control, neurodevelopment, and metabolic stability. Our findings expand the clinical and molecular spectrum of PDHA1-related PDC deficiency and underscore the importance of early diagnosis and targeted metabolic therapy. Furthermore, we report a previously undescribed radiologic pattern in one patient and propose potential structural implications of the novel variant based on protein modeling. The ketogenic diet is a high-fat, very low-carbohydrate, and moderate-protein dietary approach designed to induce nutritional ketosis. In this metabolic state, the body shifts from glucose to ketone bodies as its primary energy source. Typical macronutrient distribution includes about 55% to 60% fat, 30% to 35% protein, and 5% to 10% carbohydrates. This shift alters glucose utilization, enhances ketone production, and improves insulin sensitivity, which underlie the ketogenic diet's therapeutic and metabolic benefits.    Before the discovery of insulin in the 1920s, managing type 1 diabetes mainly involved very low-carbohydrate, low-calorie diets that were essentially ketogenic. These diets aimed to prolong survival by reducing glycosuria and hyperglycemia but often caused severe malnutrition and growth impairment, especially in children. The introduction of exogenous insulin in the 1920s replaced dietary measures as the primary treatment for diabetes. Russell Wilder, MD of the Mayo Clinic, first used the ketogenic diet to treat epilepsy in 1921. He coined the term "ketogenic diet" and observed that it reduced the frequency and severity of seizures in some of his patients who followed it. The ketogenic diet saw a decline in clinical use after the discovery of insulin and the development of anticonvulsant medications. The diet's resurgence in the 1990s was driven by renewed success in treating refractory epilepsy, later expanding to include treating a range of cardiometabolic and neurologic conditions. Today, the ketogenic diet is studied and used in various clinical and research settings, including obesity, metabolic syndrome, and type 2 diabetes, with growing interest in areas like cancer metabolism and neurodegenerative diseases, including Parkinson disease and Alzheimer disease. Multiple randomized controlled trials and meta-analyses have demonstrated its effectiveness for weight loss and blood sugar control in obesity and type 2 diabetes, resulting in reductions in body mass index, hemoglobin A1c, and triglycerides, and increased high-density lipoprotein cholesterol. Further evidence indicates improvements in insulin sensitivity and metabolic parameters in metabolic syndrome.  Although current use of the ketogenic diet includes metabolic and neurologic disorders, epilepsy remains its only universally accepted, guideline-supported indication. The diet is well established in managing drug-resistant epilepsy, glucose transporter type 1 deficiency syndrome, and pyruvate dehydrogenase deficiency, where it can substantially reduce seizure frequency and severity. Emerging applications in obesity, diabetes, metabolic dysfunction–associated steatotic liver disease, and neurodegenerative conditions remain investigational and lack guidelines from professional medical organizations. Other areas of investigation include supportive therapy for certain cancers, polycystic ovary syndrome, and psychiatric conditions, but current evidence is limited. Three principal forms of the ketogenic diet are used in clinical practice, differing in composition, level of restriction, and therapeutic goals. The traditional ketogenic diet, initially developed for treating drug-resistant epilepsy (especially in children), is a ratio-based plan where the amount of fat relative to combined protein and carbohydrate is typically 4:1; in some cases, a 3:1 ratio can be used. About 90% of total calories come from fat, with approximately 6% from protein and 4% from carbohydrates. This diet requires precise food weighing and close supervision by medical professionals and dietitians to maintain ketosis. The main goal is to achieve and sustain high, stable ketone levels to reduce seizure frequency and severity. The modified Atkins diet provides a less restrictive alternative, often used for adolescents and adults with epilepsy or when strict adherence to the traditional plan is difficult. This diet employs an approximate 1:1 ratio of fat to combined protein and carbohydrates by weight, resulting in roughly 60% to 70% of calories from fat, 25% to 30% from protein, and 5% to 10% from carbohydrates (usually less than 20 grams daily). Foods do not need to be weighed, making this approach more straightforward to implement while still promoting nutritional ketosis. The very-low-carbohydrate ketogenic diet is most often prescribed for obesity, type 2 diabetes, and metabolic syndrome. Instead of following a fixed macronutrient ratio, it limits carbohydrate intake to 20 to 50 grams daily, with moderate protein and 60% to 75% of calories from fat. This dietary pattern emphasizes carbohydrate restriction as the primary driver of ketosis, offering greater flexibility and long-term sustainability. The primary clinical goals are weight loss, improved insulin sensitivity, and favorable metabolic effects. This educational activity explores the physiological mechanisms, clinical applications, and potential risks of the ketogenic diet, along with team-based strategies for its implementation, emphasizing evidence-based, patient-centered care across healthcare professions.

Pyruvate dehydrogenase (PDH) deficiency is an uncommon condition responsible for primary refractory lactic acidosis, and PDH E1β (PDHB) subunit gene mutation rarely causes of PDH deficiency. We described a missense mutation of PDHB gene in a neonate with PDH deficiency, and verified the mutation damages PDH activity in vitro. Whole exome sequencing (WES) was used to discover the missense mutation. We constructed the recombinant eukaryotic recombinant expression vector, the phage-PDHB-wt/mut, containing human full-length wild-type (NM_000925.4) or mutant (c.575G > T) PDHB gene, and transfected vector into 293T cells. Western blot was performed to assess PDH protein stability, PDH activity was measured. A 37-week-gestation male infant was noted to have refractory lactic acidosis, growth retardation, and neurodevelopmental anomalies with abnormal brain magnetic resonance (MR) findings, starting with convulsive seizures at 3 months of age. WES analysis revealed the homozygous missense mutations in the PDHB gene, which was c.575G > T (p.Arg192Leu) in exon 6. This missense mutation of PDHB was predicted to be harmful by bioinformatics software including Sorting Intolerant From Tolerant (SIFT), Polyphen2, LRT, and Mutation Taster. Western blot showed that normal PDH protein expression was significantly decreased in the phage -PDHB-mut transfected cells than that in the phage -PDHB-wt transfected cells (P < 0.001). PDH activities analysis revealed that PDH activity was significantly decreased in the phage -PDHB-mut transfected cells than that in the phage -PDHB-wt transfected cells (P < 0.001). c.575G > T (p.Arg192Leu) in PDHB gene is a pathogenic missense mutation, which causes PDH deficiency in autosomal recessive inheritance mode.

The interesting article by Fecarotta et al. reports a 6-year-old female with pyruvate dehydrogenase (PDHC) deficiency due to the variant c.869 A > C in PDHA1, which manifested phenotypically itself with microcephaly, developmental delay, lactic acidosis, global cerebral atrophy, and subependymal gliosis lateral to the left ventricle. At the age of 6, the patient suffered acute-onset right hemiparesis, which was attributed to a stroke-like lesion (SLL) in the left cerebral peduncle. However, there are some arguments against a SLL in the index patient. First, SLLs have not yet been reported in PDHC, Second, the lesion shown in Fig. 1 does not meet the criteria for SLL. Third, the authors themselves speculate the hyperintense DWI lesion in the right globus pallidus may represent hyperperfusion. Before a peduncular DWI hyperintensity can be interpreted as SLL, ischemic stroke must be thoroughly ruled out.

The application of ketogenic diet (KD) in newborns is rare and mainly reserved for specific metabolic and seizure disorders. Furthermore, only case reports describe the effects of KD in premature infants. Here, we summarize the recent advances, indications, mechanisms of action and practical issues related to KD. We also provide a paradigm of a preterm male infant born at 34 weeks with pyruvate dehydrogenase deficiency, highlighting the therapeutic challenges and outcomes with the KD. This report underscores the complexities of managing metabolic disorders in neonates and the effects of KD.

The 6 months pilot, single arm, phase I/II, open-label clinical trial PHEMI investigated the safety and efficacy of daily administration of phenylbutyrate in reducing lactic acidosis by at least 20% in 3 children (ages 7-10 yrs) with pyruvate dehydrogenase deficiency and 6 adults with mitochondrial myopathy encephalopathy lactic acidosis and stroke-like episodes. As a side study, we investigated the response to phenylbutyrate treatment in skin fibroblasts and cybrids derived from PHEMI patients with the aim of unraveling a possible in vivo-in vitro correlation. Safety was assessed through the collection of vital signs, clinical evaluations, blood samples, and reported adverse events. Efficacy was evaluated on biochemical and clinical endpoints. In vitro analysis explored the effects of phenylbutyrate in patients' fibroblasts and cybrids. At the starting dosage regimen of 10 g/m2/day, phenylbutyrate was effective in reducing lactic acidosis (by a mean of 13%), but lead to the development of adverse events in all adults. The reduced dose of 5 g/m²/day was well tolerated but did not meet the study's primary outcome. In parallel, the in vitro analyses confirmed that phenylbutyrate led to a reduction in lactate measured in culture medium, an increase in cellular respiration, and a slight increase in the activity of the Respiratory Chain Complexes. Our study fosters further research on phenylbutyrate in individuals with primary mitochondrial disease suffering from lactic acidosis. Future investigation should focus on a highly bioavailable, easier-to-administer drug formulation that allows the administration of a lower dosage regimen.