Imaging brain glucose metabolism in vivo reveals propionate as a major anaplerotic substrate in pyruvate dehydrogenase deficiency.

A vexing problem in mitochondrial medicine is our limited capacity to evaluate the extent of brain disease in vivo. This limitation has hindered our understanding of the mechanisms that underlie the imaging phenotype in the brain of patients with mitochondrial diseases and our capacity to identify new biomarkers and therapeutic targets. Using comprehensive imaging, we analyzed the metabolic network that drives the brain structural and metabolic features of a mouse model of pyruvate dehydrogenase deficiency (PDHD). As the disease progressed in this animal, in vivo brain glucose uptake and glycolysis increased. Propionate served as a major anaplerotic substrate, predominantly metabolized by glial cells. A combination of propionate and a ketogenic diet extended lifespan, improved neuropathology, and ameliorated motor deficits in these animals. Together, intermediary metabolism is quite distinct in the PDHD brain-it plays a key role in the imaging phenotype, and it may uncover new treatments for this condition.

Pyruvate dehydrogenase-E1α deficiency presenting as generalized dystonia: A genetic diagnosis with important clinical implications.

Pyruvate dehydrogenase complex (PDC) deficiency is a genetic mitochondrial disease mostly associated with severe lactic acidosis, rapid progression of neurological symptoms and death during childhood. We present a 33-year-old male with PDC deficiency caused by a Val262Leu mutation in PDHA1gene. He demonstrated generalized dystonia affecting trunk and upper extremities and paraparesis as the most significant features, with onset of symptoms at age 8. Brain MRI showed bilaterally increased signal within the globus pallidus, typical of Leigh syndrome. A periodic lactate increase in serum and cerebrospinal fluid was detected. We describe a case of pyruvate dehydrogenase deficiency being diagnosed only 25 years after the onset of symptoms and highlight PDHC deficiency as a possible cause of treatable dystonia in childhood, which may respond well to thiamine and levodopa treatment.

Pyruvate dehydrogenase complex deficiency masked by septic shock-induced lactic acidosis: a case report.

Pyruvate dehydrogenase complex (PDHC) deficiency is a common genetic disorder leading to lactic acidosis, which can also result from several nongenetic conditions, such as septic shock. The present study reports a case of PDHC deficiency masked by septic shock-induced lactic acidosis. This case involved a 16-year-old adolescent with poor exercise tolerance compared with his peers, and no underlying diseases. The disease onset was characterized by cough, fever, and dyspnea, with hypotension and elevated lactate levels, which indicated septic shock. However, severe hypoglycemia and lactic acidosis persisted despite resolution of a pulmonary infection and correction of septic shock, requiring continuous intravenous infusion of 50% glucose. Although the patient did not experience acute kidney injury and had normal urine output, continuous renal replacement therapy was used to regulate the internal environment owing to the severity of the acidosis. The diagnosis of PDHC deficiency was considered on the basis of the persistent hypoglycemia and hyperlactatemia, before genetic mutation testing was completed. The clinical thinking process required a rich accumulation of pathophysiological knowledge. This article reports a case of PDHC deficiency masked by septic shock-induced lactic acidosis to raise awareness of the disease and avoid misdiagnosis and missed diagnosis.

Manifestations of X-linked pyruvate dehydrogenase complex deficiency in female PDHA1 carriers.

BACKGROUND AND PURPOSE: Pyruvate dehydrogenase complex deficiency is in up to 90% caused by pathogenic variants in the X-linked PDHA1 gene. We aimed to investigate female relatives of index patients with PDHA1-related disease to (i) describe the prevalence of female PDHA1 carriers, (ii) determine whether they had symptoms and signs, and (iii) delineate the associated phenotype. METHODS: In a national population-based study, we identified 37 patients with pathogenic variants in PDHA1. Sanger sequencing for the presence of the pathogenic variant was performed in their mothers and female relatives. The identified female carriers were clinically assessed, and their medical records were reviewed. RESULTS: The proportion carrying a de novo variant was 86%. We identified seven female PDHA1 carriers from five families. Five of them exhibited clinical features of the disease and were previously undiagnosed; all had signs of peripheral axonal neuropathy, four presented with strokelike episodes including two with Leigh-like lesions, and three had facial stigmata. CONCLUSIONS: PDHA1-related disease is underrecognized in heterozygous female carriers. Peripheral axonal neuropathy, strokelike and Leigh-like changes, and facial dysmorphism should raise suspicion of the disorder. Genetic analysis and clinical examination of potential female carriers are important for genetic counseling and have implications for treatment.

Amino acid ratio combinations as biomarkers for discriminating patients with pyruvate dehydrogenase complex deficiency from other inborn errors of metabolism.

BACKGROUND: Pyruvate dehydrogenase complex deficiency (PDCD) is a mitochondrial neurometabolic disorder of energy deficit, with incidence of about 1 in 42,000 live births annually in the USA. The median and mean ages of diagnosis of PDCD are about 12 and 31 months, respectively. PDCD is a major cause of primary lactic acidosis with concomitant elevation in blood alanine (Ala) and proline (Pro) concentrations depending on phenotypic severity. Alanine/Leucine (Ala/Leu) ≥4.0 and Proline/Leucine (Pro/Leu) ≥3.0 combination cutoff from dried blood spot specimens was used as a biomarker for early identification of neonates/infants with PDCD. Further investigations were needed to evaluate the sensitivity (SN), specificity (SP), and clinical utility of such amino acid (AA) ratio combination cutoffs in discriminating PDCD from other inborn errors of metabolism (IEM) for early identification of such patients. METHODS: We reviewed medical records of patients seen at UPMC in the past 11 years with molecularly or enzymatically confirmed diagnosis. We collected plasma AA analysis data from samples prior to initiation of therapeutic interventions such as total parenteral nutrition and/or ketogenic diet. Conditions evaluated included organic acidemias, primary mitochondrial disorders (MtDs), fatty acid oxidation disorders (FAOD), other IEMs on current newborn screening panels, congenital cardiac great vessel anomalies, renal tubular acidosis, and non-IEMs. The utility of specific AA ratio combinations as biomarkers were evaluated using receiver operating characteristic curves, correlation analysis, principal component analysis, and cutoff SN, SP, and positive predictive value determined from 201 subjects with broad age range. RESULTS: Alanine/Lysine (Ala/Lys) and Ala/Leu as well as (Ala + Pro)/(Leu + Lys) and Ala/Leu ratio combinations effectively discriminated subjects with PDCD from those with other MtDs and IEMs on current newborn screening panels. Specific AA ratio combinations were significantly more sensitive in identifying PDCD than Ala alone or combinations of Ala and/or Pro in the evaluated cohort of subjects. Ala/Lys ≥3.0 and Ala/Leu ≥5.0 as well as (Ala + Pro)/(Leu + Lys) ≥2.5 and Ala/Leu ≥5.0 combination cutoffs identified patients with PDCD with 100% SN and ~85% SP. CONCLUSIONS: With the best predictor of survival and positive cognitive outcome in PDCD being age of diagnosis, PDCD patients would benefit from use of such highly SN and SP AA ratio combination cutoffs as biomarkers for early identification of at-risk newborns, infants, and children, for early intervention(s) with known and/or novel therapeutics for this disorder.

X-linked pyruvate dehydrogenase complex deficiency due to a novel PDHA1 variant associated with structural brain abnormalities in a fetus.

We report a case of pyruvate dehydrogenase E1 alpha subunit deficiency associated with a novel hemizygous PDHA1 variant presenting prenatally as multiple structural brain abnormalities in a male fetus. A healthy Finnish couple was initially referred to the Fetomaternal Medical Center because of suspected fetal choroid plexus cyst at 11 + 2 weeks of pregnancy. At 20 + 0 weeks, multiple abnormalities were observed with ultrasound including narrow thorax, slightly enlarged heart, hypoplastic cerebellum, absent cerebellar vermis and ventriculomegaly. Autopsy and genetic analyses were performed after the termination of pregnancy. The findings of macroscopic examination included cleft palate, abnormally overlapping position of fingers and toes and dysmorphic facial features. Neuropathological examination confirmed the absence of corpus callosum, cerebellar hypoplasia and ventriculomegaly. Nodular neuronal heterotopia was also observed. Trio exome sequencing revealed a novel hemizygous de novo variant c.1144C>T p.(Gln382*) in the PDHA1 gene, classified as likely pathogenic. We suggest that inherited metabolic disorders should be kept in mind as differential diagnoses in fetuses with structural brain abnormalities.

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.

Recurrent Sensory-Motor Neuropathy Mimicking CIDP as Predominant Presentation of PDH Deficiency.

INTRODUCTION: Pyruvate dehydrogenase complex (PDH) deficiency (Online Mendelian Inheritance in Man # 312170) is a relatively common mitochondrial disorder, caused by mutations in the X-linked PDHA1 gene and presenting with a variable phenotypic spectrum, ranging from severe infantile encephalopathy to milder chronic neurological disorders.Isolated peripheral neuropathy as predominant clinical presentation is uncommon. RESULTS: We report on a patient, now 21 years old, presenting at the age of 2 years with recurrent symmetric weakness as first symptom of a PDH deficiency. Neurophysiological evaluation proving a sensory-motor polyneuropathy with conduction blocks and presence of elevated cerebrospinal fluid proteins, suggested a chronic inflammatory demyelinating polyneuropathy. The evidence of high serum lactate and the alterations in oxidative metabolism in muscle biopsy pointed toward the final diagnosis. After starting nutritional supplements, no further episodes occurred. A hemizygous mutation in PDHA1 (p.Arg88Cys) was identified. This mutation has been previously described in five patients with a similar phenotype. A three-dimensional reconstruction demonstrated that mutations affecting this arginine destabilize the interactions between the subunits of the E1 complex. CONCLUSION: We summarize the clinical and genetic characteristics of one patient with PDH deficiency presenting isolated peripheral nervous system involvement. This study highlights that the diagnosis of PDH deficiency should be considered in children with unexplained peripheral neuropathy, even with features suggestive of acquired forms, especially in case of early onset and limited response to treatment. A simple analysis of lactic acid could help to target the diagnosis.In addition, we suggest that the residue Arg88 is the most frequently involved in this specific phenotype of PDH deficiency.

[A case of epilepsy, movement disorders associated with a mutation in the PDHA1 gene in a preschool child]. / Klinicheskii sluchai epilepsii, dvigatel'nykh narushenii, assotsiirovannykh s mutatsiei v gene PDHA1, u rebenka doshkol'nogo vozrasta.

Deficiency of the pyruvate dehydrogenase complex E1-alpha subunit is a rare genetic disease with X-linked dominant inheritance. The clinical spectrum of the disease is extremely wide: from lethal forms in children of the first year of life with lactic acidosis to chronic neurological manifestations with structural changes in the central nervous system without increasing the level of lactate in the blood. The authors report a case of this disease in a preschool child and present the results of laboratory and instrumental studies. The importance of early diagnosis of the disease is emphasized.

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.

Simulations of Pathogenic E1α Variants: Allostery and Impact on Pyruvate Dehydrogenase Complex-E1 Structure and Function.

Pyruvate dehydrogenase complex (PDC) deficiency is a major cause of primary lactic acidemia resulting in high morbidity and mortality, with limited therapeutic options. The E1 component of the mitochondrial multienzyme PDC (PDC-E1) is a symmetric dimer of heterodimers (αß/α'ß') encoded by the PDHA1 and PDHB genes, with two symmetric active sites each consisting of highly conserved phosphorylation loops A and B. PDHA1 mutations are responsible for 82-88% of cases. Greater than 85% of E1α residues with disease-causing missense mutations (DMMs) are solvent-inaccessible, with ∼30% among those involved in subunit-subunit interface contact (SSIC). We performed molecular dynamics simulations of wild-type (WT) PDC-E1 and E1 variants with E1α DMMs at R349 and W185 (residues involved in SSIC), to investigate their impact on human PDC-E1 structure. We evaluated the change in E1 structure and dynamics and examined their implications on E1 function with the specific DMMs. We found that the dynamics of phosphorylation Loop A, which is crucial for E1 biological activity, changes with DMMs that are at least about 15 Å away. Because communication is essential for PDC-E1 activity (with alternating active sites), we also investigated the possible communication network within WT PDC-E1 via centrality analysis. We observed that DMMs altered/disrupted the communication network of PDC-E1. Collectively, these results indicate allosteric effect in PDC-E1, with implications for the development of novel small-molecule therapeutics for specific recurrent E1α DMMs such as replacements of R349 responsible for ∼10% of PDC deficiency due to E1α DMMs.

Solvent accessibility of E1α and E1ß residues with known missense mutations causing pyruvate dehydrogenase complex (PDC) deficiency: Impact on PDC-E1 structure and function.

Pyruvate dehydrogenase complex deficiency is a major cause of primary lactic acidemia resulting in high morbidity and mortality, with limited therapeutic options. PDHA1 mutations are responsible for >82% of cases. The E1 component of PDC is a symmetric dimer of heterodimers (αß/α'ß') encoded by PDHA1 and PDHB. We measured solvent accessibility surface area (SASA), utilized nearest-neighbor analysis, incorporated sequence changes using mutagenesis tool in PyMOL, and performed molecular modeling with SWISS-MODEL, to investigate the impact of residues with disease-causing missense variants (DMVs) on E1 structure and function. We reviewed 166 and 13 genetically resolved cases due to PDHA1 and PDHB, respectively, from variant databases. We expanded on 102 E1α and 13 E1ß nonduplicate DMVs. DMVs of E1α Arg112-Arg224 stretch (exons 5-7) and of E1α Arg residues constituted 40% and 39% of cases, respectively, with invariant Arg349 accounting for 22% of arginine replacements. SASA analysis showed that 86% and 84% of residues with nonduplicate DMVs of E1α and E1ß, respectively, are solvent inaccessible ("buried"). Furthermore, 30% of E1α buried residues with DMVs are deleterious through perturbation of subunit-subunit interface contact (SSIC), with 73% located in the Arg112-Arg224 stretch. E1α Arg349 represented 74% of buried E1α Arg residues involved in SSIC. Structural perturbations resulting from residue replacements in some matched neighboring pairs of amino acids on different subunits involved in SSIC at 2.9-4.0 Å interatomic distance apart, exhibit similar clinical phenotype. Collectively, this work provides insight for future target-based advanced molecular modeling studies, with implications for development of novel therapeutics for specific recurrent DMVs of E1α.

Novel imaging findings in pyruvate dehydrogenase complex (PDHc) deficiency-Results from a nationwide population-based study.

The vast clinical and radiological spectrum of pyruvate dehydrogenase complex (PDHc) deficiency continues to pose challenges both in diagnostics and disease monitoring. Prompt diagnosis is important to enable early initiation of ketogenic diet. The patients were recruited from an ongoing population-based study in Sweden. All patients with a genetically confirmed diagnosis who had been investigated with an MRI of the brain were included. Repeated investigations were assessed to study the evolution of the MRI changes. Sixty-two MRI investigations had been performed in 34 patients (23 females). The genetic cause was mutations in PDHA1 in 29, PDHX and DLAT in 2 each, and PDHB in 1. The lesions were prenatal developmental in 16, prenatal clastic in 18, and postnatal clastic in 15 individuals. Leigh-like lesions with predominant involvement of globus pallidus were present in 12, while leukoencephalopathy was present in 6 and stroke-like lesions in 3 individuals. A combination of prenatal developmental and clastic lesions was present in 15 individuals. In addition, one male with PDHA1 also had postnatal clastic lesions. The most common lesions found in our study were agenesis or hypoplasia of corpus callosum, ventriculomegaly, or Leigh-like lesions. Furthermore, we describe a broad spectrum of other MRI changes that include leukoencephalopathy and stroke-like lesions. We argue that a novel important clue, suggesting the possibility of PDHc deficiency on MRI scans, is the simultaneous presence of multiple lesions on MRI that have occurred during different phases of brain development.

Intravenous ketogenic diet therapy for neonatal-onset pyruvate dehydrogenase complex deficiency.

BACKGROUND: Pyruvate dehydrogenase complex (PDHC) deficiency is an inborn error of metabolism that causes lactic acidosis and neurodevelopmental changes. Five causative genes have been identified: PDHA1, PDHB, DLAT, DLD, and PDHX. Four neurological phenotypes have been reported: neonatal encephalopathy with lactic acidosis, non-progressive infantile encephalopathy, Leigh syndrome, and relapsing ataxia. Of these, neonatal encephalopathy has the worst mortality and morbidity and there is no effective treatment. SUBJECTS AND METHODS: We studied two girls who were clinically diagnosed with PDHC deficiency as neonates; they were subsequently found to have PDHA1 mutations. The clinical diagnosis was based on white matter loss and a lateral ventricular septum on fetal MRI, spasticity of the lower extremities, and lactic acidosis worsening after birth. Intravenous ketogenic diets were started within 24 h after birth. The ketogenic ratio was increased until the blood lactate level was controlled, while monitoring for side effects. RESULTS: In both cases, the lactic acidosis improved immediately with no apparent side effects. Both children had better developmental outcomes than previously reported cases; neither exhibited epilepsy. CONCLUSIONS: Intravenous ketogenic diet therapy is a treatment option for neonatal-onset PDHC deficiency. Further studies are needed to optimize this therapy.