Pyruvate Dehydrogenase Complex Deficiency Research Articles

Ketogenic Diet Interventions in Inborn Errors of Metabolism: A Review Article

Objective: The ketogenic diet, which has been used in the treatment of epilepsy since the 1920s, is a diet containing high fat, sufficient protein, and low carbohydrate. The ketogenic diet mimics the metabolic effects of fasting by shifting metabolism towards fat utilization. The ketogenic diet, which has different variants, such as the classical ketogenic diet, modified Atkins diet, and medium-chain triglyceride diet, is used in inborn errors of metabolism to target the underlying metabolic state by bypassing the damaged metabolic pathway or to treat the clinical symptoms of inborn errors of metabolism, such as epileptic seizures. In this review, we assessed the evidence for ketogenic diet interventions in the treatment of inborn errors of metabolism.
 Methods: The Google Scholar search engine, PubMed, Scopus, and Science Direct databases were used to find studies on the use of ketogenic diet interventions in the treatment of inborn errors of metabolism.
 Results: The beneficial effects of different variants of the ketogenic diet on glucose transport type 1 deficiency syndrome and pyruvate dehydrogenase complex deficiency have long been recognized. There are also favorable data on its use in myopathic glycogen storage diseases, mitochondrial diseases, and nonketotic hyperglycinemia accompanied by epilepsy.
 Conclusion: The evidence is mostly based on individual case reports, case series, and clinical trials with small sample sizes and is insufficient to make recommendations.

Novel Synonymous and Deep Intronic Variants Causing Primary and Secondary Pyruvate Dehydrogenase Complex Deficiency

Pyruvate dehydrogenase complex deficiency (PDCD) is a defect of aerobic carbohydrate metabolism that causes neurological disorders with varying degrees of severity. We report the clinical, biochemical, and molecular findings in patients with primary and secondary PDCD caused by novel atypical genetic variants. Whole-genome sequencing (WGS) identified the synonymous variants c.447A>G, p.(Lys149=) and c.570C>T, p.(Cys190=) in pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1), the deep intronic variants c.1023+2267G>A and c.1023+2302A>G in pyruvate dehydrogenase complex component X (PDHX), and c.185+15054G>A in thiamine pyrophosphokinase (TPK1). Analysis by Sanger and RNA sequencing of cDNA from patient blood and/or cultured fibroblasts showed that the synonymous variants in PDHA1 lead to aberrant splicing and skipping of exons 5 and 5-6 in one of the patients and transcripts lacking exon 6 in the other. The deep intronic variants in PDHX and TPK1 lead to insertion of intronic sequence in the corresponding transcripts. The splice defects in PDHA1 were more pronounced in cultured fibroblasts than in blood. Our findings expand the spectrum of pathogenic variants causing PDCD and highlight the importance of atypical variants leading to aberrant splicing. The severity of the splice defects and resulting biochemical dysfunction varied between tissues, stressing the importance of performing biochemical and transcript analysis in affected tissues. The two males with hemizygous synonymous PDHA1 variants have a mild phenotype and higher PDH enzyme activity than expected, which is consistent with aberrant but leaky splicing with a proportion of the transcripts remaining correctly spliced.

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

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. 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. 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. 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.

Evaluation of Mitochondrial Function on Pyruvate Dehydrogenase Complex Deficient Patient-derived Cell Lines.

Pyruvate Dehydrogenase Complex (PDC) is a pivotal gatekeeper between cytosolic glycolysis and mitochondrial oxidative phosphorylation, playing important role in aerobic energy metabolism. Most PDC deficiency, cases being caused by mutations in PDHA1 encoding the α subunit of the rate-limiting E1 enzyme, which is characterized by abnormal phenotypes caused by energy deprivation at peripheral/central nervous systems and muscular tissues. This study aims to evaluate the potential therapeutic effect of arginine and thiamine in ameliorating mitochondrial function in patient-derived cultured cells. PDC-deficient cell lines, carrying three different PDHA1 variants, were cultured in the absence and presence of arginine and/or thiamine at therapeutical levels, 4 mM and 100 μM, respectively. Mitochondrial bioenergetics profile was evaluated using the Seahorse extracellular flux analyzer. In physiological conditions, control cells presented standard values for all parameters evaluating the mitochondrial function, no differences being observed after supplementation of culture medium with therapeutic levels of arginine and/or thiamine. However, PDC-PDHA1 deficient cell lines consumed less oxygen than the control cells, but arginine and thiamine supplementation increased the basal respiration for values similar or higher than the control cell line. Moreover, arginine and thiamine treatment highlighted an inefficient oxidative phosphorylation carried out by PDC-deficient cell lines. Finally, this treatment showed an increased oxygen consumption by enzymes other than those in the respiratory chain, thus proving the dependence of these mutant cell lines on cytosolic sources for ATP production, namely glycolysis. This study showed that arginine and thiamine, at therapeutical levels, increase the basal oxygen consumption rate of PDC-deficient cell lines, as well as their ATP-linked respiration. This parameter measures the capacity of the cell to meet its energetic demands and, therefore, its increase reveals a higher electron flow through the respiratory chain, which is coupled to elevated oxidative phosphorylation, thus indicating an overall increased robustness in mitochondrial- related bioenergetics.

Pyruvate Dehydrogenase E3 Deficiency - Heterozygous Mutation in Dihydrolipoamide Dehydrogenase (DLD) Gene Associated with Symptomatic Hypoglycaemia. A Case Report

Background: Pyruvate dehydrogenase complex deficiency (PDCD) is a mitochondrial disorder that presents with lactic acidemia and neurological manifestations. It is a very rare genetic disorder, a potentially life-threatening one with the usual presentation of hypotonia, lethargy, and developmental delay. It is commonly associated with structural brain abnormalities. We report a very rare case of transient severe symptomatic hypoglycaemia probably due to pyruvate dehydrogenase E3 deficiency; a component of pyruvate dehydrogenase complex (PDC). Case Presentation: Our patient is a 12-day-old neonate with lethargy, and vomiting presented with severe symptomatic hypoglycaemia with a critical sample suggestive of hyperinsulinism and raised lactate levels. A TMS-GCMS for metabolic abnormality screening was normal, however, a whole genome sequencing(nuclear + mitochondrial) revealed heterozygous missense variants (c.763A>C) in exon 9 of the DLD gene that results in the amino acid substitution from Methionine to Leucine at codon 255 (p.Met255Leu) and another heterozygous mutation of heterozygous missense variant (c.5277A>T) in exon 34 of the LAMB1 gene that results in the amino acid substitution from Glutamine to Histidine at codon 1759 (p.Gln1759His). Conclusion: There is no effective treatment for PDCD but reports of treatment with supplements like thiamine, biotin, and coenzyme Q may play a role in preventing the severity of the disease.

Perioperative considerations of pyruvate dehydrogenase complex deficiency: a case report of two consecutive anesthesia.

Pyruvate dehydrogenase complex (PDHC) deficiency is a rare mitochondrial disorder caused by a genetic mutation affecting the activity of the PDHC enzyme, which plays a major role in the tricarboxylic cycle. Few cases of surgery or anesthesia have been reported. Moreover, there is no recommended anesthetic method. A 24-month-old child with a PDHC deficiency presented to the emergency room with respiratory failure, mental decline, systemic cyanosis, and lactic acidosis. During hospitalization period, the patient presented with pneumothorax, pneumoperitoneum, and multiple air pockets in the heart. Two surgeries were performed under general anesthesia using an inhalational anesthetic agent. The patient was discharged with home ventilation. Anesthesiologists should be wary of multiple factors when administering anesthesia to patients with PDHC deficiency, including airway abnormalities, acid-base imbalance, intraoperative fluid management, selection of appropriate anesthetics, and monitoring of lactic acid levels.

Sandwich-Associated Lactic Acidosis: A Case Report of a Young Adult With Pyruvate Dehydrogenase Complex Deficiency

Pyruvate dehydrogenase complex deficiency is a rare genetic disorder that can lead to severe metabolic consequences. We present the case of a young adult with pyruvate dehydrogenase complex deficiency who presented with progressive shortness of breath and subsequently required intubation in the setting of severe lactic acidemia. After resuscitation and extubation, a targeted history identified that the patient had eaten 3 grilled cheese sandwiches just before admission. In these rarely encountered cases, both detailed clinical history-gathering as well as multidisciplinary provider coordination is essential in ultimately implementing specialized dietary recommendations and thus preventing accelerated morbidity and mortality.

Thiamine-responsive pyruvate dehydrogenase complex deficiency presenting as recurrent muscle weakness: Identification of a novel mutation (p.T111I) in the PDHA1 gene.

Thiamine-responsive pyruvate dehydrogenase complex deficiency presenting as recurrent muscle weakness: Identification of a novel mutation (p.T111I) in the PDHA1 gene.

P039: Retrospective evaluation of amino acid ratios for screening and diagnostic utility for pyruvate dehydrogenase complex deficiency (PDCD) and other mitochondrial disorders (MtDs)*

P039: Retrospective evaluation of amino acid ratios for screening and diagnostic utility for pyruvate dehydrogenase complex deficiency (PDCD) and other mitochondrial disorders (MtDs)*

Partial Efficacy of Vigabatrin in an Infant With West Syndrome Due to Pyruvate Dehydrogenase Complex Deficiency: A Case Report

Pyruvate dehydrogenase complex (PDHC) deficiency is a metabolic disease associated with lactic acidosis, and mutation in PDHA1 is the major cause.1,2 The incidence rate of West syndrome among patients with PDHC deficiency was reported as 17%.3 Previous studies reported the clinical experience of antiepileptic therapies, including ketogenic diet and/or administration of vitamin B1, B6, sodium dichloroacetate, adrenocorticotropic hormone, zonisamide, valproic acid, and vigabatrin; however, few studies demonstrated the effectiveness of these treatments.

Dichloroacetate and thiamine improve survival and mitochondrial stress in a C. elegans model of dihydrolipoamide dehydrogenase deficiency.

Dihydrolipoamide dehydrogenase (DLD) deficiency is a recessive mitochondrial disorder caused by depletion of DLD from α-ketoacid dehydrogenase complexes. Caenorhabditis elegans animal models of DLD deficiency generated by graded feeding of dld-1(RNAi) revealed that full or partial reduction of DLD-1 expression recapitulated increased pyruvate levels typical of pyruvate dehydrogenase complex deficiency and significantly altered animal survival and health, with reductions in brood size, adult length, and neuromuscular function. DLD-1 deficiency dramatically increased mitochondrial unfolded protein stress response induction and adaptive mitochondrial proliferation. While ATP levels were reduced, respiratory chain enzyme activities and in vivo mitochondrial membrane potential were not significantly altered. DLD-1 depletion directly correlated with the induction of mitochondrial stress and impairment of worm growth and neuromuscular function. The safety and efficacy of dichloroacetate, thiamine, riboflavin, 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), l-carnitine, and lipoic acid supplemental therapies empirically used for human DLD disease were objectively evaluated by life span and mitochondrial stress response studies. Only dichloroacetate and thiamine showed individual and synergistic therapeutic benefits. Collectively, these C. elegans dld-1(RNAi) animal model studies demonstrate the translational relevance of preclinical modeling of disease mechanisms and therapeutic candidates. Results suggest that clinical trials are warranted to evaluate the safety and efficacy of dichloroacetate and thiamine in human DLD disease.

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 (αβ/α'β') 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.

EP457: Fetal presentation of pyruvate dehydrogenase complex deficiency diagnosed by prenatal exome sequencing

Pyruvate dehydrogenase complex deficiency is a rare X-linked inborn error of metabolism that typically presents in infancy or early childhood, rather than prenatally. The mean age of diagnosis is ∼45 months (median age of diagnosis is ∼20 months of age). Affected individuals have persistent lactic acidosis, which causes a variety of neurological manifestations. Progressive neurological deterioration is often accompanied by encephalopathy, seizures, and death. We present a prenatal case of pyruvate dehydrogenase complex deficiency diagnosed by prenatal exome sequencing, which presented with multiple nonspecific congenital anomalies.

Solvent accessibility of E1α and E1β 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 (αβ/α'β') 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 E1β 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 E1β, 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 2.9-4.0Å 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.

GLRX5-associated [Fe-S] cluster biogenesis disorder: further characterisation of the neurological phenotype and long-term outcome

BackgroundIdentification and characterisation of monogenic causes of complex neurological phenotypes are important for genetic counselling and prognostication. Bi-allelic pathogenic variants in the gene encoding GLRX5, a protein involved in the early steps of Fe-S cluster biogenesis, are rare and cause two distinct phenotypes: isolated sideroblastic anemia and a neurological phenotype with variant non-ketotic hyperglycinemia. In this study, we analysed the evolution of clinical and MRI findings and long-term outcome of patients with GLRX5 mutations.MethodsFour patients from three Australian families of Lebanese descent were identified. All patients presented in childhood and were followed up into adult life through multiple clinical assessments. All were prescribed sodium benzoate.ResultsAll patients (all females, age range 18–56 years) showed a complex neurological phenotype characterised by varying combinations of spastic paraparesis, length-dependent motor/sensory-motor axonal polyneuropathy, and psychiatric disturbances with variable intellectual disability. All had non-ketotic hyperglycinemia and a homozygous pathogenic c.151_153delAAG (p.K51del) change in GLRX5. Motor disability gradually progressed reaching moderate disability during adolescence and moderately severe disability during adult life. The major MRI finding was the upper cervical spinal cord signal changes with contrast enhancement noted in all and additional leukoencephalopathy in one. On follow up MRI, the white matter lesions diminished on a subsequent scan and then remained static over time. The spinal cord showed gliotic changes. Two patients have previously demonstrated low pyruvate dehydrogenase complex deficiency but none had plasma lactate elevation, nor biochemical evidence of branch-chain keto-dehydrogenase deficiency. Glycine levels reduced in patients that tolerated sodium benzoate, possibly stabilising clinical manifestations.ConclusionsThis report demonstrates that the p.K51del GLRX5 variant causes a distinct and predictable neurological phenotype. The clinical assessments spanning from childhood to adult life enable physicians to infer the natural history of GLRX5 related neurological disorder. There may be widespread metabolic consequences, and optimal management is unknown.

EP010 - Utility of specific amino acid ratios in screening for pyruvate dehydrogenase complex deficiencies and other disorders associated with lactic acidosis

eP010 - Utility of specific amino acid ratios in screening for pyruvate dehydrogenase complex deficiencies and other disorders associated with lactic acidosis

Mitochondrial Encephalomyopathy Associated with Pyruvate Dehydrogenase Complex Deficiency: Eight Clinical Cases

Background. Defects in pyruvate dehydrogenase complex (PDC), involved in the glycolysis products integration into the cells' energy metabolism, are one of the reasons of mitochondrial pathology development. The diagnosis of this condition can be pretty complicated also due to the lack of description of such patients with encephalomyopathy associated with PDC deficiency in Russian population. Clinical Cases Description. We have performed the analysis of clinical manifestations polymorphism of progressive mitochondrial encephalomyopathy caused by pathogenic variants in nuclear X linked gene, PDHA1 (encodes alpha subunit of pyruvate dehydrogenase), in 8 boys aged from 1 to 8 years. The adverse perinatal period was mentioned in all cases. The major features of symptom complex by the time of hospital examination were psychomotor retardation, ataxy, myopathic manifestations. Dystonic attacks were observed in 2 sibs. All patients had changes on brain magnetic resonance imaging: in basal ganglia in 6 children and ventriculomegaly in 2 children. All children had lactic acidosis. Clinical examination has shown that 4 patients had severe damage of nervous system, other 4 patients had moderate damage. Missense mutations in the PDHA1 gene were revealed in 6 children, insertions and duplications including 6 and 16 base pairs — in 2 children. The moderate positive dynamics was noticed as a result of complex treatment of children: stabilization of the overall condition, no metabolic crises, decrease in frequency of dystonic attacks. Conclusion. The clinical polymorphism of mitochondrial encephalomyopathy associated with PDC deficiency is described. The differences in manifestations of severe and moderate forms of disease are shown. The presented description may be useful for medico-genetic counseling and providing medico-genetic care for families.

Structural and functional impact of clinically relevant E1α variants causing pyruvate dehydrogenase complex deficiency

Pyruvate dehydrogenase complex (PDC) catalyzes the oxidative decarboxylation of pyruvate to acetyl-coenzyme A, hinging glycolysis and the tricarboxylic acid cycle. PDC deficiency, an inborn error of metabolism, has a broad phenotypic spectrum. Symptoms range from fatal lactic acidosis or progressive neuromuscular impairment in the neonatal period, to chronic neurodegeneration. Most disease-causing mutations in PDC deficiency affect the PDHA1 gene, encoding the α subunit of the PDC-E1 component. Detailed biophysical analysis of pathogenic protein variants is a challenging approach to support the design of therapies based on improving and correcting protein structure and function. Herein, we report the characterization of clinically relevant PDC-E1α variants identified in Portuguese PDC deficient patients. These variants bear amino acid substitutions in different structural regions of PDC-E1α. The structural and functional analyses of recombinant heterotetrameric (αα’ββ’) PDC-E1 variants, combined with molecular dynamics (MD) simulations, show a limited impact of the amino acid changes on the conformational stability, apart from the increased propensity for aggregation of the p.R253G variant as compared to wild-type PDC-E1. However, all variants presented a functional impairment in terms of lower residual PDC-E1 enzymatic activity and ≈3–100 × lower affinity for the thiamine pyrophosphate (TPP) cofactor, in comparison with wild-type PDC-E1. MD simulations neatly showed generally decreased stability (increased flexibility) of all variants with respect to the WT heterotetramer, particularly in the TPP binding region. These results are discussed in light of disease severity of the patients bearing such mutations and highlight the difficulty of developing chaperone-based therapies for PDC deficiency.

Anesthesia management for ENT surgery in a child with X‐linked pyruvate kinase deficiency

Pyruvate dehydrogenase complex deficiency (PDCD) is a rare X-linked disorder that affects glucose metabolism. There are several case reports describing the anesthetic management of patients with PDCD. This is the first case report to describe the anesthetic management of a PDCD patient requiring spontaneous ventilation using dexmedetomidine and ketamine.