RESUMEN
BACKGROUND AND OBJECTIVES: Pyruvate dehydrogenase complex deficiency (PDCD) is a disorder of mitochondrial metabolism that is caused by pathogenic variants in multiple genes, including PDHA1. Typical neonatal brain imaging findings have been described, with a focus on malformative and encephaloclastic features. Fetal brain MRI in PDCD has not been comprehensively described. The aims of this study were (1) to further characterize the fetal brain MRI findings in PDCD using comprehensive fetal imaging and genetic testing and (2) to determine whether markers of diagnosis of PDCD could be identified on prenatal imaging. METHODS: Fetuses with a diagnosis of PDCD related to a genetic etiology that had undergone fetal MRI were included. Fetuses were identified retrospectively from local databases of 4 fetal diagnostic clinics within tertiary pediatric health care centers. Electronic medical records were reviewed retrospectively: demographics, maternal and pregnancy history, fetal outcomes, and neonatal outcomes (if available) were reviewed and recorded. Fetal and neonatal imaging reports were reviewed; source fetal and neonatal brain MRI scans were reviewed by a single pediatric neuroradiologist (J.W.S.) for consistency. Genetic testing strategies and results including variant type, zygosity, inheritance pattern, and pathogenicity were recorded. Deidentified data were combined and reported descriptively. RESULTS: A total of 10 fetuses with a diagnosis of PDCD were included. 8 fetuses had corpus callosum dysgenesis, 6 had an abnormal gyration pattern, 10 had reduced brain volumes, and 9 had cystic lesions. 1 fetus had intraventricular hemorrhages. 1 fetus had a midbrain malformation with aqueductal stenosis and severe hydrocephalus. 6 fetuses imaged in the second trimester had cystic lesions involving the ganglionic eminences (GEs) while GE cysts were not present in the 4 fetuses imaged in the third trimester. DISCUSSION: Fetuses with PDCD have similar brain MRI findings to neonates described in the literature, although some of these findings are subtle early in pregnancy. Additional features, such as cystic lesions of the GEs, are noted in the second trimester in fetuses with PDCD. These may represent an early diagnostic marker of PDCD, although more data are needed to validate this association. Early diagnosis of PDCD using fetal MRI may inform genetic counseling, pregnancy decision making, and neonatal care planning.
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Encéfalo , Imagen por Resonancia Magnética , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa , Humanos , Femenino , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/diagnóstico por imagen , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/genética , Embarazo , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Encéfalo/anomalías , Estudios Retrospectivos , Masculino , Recién Nacido , Diagnóstico Prenatal , Feto/diagnóstico por imagen , Feto/anomalías , AdultoRESUMEN
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.
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Piruvato Deshidrogenasa (Lipoamida) , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa , Humanos , Masculino , Adulto , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/genética , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/complicaciones , Piruvato Deshidrogenasa (Lipoamida)/genética , Distonía/genética , Distonía/etiología , Levodopa/uso terapéutico , Trastornos Distónicos/genética , Trastornos Distónicos/diagnóstico , Imagen por Resonancia Magnética , MutaciónRESUMEN
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.
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Heterocigoto , Piruvato Deshidrogenasa (Lipoamida) , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa , Humanos , Femenino , Piruvato Deshidrogenasa (Lipoamida)/genética , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/genética , Adulto , Persona de Mediana Edad , Adolescente , Adulto Joven , Fenotipo , Niño , LinajeAsunto(s)
Mutación , Piruvato Deshidrogenasa (Lipoamida) , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa , Accidente Cerebrovascular , Femenino , Humanos , Piruvato Deshidrogenasa (Lipoamida)/genética , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/genética , Accidente Cerebrovascular/genética , NiñoRESUMEN
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.
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Anomalías Múltiples , Hidrocefalia , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa , Embarazo , Femenino , Humanos , Masculino , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/genética , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/patología , Anomalías Múltiples/diagnóstico por imagen , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Cerebelo , Feto/diagnóstico por imagen , Feto/patologíaRESUMEN
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.
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Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa , Humanos , Ácido Láctico/líquido cefalorraquídeo , Ácido Láctico/uso terapéutico , Mutación , Fenotipo , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/diagnóstico , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/diagnóstico , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/tratamiento farmacológico , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/genéticaAsunto(s)
Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa , Humanos , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/diagnóstico , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/genética , Tiamina/uso terapéutico , Debilidad Muscular/genética , MutaciónRESUMEN
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.
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Epilepsia , Trastornos del Movimiento , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa , Preescolar , Epilepsia/complicaciones , Epilepsia/diagnóstico , Epilepsia/genética , Humanos , Lactatos , Trastornos del Movimiento/diagnóstico , Trastornos del Movimiento/genética , Mutación , Piruvato Deshidrogenasa (Lipoamida)/genética , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/complicaciones , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/diagnóstico , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/genéticaRESUMEN
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.
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Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa , Humanos , Fenilbutiratos/uso terapéutico , Piruvato Deshidrogenasa (Lipoamida)/genética , Piruvato Deshidrogenasa (Lipoamida)/metabolismo , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/diagnóstico , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/tratamiento farmacológico , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/genéticaRESUMEN
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 â¼30% 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 â¼10% of PDC deficiency due to E1α DMMs.
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Piruvato Deshidrogenasa (Lipoamida) , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa , Humanos , Mitocondrias , Mutación , Piruvato Deshidrogenasa (Lipoamida)/química , Piruvato Deshidrogenasa (Lipoamida)/genética , Complejo Piruvato Deshidrogenasa/química , Complejo Piruvato Deshidrogenasa/genética , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/genéticaRESUMEN
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.
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Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa , Humanos , Mutación , Mutación Missense , Piruvato Deshidrogenasa (Lipoamida)/química , Piruvato Deshidrogenasa (Lipoamida)/genética , Piruvato Deshidrogenasa (Lipoamida)/metabolismo , Complejo Piruvato Deshidrogenasa/química , Complejo Piruvato Deshidrogenasa/genética , Complejo Piruvato Deshidrogenasa/metabolismo , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/genética , SolventesRESUMEN
BACKGROUND: Pyruvate dehydrogenase complex (PDHC) deficiency is a common neurodegenerative disease associated with abnormal mitochondrial energy metabolism. The diagnosis of PDHC is difficult because of the lack of a rapid, accurate, and cost-effective clinical diagnostic method. METHODS: A 4-year-old boy was preliminarily diagnosed with putative Leigh syndrome based on the clinical presentation. PDHC activity in peripheral blood leukocytes and a corresponding gene analysis were subsequently undertaken. Sodium pyruvate 1-13 C was used for the analysis of PDHC activity in peripheral leukocytes. The genes encoding PDHC were then scanned for mutations. RESULTS: The results showed that the corresponding PDHC activity was dramatically decreased to 10.5 nmol/h/mg protein as compared with that of healthy controls (124.6 ± 7.1 nmol/h/mg). The ratio of PDHC to citrate synthase was 2.1% (control: 425.3 ± 27.1). The mutation analysis led to the identification of a missense mutation, NM_000284.4:g214C>T, in exon 3 of PDHC. CONCLUSION: The peripheral blood leukocyte PDHC activity assay may provide a practical enzymatic diagnostic method for PDHC-related mitochondrial diseases.
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Pruebas Enzimáticas Clínicas/métodos , Leucocitos/metabolismo , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/diagnóstico , Complejo Piruvato Deshidrogenasa/metabolismo , Preescolar , Pruebas Genéticas/métodos , Humanos , Masculino , Mutación Missense , Complejo Piruvato Deshidrogenasa/genética , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/genética , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/metabolismoRESUMEN
We report a 5-year-old male with a PDHA1 variant who presented with alternating hemiplegia of childhood and later developed developmental regression, basal ganglia injury and episodic lactic acidosis. Enzyme assay in lymphocytes confirmed a diagnosis of Pyruvate Dehydrogenase Complex (PDC) deficiency. His mother who was heterozygous for the same variant suffered from ophthalmoplegia, chronic migraine and developed flaccid paralysis at 36 years of age. PDHA1 is the most common genetic cause of PDC deficiency and presents with a myriad of neurological phenotypes including neonatal form with lactic acidosis, non-progressive infantile encephalopathy, Leigh syndrome subtype and intermittent ataxia. The presentations in our 2 patients contribute to the clinical heterogeneity of this neurogenetic condition.
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Síndrome de Guillain-Barré/genética , Hemiplejía/genética , Madres , Piruvato Deshidrogenasa (Lipoamida)/genética , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/genética , Adulto , Preescolar , Femenino , Hemicigoto , Heterocigoto , Humanos , Masculino , Paraplejía/genética , Linaje , Fenotipo , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/diagnósticoRESUMEN
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'ßß') 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.
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Simulación de Dinámica Molecular , Mutación Missense , Piruvato Deshidrogenasa (Lipoamida)/química , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa , Tiamina Pirofosfato/química , Sustitución de Aminoácidos , Estabilidad de Enzimas , Humanos , Piruvato Deshidrogenasa (Lipoamida)/genética , Piruvato Deshidrogenasa (Lipoamida)/metabolismo , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/enzimología , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/genética , Tiamina Pirofosfato/genética , Tiamina Pirofosfato/metabolismoAsunto(s)
Acidosis Láctica , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa , Acidosis Láctica/diagnóstico , Acidosis Láctica/genética , Exones/genética , Heterocigoto , Humanos , Lactante , Mutación , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/diagnóstico , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/genéticaAsunto(s)
Acidosis Láctica , Piruvato Deshidrogenasa (Lipoamida)/genética , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa , Acidosis Láctica/etiología , Acidosis Láctica/genética , Exones/genética , Heterocigoto , Humanos , Lactante , Mutación , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/diagnóstico , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/genéticaRESUMEN
BACKGROUND: The pyruvate dehydrogenase complex (PDC) catalyzes the irreversible decarboxylation of pyruvate into acetyl-CoA. PDC deficiency can be caused by alterations in any of the genes encoding its several subunits. The resulting phenotype, though very heterogeneous, mainly affects the central nervous system. The aim of this study is to describe and discuss the clinical, biochemical and genotypic information from thirteen PDC deficient patients, thus seeking to establish possible genotype-phenotype correlations. RESULTS: The mutational spectrum showed that seven patients carry mutations in the PDHA1 gene encoding the E1α subunit, five patients carry mutations in the PDHX gene encoding the E3 binding protein, and the remaining patient carries mutations in the DLD gene encoding the E3 subunit. These data corroborate earlier reports describing PDHA1 mutations as the predominant cause of PDC deficiency but also reveal a notable prevalence of PDHX mutations among Portuguese patients, most of them carrying what seems to be a private mutation (p.R284X). The biochemical analyses revealed high lactate and pyruvate plasma levels whereas the lactate/pyruvate ratio was below 16; enzymatic activities, when compared to control values, indicated to be independent from the genotype and ranged from 8.5% to 30%, the latter being considered a cut-off value for primary PDC deficiency. Concerning the clinical features, all patients displayed psychomotor retardation/developmental delay, the severity of which seems to correlate with the type and localization of the mutation carried by the patient. The therapeutic options essentially include the administration of a ketogenic diet and supplementation with thiamine, although arginine aspartate intake revealed to be beneficial in some patients. Moreover, in silico analysis of the missense mutations present in this PDC deficient population allowed to envisage the molecular mechanism underlying these pathogenic variants. CONCLUSION: The identification of the disease-causing mutations, together with the functional and structural characterization of the mutant protein variants, allow to obtain an insight on the severity of the clinical phenotype and the selection of the most appropriate therapy.
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Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa , Humanos , Mutación/genética , Portugal , Piruvato Deshidrogenasa (Lipoamida)/genética , Complejo Piruvato Deshidrogenasa/genética , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/genéticaRESUMEN
Pyruvate dehydrogenase complex (PDC) deficiency caused by mutations in the X-linked PDHA1 gene has a broad clinical presentation, and the pattern of X-chromosome inactivation has been proposed as a major factor contributing to its variable expressivity in heterozygous females. Here, we report the first set of monozygotic twin females with PDC deficiency, caused by a novel, de novo heterozygous missense mutation in exon 11 of PDHA1 (NM_000284.3: c.1100A>T). Both twins presented in infancy with a similar clinical phenotype including developmental delay, episodes of hypotonia or encephalopathy, epilepsy, and slowly progressive motor impairment due to pyramidal, extrapyramidal, and cerebellar involvement. However, they exhibited clear differences in disease severity that correlated well with residual PDC activities (approximately 60% and 20% of mean control values, respectively) and levels of immunoreactive E1α subunit in cultured skin fibroblasts. To address whether the observed clinical and biochemical differences could be explained by the pattern of X-chromosome inactivation, we undertook an androgen receptor assay in peripheral blood. In the less severely affected twin, a significant bias in the relative activity of the two X chromosomes with a ratio of approximately 75:25 was detected, while the ratio was close to 50:50 in the other twin. Although it may be difficult to extrapolate these results to other tissues, our observation provides further support to the hypothesis that the pattern of X-chromosome inactivation may influence the phenotypic expression of the same mutation in heterozygous females and broadens the clinical and genetic spectrum of PDC deficiency.
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Mutación , Piruvato Deshidrogenasa (Lipoamida)/genética , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/genética , Enfermedad por Deficiencia del Complejo Piruvato Deshidrogenasa/patología , Inactivación del Cromosoma X , Femenino , Humanos , Masculino , Linaje , Fenotipo , Pronóstico , Piruvato Deshidrogenasa (Lipoamida)/deficiencia , Gemelos MonocigóticosRESUMEN
LonP1 is crucial for maintaining mitochondrial proteostasis and mitigating cell stress. We identified a novel homozygous missense LONP1 variant, c.2282 C > T, (p.Pro761Leu), by whole-exome and Sanger sequencing in two siblings born to healthy consanguineous parents. Both siblings presented with stepwise regression during infancy, profound hypotonia and muscle weakness, severe intellectual disability and progressive cerebellar atrophy on brain imaging. Muscle biopsy revealed the absence of ragged-red fibers, however, scattered cytochrome c oxidase-negative staining and electron dense mitochondrial inclusions were observed. Primary cultured fibroblasts from the siblings showed normal levels of mtDNA and mitochondrial transcripts, and normal activities of oxidative phosphorylation complexes I through V. Interestingly, fibroblasts of both siblings showed glucose-repressed oxygen consumption compared to their mother, whereas galactose and palmitic acid utilization were similar. Notably, the siblings' fibroblasts had reduced pyruvate dehydrogenase (PDH) activity and elevated intracellular lactate:pyruvate ratios, whereas plasma ratios were normal. We demonstrated that in the siblings' fibroblasts, PDH dysfunction was caused by increased levels of the phosphorylated E1α subunit of PDH, which inhibits enzyme activity. Blocking E1α phosphorylation activated PDH and reduced intracellular lactate concentrations. In addition, overexpressing wild-type LonP1 in the siblings' fibroblasts down-regulated phosphoE1α. Furthermore, in vitro studies demonstrated that purified LonP1-P761L failed to degrade phosphorylated E1α, in contrast to wild-type LonP1. We propose a novel mechanism whereby homozygous expression of the LonP1-P761L variant leads to PDH deficiency and energy metabolism dysfunction, which promotes severe neurologic impairment and neurodegeneration.