RESUMO
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.
Assuntos
Piruvato Desidrogenase (Lipoamida) , Doença da Deficiência do Complexo de Piruvato Desidrogenase , Humanos , Masculino , Adulto , Doença da Deficiência do Complexo de Piruvato Desidrogenase/genética , Doença da Deficiência do Complexo de Piruvato Desidrogenase/complicações , Piruvato Desidrogenase (Lipoamida)/genética , Distonia/genética , Distonia/etiologia , Levodopa/uso terapêutico , Distúrbios Distônicos/genética , Distúrbios Distônicos/diagnóstico , Imageamento por Ressonância Magnética , MutaçãoRESUMO
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.
Assuntos
Coreia , Distonia , Doença da Deficiência do Complexo de Piruvato Desidrogenase , Masculino , Humanos , Pré-Escolar , Doença da Deficiência do Complexo de Piruvato Desidrogenase/complicações , Distonia/etiologia , Coreia/complicações , Ácido Láctico , Ácido PirúvicoAssuntos
Doença da Deficiência do Complexo de Piruvato Desidrogenase , Espasmos Infantis , Lactente , Humanos , Espasmos Infantis/tratamento farmacológico , Espasmos Infantis/etiologia , Vigabatrina/uso terapêutico , Doença da Deficiência do Complexo de Piruvato Desidrogenase/complicações , Doença da Deficiência do Complexo de Piruvato Desidrogenase/tratamento farmacológico , Anticonvulsivantes/efeitos adversos , Hormônio Adrenocorticotrópico/uso terapêuticoRESUMO
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.
Assuntos
Epilepsia , Transtornos dos Movimentos , Doença da Deficiência do Complexo de Piruvato Desidrogenase , Pré-Escolar , Epilepsia/complicações , Epilepsia/diagnóstico , Epilepsia/genética , Humanos , Lactatos , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/genética , Mutação , Piruvato Desidrogenase (Lipoamida)/genética , Doença da Deficiência do Complexo de Piruvato Desidrogenase/complicações , Doença da Deficiência do Complexo de Piruvato Desidrogenase/diagnóstico , Doença da Deficiência do Complexo de Piruvato Desidrogenase/genéticaAssuntos
Doença de Leigh/diagnóstico , Doença de Leigh/etiologia , Debilidade Muscular/etiologia , Doença da Deficiência do Complexo de Piruvato Desidrogenase/complicações , Doença da Deficiência do Complexo de Piruvato Desidrogenase/diagnóstico , Baclofeno/uso terapêutico , Carnitina/uso terapêutico , Pré-Escolar , Diagnóstico Diferencial , Dieta Cetogênica/métodos , Humanos , Doença de Leigh/terapia , Masculino , Relaxantes Musculares Centrais/uso terapêutico , Debilidade Muscular/tratamento farmacológico , Doença da Deficiência do Complexo de Piruvato Desidrogenase/terapia , Ubiquinona/análogos & derivados , Ubiquinona/uso terapêutico , Vitaminas/uso terapêuticoRESUMO
INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 OF EVIDENCE: Level IV-prognostic study.
Assuntos
Ortopedia , Acidemia Propiônica/complicações , Acidemia Propiônica/cirurgia , Adolescente , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Encefalopatias Metabólicas/complicações , Criança , Pré-Escolar , Feminino , Glutaril-CoA Desidrogenase/deficiência , Humanos , Masculino , Doença da Urina de Xarope de Bordo/complicações , Doença da Urina de Xarope de Bordo/cirurgia , Pessoa de Meia-Idade , Doença da Deficiência do Complexo de Piruvato Desidrogenase/complicações , Doença da Deficiência do Complexo de Piruvato Desidrogenase/cirurgia , Estudos RetrospectivosAssuntos
Acidose Láctica/complicações , Autoantígenos/genética , Di-Hidrolipoil-Lisina-Resíduo Acetiltransferase/genética , Discinesias/etiologia , Exercício Físico , Proteínas Mitocondriais/genética , Doença da Deficiência do Complexo de Piruvato Desidrogenase/complicações , Adulto , Consanguinidade , Discinesias/genética , Discinesias/fisiopatologia , Humanos , Masculino , Adulto JovemAssuntos
Encéfalo/diagnóstico por imagem , Síndrome de Down/diagnóstico por imagem , Doença da Deficiência do Complexo de Piruvato Desidrogenase/diagnóstico por imagem , Encéfalo/anormalidades , Síndrome de Down/complicações , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Doença da Deficiência do Complexo de Piruvato Desidrogenase/complicaçõesAssuntos
Acidose , Dieta Cetogênica/métodos , Doença da Deficiência do Complexo de Piruvato Desidrogenase , Complexo Piruvato Desidrogenase/genética , Equilíbrio Ácido-Base , Acidose/diagnóstico , Acidose/etiologia , Acidose/metabolismo , Acidose/terapia , Criança , Diagnóstico Diferencial , Gerenciamento Clínico , Etnicidade , Feminino , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/etiologia , Humanos , Concentração de Íons de Hidrogênio , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/etiologia , Espasticidade Muscular/diagnóstico , Espasticidade Muscular/etiologia , Mutação , Doença da Deficiência do Complexo de Piruvato Desidrogenase/complicações , Doença da Deficiência do Complexo de Piruvato Desidrogenase/metabolismo , Doença da Deficiência do Complexo de Piruvato Desidrogenase/fisiopatologia , Doença da Deficiência do Complexo de Piruvato Desidrogenase/terapiaRESUMO
The pyruvate dehydrogenase complex (PDHc) is a member of a family of multienzyme complexes that provides the link between glycolysis and the tricarboxylic acid (TCA) cycle by catalyzing the physiologically irreversible decarboxylation of various 2-oxoacid substrates to their corresponding acyl-CoA derivatives, NADH and CO2. PDHc deficiency is a metabolic disorder commonly associated with lactic acidosis, progressive neurological and neuromuscular degeneration that vary with age and gender. In this review, we aim to discuss the relationship between occurrence of epilepsy and PDHc deficiency associated with the pyruvate dehydrogenase complex (E1α subunit (PDHA1) and E1ß subunit (PDHB)) and PDH phosphatase (PDP) deficiency. PDHc plays a crucial role in the aerobic carbohydrate metabolism and regulates the use of carbohydrate as the source of oxidative energy. In severe PDHc deficiency, the energy deficit impairs brain development in utero resulting in physiological and structural changes in the brain that contributes to the subsequent onset of epileptogenesis. Epileptogenesis in PDHc deficiency is linked to energy failure and abnormal neurotransmitter metabolism that progressively alters neuronal excitability. This metabolic blockage might be restricted via inclusion of ketogenic diet that is broken up by ß-oxidation and directly converting it to acetyl-CoA, and thereby improving the patient's health condition. Genetic counseling is essential as PDHA1 deficiency is X-linked. The demonstration of the X-chromosome localization of PDHA1 resolved a number of questions concerning the variable phenotype displayed by patients with E1 deficiency. Most patients show a broad range of neurological abnormalities, with the severity showing some dependence on the nature of the mutation in the Elα gene, while PDHB and PDH phosphatase (PDP) deficiencies are of autosomal recessive inheritance. However, in females, the disorder is further complicated by the pattern of X-chromosome inactivation, i.e., unfavorable lyonization. Furthermore research should focus on epileptogenic animal models; this might pave a new way toward identification of the pathophysiology of this challenging disorder.
Assuntos
Epilepsia/etiologia , Doença da Deficiência do Complexo de Piruvato Desidrogenase/complicações , Animais , Epilepsia/genética , Humanos , Piruvato Desidrogenase (Lipoamida)/genética , Piruvato Desidrogenase (Lipoamida)/metabolismo , Doença da Deficiência do Complexo de Piruvato Desidrogenase/genéticaRESUMO
BACKGROUND: Pyruvate dehydrogenase (PDH) deficiency is a disorder of energy metabolism with variable clinical presentations, ranging from severe infantile lactic acidosis to milder chronic neurological disorders. The spectrum of clinical manifestations is continuously expanding. METHODS AND RESULTS: We report on a 19-year-old intelligent female with PDH deficiency caused by a Leu216Ser mutation in PDHA1. She presented with recurrent hemidystonic attacks, triggered by prolonged walking or running, as the unique clinical manifestation that manifested since childhood. Laboratory workup and neuroimages were initially normal but bilateral globus pallidum involvement appeared later on brain MRI. Dystonia completely remitted after high doses of thiamine, remaining free of symptoms after 3 years of follow up. We reviewed the literature for similar observations. CONCLUSIONS: Dystonia precipitated by exercise may be the only symptom of a PDH deficiency, and the hallmark of the disease as high serum lactate or bilateral striatal necrosis at neuroimaging may be absent. A high index of suspicion and follow up is necessary for diagnosis. The clinical presentation of this patient meets the criteria for a Paroxysmal Exercise induced Dystonia, leading us to add this entity as another potential etiology for this type of paroxysmal dyskinesia, which is besides a treatable condition that responds to thiamine supplementation.
Assuntos
Suplementos Nutricionais , Distúrbios Distônicos/etiologia , Doença da Deficiência do Complexo de Piruvato Desidrogenase/complicações , Doença da Deficiência do Complexo de Piruvato Desidrogenase/tratamento farmacológico , Tiamina/uso terapêutico , Encéfalo/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Doença da Deficiência do Complexo de Piruvato Desidrogenase/diagnóstico , Adulto JovemAssuntos
Síndrome de Down/complicações , Futilidade Médica/legislação & jurisprudência , Cuidados Paliativos/legislação & jurisprudência , Doença da Deficiência do Complexo de Piruvato Desidrogenase/complicações , Síndrome de Down/terapia , Permeabilidade do Canal Arterial/complicações , Permeabilidade do Canal Arterial/cirurgia , Humanos , Lactente , Masculino , New South Wales , Doença da Deficiência do Complexo de Piruvato Desidrogenase/terapia , Respiração Artificial , Medição de Risco/legislação & jurisprudênciaRESUMO
UNLABELLED: Pyruvate dehydrogenase (PDH) complex (PDC) deficiency is an inborn error of pyruvate metabolism causing a variety of neurologic manifestations. Systematic analyses of development of affected brain structures and the cellular processes responsible for their impairment have not been performed due to the lack of an animal model for PDC deficiency. METHODS: In the present study we investigated a murine model of systemic PDC deficiency by interrupting the X-linked Pdha1 gene encoding the α subunit of PDH to study its role on brain development and behavioral studies. RESULTS: Male embryos died prenatally but heterozygous females were born. PDC activity was reduced in the brain and other tissues in female progeny compared to age-matched control females. Immunohistochemical analysis of several brain regions showed that approximately 40% of cells were PDH(-). The oxidation of glucose to CO2 and incorporation of glucose-carbon into fatty acids were reduced in brain slices from 15 day-old PDC-deficient females. Histological analyses showed alterations in several structures in white and gray matters in 35 day-old PDC-deficient females. Reduction in total cell number and reduced dendritic arbors in Purkinje neurons were observed in PDC-deficient females. Furthermore, cell proliferation, migration and differentiation into neurons by newly generated cells were reduced in the affected females during pre- and postnatal periods. PDC-deficient mice had normal locomotor activity in a novel environment but displayed decreased startle responses to loud noises and there was evidence of abnormal pre-pulse inhibition of the startle reflex. CONCLUSIONS: The results show that a reduction in glucose metabolism resulting in deficit in energy production and fatty acid biosynthesis impairs cellular differentiation and brain development in PDC-deficient mice.
Assuntos
Encefalopatias/patologia , Encéfalo/anormalidades , Modelos Animais de Doenças , Doença da Deficiência do Complexo de Piruvato Desidrogenase/complicações , Complexo Piruvato Desidrogenase/fisiologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Encefalopatias/etiologia , Metabolismo dos Carboidratos , Feminino , Lipogênese/fisiologia , Masculino , Camundongos , Camundongos Knockout , Doença da Deficiência do Complexo de Piruvato Desidrogenase/fisiopatologiaRESUMO
This study assessed technology-aided programs for helping two post-coma persons, who had emerged from a minimally conscious state and were affected by multiple disabilities, to (a) engage with leisure stimuli and request caregiver's procedures, (b) send out and listen to text messages for communication with distant partners, and (c) combine leisure engagement and procedure requests with text messaging within the same sessions. The program for leisure engagement and procedure requests relied on the use of a portable computer with commercial software, and a microswitch for the participants' response. The program for text messaging communication involved the use of a portable computer, a GSM modem, a microswitch for the participants' response, and specifically developed software. Results indicated that the participants were successful at each of the three stages of the study, thus providing relevant evidence concerning performance achievements only minimally documented. The implications of the findings in terms of technology and practical opportunities for post-coma persons with multiple disabilities are discussed.
Assuntos
Coma/reabilitação , Auxiliares de Comunicação para Pessoas com Deficiência , Pessoas com Deficiência/reabilitação , Atividades de Lazer , Estado Vegetativo Persistente/reabilitação , Adulto , Hemorragia Cerebral/complicações , Coma/etiologia , Comunicação , Estado de Consciência , Feminino , Humanos , Aneurisma Intracraniano/complicações , Masculino , Estado Vegetativo Persistente/etiologia , Doença da Deficiência do Complexo de Piruvato Desidrogenase/complicações , Estado Epiléptico/complicações , Envio de Mensagens de Texto , Adulto JovemRESUMO
The pyruvate dehydrogenase complex (PDHc) is a mitochondrial matrix multienzyme complex that provides the link between glycolysis and the tricarboxylic acid (TCA) cycle by catalyzing the conversion of pyruvate into acetyl-CoA. PDHc deficiency is one of the commoner metabolic disorders of lactic acidosis presenting with neurological phenotypes that vary with age and gender. In this mini-review, we postulate mechanisms of epilepsy in the setting of PDHc deficiency using two illustrative cases (one with pyruvate dehydrogenase complex E1-alpha polypeptide (PDHA1) deficiency and the second one with pyruvate dehydrogenase complex E1-beta subunit (PDHB) deficiency (a rare subtype of PDHc deficiency)) and a selected review of published case series. PDHc plays a critical role in the pathway of carbohydrate metabolism and energy production. In severe deficiency states the resulting energy deficit impacts on brain development in utero resulting in structural brain anomalies and epilepsy. Milder deficiency states present with variable manifestations that include cognitive delay, ataxia, and seizures. Epileptogenesis in PDHc deficiency is linked to energy failure, development of structural brain anomalies and abnormal neurotransmitter metabolism. The use of the ketogenic diet bypasses the metabolic block, by providing a direct source of acetyl-CoA, leading to amelioration of some symptoms. Genetic counseling is essential as PDHA1 deficiency (commonest defect) is X-linked although females can be affected due to unfavorable lyonization, while PDHB and PDH phosphatase (PDP) deficiencies (much rarer defects) are of autosomal recessive inheritance. Research is in progress for looking into animal models to better understand pathogenesis and management of this challenging disorder.
Assuntos
Epilepsia/etiologia , Doença da Deficiência do Complexo de Piruvato Desidrogenase/complicações , Complexo Piruvato Desidrogenase/metabolismo , Criança , Epilepsia/diagnóstico , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Redes e Vias Metabólicas , Doença da Deficiência do Complexo de Piruvato Desidrogenase/diagnóstico , Doença da Deficiência do Complexo de Piruvato Desidrogenase/etiologiaRESUMO
Pyruvate dehydrogenase complex is a key intramitochondrial multienzyme complex required for the conversion of pyruvate to acetyl-CoA. Most patients with pyruvate dehydrogenase deficiency have a defect in the E1 alpha subunit, associated with mutations in the PDHA1 gene. In this report, we submit detailed magnetic resonance images in 4 affected female patients with PDHA1 mutations who had with severe cortical atrophy, dilated ventricles, and an incomplete corpus callosum. In one of these patients, the magnetic resonance imaging pattern prompted molecular diagnostic testing when enzymatic testing was normal. We underscore that this constellation of features, which may be misdiagnosed as periventricular leukomalacia, illustrates a pattern highly suggestive of a deficiency of pyruvate dehydrogenase E1 alpha in female patients and should trigger appropriate diagnostic investigations.
Assuntos
Encéfalo/patologia , Imageamento por Ressonância Magnética/métodos , Piruvato Desidrogenase (Lipoamida)/deficiência , Doença da Deficiência do Complexo de Piruvato Desidrogenase/diagnóstico , Corpo Caloso/patologia , Feminino , Humanos , Lactente , Piruvato Desidrogenase (Lipoamida)/metabolismo , Doença da Deficiência do Complexo de Piruvato Desidrogenase/complicaçõesRESUMO
A number of medications have been used with varying success to treat the symptoms of generalized, focal, and paroxysmal dyskinesias; these agents include anticonvulsant, benzodiazepine, neuroleptic, dopaminergic, dopamine antagonist, and carbonic anhydrase inhibitor types. The carbonic anhydrase inhibitor drug group is best represented by acetazolamide, which has been widely applied in the treatment of paroxysmal dyskinesias. Zonisamide, which has several putative pharmacologic mechanisms of action, is a member of the carbonic anhydrase inhibitor drug group. Zonisamide was chosen for treatment of secondary paroxysmal dystonia in a patient with pyruvate dehydrogenase deficiency (case 1) and in two patients with neonatal hemochromatosis and family history of neonatal hemochromatosis (cases 2 and 3). Although zonisamide ameliorated the symptoms of secondary paroxysmal dystonia in these three patients, the precise biochemical mechanism remains unclear, and further studies are needed to substantiate and explain this finding.
Assuntos
Antioxidantes/uso terapêutico , Distúrbios Distônicos/tratamento farmacológico , Isoxazóis/uso terapêutico , Adolescente , Criança , Feminino , Hemocromatose/complicações , Hemocromatose/tratamento farmacológico , Humanos , Masculino , Doença da Deficiência do Complexo de Piruvato Desidrogenase/complicações , Doença da Deficiência do Complexo de Piruvato Desidrogenase/tratamento farmacológico , ZonisamidaRESUMO
We present three patients with intractable aspiration pneumonia in the setting of permanent neurologic impairment, who had received a tracheostomy and showed a juxtaposition of the innominate artery against the trachea. Neurologically impaired patients often show a juxtaposition or compression of the innominate artery against the trachea by chest deformity in the setting of severe scoliosis, which could result in a trachea-innominate artery fistula. For intractable aspiration, laryngotracheal separation is safely performed and effective in controlling aspiration, but is occasionally complicated by trachea-innominate artery fistula. As an alternative procedure, we performed a closure of the larynx in these three cases, using double flaps of the vocal folds and false vocal folds, as a treatment for intractable aspiration. After operation, the patients did well without complication or clinical evidence of recurrent aspiration.
Assuntos
Laringe/anormalidades , Laringe/cirurgia , Pneumonia Aspirativa/etiologia , Pneumonia Aspirativa/prevenção & controle , Tronco Braquiocefálico/anormalidades , Criança , Pré-Escolar , Epilepsia/complicações , Feminino , Humanos , Deficiência Intelectual/complicações , Masculino , Pneumonia Aspirativa/diagnóstico por imagem , Doença da Deficiência do Complexo de Piruvato Desidrogenase/complicações , Radiografia Torácica , Respiração Artificial/efeitos adversos , Tomografia Computadorizada por Raios X , Traqueostomia , Adulto JovemRESUMO
The association of progressive episodic dystonia and learning disability with distinctive neuroimaging findings may lead to consideration of atypical Pantothenate Kinase Associated Neurodegeneration (PKAN) and investigations directed towards that diagnosis. Recent reports indicate that deficiency of dihydrolipoamide acetyltransferase, the E2 component of the pyruvate dehydrogenase complex, may present similarly, and that this disorder should also be considered in the differential diagnosis. We describe two sisters with early onset episodic dystonia and pyruvate dehydrogenase deficiency caused by defects in the E2 subunit. Both have neuroimaging features similar to previously described patients and have mutations in the DLAT gene. As this condition is potentially treatable with a ketogenic diet, the possibility of this diagnosis should be considered in similar cases.