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2.
Mol Genet Metab ; 126(4): 397-405, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30827756

RESUMO

BACKGROUND AND AIM: Patients with methylmalonic acidemia (MMA) and propionic acidemia (PA) and urea cycle disorders (UCD), treated with a protein restricted diet, are prone to growth failure. To obtain optimal growth and thereby efficacious protein incorporation, a diet containing the essential and functional amino acids for growth is necessary. Optimal growth will result in improved protein tolerance and possibly a decrease in the number of decompensations. It thus needs to be determined if amino acid deficiencies are associated with the growth retardation in these patient groups. We studied the correlations between plasma L-arginine levels, plasma branched chain amino acids (BCAA: L-isoleucine, L-leucine and L-valine) levels (amino acids known to influence growth), and height in MMA/PA and UCD patients. METHODS: We analyzed data from longitudinal visits made in stable metabolic periods by patients registered at the European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD, Chafea no. 2010 12 01). RESULTS: In total, 263 MMA/PA and 311 UCD patients were included, all aged below 18 years of age. In patients with MMA and PA, height z-score was positively associated with patients' natural-protein-to-energy prescription ratio and their plasma L-valine and L-arginine levels, while negatively associated with the amount of synthetic protein prescription and their age at visit. In all UCDs combined, height z-score was positively associated with the natural-protein-to-energy prescription ratio. In those with carbamylphosphate synthetase 1 deficiency (CPS1-D), those with male ornithine transcarbamylase deficiency (OTC-D), and those in the hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome subgroup, height z-score was positively associated with patients' plasma L-leucine levels. In those with argininosuccinate synthetase deficiency (ASS-D) and argininosuccinate lyase deficiency (ASL-D), height was positively associated with patients' plasma L-valine levels. CONCLUSION: Plasma L-arginine and L-valine levels in MMA/PA patients and plasma L-leucine and L-valine levels in UCD patients, as well as the protein-to-energy prescription ratio in both groups were positively associated with height. Optimization of these plasma amino acid levels is essential to support normal growth and increase protein tolerance in these disorders. Consequently this could improve the protein-to-energy intake ratio.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/complicações , Aminoácidos de Cadeia Ramificada/sangue , Arginina/sangue , Transtornos do Crescimento/etiologia , Acidemia Propiônica/complicações , Distúrbios Congênitos do Ciclo da Ureia/complicações , Adolescente , Erros Inatos do Metabolismo dos Aminoácidos/dietoterapia , Estatura , Criança , Pré-Escolar , Dieta , Europa (Continente) , Feminino , Transtornos do Crescimento/dietoterapia , Humanos , Estudos Longitudinais , Masculino , Sistema de Registros
3.
Pediatr Transplant ; 22(8): e13310, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30338622

RESUMO

OBJECTIVE: To investigate Doppler US and catheter venogram correlates to improve detection of transplant HVOO and avoid unnecessary invasive imaging procedures. MATERIALS AND METHODS: A retrospective review was performed in all pediatric OLT patients undergoing catheter venography of the hepatic veins between 2007 and 2017 at a single large tertiary pediatric liver transplant institution. RESULTS: Forty-four transplant hepatic venograms in 32 OLT patients were included (mean 1.38, range 1-4 venograms per patient). All venograms were preceded by an independent Doppler US examination. Twenty-one (47.7%) venograms were performed for the investigation of suspected HVOO based on Doppler US alone, 19 (43.2%) were performed for TJLB without suspected HVOO, 4 (9.1%) were performed for both. Sixteen (36.3%) instances of >50% anastomotic stenosis were identified. Mean peak anastomotic velocities were 208 cm/s and 116 cm/s in the presence and absence of a >50% venographic stenosis, respectively (P < 0.004). In all cases where there was a monophasic waveform seen on Doppler US, there was a > 50% stenosis seen on hepatic vein venogram. In all cases where a triphasic waveform was seen on Doppler US, there was no stenosis seen on hepatic vein venogram. CONCLUSION: While a Doppler US velocity threshold providing both high sensitivity and specificity has yet to be identified, increasing peak anastomotic velocity and decreasing intrahepatic venous velocity correlate strongly with venographic outflow stenosis. The presence of a triphasic intrahepatic waveform provides good NPV.


Assuntos
Síndrome de Budd-Chiari/diagnóstico por imagem , Fígado/diagnóstico por imagem , Fígado/cirurgia , Flebografia , Ultrassonografia Doppler , Adolescente , Anastomose Cirúrgica , Angiografia , Cateteres , Criança , Pré-Escolar , Constrição Patológica , Feminino , Veias Hepáticas/diagnóstico por imagem , Humanos , Lactente , Masculino , Veia Porta/diagnóstico por imagem , Acidemia Propiônica/complicações , Estudos Retrospectivos , Procedimentos Desnecessários , Adulto Jovem
4.
J Inherit Metab Dis ; 41(6): 1179-1187, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30159853

RESUMO

BACKGROUND: There is increasing evidence that long-term complications in organic acidemias are caused by impaired mitochondrial metabolism. Currently, there is no specific biomarker to monitor mitochondrial dysfunction in organic acidemias. Serum fibroblast growth factor 21 (FGF-21) is a biomarker for mitochondrial disease and could be a candidate to monitor mitochondrial function in the deleterious course of disease. METHODS: Data of 17 patients with classical organic acidemias (11 propionic acidemia (PA), four methylmalonic acidemia (MMA) and two isovaleric acidemia (IVA) patients) were included. The clinical course was evaluated; metabolic decompensations and long-term complications were correlated with plasma FGF-21 levels. Cardiomyopathy, prolonged QT interval, renal failure, and optic neuropathy were defined as long-term complications. RESULTS: Patients ages ranged from 16 months up to 32 years. Serious long-term complications occurred in eight patients (five PA and three MMA patients). In MMA and PA patients plasma FGF-21 levels during stable metabolic periods were significantly higher in patients with long-term complications (Mdn = 2556.0 pg/ml) compared to patients without (Mdn = 287.0 pg/ml). A median plasma FGF-21 level above 1500 pg/ml during a stable metabolic period, measured before the occurrence of long-term complications, had a positive predictive value of 0.83 and a negative predictive value of 1.00 on long-term complications in MMA and PA patients. CONCLUSION: This study demonstrates the potential role of FGF-21 as a biomarker for long-term complications in classical organic acidemias, attributed to mitochondrial dysfunction.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/complicações , Fatores de Crescimento de Fibroblastos/sangue , Isovaleril-CoA Desidrogenase/deficiência , Doenças Mitocondriais/sangue , Acidemia Propiônica/complicações , Adolescente , Adulto , Biomarcadores/sangue , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Doenças Mitocondriais/complicações , Adulto Jovem
6.
J Child Neurol ; 33(11): 713-717, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30014764

RESUMO

Propionic acidemia is an inborn error of metabolism that is inherited in an autosomal recessive manner. It is characterized by a deficient propionyl-CoA carboxylase due to mutations in either of its beta or alpha subunits. In the literature, there is a clear association between propionic acidemia and epilepsy. In this cohort, we retrospectively reviewed the data of 14 propionic acidemia patients in Saudi Arabia and compared the findings to those of former studies. Six of the 14 (43%) patients developed epileptic seizure, mainly focal seizures. All patients were responsive to conventional antiepileptic drugs as their seizures are controlled. The predominant electroencephalographic (EEG) findings were diffuse slowing in 43% and multifocal epileptiform discharges in 14% of the patients. In 1 patient, burst suppression pattern was detected, a pattern never before reported in patients with propionic acidemia. Brain magnetic resonance imaging (MRI) findings mainly consisted of signal changes of the basal ganglia (36%), generalized brain atrophy (43%), and delayed myelination (43%).The most common genotype in our series is the homozygous missense mutation in the PCCA gene (c.425G>A; p. Gly142Asp). However, there is no clear genotype-seizure correlation. We conclude that seizure is not an uncommon finding in patients with propionic acidemia and not difficult to control. Additional studies are needed to further elaborate on genotype-seizure correlation.


Assuntos
Epilepsia/etiologia , Acidemia Propiônica/complicações , Adolescente , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Eletroencefalografia , Epilepsia/diagnóstico por imagem , Epilepsia/genética , Feminino , Genótipo , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Metilmalonil-CoA Descarboxilase/genética , Mutação de Sentido Incorreto/genética , Exame Neurológico , Acidemia Propiônica/genética , Estudos Retrospectivos , Arábia Saudita
9.
Mol Genet Metab ; 123(4): 433-440, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29433791

RESUMO

BACKGROUND AND OBJECTIVES: Patients affected with methylmalonic acidemia (MMA) and propionic acidemia (PA) exhibit diverse long-term complications and poor outcome. Liver disease is not a reported complication. The aim of this study was to characterize and extensively evaluate long-term liver involvement in MMA and PA patients. PATIENTS AND METHODS: We first describe four patients who had severe liver involvement during the course of their disease. Histology showed fibrosis and/or cirrhosis in 3 patients. Such liver involvement led us to retrospectively collect liver (clinical, laboratory and ultrasound) data of MMA (N = 12) or PA patients (N = 16) from 2003 to 2016. RESULTS: Alpha-fetoprotein (αFP) levels were increased in 8/16 and 3/12 PA and MMA patients, respectively, and tended to increase with age. Moderate and recurrent increase of GGT was observed in 4/16 PA patients and 4/12 MMA patients. Abnormal liver ultrasound with either hepatomegaly and/or hyperechoic liver was observed in 7/9 PA patients and 3/9 MMA patients. CONCLUSIONS: These data demonstrate that approximately half of the patients affected by MMA or PA had signs of liver abnormalities. The increase of αFP with age suggests progressive toxicity, which might be due to the metabolites accumulated in PA and MMA. These metabolites (e.g., methylmalonic acid and propionic acid derivatives) have previously been reported to have mitochondrial toxicity; this toxicity is confirmed by the results of histological and biochemical mitochondrial analyses of the liver in two of our MMA patients. In contrast to the moderate clinical, laboratory or ultrasound expression, severe pathological expression was found for three of the 4 patients who underwent liver biopsy, ranging from fibrosis to cirrhosis. These results emphasize the need for detailed liver function evaluation in organic aciduria patients, including liver biopsy when liver disease is suspected. TAKE HOME MESSAGE: MMA and PA patients exhibit long-term liver abnormalities.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/complicações , Hepatopatias/etiologia , Hepatopatias/patologia , Acidemia Propiônica/complicações , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Adulto Jovem
10.
Mol Genet Metab ; 122(4): 145-152, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29033250

RESUMO

Propionyl-CoA carboxylase (PCC) is the enzyme which catalyzes the carboxylation of propionyl-CoA to methylmalonyl-CoA and is encoded by the genes PCCA and PCCB to form a hetero-dodecamer. Dysfunction of PCC leads to the inherited metabolic disorder propionic acidemia, which can result in an affected individual presenting with metabolic acidosis, hyperammonemia, lethargy, vomiting and sometimes coma and death if not treated. Individuals with propionic acidemia also have a number of long term complications resulting from the dysfunction of the PCC enzyme. Here we present an overview of the current knowledge about the structure and function of PCC. We review an updated list of human variants which are published and provide an overview of the disease.


Assuntos
Carbono-Carbono Ligases/química , Carbono-Carbono Ligases/metabolismo , Acidemia Propiônica/enzimologia , Carbono-Carbono Ligases/genética , Humanos , Hiperamonemia/complicações , Ácido Láctico/análogos & derivados , Ácido Láctico/metabolismo , Metilmalonil-CoA Descarboxilase/genética , Mutação , Acidemia Propiônica/complicações , Acidemia Propiônica/genética , Acidemia Propiônica/fisiopatologia , Relação Estrutura-Atividade
11.
Eur J Hum Genet ; 25(11): 1195-1201, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28853722

RESUMO

Dilated cardiomyopathy (DCM) is extremely heterogeneous with a large proportion due to dominantly inherited disease-causing variants in sarcomeric genes. Recessive metabolic diseases may cause DCM, usually with onset in childhood, and in the context of systemic disease. Whether metabolic defects can also cause adult-onset DCM is currently unknown. Therefore, we performed an extensive metabolic screening in 36 consecutive adult-onset DCM patients. Diagnoses were confirmed by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). Measurement of propionyl-CoA carboxylase (PCC) activity was done in fibroblasts. Whole exome sequencing (WES) data of 157 additional DCM patients were analyzed for genetic defects. We found a metabolic profile characteristic for propionic acidemia in a patient with severe DCM from 55 years of age. Genetic analysis demonstrated compound heterozygous variants in PCCA. Enzymatic activity of PCC in fibroblasts was markedly reduced. A targeted analysis of the PCCA and PCCB genes using available WES data from 157 further DCM patients subsequently identified another patient with propionic acidemia. This patient had compound heterozygous variants in PCCB, and developed severe DCM from 42 years of age. Adult-onset DCM can be caused by propionic acidemia, an autosomal recessive inheritable metabolic disorder usually presenting as neonatal or childhood disease. Current guidelines advise a low-protein diet to ameliorate or prevent detrimental aspects of the disease. Long-term follow-up of a larger group of patients may show whether this diet would also ameliorate DCM. Our results suggest that diagnostic metabolic screening to identify propionic acidemia and related disorders in DCM patients is justified.


Assuntos
Cardiomiopatia Dilatada/genética , Metilmalonil-CoA Descarboxilase/genética , Acidemia Propiônica/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Cardiomiopatia Dilatada/sangue , Cardiomiopatia Dilatada/etiologia , Cardiomiopatia Dilatada/urina , Células Cultivadas , Feminino , Fibroblastos/metabolismo , Heterozigoto , Humanos , Masculino , Metilmalonil-CoA Descarboxilase/metabolismo , Pessoa de Meia-Idade , Mutação , Linhagem , Acidemia Propiônica/genética
12.
J Pediatr Endocrinol Metab ; 30(10): 1133-1136, 2017 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-28820736

RESUMO

Propionic acidemia (PA) is a rare autosomal recessive metabolic disorder caused by deficiency of the mitochondrial enzyme propionyl-CoA carboxylase (PCC). This disorder mostly progresses with episodes of metabolic acidosis. Cardiomyopathy is among the cardiac complications known to occur during metabolic decompensation episodes. However, several recent papers emphasized the association of PA and long QT syndrome (LQTS) which may lead to extremely serious and fatal consequences. In this report, we describe two sisters with PA who have prolonged QT duration that were incidentally detected in an outpatient setting. LQTS was verified by electrocardiogram, stress test and 24 h rhythm holter monitoring. By this report, we want to emphasize the importance of early diagnosis of LQTS in asymptomatic patients with PA to prevent fatal complications.


Assuntos
Carbono-Carbono Ligases/genética , Síndrome do QT Longo/diagnóstico , Acidemia Propiônica/complicações , Criança , Eletrocardiografia , Feminino , Humanos , Lactente , Síndrome do QT Longo/complicações , Síndrome do QT Longo/genética , Acidemia Propiônica/genética , Irmãos
13.
Orphanet J Rare Dis ; 12(1): 30, 2017 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-28193246

RESUMO

Propionic acidemia is an inborn error of metabolism caused by deficiency of the mitochondrial enzyme propionyl-CoA carboxylase. Sensorineural deafness and severe hearing loss have been described as long-term complications of this disease, however, the mechanism has not yet been elucidated. We have recently shown by patch clamping experiments and Western blots that acute and chronic effects of accumulating metabolites such as propionic acid, propionylcarnitine and methylcitrate on the KvLQT1/KCNE1 channel complex cause long QT syndrome in patients with propionic acidemia by inhibition of K+ flow via this channel. The same KvLQT1/KCNE1 channel complex is expressed in the inner ear and essential for luminal potassium secretion into the endolymphatic space. A disruption of this K+ flow results in sensorineural hearing loss or deafness. It can be assumed that acute and chronic effects of accumulating metabolites on the KvLQT1/KCNE1 channel protein may similarly cause the hearing impairment of patients with propionic acidemia.


Assuntos
Perda Auditiva Neurossensorial/etiologia , Acidemia Propiônica/complicações , Animais , Regulação da Expressão Gênica/fisiologia , Perda Auditiva Neurossensorial/metabolismo , Humanos , Canal de Potássio KCNQ1/genética , Canal de Potássio KCNQ1/metabolismo , Camundongos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/genética , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo
15.
Mol Genet Metab ; 119(4): 317-321, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27825584

RESUMO

Certain inborn errors of metabolism have been suggested to increase the risk of autistic behavior. In an animal model, propionic acid ingestion triggered abnormal behavior resembling autism. So far only a few cases were reported with propionic acidemia and autistic features. From a series of twelve consecutively diagnosed cases with propionic acidemia, we report on eight patients with autistic features. The patients were followed 2-4 times a year and underwent regular clinical, dietary and laboratory investigations. Psychological evaluation was performed every second to fourth year. All patients were compliant with the standard diet and carnitine supplementation. None of the patients had frequent metabolic decompensations. From the metabolic factors known to impact neuropsychological outcome we detected chronically decreased valine levels and altered valine to leucine ratios in five out of the eight patients. Recurrent lactic acid elevations were present in six out of the eight patients. Five of the eight patients were diagnosed with Autism Spectrum Disorder, four of them had pathogenic variants in PCCB. Disorder according to DSM-IV and/or DSM-5 criteria. One of the patients diagnosed with propionic acidemia by newborn screening had the most significant behavioral features and another was diagnosed with Autism Spectrum Disorder prior to propionic acidemia. We hypothesize that chronic suboptimal intracellular metabolic balance may be responsible for the increased risk for autistic features in propionic acidemia. We propose that patients diagnosed with propionic acidemia should be screened for Autism Spectrum Disorder.


Assuntos
Transtorno do Espectro Autista/genética , Metilmalonil-CoA Descarboxilase/genética , Triagem Neonatal , Acidemia Propiônica/genética , Adolescente , Adulto , Animais , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/fisiopatologia , Criança , Feminino , Humanos , Recém-Nascido , Leucina/metabolismo , Masculino , Propionatos/metabolismo , Acidemia Propiônica/complicações , Acidemia Propiônica/diagnóstico , Acidemia Propiônica/fisiopatologia , Adulto Jovem
17.
Curr Opin Pediatr ; 28(6): 682-693, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27653704

RESUMO

PURPOSE OF REVIEW: Recent clinical studies and management guidelines for the treatment of the organic acidopathies methylmalonic acidemia (MMA) and propionic acidemia address the scope of interventions to maximize health and quality of life. Unfortunately, these disorders continue to cause significant morbidity and mortality due to acute and chronic systemic and end-organ injury. RECENT FINDINGS: Dietary management with medical foods has been a mainstay of therapy for decades, yet well controlled patients can manifest growth, development, cardiac, ophthalmological, renal, and neurological complications. Patients with organic acidopathies suffer metabolic brain injury that targets specific regions of the basal ganglia in a distinctive pattern, and these injuries may occur even with optimal management during metabolic stress. Liver transplantation has improved quality of life and metabolic stability, yet transplantation in this population does not entirely prevent brain injury or the development of optic neuropathy and cardiac disease. SUMMARY: Management guidelines should identify necessary screening for patients with methylmalonic acidemia and propionic acidemia, and improve anticipatory management of progressive end-organ disease. Liver transplantation improves overall metabolic control, but injury to nonregenerative tissues may not be mitigated. Continued use of medical foods in these patients requires prospective studies to demonstrate evidence of benefit in a controlled manner.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Acidemia Propiônica , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/dietoterapia , Erros Inatos do Metabolismo dos Aminoácidos/cirurgia , Lesão Encefálica Crônica/etiologia , Lesão Encefálica Crônica/prevenção & controle , Alimentos Formulados , Humanos , Transplante de Fígado , Acidemia Propiônica/complicações , Acidemia Propiônica/diagnóstico , Acidemia Propiônica/dietoterapia , Acidemia Propiônica/cirurgia
18.
J Pediatr ; 175: 231-2, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27283461

RESUMO

Late-preterm twins with propionic acidemia developed severe hyperammonemic encephalopathy at 5 days of age. Continuous venovenous hemodialysis was performed successfully for both infants via extracorporeal membrane oxygenation pump, and both rapidly improved. They were taken off continuous venovenous hemodialysis and extracorporeal membrane oxygenation and discharged with dietary therapy. At 3 years of age, neurodevelopment showed globally delayed milestones.


Assuntos
Doenças em Gêmeos/terapia , Oxigenação por Membrana Extracorpórea , Hiperamonemia/terapia , Doenças do Prematuro/terapia , Acidemia Propiônica/complicações , Diálise Renal/métodos , Gêmeos Monozigóticos , Doenças em Gêmeos/etiologia , Humanos , Hiperamonemia/etiologia , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/etiologia , Masculino
19.
Heart Rhythm ; 13(6): 1335-45, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26854997

RESUMO

BACKGROUND: Propionic acidemia (PROP) is a rare metabolic disorder caused by deficiency of propionyl-CoA carboxylase. PROP patients demonstrate QT prolongations associated with ventricular tachycardia and syncopes. Mechanisms responsible for this acquired long QT syndrome (acqLQTS) are unknown. OBJECTIVE: The aim of the study was to investigate acute and chronic effects of metabolites accumulating in PROP patients on major repolarizing potassium currents (IKs and IKr) and their channel subunits. METHODS: Voltage clamp studies were performed in CHO-KCNQ1/KCNE1 or HEK-KCNH2 cells to determine effects of propionic acid (PA; 1-10 mM), propionylcarnitine (PC; 25 µM-10 mM), methylcitrate (MC; 25 µM-10 mM), 0.2 M phosphate buffer (PB), or patient serum on IKs and IKr currents. Metabolite effects on action potentials were recorded in current clamp mode in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). Protein expression of α- and ß-subunits of IKs (KCNQ1/KCNE1) and IKr (KCNH2) was evaluated with Western blots. RESULTS: Acute application of PA, PC, MC, and patient serum had no direct effect on net IKr densities (and KCNH2 expression), although it changed IKr gating kinetics. In contrast, PA, PC, MC, and patient serum all reduced IKs-tail (-67% ± 4.2%, -27% ± 6.7%, -16% ± 6.3%, -42.8% ± 5.15; P < .001) and IKs-end pulse currents. PA significantly prolonged action potential duration (APD) in hiPSC-CM and QT interval in wild-type but not in LQT1 rabbits lacking IKs. Moreover, PC and MC (1 mM) decreased KCNQ1 protein expression (relative density: 0.58 ± 0.08 and 0.16 ± 0.05; P < .01). Chronic exposure to 10 mM PA, in contrast, increased KCNQ1 5.4-fold (P < .001) owing to decreased protein degradation. CONCLUSION: Acute reduction of IKs by PROP metabolites may be responsible for APD prolongation and acqLQTS observed in PROP patients.


Assuntos
Metilmalonil-CoA Descarboxilase/metabolismo , Acidemia Propiônica , Animais , Sistema de Condução Cardíaco/metabolismo , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/etiologia , Síndrome do QT Longo/fisiopatologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Acidemia Propiônica/complicações , Acidemia Propiônica/metabolismo , Acidemia Propiônica/fisiopatologia , Coelhos , Taquicardia Ventricular/etiologia , Taquicardia Ventricular/prevenção & controle
20.
Br J Ophthalmol ; 100(1): 98-104, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26209586

RESUMO

BACKGROUND: Methylmalonic acidemia (MMA) and propionic acidemia (PA) are rare hereditary disorders of protein metabolism, manifesting early in life with ketoacidosis and encephalopathy and often resulting in chronic complications. Optic neuropathy (ON) has been increasingly recognised in both conditions, mostly through isolated case reports or small cases series. We here report the clinical features and visual outcomes of a case series of paediatric patients with a diagnosis of MMA or PA. METHODS: Retrospective observational case series. A database of patients attending the Willink Biochemical Genetics unit in Manchester was interrogated. Fifty-three patients had a diagnosis of either isolated MMA or PA, of which 12 had been referred for ophthalmic review. RESULTS: Seven patients had clinical findings compatible with ON. Visual outcomes in these patients were poor, with slow clinical progression or stability over time in five cases with follow-up. Presentation was acute in a context of metabolic crisis in two of the cases. Four patients with ON had electrodiagnostics showing absent pattern evoked potentials, with one showing a preserved flash response. All four showed marked attenuation of the dark-adapted electroretinogram with better preservation of the light-adapted response. CONCLUSIONS: Our study suggests that ON is under-reported in patients with MMA and PA. Clinical presentation can be acute or insidious, and episodes of acute metabolic decompensation appear to trigger visual loss. Photoreceptor involvement may coexist. Active clinical surveillance of affected patients is important as comorbidities and cognitive impairment may delay diagnosis.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/complicações , Doenças do Nervo Óptico/etiologia , Acidemia Propiônica/complicações , Adolescente , Criança , Eletrorretinografia , Potenciais Evocados Visuais , Feminino , Humanos , Masculino , Disco Óptico/patologia , Doenças do Nervo Óptico/diagnóstico , Tomografia de Coerência Óptica
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