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1.
Rev Neurol (Paris) ; 174(10): 731-735, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30318261

RESUMO

We describe two patients with mitochondrial DNA mutations in the gene encoding cytochrome b (m.15579A>G, p.Tyr278Cys and m.15045G>A p.Arg100Gln), which presented as a pure myopathic form (exercise intolerance), with an onset in childhood. Diagnosis was delayed, because acylcarnitine profile showed an increase in medium and long-chain acylcarnitines, suggestive of multiple acyl-CoA dehydrogenase deficiency, riboflavin transporter deficiency or FAD metabolism disorder. Implication of cytochrome b in fatty acid oxidation, and physiopathology of the mutations are discussed.


Assuntos
Citocromos b/genética , Deficiência Múltipla de Acil Coenzima A Desidrogenase/diagnóstico , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Mutação de Sentido Incorreto , Adulto , Idoso , DNA Mitocondrial/genética , Diagnóstico Diferencial , Tolerância ao Exercício/genética , Humanos , Masculino , Deficiência Múltipla de Acil Coenzima A Desidrogenase/genética
2.
Clin Genet ; 92(3): 306-317, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28255985

RESUMO

BACKGROUND: Tyrosinemia type II, also known as Richner-Hanhart Syndrome, is an extremely rare autosomal recessive disorder, caused by mutations in the gene encoding hepatic cytosolic tyrosine aminotransferase, leading to the accumulation of tyrosine and its metabolites which cause ocular and skin lesions, that may be accompanied by neurological manifestations, mostly intellectual disability. AIMS: To update disease-causing mutations and current clinical knowledge of the disease. MATERIALS AND METHODS: Genetic and clinical information were obtained from a collection of both unreported and previously reported cases. RESULTS: We report 106 families, represented by 143 individuals, carrying a total of 36 genetic variants, 11 of them not previously known to be associated with the disease. Variants include 3 large deletions, 21 non-synonymous and 5 nonsense amino-acid changes, 5 frameshifts and 2 splice variants. We also report 5 patients from Gran Canaria, representing the largest known group of unrelated families sharing the same P406L mutation. CONCLUSIONS: Data analysis did not reveal a genotype-phenotype correlation, but stressed the need of early diagnosis: All patients improved the oculocutaneous lesions after dietary treatment but neurological symptoms prevailed. The discovery of founder mutations in isolated populations, and the benefits of early intervention, should increase diagnostic awareness in newborns.


Assuntos
Efeito Fundador , Estudos de Associação Genética , Mutação , Fenótipo , Tirosinemias/diagnóstico , Tirosinemias/genética , Adolescente , Idade de Início , Alelos , Criança , Pré-Escolar , Feminino , Loci Gênicos , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único , Tirosina Transaminase/genética , Tirosinemias/dietoterapia , Adulto Jovem
3.
JIMD Rep ; 31: 85-93, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27147232

RESUMO

Aromatic L-amino acid decarboxylase (AADC) deficiency is an autosomal recessive inborn error of metabolism, affecting catecholamines and serotonin biosynthesis. Cardinal signs consist in psychomotor delay, hypotonia, oculogyric crises, dystonia, and extraneurological symptoms. PATIENTS AND METHODS: We present a retrospective descriptive multicentric study concerning ten French children with a biochemical and molecular confirmed diagnosis of AADC deficiency. RESULTS: Clinical presentation of most of our patients was consistent with the previous descriptions from the literature (hypotonia (nine children), autonomic signs (nine children), sleep disorders (eight children), oculogyric crises (eight children), motor disorders like hypertonia and involuntary movements (seven children)). We described however some phenotypic particularities. Two patients exhibited normal intellectual abilities (patients already described in the literature). We also underlined the importance of digestive symptoms like diarrhea, which occurred in five among the ten patients. We report in particular two children with chronic diarrhea, complicated by severe failure to thrive. Vanillactic acid (VLA) elevation in urines of one of these two patients led to suspect the diagnosis of AADC deficiency, as in two other patients from our population. CONCLUSION: Some symptoms like chronic diarrhea were atypical and have been poorly described in the literature up to now. Diagnosis of the AADC deficiency is sometimes difficult because of the phenotypic heterogeneity of the disease and VLA elevation in urines should suggest the diagnosis.

4.
Rev Neurol (Paris) ; 172(3): 231-41, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27038534

RESUMO

INTRODUCTION: Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare, treatable, beta-oxidation disorder responsible for neuromuscular symptoms in adults. This case series describes the clinical and biochemical features of 13 French patients with late-onset MADD. METHODS AND RESULTS: Thirteen ambulant patients (eight women, five men), with a median age at onset of 27 years, initially experienced exercise intolerance (n=9), isolated muscle weakness (n=1) and a multisystemic pattern with either central nervous system or hepatic dysfunction (n=3). During the worsening period, moderate rhabdomyolysis (n=5), a pseudomyasthenic pattern (n=5) and acute respiratory failure (n=1) have been observed. Weakness typically affected the proximal limbs and axial muscles, and there was sometimes facial asymmetry (n=3). Moderate respiratory insufficiency was noted in one case. Median baseline creatine kinase was 190IU/L. Lactacidemia was sometimes moderately increased at rest (3/10) and after exercise (1/3). The acylcarnitine profile was characteristic, with increases in all chain-length acylcarnitine species. Electromyography revealed a myogenic pattern, while muscle biopsy showed lipidosis, sometimes with COX-negative fibers (n=2). The mitochondrial respiratory chain was impaired in five cases, with coenzyme Q10 decreased in two cases. All patients harbored mutations in the ETFDH gene (four homozygous, seven compound heterozygous, two single heterozygous), with nine previously unidentified mutations. All patients were good responders to medical treatment, but exercise intolerance and/or muscular weakness persisted in 11 of them. CONCLUSION: Late-onset forms of MADD may present as atypical beta-oxidation disorders. Acylcarnitine profiling and muscle biopsy remain the most decisive investigations for assessing the diagnosis. These tests should thus probably be performed more widely, particularly in unexplained cases of neuromuscular and multisystemic disorders.


Assuntos
Erros Inatos do Metabolismo Lipídico/enzimologia , Erros Inatos do Metabolismo Lipídico/terapia , Deficiência Múltipla de Acil Coenzima A Desidrogenase/complicações , Deficiência Múltipla de Acil Coenzima A Desidrogenase/genética , Doenças Neuromusculares/enzimologia , Doenças Neuromusculares/terapia , Adulto , Idade de Início , Biópsia , Carnitina/análogos & derivados , Carnitina/metabolismo , Eletromiografia , Flavoproteínas Transferidoras de Elétrons/genética , Exercício Físico , Feminino , França , Humanos , Proteínas Ferro-Enxofre/genética , Erros Inatos do Metabolismo Lipídico/genética , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/enzimologia , Músculo Esquelético/patologia , Mutação/genética , Doenças Neuromusculares/genética , Oxirredução , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Rabdomiólise/etiologia , Adulto Jovem
5.
JIMD Rep ; 30: 23-31, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26898293

RESUMO

The analysis of acylcarnitines (AC) in plasma/serum is established as a useful test for the biochemical diagnosis and the monitoring of treatment of organic acidurias and fatty acid oxidation defects. External quality assurance (EQA) for qualitative and quantitative AC is offered by ERNDIM and CDC in dried blood spots but not in plasma/serum samples. A pilot interlaboratory comparison between 14 European laboratories was performed over 3 years using serum/plasma samples from patients with an established diagnosis of an organic aciduria or fatty acid oxidation defect. Twenty-three different samples with a short clinical description were circulated. Participants were asked to specify the method used to analyze diagnostic AC, to give quantitative data for diagnostic AC with the corresponding reference values, possible diagnosis, and advice for further investigations.Although the reference and pathological concentrations of AC varied among laboratories, elevated marker AC for propionic acidemia, isovaleric acidemia, medium-chain acyl-CoA dehydrogenase, very long-chain acyl-CoA dehydrogenase, and multiple acyl-CoA dehydrogenase deficiencies were correctly identified by all participants allowing the diagnosis of these diseases. Conversely, the increased concentrations of dicarboxylic AC were not always identified, and therefore the correct diagnosis was not reach by some participants, as exemplified in cases of malonic aciduria and 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. Misinterpretation occurred in those laboratories that used multiple-reaction monitoring acquisition mode, did not derivatize, or did not separate isomers. However, some of these laboratories suggested further analyses to clarify the diagnosis.This pilot experience highlights the importance of an EQA scheme for AC in plasma.

6.
Arch Pediatr ; 21(1): 78-85, 2014 Jan.
Artigo em Francês | MEDLINE | ID: mdl-24321868

RESUMO

L-2-hydroxyglutaric aciduria is a rare genetic neurometabolic disease. It occurs in childhood with mental retardation, cerebellar ataxia, and epilepsy. Macrocephaly is present in half of the cases. Diagnosis is based on clinical symptoms, biological and radiological findings, and molecular testing. Specific treatments can improve the spontaneous progression of the disease. We examined two independent patients who presented with L-2-hydroxyglutaric aciduria. Clinical presentation led to cerebral MRI and urinary organic acid chromatography. The genetic analysis confirmed the diagnosis. Under specific treatment, the progression of the disease was subsequently stopped. L-2-hydroxyglutaric aciduria shares common symptoms with other genetic and metabolic diseases. However, the association of a distinct phenotype and typical MRI abnormalities (such as a high signal in the subcortical white matter, pallidum, and dentate nuclei) should draw the clinician's attention to this diagnosis. It can easily be suspected with a simple urinary analysis and can then be confirmed by genetic testing. With this case report, we show the importance of genetic identification to begin treatment with riboflavin. Early detection of L-2-hydroxyglutaric aciduria based on MRI abnormalities can enable rapid initiation of treatment and prevent disease progression.


Assuntos
Oxirredutases do Álcool/genética , Encefalopatias Metabólicas Congênitas/diagnóstico , Encéfalo/patologia , Encefalopatias Metabólicas Congênitas/tratamento farmacológico , Encefalopatias Metabólicas Congênitas/genética , Carnitina/uso terapêutico , Criança , Pré-Escolar , Cromossomos Humanos Par 14/genética , Consanguinidade , Análise Mutacional de DNA , Quimioterapia Combinada , Diagnóstico Precoce , Intervenção Médica Precoce , Feminino , Seguimentos , Triagem de Portadores Genéticos , Humanos , Imageamento por Ressonância Magnética , Masculino , Prognóstico , Riboflavina/uso terapêutico
7.
Arch Pediatr ; 19(9): 959-69, 2012 Sep.
Artigo em Francês | MEDLINE | ID: mdl-22884749

RESUMO

Inherited metabolic diseases are mostly due to enzyme deficiency in one of numerous metabolic pathways, leading to absence of a compound downstream from and the accumulation of a compound upstream from the deficient metabolite(s). Diseases of intoxication by proteins (aminoacidopathies, organic acidurias, urea cycle defects) and by sugars (galactosemia, fructosemia) usually do not give prenatal symptoms since mothers protect their fetuses from pathological metabolite accumulation. A well-known exception is hypoplasia of corpus callosum, as is sometimes observed in nonketotic hyperglycinemia and sulfite oxidase deficiency. Conversely, women with phenylketonuria "poison" their fetus if they are not treated (spontaneous abortions, intrauterine growth restriction [IUGR], cardiac malformations, and brain disease). Amino acid synthesis defects can lead to prenatal symptoms: microcephaly in serine deficiency (detectable by amino acid analysis in fetal cord blood), and brain malformations in glutamine synthetase deficiency. Impaired folate metabolism is involved in a large fraction of neurodevelopmental defects referred to as spina bifida, yet the underlying genetic component(s) are largely unknown. Energy metabolism diseases caused by defects in the synthesis or utilization of relevant metabolites lead to organ dysfunctions or malformations, but prenatal diagnosis is usually impossible unless genetic analysis can rely on a previously affected child in the family. A somewhat intermediate condition is defects of mitochondrial beta-oxidation of fatty acids, as they may sometimes be symptomatic prenatally (notably the HELLP syndrome or other presentations), and in this case, organic acid and acylcarnitine analysis in amniotic fluid can be informative in the absence of an index case. In contrast, complex molecule diseases commonly give prenatal symptoms that may permit the diagnosis even in the absence of index cases: hydrops fetalis and skeletal anomalies in lysosomal storage diseases, hydrops fetalis in congenital disorders of glycosylation (CDG) and transaldolase deficiency, brain malformations in O-glycosylation defects, brain malformations, kidney cysts and skeletal anomalies in peroxysomal diseases (Zellweger syndrome), syndactyly, genitalia malformations, and IUGR in Smith-Lemli-Opitz (SLO) syndrome. Although many metabolic disorders show biochemical abnormalities during fetal development that are informative for prenatal diagnosis, only a fraction of them are clinically/sonographically symptomatic before birth, thus allowing for prenatal diagnosis in the absence of an index case, i.e., serine deficiency, some fatty acid beta-oxidation defects, transaldolase deficiency, lysosomal diseases, CDG, Zellweger syndrome, and SLO syndrome.


Assuntos
Doenças Fetais/diagnóstico , Erros Inatos do Metabolismo/diagnóstico , Diagnóstico Pré-Natal , Metabolismo Energético , Feminino , Humanos , Substâncias Macromoleculares/metabolismo , Guias de Prática Clínica como Assunto , Gravidez , Complicações na Gravidez
8.
Arch Pediatr ; 19(2): 184-93, 2012 Feb.
Artigo em Francês | MEDLINE | ID: mdl-22244319

RESUMO

MCAD deficiency is the most common fatty acid oxidation disorder, with the prevalence varying from 1/10,000 to 1/27,000 in the countries adjacent to France. As the High Authority for Health has recently proposed including MCAD deficiency in the panel of diseases neonatally screened for in France, a consensus was written for the management of MCAD deficiency diagnosed either clinically or by neonatal screening. Patients may present acutely with hyperammonemia, hypoglycemia, encephalopathy, and hepatomegaly, mainly after a prolonged fast of intercurrent infection. Sudden death related to heartbeat disorders may also occur. The diagnosis of MCAD deficiency is suspected on the plasma acylcarnitine and/or the urinary organic acid profile. The diagnosis is confirmed by molecular biology and the enzymatic activity for patients who are not homozygous for the main mutation c.985A>G. However, some MCAD-deficient individuals may remain asymptomatic throughout life. The mainstay of treatment consists in avoiding prolonged fast and prescribing l-carnitine for patients who exhibit a deficiency in plasma carnitine. This management has radically modified the natural history of MCAD deficiency. This consensus will allow homogeneous management of these patients once the neonatal screening of MCAD deficiency has been introduced in France.


Assuntos
Erros Inatos do Metabolismo Lipídico/diagnóstico , Erros Inatos do Metabolismo Lipídico/terapia , Triagem Neonatal , Acil-CoA Desidrogenase/deficiência , Árvores de Decisões , França , Humanos , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/fisiopatologia
9.
Mol Genet Metab ; 103(4): 341-8, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21549624

RESUMO

BACKGROUND: Deficiency of mitochondrial trifunctional protein (MTP) is caused by mutations in the HADHA and HADHB genes, which have been mostly delineated at the genomic DNA level and have not been always elucidated. AIM: To identify mutations in a French cohort of 52 MTP deficient patients and the susceptibility of mutations generating premature termination codons (PTCs) to the nonsense mRNA mediated decay (NMD). METHODS: Mutation screening in fibroblasts was performed at the cDNA level and real-time RT-PCR was used to compare the levels of the different PTC-bearing mRNAs before and after a treatment of fibroblasts by emetine, a translation inhibitor. RESULTS: A mutation detection rate of 100% was achieved. A total of 22 novel mutations were identified, including a large-sized genomic deletion in HADHB gene. A high proportion of all identified mutations were non-sense, frameshift and splicing mutations, generating (PTCs), distributed essentially on HADHA coding regions. We could demonstrate that the majority of mutations resulting in PTCs conform to the established rules governing the susceptibility to NMD. CONCLUSION: Our results emphasize the value of cDNA analysis in the characterization of HADHA and HADHB mutations and further strengthen the model of haploinsufficiency as a major pathomechanism in MTP defects.


Assuntos
DNA Complementar/genética , Transtornos do Metabolismo dos Lipídeos/genética , Doenças Mitocondriais/genética , Proteínas Mitocondriais/genética , Complexos Multienzimáticos/genética , Mutação , Sequência de Bases , Estudos de Coortes , Feminino , França , Haploinsuficiência , Humanos , Masculino , Proteína Mitocondrial Trifuncional , Subunidade alfa da Proteína Mitocondrial Trifuncional , Subunidade beta da Proteína Mitocondrial Trifuncional , Dados de Sequência Molecular , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA
10.
Rev Neurol (Paris) ; 166(3): 289-94, 2010 Mar.
Artigo em Francês | MEDLINE | ID: mdl-19592060

RESUMO

INTRODUCTION: Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare genetic disease involving fatty acid oxidation. It is due to the deficiency of one of the two electron transporters: electron transfer flavoprotein (ETF) or electron transfer flavoprotein ubiquinone oxydoreductase (ETF-QO). Symptoms begin more often in childhood or in young adulthood with a multisystemic disease with encephalopathy or muscular weakness. CASE REPORTS: We report here two adult cases with ETF-QO deficiency, confirmed by mutation analysis (ETFDH gene), revealed by a muscular weakness associated with muscle lipidosis. One of our patients presented an acute encephalopathy with vomiting ten years before the onset of muscular symptoms. The second patient exhibited a slowly progressive pelvic girdle muscle weakness. Diagnosis was established by characteristic abnormalities of acylcarnitine profile by tandem mass spectrometry. For both patients, a dramatic clinical improvement was observed under treatment with riboflavine and L-carnitine. CONCLUSION: Since it is a treatable disorder, this diagnosis must be considered by performing an acylcarnitine profile in all patients presenting with an unexplained muscular weakness.


Assuntos
Acil-CoA Desidrogenases/deficiência , Erros Inatos do Metabolismo Lipídico/enzimologia , Erros Inatos do Metabolismo Lipídico/genética , Lipidoses/tratamento farmacológico , Lipidoses/genética , Adulto , Biópsia , Encefalopatias Metabólicas/genética , Carnitina/análogos & derivados , Carnitina/análise , Carnitina/metabolismo , Corantes , Análise Mutacional de DNA , Transporte de Elétrons/genética , Flavoproteínas Transferidoras de Elétrons/genética , Flavoproteínas Transferidoras de Elétrons/metabolismo , Feminino , Humanos , Erros Inatos do Metabolismo Lipídico/patologia , Lipidoses/patologia , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/etiologia , Debilidade Muscular/genética , Músculo Esquelético/patologia , Riboflavina/metabolismo , Espectrometria de Massas em Tandem , Adulto Jovem
11.
Prog. diagn. trat. prenat. (Ed. impr.) ; 21(4): 213-217, oct.-dic. 2009. ilus, tab
Artigo em Português | IBECS | ID: ibc-75429

RESUMO

O diagnóstico pré-natal de doenças hereditárias dometabolismo permite aos casais de risco equacionarem assuas opções reprodutivas de modo a só terem descendentesnão afectados. No caso de défice em proteína trifuncionalmitocondrial (MIM #6090015) ou MPT (complexo multienzimáticoessencial à β-oxidação dos ácidos gordos de cadeialonga de C12 a C18) essa situação reveste-se de grandeimportância dada a elevada letalidade associada à patologia.Os autores apresentam um caso clínico de défice em proteínatrifuncional fatal. O diagnóstico pré-natal (DPN) foidisponibilizado em três gestações, sendo os dois primeirospor doseamento enzimático e o último através de estudomolecular(AU)


The prenatal diagnosis of inherited metabolic diseaseoffers, to at-risk couples, the opportunity to plan theirreproductive options in order to have only unaffectedoffspring.In cases of mitochondrial protein trifunctional deficiency(MIM #6090015) or MPT (multienzyme complexinvolved in the β-oxidation of fatty acids with lengths ofC12-C18) this is an important issue because a high rateof mortality is associated with this disorder.The authors report a neonatal fatal case of MPT deficiency.Prenatal diagnosis was offered in the following 3pregnancies: two by a biochemical approach and the lastone by mutational analysis(AU)


Assuntos
Humanos , Masculino , Feminino , Doenças Genéticas Inatas/genética , Deficiência de Proteína/congênito , Deficiência de Proteína/genética , Ácidos Graxos/síntese química , Ácidos Graxos/genética , Diagnóstico Pré-Natal/instrumentação , Diagnóstico Pré-Natal/métodos
12.
J Inherit Metab Dis ; 32(6): 713, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19821142

RESUMO

L-2-hydroxyglutaric aciduria (L-2-HGA) is a rare inherited autosomal recessive neurometabolic disorder caused by mutations in the gene encoding L-2-hydroxyglutarate dehydrogenase. An assay to evaluate L-2-hydroxyglutarate dehydrogenase (L-2-HGDH) activity in fibroblast, lymphoblast and/or lymphocyte lysates has hitherto been unavailable. We developed an L-2-HGDH enzyme assay in cell lysates based on the conversion of stable-isotope-labelled L-2-hydroxyglutarate to 2-ketoglutarate, which is converted into L-glutamate in situ. The formation of stable isotope labelled L-glutamate is therefore a direct measure of L-2-HGDH activity, and this product is detected by liquid chromatography-tandem mass spectrometry. A deficiency of L-2-HGDH activity was detected in cell lysates from 15 out of 15 L-2-HGA patients. Therefore, this specific assay confirmed the diagnosis unambiguously affirming the relationship between molecular and biochemical observations. Residual activity was detected in cells derived from one L-2-HGA patient. The L-2-HGDH assay will be valuable for examining in vitro riboflavin/FAD therapy to rescue L-2-HGDH activity.


Assuntos
Oxirredutases do Álcool/análise , Oxirredutases do Álcool/deficiência , Encefalopatias Metabólicas Congênitas/diagnóstico , Extratos Celulares/química , Ensaios Enzimáticos/métodos , Oxirredutases do Álcool/líquido cefalorraquidiano , Animais , Encefalopatias Metabólicas Congênitas/líquido cefalorraquidiano , Encefalopatias Metabólicas Congênitas/patologia , Calibragem , Extratos Celulares/análise , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida/métodos , Ensaios Enzimáticos/normas , Fibroblastos/química , Fibroblastos/enzimologia , Humanos , Linfócitos/química , Linfócitos/enzimologia , Modelos Biológicos , Modelos Moleculares , Ratos , Projetos de Pesquisa , Espectrometria de Massas em Tandem/métodos
13.
J Inherit Metab Dis ; 31(6): 680-9, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19016343

RESUMO

External quality assurance (EQA) schemes are essential for improvement of accuracy, reliability and comparability of results of biochemical genetic tests. ERNDIM (European Research Network for evaluation and improvement of screening, Diagnosis and treatment of Inherited disorders of Metabolism), established in 1994, operates nine EQA schemes for biochemical genetic testing according to international norms and recommendations. These comprise qualitative schemes for amino acids, organic acids, purines and pyrimidines, special assays in serum and urine and white cell cystine, qualitative organic acid and acylcarnitine schemes, as well as diagnostic proficiency testing. The total number of participants has increased from 123 in 1994 to 268 in 2007. Additional activities include participation in the Eurogentest project, a laboratory directory, training, education and development of guidelines. Results from the quantitative amino acid scheme with 170 participants reveal good variation within and between laboratories of below 10% for 10 amino acids; good within-laboratory variation but intermediate inter-laboratory variation of 10-22% for 11 amino acids; and higher variation within and between laboratories for 8 amino acids. Results on samples from 51 inherited metabolic disorders from two of five centres organizing diagnostic proficiency testing indicate overall diagnostic efficiency above 80% and improved performance of individual laboratories. Comparison of results for 10 and 12 compounds in the serum and urine special assay schemes respectively for 2000 and 2007 reveal clear improvement of precision within laboratories and in inter-laboratory variation. There is considerable evidence that performance in biochemical genetic testing has improved since the introduction of ERNDIM schemes.


Assuntos
Doenças Metabólicas/diagnóstico , Erros Inatos do Metabolismo/diagnóstico , Aminoácidos/análise , Química Clínica/normas , Europa (Continente) , Humanos , Doenças Metabólicas/sangue , Doenças Metabólicas/urina , Erros Inatos do Metabolismo/sangue , Erros Inatos do Metabolismo/urina , Garantia da Qualidade dos Cuidados de Saúde , Controle de Qualidade , Reprodutibilidade dos Testes
14.
Neuropediatrics ; 38(2): 78-82, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17712735

RESUMO

Ethylmalonic encephalopathy (EE) is a rare, recently defined inborn error of metabolism which affects the brain, gastrointestinal system and peripheral blood vessels and is characterized by a unique constellation of clinical and biochemical features. A 7-month-old male, who presented with psychomotor retardation, chronic diarrhea and relapsing petechiae is described with the objective of highlighting the biochemical and neuroradiological features of this disorder as well as the effect of high-dose riboflavin therapy. Urinary organic acid analysis revealed markedly increased excretion of ethylmalonic acid, isobutyrylglycine, 2-methylbutyrylglycine and isovalerylglycine. Acylcarnitine analysis in dried blood spots showed increased butyrylcarnitine. Short-chain acyl-CoA dehydrogenase (SCAD) activity in muscle was normal as were mitochondrial OXPHOS enzyme activities in cultured skin fibroblasts. In skeletal muscle the catalytic activity of complex II was decreased. Brain MRI revealed bilateral and symmetrical atrophy in the fronto-temporal areas, massive enlargement of the subarachnoid spaces and hyperdensities on T (2) sequences of the basal ganglia. Mutation analysis of the ETHE1 gene demonstrated homozygosity for the Arg163Gly mutation, confirming the diagnosis of EE at a molecular level. On repeat MRI, a significant deterioration was seen, correlating well with the clinical deterioration of the patient.


Assuntos
Encefalopatias Metabólicas Congênitas/diagnóstico , Malonatos/metabolismo , Encefalopatias Metabólicas Congênitas/genética , Encefalopatias Metabólicas Congênitas/metabolismo , Evolução Fatal , Humanos , Lactente , Masculino , Proteínas Mitocondriais/genética , Proteínas de Transporte Nucleocitoplasmático/genética
15.
Mol Genet Metab ; 91(4): 362-9, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17540595

RESUMO

Two horses (a 7-year-old Groninger warmblood gelding and a six-month-old Trakehner mare) with pathologically confirmed rhabdomyolysis were diagnosed as suffering from multiple acyl-CoA dehydrogenase deficiency (MADD). This disorder has not been recognised in animals before. Clinical signs of both horses were a stiff, insecure gait, myoglobinuria, and finally recumbency. Urine, plasma, and muscle tissues were investigated. Analysis of plasma showed hyperglycemia, lactic acidemia, increased activity of muscle enzymes (ASAT, LDH, CK), and impaired kidney function (increased urea and creatinine). The most remarkable findings of organic acids in urine of both horses were increased lactic acid, ethylmalonic acid (EMA), 2-methylsuccinic acid, butyrylglycine (iso)valerylglycine, and hexanoylglycine. EMA was also increased in plasma of both animals. Furthermore, the profile of acylcarnitines in plasma from both animals showed a substantial elevation of C4-, C5-, C6-, C8-, and C5-DC-carnitine. Concentrations of acylcarnitines in urine of both animals revealed increased excretions of C2-, C3-, C4-, C5-, C6-, C5-OH-, C8-, C10:1-, C10-, and C5-DC-carnitine. In addition, concentrations of free carnitine were also increased. Quantitative biochemical measurement of enzyme activities in muscle tissue showed deficiencies of short-chain acyl-CoA dehydrogenase (SCAD), medium-chain acyl-CoA dehydrogenase (MCAD), and isovaleryl-CoA dehydrogenase (IVD) also indicating MADD. Histology revealed extensive rhabdomyolysis with microvesicular lipidosis predominantly in type 1 muscle fibers and mitochondrial damage. However, the ETF and ETF-QO activities were within normal limits indicating the metabolic disorder to be acquired rather than inherited. To our knowledge, these are the first cases of biochemical MADD reported in equine medicine.


Assuntos
Acil-CoA Desidrogenase/deficiência , Doenças dos Cavalos/enzimologia , Rabdomiólise/veterinária , Acil-CoA Desidrogenase/genética , Animais , Feminino , Doenças dos Cavalos/patologia , Cavalos , Masculino , Rabdomiólise/enzimologia , Rabdomiólise/patologia
16.
Neurology ; 67(9): 1713-4, 2006 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-17101918
17.
J Clin Forensic Med ; 13(6-8): 339-40, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17055402

RESUMO

An observation of homicide in which the victim was frozen, then burned, was reported. This confirmed the usefulness of measuring SCHAD (short-chain 3-hydroxyacyl-CoA dehydrogenase) activity in the freezing of a human corpse despite unusual circumstances.


Assuntos
3-Hidroxiacil-CoA Desidrogenases/química , Traumatismos Craniocerebrais/patologia , Congelamento , Homicídio , Músculo Esquelético/patologia , Adulto , Autopsia , Queimaduras/patologia , Diagnóstico Diferencial , Medicina Legal , Humanos , Masculino
18.
J Inherit Metab Dis ; 29(5): 685, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16906473

RESUMO

High concentrations of butyryl/isobutyrylcarnitine (C(4)-carnitine) in plasma with increase of ethylmalonic acid (EMA) in urine point to different genetic entities, and further investigations are required to differentiate the possible underlying defect. Here we report three unrelated cases, two neurologically affected and one asymptomatic, with this abnormal metabolite pattern due either to mutations in the ETHE1 gene or to a short-chain acyl-CoA dehydrogenase (SCAD) defect.


Assuntos
Encefalopatias/diagnóstico , Butiril-CoA Desidrogenase/genética , Carnitina/análogos & derivados , Carnitina/sangue , Humanos , Malonatos/urina , Proteínas Mitocondriais/genética , Doenças do Sistema Nervoso , Proteínas de Transporte Nucleocitoplasmático/genética
19.
Mol Genet Metab ; 87(1): 40-7, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16297647

RESUMO

The differentiation of carnitine-acylcarnitine translocase deficiency (CACT) from carnitine palmitoyltransferase type II deficiency (CPT-II) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency from mitochondrial trifunctional protein deficiency (MTP) continues to be ambiguous using current acylcarnitine profiling techniques either from plasma or blood spots, or in the intact cell system (fibroblasts/amniocytes). Currently, enzyme assays are required to unequivocally differentiate CACT from CPT-II, and LCHAD from MTP. Over the years we have studied the responses of numerous FOD deficient cell lines to both even and odd numbered fatty acids of various chain lengths as well as branched-chain amino acids. In doing so, we discovered diagnostic elevations of unlabeled butyrylcarnitine detected only in CACT deficient cell lines when incubated with a shorter chain fatty acid, [7-2H3]heptanoate plus l-carnitine compared to the routinely used long-chain fatty acid, [16-2H3]palmitate. In monitoring the unlabeled C4/C5 acylcarnitine ratio, further differentiation from ETF/ETF-DH is also achieved. Similarly, incubating LCHAD and MTP deficient cell lines with the long-chain branched fatty acid, pristanic acid, and monitoring the C11/C9 acylcarnitine ratio has allowed differentiation between these disorders. These methods may be considered useful alternatives to specific enzyme assays for differentiation between these long-chain fatty acid oxidation disorders, as well as provide insight into new treatment strategies.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/genética , Carnitina/análogos & derivados , Erros Inatos do Metabolismo Lipídico/diagnóstico , Complexos Multienzimáticos/deficiência , 3-Hidroxiacil-CoA Desidrogenases/deficiência , 3-Hidroxiacil-CoA Desidrogenases/genética , 3-Hidroxiacil-CoA Desidrogenases/metabolismo , Acetil-CoA C-Aciltransferase/deficiência , Acetil-CoA C-Aciltransferase/genética , Acetil-CoA C-Aciltransferase/metabolismo , Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Adolescente , Isomerases de Ligação Dupla Carbono-Carbono/deficiência , Isomerases de Ligação Dupla Carbono-Carbono/genética , Isomerases de Ligação Dupla Carbono-Carbono/metabolismo , Carnitina/metabolismo , Células Cultivadas , Ensaios Enzimáticos Clínicos , DNA Complementar , Diagnóstico Diferencial , Enoil-CoA Hidratase/deficiência , Enoil-CoA Hidratase/genética , Enoil-CoA Hidratase/metabolismo , Ácidos Graxos/farmacologia , Fibroblastos/metabolismo , Testes Genéticos , Humanos , Recém-Nascido , Proteína Mitocondrial Trifuncional , Complexos Multienzimáticos/genética , Oxirredução , Racemases e Epimerases/deficiência , Racemases e Epimerases/genética , Racemases e Epimerases/metabolismo
20.
Rapid Commun Mass Spectrom ; 19(22): 3287-97, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16235234

RESUMO

Seventy-six compounds of biological interest for the diagnosis of inherited disorders of amino acids (AA) metabolism have previously been demonstrated to be detectable in positive mode electrospray ionisation tandem mass spectrometry (ESI-MS/MS), after separation by ion-pairing reversed-phase liquid chromatography (RPLC). The separation method used tridecafluoroheptanoic acid as ion-pairing agent, and a gradient of acetonitrile for the elution of the most retained compounds. This method had previously been demonstrated to be suitable for the qualitative diagnosis of many AA disorders, and for the quantitative measurement of 16 AA in biological fluids, using their stable isotope labelled (SIL) AA as internal standard. For quantification of the other AA, an internal standard was chosen among the available SIL-AA, as close as possible to the analyte to be measured, in terms of structural analogy, and of retention time in the chromatographic system. The performances of the quantitative analysis of the other AA to be measured are reported here. They show validated results for several AA, allowing their accurate quantification, with another SIL-AA as internal standard. For some other AA, quantitative results were not accurate, allowing only semi-quantitative or qualitative determination for these parameters.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Aminoácidos/análise , Aminoácidos/química , Cromatografia Líquida/métodos , Espectrometria de Massas/métodos , Aminoácidos/metabolismo , Calibragem , Humanos , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
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