RESUMO
UNLABELLED: Blood ammonia and glutamine levels are used as biomarkers of control in patients with urea cycle disorders (UCDs). This study was undertaken to evaluate glutamine variability and utility as a predictor of hyperammonemic crises (HACs) in UCD patients. METHODS: The relationships between glutamine and ammonia levels and the incidence and timing of HACs were evaluated in over 100 adult and pediatric UCD patients who participated in clinical trials of glycerol phenylbutyrate. RESULTS: The median (range) intra-subject 24-hour coefficient of variation for glutamine was 15% (8-29%) as compared with 56% (28%-154%) for ammonia, and the correlation coefficient between glutamine and concurrent ammonia levels varied from 0.17 to 0.29. Patients with baseline (fasting) glutamine values >900 µmol/L had higher baseline ammonia levels (mean [SD]: 39.6 [26.2]µmol/L) than patients with baseline glutamine ≤ 900 µmol/L (26.6 [18.0]µmol/L). Glutamine values >900 µmol/L during the study were associated with an approximately 2-fold higher HAC risk (odds ratio [OR]=1.98; p=0.173). However, glutamine lost predictive significance (OR=1.47; p=0.439) when concomitant ammonia was taken into account, whereas the predictive value of baseline ammonia ≥ 1.0 upper limit of normal (ULN) was highly statistically significant (OR=4.96; p=0.013). There was no significant effect of glutamine >900 µmol/L on time to first HAC crisis (hazard ratio [HR]=1.14; p=0.813), but there was a significant effect of baseline ammonia ≥ 1.0 ULN (HR=4.62; p=0.0011). CONCLUSIONS: The findings in this UCD population suggest that glutamine is a weaker predictor of HACs than ammonia and that the utility of the predictive value of glutamine will need to take into account concurrent ammonia levels.
Assuntos
Amônia/sangue , Glutamina/sangue , Hiperamonemia/sangue , Distúrbios Congênitos do Ciclo da Ureia/sangue , Adolescente , Adulto , Biomarcadores/sangue , Criança , Pré-Escolar , Jejum , Feminino , Glicerol/análogos & derivados , Glicerol/uso terapêutico , Humanos , Hiperamonemia/etiologia , Masculino , Fenilbutiratos/uso terapêutico , Valor Preditivo dos Testes , Distúrbios Congênitos do Ciclo da Ureia/tratamento farmacológico , Adulto JovemRESUMO
BACKGROUND: Phenylacetic acid (PAA) is the active moiety in sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB, HPN-100). Both are approved for treatment of urea cycle disorders (UCDs) - rare genetic disorders characterized by hyperammonemia. PAA is conjugated with glutamine in the liver to form phenylacetyleglutamine (PAGN), which is excreted in urine. PAA plasma levels ≥ 500 µg/dL have been reported to be associated with reversible neurological adverse events (AEs) in cancer patients receiving PAA intravenously. Therefore, we have investigated the relationship between PAA levels and neurological AEs in patients treated with these PAA pro-drugs as well as approaches to identifying patients most likely to experience high PAA levels. METHODS: The relationship between nervous system AEs, PAA levels and the ratio of plasma PAA to PAGN were examined in 4683 blood samples taken serially from: [1] healthy adults [2], UCD patients of ≥ 2 months of age, and [3] patients with cirrhosis and hepatic encephalopathy (HE). The plasma ratio of PAA to PAGN was analyzed with respect to its utility in identifying patients at risk of high PAA values. RESULTS: Only 0.2% (11) of 4683 samples exceeded 500 µg/ml. There was no relationship between neurological AEs and PAA levels in UCD or HE patients, but transient AEs including headache and nausea that correlated with PAA levels were observed in healthy adults. Irrespective of population, a curvilinear relationship was observed between PAA levels and the plasma PAA:PAGN ratio, and a ratio>2.5 (both in µg/mL) in a random blood draw identified patients at risk for PAA levels>500 µg/ml. CONCLUSIONS: The presence of a relationship between PAA levels and reversible AEs in healthy adults but not in UCD or HE patients may reflect intrinsic differences among the populations and/or metabolic adaptation with continued dosing. The plasma PAA:PAGN ratio is a functional measure of the rate of PAA metabolism and represents a useful dosing biomarker.
Assuntos
Glutamina/análogos & derivados , Encefalopatia Hepática/sangue , Fenilacetatos/sangue , Distúrbios Congênitos do Ciclo da Ureia/sangue , Biomarcadores/sangue , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/sangue , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Glutamina/administração & dosagem , Glutamina/sangue , Glicerol/administração & dosagem , Glicerol/análogos & derivados , Encefalopatia Hepática/etiologia , Encefalopatia Hepática/patologia , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Fenilacetatos/administração & dosagem , Fenilbutiratos/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Distúrbios Congênitos do Ciclo da Ureia/epidemiologia , Distúrbios Congênitos do Ciclo da Ureia/etiologia , Distúrbios Congênitos do Ciclo da Ureia/patologiaRESUMO
UNLABELLED: We have analyzed pharmacokinetic data for glycerol phenylbutyrate (also GT4P or HPN-100) and sodium phenylbutyrate with respect to possible dosing biomarkers in patients with urea cycle disorders (UCD). STUDY DESIGN: These analyses are based on over 3000 urine and plasma data points from 54 adult and 11 pediatric UCD patients (ages 6-17) who participated in three clinical studies comparing ammonia control and pharmacokinetics during steady state treatment with glycerol phenylbutyrate or sodium phenylbutyrate. All patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate or sodium phenylbutyrate in a cross over fashion and underwent 24-hour blood samples and urine sampling for phenylbutyric acid, phenylacetic acid and phenylacetylglutamine. RESULTS: Patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate ranging from 1.5 to 31.8 g/day and of sodium phenylbutyrate ranging from 1.3 to 31.7 g/day. Plasma metabolite levels varied widely, with average fluctuation indices ranging from 1979% to 5690% for phenylbutyric acid, 843% to 3931% for phenylacetic acid, and 881% to 1434% for phenylacetylglutamine. Mean percent recovery of phenylbutyric acid as urinary phenylacetylglutamine was 66.4 and 69.0 for pediatric patients and 68.7 and 71.4 for adult patients on glycerol phenylbutyrate and sodium phenylbutyrate, respectively. The correlation with dose was strongest for urinary phenylacetylglutamine excretion, either as morning spot urine (r = 0.730, p < 0.001) or as total 24-hour excretion (r = 0.791 p<0.001), followed by plasma phenylacetylglutamine AUC(24-hour), plasma phenylacetic acid AUC(24-hour) and phenylbutyric acid AUC(24-hour). Plasma phenylacetic acid levels in adult and pediatric patients did not show a consistent relationship with either urinary phenylacetylglutamine or ammonia control. CONCLUSION: The findings are collectively consistent with substantial yet variable pre-systemic (1st pass) conversion of phenylbutyric acid to phenylacetic acid and/or phenylacetylglutamine. The variability of blood metabolite levels during the day, their weaker correlation with dose, the need for multiple blood samples to capture trough and peak, and the inconsistency between phenylacetic acid and urinary phenylacetylglutamine as a marker of waste nitrogen scavenging limit the utility of plasma levels for therapeutic monitoring. By contrast, 24-hour urinary phenylacetylglutamine and morning spot urine phenylacetylglutamine correlate strongly with dose and appear to be clinically useful non-invasive biomarkers for compliance and therapeutic monitoring.
Assuntos
Amônia/urina , Glutamina/análogos & derivados , Glicerol/análogos & derivados , Fenilacetatos/urina , Fenilbutiratos/urina , Distúrbios Congênitos do Ciclo da Ureia/tratamento farmacológico , Distúrbios Congênitos do Ciclo da Ureia/urina , Adolescente , Adulto , Amônia/sangue , Biomarcadores Farmacológicos/sangue , Biomarcadores Farmacológicos/urina , Criança , Estudos Cross-Over , Esquema de Medicação , Feminino , Glutamina/sangue , Glutamina/urina , Glicerol/sangue , Glicerol/farmacocinética , Glicerol/urina , Humanos , Masculino , Fenilacetatos/sangue , Fenilbutiratos/sangue , Fenilbutiratos/farmacocinética , Distúrbios Congênitos do Ciclo da Ureia/sangueRESUMO
Urinary phenylacetylglutamine (U-PAGN) concentrations in spot urine samples were analyzed as a dosing biomarker during glycerol phenylbutyrate (GPB) dosing in 68 healthy adults and 66 adult and pediatric patients with urea cycle disorders who participated in GPB clinical trials. Age- and body surface area (BSA)-specific 25th percentile cutoff points for spot U-PAGN concentrations (<~9000 µg/mL for < 2 years old patients, < 7000 µg/mL for > 2 years with BSA ≤ 1.3 m2, and <~5000 µg/mL for > 2 years of age with BSA > 1.3 m2) were determined as an approach to identify patients for whom increased dosing and/or adherence to prescribed dosing should be assessed.
RESUMO
Oculocerebrocutaneous syndrome (OCCS), or Delleman syndrome, is a multiple congenital anomaly syndrome characterized by orbital cysts, cerebral malformations, and focal dermal hypoplasia [Delleman and Oorthuys, 1981, Clin Genet 19:191-198; Delleman et al., 1984, Clin Genet 25:470-472]. Two previous reports presented children having what is suggested as the more severe form of the OCCS syndrome who also had anophthalmia, congenital hydrocephalus, and cleft lip and palate [Leichtman et al., 1994, Am J Med Genet 50:39-41; Angle and Hersh, 1997, Am J Med Genet 68:39-42]. We report on a third case of severe OCCS, an infant girl with a similar constellation of findings and additional anomalies including lateral facial cleft, vertebral anomaly, and ventricular septal defect. The additional findings in our patient highlight the phenotypic overlap of OCCS and the Goldenhar anomaly, an overlap previously noted by Delleman and Oorthuys [1981], and others [Al-Gazali et al., 1988, J Med Genet 25: 773-778]. We suggest that the minimal diagnostic criteria for Delleman syndrome include central nervous system cyst or hydrocephalus, orbital cysts or microphthalmia, and focal skin defects.
Assuntos
Anormalidades Múltiplas , Encéfalo/anormalidades , Anormalidades do Olho , Síndrome de Goldenhar , Anormalidades da Pele , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/etiologia , Consumo de Bebidas Alcoólicas , Fenda Labial , Fissura Palatina , Cocaína , Diagnóstico Diferencial , Evolução Fatal , Feminino , Síndrome de Goldenhar/diagnóstico , Cardiopatias Congênitas , Humanos , Lactente , Fenótipo , Gravidez , Complicações na Gravidez , Anormalidades da Pele/diagnóstico , Crânio/anormalidadesRESUMO
Our aim was to determine if the high frequency of metachromatic leukodystrophy (MLD) in Navajo Indians of the Southwestern United States is the result of a "genetic bottleneck" that occurred in the mid 19th century. Navajo Nation, Indian Health Service, and other national databases were queried for Native American patients with MLD. Pedigrees, including birth location, were established by interviewing relatives. We found that cases of MLD and their ancestors are clustered in a portion of the western Navajo Nation to which a small number of Navajo fled after armed conflict with the United States Army in the 1860s. The observed incidence of MLD on the western Navajo Nation is 1/2,520 live births, with an estimated carrier frequency of 1/25 to 1/50. No cases were observed in the eastern part of the Navajo Nation over a period of 18 years (60,000 births). The high incidence of MLD in the western Navajo Nation appears to be the result of a genetic bottleneck and probable founder effect from the mid 19th century: This mechanism may also explain the high incidence of a number of other unique, heritable disorders among the Navajo. The history of the Navajo may also be relevant to other American Indian and Alaskan Native groups that have undergone severe population reduction since the arrival of Europeans in North America.
Assuntos
Indígenas Norte-Americanos/genética , Leucodistrofia Metacromática/genética , Feminino , Efeito Fundador , Frequência do Gene , Heterozigoto , História do Século XIX , História do Século XX , Humanos , Indígenas Norte-Americanos/estatística & dados numéricos , Leucodistrofia Metacromática/etnologia , Masculino , Linhagem , Sistema de Registros , Estados Unidos , United States Indian Health Service , GuerraRESUMO
Disorganization (Ds) is a mouse mutant best known for producing an exceptional variety of unusual developmental anomalies, such as mirror-limb duplications and hamartomatous skin papillae. So great is the range of malformations that no two affected mice are identical. Several patients with a similar variety of exceptional anomalies have been reported, raising the possibility of the existence of a human homologue of Ds. However, although these human cases represent the most striking findings seen in Ds mice, they do not represent the full range of defects. Most affected mice have only a single malformation, and most of these malformations are similar to both common (neural tube defects, orofacial clefting, gastroschisis, limb reductions) and rare (anophthalmia, duplicated rectum) human birth defects. It is therefore possible that the full spectrum of the human homologue of Ds includes not only patients with the unusual combination of anomalies but also common sporadic birth defects. We suggest that the low penetrance (approximately 0-30%) and highly variable expression of Ds make it a paradigm for understanding the genetic basis for many seemingly sporadic birth defects.
Assuntos
Anormalidades Múltiplas/genética , Camundongos Mutantes/genética , Animais , Variação Genética , Humanos , Camundongos , Mutação , FenótipoRESUMO
We recently evaluated a mentally retarded 48 year old man found to have a cytogenetic deletion of chromosome 10 [46,XY,del(10) (q25. 1q25.3)]. Of interest, he shares many clinical findings with those described in Coffin-Lowry syndrome (CLS). These include severe mental retardation, short stature and a coarse facial appearance with widely spaced eyes, and patulous lips. He also had an extra transverse hypothenar crease, a finding that is seen in CLS. Furthermore, he has characteristic radiographic hand findings described in 95% of patients with CLS. The CLS gene, located at Xp22. 2, has recently been identified, and mutations in the Rsk-2 gene have been identified in several CLS patients. Rsk2 is part of a gene family implicated in cell cycle regulation through the mitogen-activated protein (MAP) kinase cascade. None of the currently recognized components of this pathway maps to the region deleted in our patient, nor are we able to identify any likely candidate genes in the deleted region, although several G protein coupled receptors have been cloned from the region. This patient's findings have some overlap with those seen in CLS, suggesting that a gene involved in MAP kinase signaling may be present in the deleted region of chromosome 10q25.1-25.3. Patients with a phenotype consistent with CLS, but lacking a family history suggestive of an X-linked disorder, should be evaluated with chromosome analysis paying particular attention to the region 10q25.
Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Cromossomos Humanos Par 10 , Fácies , Deformidades Congênitas da Mão/diagnóstico por imagem , Humanos , Deficiência Intelectual/genética , Sistema de Sinalização das MAP Quinases/genética , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Radiografia , Proteínas Quinases S6 Ribossômicas/genética , Síndrome , Cromossomo X/genéticaRESUMO
BACKGROUND: Chromosome 22q11 deletion (del22q11), the most common microdeletion syndrome, causes a wide spectrum of clinical disorders. Recent studies have suggested that significant psychiatric and behavioral disturbances occur in up to 60% of these individuals. OBJECTIVE: To illustrate the spectrum of behavioral and psychiatric abnormalities associated with del22q11 and the subtle nature of its associated physical findings. PATIENTS AND METHODS: Case series describing psychiatric and behavioral findings in 3 patients with del22q11. RESULTS AND CONCLUSIONS: Behavioral and psychiatric problems are common in patients with del22q11 syndrome. Because the physical manifestations of the disorder are so variable and may be subtle, the behavioral and psychiatric manifestations may be the presenting problem. Providers must therefore consider del22q11 as a potential diagnosis in children and adults with behavioral and psychiatric problems. Furthermore, behavioral and psychiatric problems need to be looked for when caring for children and adolescents with a known diagnosis of del22q11.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 22/genética , Transtornos Mentais/genética , Adolescente , Criança , Comportamento Infantil , Transtornos do Comportamento Infantil/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , SíndromeRESUMO
Psychological evaluations were performed on two children with X-linked adrenoleukodystrophy. Case histories are presented that describe the natural history of the disorder and its symptom patterns, some of which mirror psychiatric disorders of childhood. Psychological evaluation test scores for both boys are displayed in a table, and commonalities and differences are discussed. Findings are reviewed to expedite the referral process for a definitive diagnosis. Guidelines are provided regarding the differential diagnosis of adrenoleukodystrophy and other neurodegenerative disorders of childhood from the more prevalent disorders of behavior and learning that may present in a developmental clinic. Finally, recommendations for psychological interventions with the affected child and family members are provided.
Assuntos
Adrenoleucodistrofia/complicações , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/etiologia , Transtornos Cognitivos/etiologia , Adrenoleucodistrofia/genética , Adrenoleucodistrofia/psicologia , Criança , Progressão da Doença , Ligação Genética , Humanos , Masculino , Testes Neuropsicológicos , Comportamento Social , Escalas de Wechsler , Cromossomo XRESUMO
Congenital cytomegalovirus infection can cause a wide variety of symptoms. We report three infants with congenital cytomegalovirus infection presenting with respiratory insufficiency associated with persistent diaphragmatic dysfunction. Congenital cytomegalovirus infection should be considered in the differential diagnosis of neonatal diaphragmatic dysfunction.
Assuntos
Infecções por Citomegalovirus/congênito , Infecções por Citomegalovirus/fisiopatologia , Diafragma/fisiopatologia , Insuficiência Respiratória/etiologia , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/diagnóstico por imagem , Infecções por Citomegalovirus/terapia , Diafragma/diagnóstico por imagem , Evolução Fatal , Feminino , Humanos , Recém-Nascido , Gravidez , Radiografia , Respiração Artificial , Insuficiência Respiratória/fisiopatologia , Insuficiência Respiratória/virologia , TraqueostomiaRESUMO
North Carolina (NC) was the first US state to initiate universal tandem mass spectrometry (MS/MS) newborn screening. This began as a statewide pilot project in 1997 to determine the incidence and feasibility of screening for fatty acid oxidation, organic acid and selected amino acid disorders. The MS/MS analyses were done by a commercial laboratory and all follow-up and confirmatory testing was performed through the NC Newborn Screening (NBS) Program. In April 1999, the NC NBS Laboratory began the MS/MS analyses in-house. Between 28 July 1997 and 28 July 2005, 944,078 infants were screened and 219 diagnoses were confirmed on newborns with elevated screening results, for an overall incidence of 1:4,300. Ninety-nine infants were identified with fatty acid oxidation disorders, 58 with organic acidaemias and 62 with aminoacidopathies. Medium-chain acyl-CoA dehydrogenase deficiency, 3-methylcrotonyl-CoA carboxylase deficiency and disorders of phenylalanine metabolism were the most common disorders detected. Identification of affected infants has allowed retrospective testing of other family members, resulting in an additional 16 diagnoses. Seven neonates died from complications of their metabolic disorders/prematurity despite timely MS/MS screening. In addition, there were six infants who were not identified by elevated NBS results but who presented with symptoms later in infancy. The NC MS/MS NBS Program uses a two-tier system, categorizing results as either 'borderline' or 'diagnostic' elevated, for both the cutoffs and follow-up protocol. Infants with an initial borderline result had only a repeat screen. Infants with a diagnostic or two borderline results were referred for confirmatory testing. The positive predictive value of the NC MS/MS NBS for those infants requiring confirmatory testing was 53% for 2003 and 2004. The success of the NC MS/MS NBS Program in identifying infants with metabolic disorders was dependent on a comprehensive follow-up protocol integrating the public health laboratory and the academic metabolic centres.
Assuntos
Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/epidemiologia , Triagem Neonatal/métodos , Triagem Neonatal/normas , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas por Ionização por Electrospray/normas , Coleta de Amostras Sanguíneas/métodos , Reações Falso-Negativas , Ácidos Graxos/metabolismo , Feminino , Seguimentos , Humanos , Incidência , Recém-Nascido , Masculino , Triagem Neonatal/tendências , North Carolina , Fenilalanina/metabolismo , Projetos Piloto , Espectrometria de Massas por Ionização por Electrospray/tendênciasRESUMO
We describe 3 sets of twins with discordance for urological malformations. Zygosity was documented by HLA and blood group typing. It is suggested that evaluation of the identical twin of an affected patient should include the entire urinary tract because of the potential for different lesions.
Assuntos
Doenças em Gêmeos , Sistema Urinário/anormalidades , Tipagem e Reações Cruzadas Sanguíneas , Pré-Escolar , Doenças em Gêmeos/genética , Feminino , Antígenos HLA/sangue , Humanos , Lactente , Recém-Nascido , Masculino , Gêmeos MonozigóticosRESUMO
Anomalies in folate and homocysteine metabolism can result in homocysteinemia and are implicated in disorders ranging from vascular disease to neural tube defects. Two enzymes are known to methylate homocysteine, vitamin B(12)-dependent methionine synthase (MTR) and betaine-homocysteine methyltransferase (BHMT). BHMT uses betaine, an intermediate of choline oxidation, as a methyl donor and is expressed primarily in the liver and kidney. We report the discovery of a novel betaine-homocysteine methyltransferase gene in humans and mice. The human BHMT2 gene is predicted to encode a 363-amino-acid protein (40.3 kDa) that shows 73% amino acid identity to BHMT. The BHMT2 transcript in humans is most abundant in adult liver and kidney and is found at reduced levels in the brain, heart, and skeletal muscle. The mouse Bhmt2 gene shows 69% amino acid identity and 79% similarity to the mouse Bhmt gene and 82% amino acid identity and 87% similarity to the human BHMT2 gene. Bhmt2 is expressed in fetal heart, lung, liver, kidney and eye. The discovery of a third gene with putative homocysteine methyltransferase activity is important for understanding the biochemical balance in using methyltetrahydrofolate and betaine as methyl donors as well as the metabolic flux between folate and choline metabolism in health and disease.
Assuntos
Betaína , Homocisteína , Metiltransferases/genética , Sequência de Aminoácidos , Amiloide , Animais , Betaína-Homocisteína S-Metiltransferase , Mapeamento Cromossômico , Cromossomos Humanos Par 5 , Humanos , Hibridização in Situ Fluorescente , Camundongos , Dados de Sequência Molecular , Proteínas Priônicas , Príons , Precursores de Proteínas , Análise de Sequência de DNA , Homologia de Sequência de Aminoácidos , Técnicas do Sistema de Duplo-HíbridoRESUMO
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most frequently diagnosed mitochondrial beta-oxidation defect, and it is potentially fatal. Eighty percent of patients are homozygous for a common mutation, 985A-->G, and a further 18% have this mutation in only one disease allele. In addition, a large number of rare disease-causing mutations have been identified and characterized. There is no clear genotype-phenotype correlation. High 985A-->G carrier frequencies in populations of European descent and the usual avoidance of recurrent disease episodes by patients diagnosed with MCAD deficiency who comply with a simple dietary treatment suggest that MCAD deficiency is a candidate in prospective screening of newborns. Therefore, several such screening programs employing analysis of acylcarnitines in blood spots by tandem mass spectrometry (MS/MS) are currently used worldwide. No validation of this method by mutation analysis has yet been reported. We investigated for MCAD mutations in newborns from US populations who had been identified by prospective MS/MS-based screening of 930,078 blood spots. An MCAD-deficiency frequency of 1/15,001 was observed. Our mutation analysis shows that the MS/MS-based method is excellent for detection of MCAD deficiency but that the frequency of the 985A-->G mutant allele in newborns with a positive acylcarnitine profile is much lower than that observed in clinically affected patients. Our identification of a new mutation, 199T-->C, which has never been observed in patients with clinically manifested disease but was present in a large proportion of the acylcarnitine-positive samples, may explain this skewed ratio. Overexpression experiments showed that this is a mild folding mutation that exhibits decreased levels of enzyme activity only under stringent conditions. A carrier frequency of 1/500 in the general population makes the 199T-->C mutation one of the three most prevalent mutations in the enzymes of fatty-acid oxidation.
Assuntos
Acil-CoA Desidrogenases/deficiência , Acil-CoA Desidrogenases/genética , Carnitina/análogos & derivados , Carnitina/sangue , Testes Genéticos/métodos , Mutação de Sentido Incorreto/genética , Acil-CoA Desidrogenase , Acil-CoA Desidrogenases/química , Acil-CoA Desidrogenases/metabolismo , Alelos , Chaperonina 10/genética , Chaperonina 10/metabolismo , Chaperonina 60/genética , Chaperonina 60/metabolismo , Análise Mutacional de DNA , Estabilidade Enzimática , Escherichia coli/genética , Éxons/genética , Haplótipos/genética , Heterozigoto , Homozigoto , Humanos , Recém-Nascido , Espectrometria de Massas , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida/genética , Polimorfismo de Nucleotídeo Único/genética , Dobramento de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Reprodutibilidade dos Testes , TemperaturaRESUMO
Since the addition of tandem mass spectrometry (MS/MS) to the North Carolina Newborn Screening Program, 20 infants with two consecutive elevated 3-hydroxyisovalerylcarnitine (C5OH) levels have been evaluated for evidence of inborn errors of metabolism associated with this metabolite. Ten of these 20 infants had significant concentrations of both 3-hydroxyisovaleric acid and 3-methylcrotonylglycine in their urine, suggestive of 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency. Four of these 10 were infants whose abnormal metabolites were found to be of maternal origin. Of 8 patients with probable 3-MCC deficiency, 7 have been tested and found to have the enzyme deficiency confirmed in lymphoblasts or cultured fibroblasts; one of these 7 infants had only marginally decreased 3-MCC activity in lymphocytes but deficient 3-MCC in fibroblasts. We estimate the incidence of 3-MCC deficiency at 1:64000 live births in North Carolina. We conclude that MS/MS newborn screening will detect additional inborn errors of metabolism, such as 3-MCC deficiency, not traditionally associated with newborn screening. The evaluation of newborns with two abnormally elevated C5OH levels on MS/MS newborn screening should include, at least, urine organic acid analysis by capillary GC-MS and a plasma acylcarnitine profile by MS/MS. Long-term follow-up is needed to determine the outcome of presymptomatically diagnosed patients with 3-MCC deficiency by MS/MS newborn screening.