RESUMO
BACKGROUND: This retrospective clinical study performed at a single clinical center aimed to identify the prevalence of seizures in individuals with urea cycle disorders (UCDs) with and without hyperammonemic (HA) crises. In addition, we sought to correlate the utility of biochemical markers and electroencephalography (EEG) in detecting subclinical seizures during HA. METHODS: Medical records of individuals with UCDs enrolled in Urea Cycle Disorders Consortium Longitudinal Study (UCDC-LS) (NCT00237315) at Children's National Hospital between 2006 and 2022 were reviewed for evidence of clinical and subclinical seizuress during HA crises, and initial biochemical levels concurrently. RESULTS: Eighty-five individuals with UCD were included in the analyses. Fifty-six of the 85 patients (66%) experienced HA crises, with a total of 163 HA events. Seizures are observed in 13% of HA events. Among all HA events with concomitant EEG, subclinical seizures were identified in 27% of crises of encephalopathy without clinical seizures and 53% of crises with clinical seizures. The odds of seizures increases 2.65 (95% confidence interval [CI], 1.51 to 4.66) times for every 100 µmol/L increase in ammonia and 1.14 (95% CI, 1.04 to 1.25) times for every 100 µmol/L increase in glutamine. CONCLUSIONS: This study highlights the utility of EEG monitoring during crises for patients presenting with clinical seizures or encephalopathy with HA. During HA events, measurement of initial ammonia and glutamine can help determine risk for seizures and guide EEG monitoring decisions.
RESUMO
BACKGROUND: Exome sequencing (ES) is a useful tool in diagnosing suspected mitochondrial disease but can miss pathogenic variants for several reasons. Additional testing, such as muscle biopsy or biochemical testing, can be helpful in exome-negative cases. METHODS: We report a patient who presented with repeated episodes of lactic acidosis and failure to thrive. RESULTS: ES and mitochondrial sequencing were initially negative but clinical suspicion for mitochondrial disease remained high. After muscle biopsy showed evidence of mitochondrial dysfunction, the ES was reanalyzed and revealed novel variants in AARS2. CONCLUSION: This case demonstrates the importance of muscle biopsy and biochemical testing in evaluating patients with a high suspicion of mitochondrial disease, even in the genomics era. Closed-loop communication between molecular genetics laboratories and clinical geneticists is an important step to help establish diagnosis in unsolved cases.
Assuntos
Doenças Mitocondriais , Músculo Esquelético , Fenótipo , Feminino , Humanos , Lactente , Alanina-tRNA Ligase , Biópsia , Exoma , Sequenciamento do Exoma , Doenças Mitocondriais/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/patologia , Músculo Esquelético/patologiaRESUMO
Deleterious mutations in the X-linked gene encoding ornithine transcarbamylase (OTC) cause the most common urea cycle disorder, OTC deficiency. This rare but highly actionable disease can present with severe neonatal onset in males or with later onset in either sex. Individuals with neonatal onset appear normal at birth but rapidly develop hyperammonemia, which can progress to cerebral edema, coma, and death, outcomes ameliorated by rapid diagnosis and treatment. Here, we develop a high-throughput functional assay for human OTC and individually measure the impact of 1,570 variants, 84% of all SNV-accessible missense mutations. Comparison to existing clinical significance calls, demonstrated that our assay distinguishes known benign from pathogenic variants and variants with neonatal onset from late-onset disease presentation. This functional stratification allowed us to identify score ranges corresponding to clinically relevant levels of impairment of OTC activity. Examining the results of our assay in the context of protein structure further allowed us to identify a 13 amino acid domain, the SMG loop, whose function appears to be required in human cells but not in yeast. Finally, inclusion of our data as PS3 evidence under the current ACMG guidelines, in a pilot reclassification of 34 variants with complete loss of activity, would change the classification of 22 from variants of unknown significance to clinically actionable likely pathogenic variants. These results illustrate how large-scale functional assays are especially powerful when applied to rare genetic diseases.
Assuntos
Hiperamonemia , Doença da Deficiência de Ornitina Carbomoiltransferase , Ornitina Carbamoiltransferase , Humanos , Substituição de Aminoácidos , Hiperamonemia/etiologia , Hiperamonemia/genética , Mutação de Sentido Incorreto/genética , Ornitina Carbamoiltransferase/genética , Doença da Deficiência de Ornitina Carbomoiltransferase/genética , Doença da Deficiência de Ornitina Carbomoiltransferase/diagnóstico , Doença da Deficiência de Ornitina Carbomoiltransferase/terapiaRESUMO
De novo variants in QRICH1 (Glutamine-rich protein 1) has recently been reported in 11 individuals with intellectual disability (ID). The function of QRICH1 is largely unknown but it is likely to play a key role in the unfolded response of endoplasmic reticulum stress through transcriptional control of proteostasis. In this study, we present 27 additional individuals and delineate the clinical and molecular spectrum of the individuals (n = 38) with QRICH1 variants. The main clinical features were mild to moderate developmental delay/ID (71%), nonspecific facial dysmorphism (92%) and hypotonia (39%). Additional findings included poor weight gain (29%), short stature (29%), autism spectrum disorder (29%), seizures (24%) and scoliosis (18%). Minor structural brain abnormalities were reported in 52% of the individuals with brain imaging. Truncating or splice variants were found in 28 individuals and 10 had missense variants. Four variants were inherited from mildly affected parents. This study confirms that heterozygous QRICH1 variants cause a neurodevelopmental disorder including short stature and expands the phenotypic spectrum to include poor weight gain, scoliosis, hypotonia, minor structural brain anomalies, and seizures. Inherited variants from mildly affected parents are reported for the first time, suggesting variable expressivity.
Assuntos
Transtorno do Espectro Autista , Nanismo , Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Escoliose , Transtorno do Espectro Autista/genética , Humanos , Deficiência Intelectual/genética , Hipotonia Muscular , Transtornos do Neurodesenvolvimento/genética , Convulsões , Aumento de PesoRESUMO
Elevated citrulline and C5-OH levels are reported as part of the newborn screening of core and secondary disorders on the Recommended Uniform Screening Panel (RUSP). Additionally, some state laboratory newborn screening programs report low citrulline levels, which may be observed in proximal urea cycle disorders. We report six patients who were found on newborn screening to have low citrulline and/or elevated C5-OH levels in whom confirmatory testing showed the combination of these two abnormal analytes. Mitochondrial sequencing revealed known pathogenic variants in MT-ATP6 at high heteroplasmy levels in all cases. MT-ATP6 at these heteroplasmy levels is associated with Leigh syndrome, a progressive neurodegenerative disease. Patients were treated with supplemental citrulline and, in some cases, mitochondrial cofactor therapy. These six patients have not experienced metabolic crises or developmental regression, and early diagnosis and management may help prevent the neurological sequelae of Leigh syndrome. The affected mothers and siblings are asymptomatic or paucisymptomatic (e.g. intellectual disability, depression, migraines, obsessive-compulsive disorder, and poor balance) despite high heteroplasmy or apparent homoplasmy of the familial variant, thus expanding the clinical spectrum seen in pathogenic variants of MT-ATP6. Confirmatory plasma amino acid analysis and acylcarnitine profiling should be ordered in a patient with either low citrulline and/or elevated C5-OH, as this combination appears specific for pathogenic variants in MT-ATP6.
Assuntos
Testes Genéticos/métodos , Doença de Leigh/diagnóstico , Doença de Leigh/genética , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/genética , ATPases Mitocondriais Próton-Translocadoras/genética , Triagem Neonatal/métodos , Carnitina/sangue , Carnitina/química , Citrulina/sangue , DNA Mitocondrial/genética , Feminino , Humanos , Recém-Nascido , Masculino , Estudos ProspectivosRESUMO
BACKGROUND/AIMS: Neonatal onset Urea cycle disorders (UCDs) can be life threatening with severe hyperammonemia and poor neurological outcomes. Glycerol phenylbutyrate (GPB) is safe and effective in reducing ammonia levels in patients with UCD above 2 months of age. This study assesses safety, ammonia control and pharmacokinetics (PK) of GPB in UCD patients below 2 months of age. METHODS: This was an open-label study in UCD patients aged 0 - 2 months, consisting of an initiation/transition period (1 - 4 days) to GPB, followed by a safety extension period (6 months to 2 years). Patients presenting with a hyperammonemic crisis (HAC) did not initiate GPB until blood ammonia levels decreased to below 100 µmol/L while receiving sodium phenylacetate/sodium benzoate and/or hemodialysis. Ammonia levels, PK analytes and safety were evaluated during transition and monthly during the safety extension for 6 months and every 3 months thereafter. RESULTS: All 16 patients with UCD (median age 0.48 months, range 0.1 to 2.0 months) successfully transitioned to GPB within 3 days. Average plasma ammonia level excluding HAC was 94.3 µmol/L at baseline and 50.4 µmol/L at the end of the transition period (p = 0.21). No patient had a HAC during the transition period. During the safety extension, the majority of patients had controlled ammonia levels, with mean plasma ammonia levels lower during GPB treatment than baseline. Mean glutamine levels remained within normal limits throughout the study. PK analyses indicate that UCD patients <2 months are able to hydrolyze GPB with subsequent absorption of phenylbutyric acid (PBA), metabolism to phenylacetic acid (PAA) and conjugation with glutamine. Plasma concentrations of PBA, PAA, and phenylacetylglutamine (PAGN) were stable during the safety extension phase and mean plasma phenylacetic acid: phenylacetylglutamine ratio remained below 2.5 suggesting no accumulation of GPB. All patients reported at least 1 treatment emergent adverse event with gastroesophageal reflux disease, vomiting, hyperammonemia, diaper dermatitis (37.5% each), diarrhea, upper respiratory tract infection and rash (31.3% each) being the most frequently reported. CONCLUSIONS: This study supports safety and efficacy of GPB in UCD patients aged 0 -2 months who cannot be managed by dietary protein restriction and/or amino acid supplementation alone. GPB undergoes intestinal hydrolysis with no accumulation in this population.
Assuntos
Glicerol/análogos & derivados , Hiperamonemia/tratamento farmacológico , Fenilbutiratos/administração & dosagem , Distúrbios Congênitos do Ciclo da Ureia/tratamento farmacológico , Idade de Início , Amônia/sangue , Pré-Escolar , Feminino , Glicerol/administração & dosagem , Humanos , Hiperamonemia/sangue , Hiperamonemia/patologia , Lactente , Recém-Nascido , Masculino , Pediatria , Fenilacetatos/administração & dosagem , Diálise Renal , Distúrbios Congênitos do Ciclo da Ureia/sangue , Distúrbios Congênitos do Ciclo da Ureia/metabolismo , Distúrbios Congênitos do Ciclo da Ureia/patologiaRESUMO
Current rhabdomyolysis treatment guidelines vary based on the etiology and diagnosis, yet many cases evade conclusive diagnosis. In these cases, treatment options remain largely limited to fluids and supportive therapy. We present two cases of acute rhabdomyolysis diagnosed in the emergency department: a 5-year-old boy with sudden onset bilateral flank pain, and a 13-year-old boy with 2-3 days of worsening pectoral and shoulder pain. Each patient had a prior similar episode requiring hospitalization in the past. The 5-year-old had no inciting trauma or trigger, medication use, or illness. The 13-year-old previously had an upper respiratory infection during the week prior and had been strenuously exercising at the time of onset. Genetic testing results were unknown for both patients during their hospitalizations, and insurance and other barriers led to delay. Later results for the first patient revealed a heterozygous deletion in intron 19 on the LPIN1 gene interpreted as a variant of unknown significance. During their hospitalizations, both children were started on intravenous (i.v.) fluids, and creatine kinase (CK) initially trended downward, but then began to rise or plateau. After reviewing the cases, prior literature, and anecdotal evidence of benefit from corticosteroid therapy in rhabdomyolysis with our consultant metabolic physicians, dexamethasone was initiated. In both patients, dexamethasone use correlated with relief of patient symptoms, significantly decreased CK value, and our ability to discharge these patients home quickly. Our cases, discussion, and literature review all lead to the consideration of the use of dexamethasone in conjunction with standard therapy for acute rhabdomyolysis.
Assuntos
Creatina Quinase/genética , Dexametasona/administração & dosagem , Mioglobinúria/tratamento farmacológico , Fosfatidato Fosfatase/genética , Adolescente , Corticosteroides/administração & dosagem , Pré-Escolar , Deleção de Genes , Heterozigoto , Humanos , Masculino , Mioglobinúria/genética , Mioglobinúria/patologia , PediatriaAssuntos
COVID-19/complicações , Síndrome Metabólica/prevenção & controle , Educação de Pacientes como Assunto , Guias de Prática Clínica como Assunto , Comportamento de Redução do Risco , SARS-CoV-2/isolamento & purificação , COVID-19/transmissão , COVID-19/virologia , Humanos , Síndrome Metabólica/virologiaRESUMO
Urea cycle disorders (UCD) are inborn errors of metabolism caused by deficiency of enzymes required to transfer nitrogen from ammonia into urea. Current paradigms of treatment focus on dietary manipulations, ammonia scavenger drugs, and orthotopic liver transplantation. In the last years, there has been intense preclinical research aiming at developing more effective treatments for UCD, and as a result, several novel approaches based on new knowledge of the disease pathogenesis, cell and gene therapies are currently under clinical investigation. We provide an overview of the latest advances for the development of novel therapies for UCD.
Assuntos
Distúrbios Congênitos do Ciclo da Ureia/terapia , Animais , Terapia Baseada em Transplante de Células e Tecidos , Terapia Combinada , Gerenciamento Clínico , Suscetibilidade a Doenças , Terapia de Reposição de Enzimas , Terapia Genética , Humanos , Transplante de Fígado/métodos , Redes e Vias Metabólicas , Resultado do Tratamento , Ureia/metabolismo , Distúrbios Congênitos do Ciclo da Ureia/diagnóstico , Distúrbios Congênitos do Ciclo da Ureia/etiologia , Distúrbios Congênitos do Ciclo da Ureia/metabolismoRESUMO
BACKGROUND: The 'classic' organic acidaemias (OAs) (propionic, methylmalonic and isovaleric) typically present in neonates or infants as acute metabolic decompensation with encephalopathy. This is frequently accompanied by severe hyperammonaemia and constitutes a metabolic emergency, as increased ammonia levels and accumulating toxic metabolites are associated with life-threatening neurological complications. Repeated and frequent episodes of hyperammonaemia (alongside metabolic decompensations) can result in impaired growth and intellectual disability, the severity of which increase with longer duration of hyperammonaemia. Due to the urgency required, diagnostic evaluation and initial management of patients with suspected OAs should proceed simultaneously. Paediatricians, who do not have specialist knowledge of metabolic disorders, have the challenging task of facilitating a timely diagnosis and treatment. This article outlines how the underlying pathophysiology and biochemistry of the organic acidaemias are closely linked to their clinical presentation and management, and provides practical advice for decision-making during early, acute hyperammonaemia and metabolic decompensation in neonates and infants with organic acidaemias. CLINICAL MANAGEMENT: The acute management of hyperammonaemia in organic acidaemias requires administration of intravenous calories as glucose and lipids to promote anabolism, carnitine to promote urinary excretion of urinary organic acid esters, and correction of metabolic acidosis with the substitution of bicarbonate for chloride in intravenous fluids. It may also include the administration of ammonia scavengers such as sodium benzoate or sodium phenylbutyrate. Treatment with N-carbamyl-L-glutamate can rapidly normalise ammonia levels by stimulating the first step of the urea cycle. CONCLUSIONS: Our understanding of optimal treatment strategies for organic acidaemias is still evolving. Timely diagnosis is essential and best achieved by the early identification of hyperammonaemia and metabolic acidosis. Correcting metabolic imbalance and hyperammonaemia are critical to prevent brain damage in affected patients.
Assuntos
Hiperamonemia/tratamento farmacológico , Amônia/metabolismo , Glucose/uso terapêutico , Glutamatos/uso terapêutico , Humanos , Acidemia Propiônica/tratamento farmacológicoRESUMO
The ornithine transcarbamylase (OTC) gene is on the X chromosome and its product catalyzes the formation of citrulline from ornithine and carbamylphosphate in the urea cycle. About 10%-15% of patients, clinically diagnosed with OTC deficiency (OTCD), lack identifiable mutations in the coding region or splice junctions of the OTC gene on routine molecular testing. We collected DNA from such patients via retrospective review and by prospective enrollment. In nine of 38 subjects (24%), we identified a sequence variant in the OTC regulatory regions. Eight subjects had unique sequence variants in the OTC promoter and one subject had a novel sequence variant in the OTC enhancer. All sequence variants affect positions that are highly conserved in mammalian OTC genes. Functional studies revealed reduced reporter gene expression with all sequence variants. Two sequence variants caused decreased binding of the HNF4 transcription factor to its mutated binding site. Bioinformatic analyses combined with functional assays can be used to identify and authenticate pathogenic sequence variants in regulatory regions of the OTC gene, in other urea cycle disorders or other inborn errors of metabolism.
Assuntos
Elementos Facilitadores Genéticos , Doença da Deficiência de Ornitina Carbomoiltransferase/genética , Regiões Promotoras Genéticas , Sítios de Ligação/genética , Regulação da Expressão Gênica , Fator 4 Nuclear de Hepatócito/metabolismo , Humanos , Masculino , Mutação , Ornitina/metabolismo , Estudos Prospectivos , Estudos RetrospectivosRESUMO
Organic acidemias and urea cycle disorders are ultra-rare inborn errors of metabolism characterized by episodic acute decompensation, often associated with hyperammonemia, resulting in brain edema and encephalopathy. Retrospective reports and translational studies suggest that N-carbamylglutamate (NCG) may be effective in reducing ammonia levels during acute decompensation in two organic acidemias, propionic and methylmalonic acidemia (PA and MMA), and in two urea cycle disorders, carbamylphosphate synthetase 1 and ornithine transcarbamylase deficiency (CPSD and OTCD). We established the 9-site N-carbamylglutamate Consortium (NCGC) in order to conduct two randomized double-blind, placebo-controlled trials of NCG in acute hyperammonemia of PA, MMA, CPSD and OTCD. Conducting clinical trials is challenging in any disease, but poses unique barriers and risks in the ultra-rare disorders. As the number of clinical trials in orphan diseases increases, evaluating the successes and opportunities for improvement in such trials is essential. We summarize herein the design, methods, experiences, challenges and lessons from the NCGC-conducted trials.
RESUMO
Hyperphenylalaninemia (HPA) is a disorder diagnosed only incidentally by newborn screening, a by-product of screening for classic phenylketonuria (PKU) which, if untreated, causes irreversible neurologic sequelae. In contrast, HPA is thought to have a benign phenotype because phenylalanine (Phe) levels are insufficiently elevated to cause neurological damage, obviating the need for rigorous dietary protein restriction. Phenylalanine below 360µmol/L is generally considered safe, thus this threshold is both the upper therapeutic range for treated PKU and the highest Phe expected to be possible for most individuals with HPA. However, the published literature and even expert consensus provides limited guidance on long-term follow-up of Phe after this diagnosis. In particular, how frequently and vigilantly to monitor levels to evaluate for subsequent elevations above the 'safe' range. Upon retrospective review we identified 22 patients with HPA, ascertained via newborn screen and currently aged two to thirty-six years. All patients had an initial untreated Phe between 90µmol/L (our upper limit of normal) and 360µmol/L. Of these patients, seven subsequently demonstrated either fluctuating or sustained increases in Phe above 360µmol/L. Five have been treated successfully with sapropterin therapy without dietary intervention and two have been treated with mild to moderate protein restriction. Our experience demonstrates successful treatment of these children without the traditional highly restrictive PKU diet. However, a better understanding of this disorder is necessary to more safely and appropriately identify, monitor and manage children with HPA. SYNOPSIS: One clinics' experience with diagnostic differences in a population of Hyperphenylalaninemia patients that required treatment.
Assuntos
Triagem Neonatal , Fenilalanina/sangue , Fenilcetonúrias/dietoterapia , Fenilcetonúrias/tratamento farmacológico , Adolescente , Adulto , Biopterinas/administração & dosagem , Biopterinas/análogos & derivados , Biopterinas/uso terapêutico , Criança , Pré-Escolar , Dieta com Restrição de Proteínas , Humanos , Recém-Nascido , Fenótipo , Fenilalanina/metabolismo , Fenilcetonúrias/diagnóstico , Fenilcetonúrias/genética , Projetos de Pesquisa , Estudos Retrospectivos , Adulto JovemRESUMO
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-AtividadeRESUMO
PurposeCurrent guidelines recommend first-tier chromosome microarray analysis (CMA) and fragile X syndrome (FX) testing for males with isolated intellectual disabilities/learning delay (ID/LD) and autism spectrum disorders (ASDs).MethodsMales in our clinic with ID/LD or ASD (310) were analyzed for positive results from CMA and/or FX testing.ResultsCMA detected abnormalities in 29% of males with ID/LD and only 9% of males with ASD (including variants of uncertain significance and absence of heterozygosity). When males with ID/LD were tested for FX, the detection rate was 2.5% (2 of 80). Both patients had dysmorphic features and maternal family history. No males with ASD had positive FX test results.ConclusionsThe detection rate of CMA in males with isolated ID/LD in this study was higher than in the literature (10-20%). CMA results for males with ASD (9%) and FX testing for males with ID/LD (2.5%) overlap with the literature (7-10% and 2%, respectively). The yield of FX testing for patients with ASD was zero, which is close to that of the literature (0.5-2%). These results suggest that FX testing as a first-tier test may not be necessary, unless other criteria suggest FX.
Assuntos
Síndrome do Cromossomo X Frágil/diagnóstico , Síndrome do Cromossomo X Frágil/genética , Testes Genéticos/métodos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Adolescente , Algoritmos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Deficiências da Aprendizagem/diagnóstico , Deficiências da Aprendizagem/genética , Masculino , Fenótipo , Adulto JovemRESUMO
This study documents the disparate therapeutic effect of N-carbamyl-l-glutamate (NCG) in the activation of two different disease-causing mutants of carbamyl phosphate synthetase 1 (CPS1). We investigated the effects of NCG on purified recombinant wild-type (WT) mouse CPS1 and its human corresponding E1034G (increased ureagenesis on NCG) and M792I (decreased ureagenesis on NCG) mutants. NCG activates WT CPS1 sub-optimally compared to NAG. Similar to NAG, NCG, in combination with MgATP, stabilizes the enzyme, but competes with NAG binding to the enzyme. NCG supplementation activates available E1034G mutant CPS1 molecules not bound to NAG enhancing ureagenesis. Conversely, NCG competes with NAG binding to the scarce M792I mutant enzyme further decreasing residual ureagenesis. These results correlate with the respective patient's response to NCG. Particular caution should be taken in the administration of NCG to patients with hyperammonemia before their molecular bases of their urea cycle disorders is known.
Assuntos
Trifosfato de Adenosina/administração & dosagem , Carbamoil-Fosfato Sintase (Amônia)/química , Carbamoil-Fosfato Sintase (Amônia)/genética , Doença da Deficiência da Carbamoil-Fosfato Sintase I/tratamento farmacológico , Glutamatos/administração & dosagem , Trifosfato de Adenosina/farmacologia , Animais , Doença da Deficiência da Carbamoil-Fosfato Sintase I/enzimologia , Quimioterapia Combinada , Feminino , Glutamatos/farmacologia , Humanos , Masculino , Camundongos , Mutação , Medicina de Precisão , Estabilidade Proteica/efeitos dos fármacos , Estrutura Terciária de Proteína , Doenças Raras/tratamento farmacológico , Doenças Raras/enzimologiaRESUMO
For most inherited metabolic disorders on newborn screening (NBS) panels, prompt, expert confirmation and treatment are critical to optimize clinical outcomes for children with inherited metabolic diseases (IMD). In the Washington Metropolitan Area (WMA), 3 different short-term follow-up (STFU) systems exist for linking infants with positive newborn screens for IMD to appropriate specialty care. We diagrammed the STFU systems for the District of Columbia, Maryland and Virginia and calculated clinically relevant intervals of time between NBS collection and diagnosis/treatment initiation. We also surveyed representatives from 48 other state NBS programs to classify the STFU systems in the rest of the country. We found that in the WMA the STFU system that did not include the IMD specialist at the same time as the primary care provider (PCP) was associated with a longer median collection-to-specialist contact interval for true positive NBS for critical diagnoses (p=0.013). Nationally, 25% of state NBS programs report having a STFU system that does not include the IMD specialist at the same time as the PCP. In conclusion, there is variability among the STFU systems employed by NBS programs in the US which may lead to delays in diagnosis confirmation and treatment. National standards for STFU systems that include early involvement of an IMD specialist for all presumed positive NBS results may decrease the collection-to-specialist contact interval which could improve clinical outcomes in children with IMD.
Assuntos
Erros Inatos do Metabolismo/diagnóstico , Triagem Neonatal/organização & administração , Tempo para o Tratamento/estatística & dados numéricos , District of Columbia , Feminino , Pesquisas sobre Atenção à Saúde , Humanos , Lactente , Recém-Nascido , Masculino , Maryland , Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/terapia , Médicos de Atenção Primária/organização & administração , VirginiaRESUMO
Identical studies using stable isotopes were performed before and after a 3-day trial of oral N-carbamyl-l-glutamate (NCG) in 5 subjects with late-onset carbamyl phosphate synthetase deficiency. NCG augmented ureagenesis and decreased plasma ammonia in 4 of 5 subjects. There was marked improvement in nitrogen metabolism with long-term NCG administration in 1 subject.