RESUMEN
Very long chain fatty acid dehydrogenase (VLCAD) deficiency is a rare but treatable cause of cardiomyopathy, fatty liver, skeletal myopathy, pericardial effusions, ventricular arrhythmias, and sudden death. Unrecognized, VLCAD deficiency may be rapidly progressive and fatal, secondary to its cardiac involvement. Because early diagnosis improves outcome, we present a neonate with VLCAD deficiency in whom retrospective analysis of the newborn screening card revealed that a correct diagnosis could have been made by newborn screening using tandem mass spectrometry. Our patient demonstrated a classic neonatal course with transient hypoglycemia at birth, interpreted as culture-negative sepsis, followed by a quiescent period notable only for hypotonia and poor feeding. At 3 months, he presented with cardiorespiratory failure and pericardial effusions, requiring pericardiocentesis, tracheostomy, and prolonged mechanical ventilation. Plasma free-fatty acid and acylcarnitine profiles demonstrated small but significant elevations of C14:2, C14:1, C16, and C18:1 acylcarnitine species, findings consistent with a biochemical diagnosis of VLCAD deficiency. Enteral feeds were changed to Portagen formula with marked improvement in cardiac symptoms over several weeks. To confirm the biochemical diagnosis, molecular analysis was performed by analysis of genomic DNA on a blood sample of the patient. Sequencing analysis and delineation of VLCAD mutations were performed using polymerase chain reaction and genomic sequencing. The patient was heterozygous for 2 different disease-causing mutations at the VLCAD locus. The maternal mutation was a deletion of bp 842-3 in exon 8, causing a shift in the reading frame. The paternal mutation was G+1A in the consensus donor splice site after exon 1; this splice-site mutation would likely result in decreased mRNA. The likely consequence of these mutations is essentially a null phenotype. To determine whether this case could have been picked up by tandem mass spectrometry analysis at birth when the patient was asymptomatic, acylcarnitine analysis was performed on the patient's original newborn card (after obtaining parental consent, the original specimen was provided courtesy of Dr Kenneth Pass, Director, New York State Newborn Screening Program). The blood sample had been obtained at 1 week of age and stored at room temperature for 6 months and at 70 degrees C thereafter for 18 months. Electrospray tandem mass spectrometry used a LC-MS/MS API 2000 operated in ion evaporation mode with the TurboIonSpray ionization probe source. The acylcarnitine profile obtained from the patient's original newborn card was analyzed 2 years after it was obtained. In comparison with a normal control, there was a significant accumulation of long chain acylcarnitine species, with a prominent peak of tetradecenoylcarnitine (C14:1), the most characteristic metabolic marker of VLCAD deficiency. This profile would have likely been even more significant if it had been analyzed at the time of collection, yet 2 years later is sufficient to provide strong biochemical evidence of the underlying disorder. Discussion. VLCAD was first discovered in 1992, and clinical experience with VLCAD deficiency has been accumulating rapidly. Indeed, the patients originally diagnosed with long chain acyl-CoA deficiency suffer instead from VLCAD deficiency. The phenotype of VLCAD deficiency is heterogeneous, ranging from catastrophic metabolic and cardiac failure in infancy to mild hypoketotic, hypoglycemia, and exertional rhabdomyolysis in adults. This case demonstrates that VLCAD deficiency could have been detected from the patient's own neonatal heel-stick sample. Most likely, a presymptomatic diagnosis would have avoided at least part of a lengthy and intensive prediagnosis hospitalization that had an estimated cost of $400 000. Although VLCAD is relatively rare, timely and correct diagnosis leads to dramatic recovery, so that detection by newborn screening could prevent the onset of arrhythmias, heart failure, metabolic insufficiency, and death. Fatty acid oxidation defects, including VLCAD deficiency, may account for as many as 5% of sudden infant death patients. Recent instrumentation advances have made automated tandem mass spectrometry of routine neonatal heel-stick samples technically feasible. Pilot studies have demonstrated an incidence of fatty acid oxidation defects, including short chain, medium chain, and very long chain acyl-CoA dehydrogenase deficiencies, of approximately 1/12 000. As a result, cost-benefit ratios for this approach should be systematically examined.
Asunto(s)
Acil-CoA Deshidrogenasa de Cadena Larga/deficiencia , Errores Diagnósticos , Errores Innatos del Metabolismo/complicaciones , Errores Innatos del Metabolismo/diagnóstico , Mutación , Diagnóstico Diferencial , Hepatomegalia/genética , Humanos , Lactante , Recién Nacido , Masculino , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/metabolismo , Reflejo Anormal/genética , Análisis de Secuencia de ADNAsunto(s)
Pruebas Genéticas , Tamizaje Neonatal , Pediatría , Niño , Enfermedades Genéticas Congénitas/diagnóstico , Humanos , Recién NacidoAsunto(s)
Sordera/congénito , Tamizaje Neonatal/métodos , Preescolar , Sordera/diagnóstico , Sordera/genética , Humanos , Lactante , Recién NacidoRESUMEN
Glucose transporter type 1 (GLUT1) deficiency is an inborn error of glucose transport. Clinical manifestations are presumed secondary to reduced glucose transport across the blood brain barrier, and include seizures, abnormal tone, developmental delay and hypoglycorrhachia. A high index of suspicion is important as GLUT1 deficiency is a potentially treatable cause of mental retardation. We studied two affected children by continuous video-EEG in order to better understand the cause of the clinical manifestations and improvement on a ketogenic diet. The EEG was characterized by generalized paroxysmal 2-2.5 Hz spike-wave discharges, although normal EEGs were also obtained. Atypical absence seizures were the most prominent clinical seizure. Epileptiform activity and clinical seizures occurred in both children while acutely ketotic and non-ketotic, but were markedly more frequent in one child when non-ketotic. Discharges were not associated with a reduction in substrate for brain metabolism in the blood at that time. Conclusion Atypical absence seizures are common in glucose transporter type 1 deficiency and should alert the clinician to the possibility of this treatable disorder when present in a young child with developmental delay. Our data suggest that the therapeutic mechanism of the ketogenic diet in this disorder is more complicated than simply delivering ketones as an alternative substrate for brain metabolism.
Asunto(s)
Proteínas de Transporte de Monosacáridos/deficiencia , Niño , Grasas de la Dieta/administración & dosificación , Electroencefalografía/métodos , Glucosa/metabolismo , Humanos , Discapacidad Intelectual/etiología , Cetosis , Masculino , Errores Innatos del Metabolismo/complicaciones , Errores Innatos del Metabolismo/dietoterapia , Convulsiones/diagnóstico , Convulsiones/etiología , Convulsiones/terapiaRESUMEN
OBJECTIVE: To convene a small group of experts in diagnosis and management of PKU to discuss the following issues: the Subject Review of PKU management being performed by the American Academy of Pediatrics (AAP) Committee on Genetics (COG), the published British guidelines on PKU management, and the feasibility, suitability, and mechanism of developing PKU management guidelines for the United States. METHODS: A 1-day meeting was held at the National Institutes of Health under the auspices of National Institute of Child Health and Human Development, convening experts in PKU diagnosis and management and members of the AAP/COG. RESULTS: The group reviewed the published reports of outcomes of treatment of PKU and the British guidelines that were developed based on those data. It also reviewed the results of surveys of directors of clinics that manage PKU, parents of children with PKU, and young adults with PKU. CONCLUSION: The group supported the efforts of the AAP/COG to perform this review of PKU management. The group concluded that significant issues need to be resolved to provide sufficient information to establish US guidelines for PKU management. The establishment of such guidelines is an important next step in PKU management in the United States.
Asunto(s)
Fenilcetonurias/terapia , Guías de Práctica Clínica como Asunto , Adulto , Niño , Recolección de Datos , Europa (Continente) , Humanos , Pediatría , Fenilalanina/sangre , Fenilcetonurias/sangre , Sociedades Médicas , Estados UnidosRESUMEN
OBJECTIVE: The development of guidelines for phenylketonuria (PKU) management in the United Kingdom has resulted in much discussion in the community of parents and PKU clinics and parents have asked why the United States does not have such guidelines. The objective of this report is to discuss PKU management in the United States, the British guidelines on PKU management, and the feasibility, suitability, and mechanism of developing PKU management guidelines in the United States. METHODS: Members of the American Academy of Pediatrics (AAP) Committee on Genetics (COG) reviewed the literature and conducted surveys of parents of children with PKU, young adults with PKU, and directors of PKU clinics in the United States. A meeting was held at the National Institute of Child Health and Human Development to review the AAP/COG efforts at reviewing the status of PKU management and guideline development in the United States. RESULTS: The British guidelines are more stringent than the PKU management practices in many parts of the United States. Evidence exists that stricter management improves developmental outcome. The parents who responded to the surveys indicated willingness to comply with more stringent dietary management if that would improve outcome. They also identified problems that make such management difficult. The clinic directors supported the timeliness of the review. Some had begun a trend toward more stringent control of blood phenylalanine concentrations, at least in the first 4 years of life. CONCLUSION: The AAP Committee on Genetics will complete its subject review of the management of PKU. Guidelines for care of PKU in the United States probably would look quite similar to the existing guidelines in other countries. The parents surveyed supported more stringent PKU management, but information from a broader distribution of parents would provide a more representative view. The status of the US health care system creates problems for improved PKU management in the United States that do not exist in the countries already following stricter guidelines.
Asunto(s)
Fenilcetonurias/dietoterapia , Guías de Práctica Clínica como Asunto , Adulto , Instituciones de Atención Ambulatoria , Actitud , Niño , Recolección de Datos , Dietoterapia/economía , Humanos , Padres , Fenilalanina/sangre , Fenilcetonurias/sangre , Médicos , Reino Unido , Estados UnidosRESUMEN
Newborn screening for inborn errors of metabolism has improved the diagnosis and treatment of these disorders since the 1960s. Recently tandem mass spectrometry (MS/MS) was developed as a technique for expanding the scope and efficiency of newborn screening for inborn errors. It may offer more efficient identification of phenylketonuria, branched chain ketoaciduria (maple syrup urine disease) and homocystinuria, which are currently screened for by the use of bacterial inhibition assays. MS/MS also identifies analytes characteristic of disorders of fatty acid metabolism and organic acid metabolism, which are not identified in current programs. Recent studies indicate that MS/MS offers the opportunity to expand and advance newborn screening for inborn errors.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Espectrometría de Masas/métodos , Tamizaje Neonatal/métodos , Errores Innatos del Metabolismo de los Aminoácidos/terapia , Reacciones Falso Negativas , Reacciones Falso Positivas , Humanos , Recién Nacido , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
The clbC form of methylmalonic acidaemia is a rare and poorly understood condition which results from impaired biosynthesis of methylcobalamin and adenosylcobalamin. The consequent functional deficiencies of methylmalonyl-CoA mutase and methionine synthase produce both methylmalonic aciduria and homocystinuria. Systemic symptoms and neurological decompensation comprise the clinical phenotype. In an effort to clarify the phenotype and prognosis, we obtained clinical information on 50 patients with methylmalonic acidaemia whose cells had been assigned to the cblC complementation group. We identified two distinct phenotypes; they differed in age of onset, presence of systemic symptoms, type of neurological symptoms, and outcome after diagnosis and treatment. Forty-four patients presented in the first year of life. Feeding difficulties, neurological dysfunction (hypotonia, seizures, developmental delay), and ophthalmological and haematological abnormalities characterized their clinical picture. About one-quarter of those patients died. Survival was associated with neurological impairment; only one infant was neurologically intact at follow-up. Onset in childhood, in contrast, was associated with less severe haematological abnormalities, largely involving the red cell series. Extrapyramidal signs, dementia, delirium or psychosis characterized the neurological findings. Survival, with mild to moderate disability in some, was typical in patients with later onset. Treatment in both groups included hydroxycobalamin, betaine and carnitine; complete normalization of biochemical parameters was rare.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Homocistinuria/fisiopatología , Ácido Metilmalónico/orina , Adolescente , Edad de Inicio , Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/orina , Causas de Muerte , Niño , Preescolar , Femenino , Prueba de Complementación Genética , Homocistinuria/genética , Homocistinuria/orina , Humanos , Lactante , Recién Nacido , Masculino , Ácido Metilmalónico/sangre , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/fisiopatología , Fenotipo , Embarazo , Pronóstico , Resultado del TratamientoRESUMEN
We describe a newborn with acute monocytic leukemia who underwent spontaneous remission. Chromosomal analysis of this patient's leukemic blasts identified a translocation between 5q31 and 6q21. Chromosome 5 has been implicated in adult leukemogenesis but only rarely in childhood leukemia. Several hematopoietic growth factors and growth factor receptors have been mapped to the long arm of chromosome 5. This report discusses the possible role of these gene products in inducing leukemia in our index case.
Asunto(s)
Cromosomas Humanos Par 5 , Cromosomas Humanos Par 6 , Leucemia Monocítica Aguda/congénito , Leucemia Monocítica Aguda/genética , Translocación Genética/genética , Médula Ósea/patología , Femenino , Humanos , Recién Nacido , Cariotipificación , Leucemia Monocítica Aguda/patología , Remisión EspontáneaRESUMEN
Disorders of the CNS are the major causes of morbidity and mortality observed in untreated subjects with phenylketonuria (PKU). A method to measure cerebral concentrations of phenylalanine (Phe) in vivo would greatly enhance the ability to investigate both the pathophysiology and the efficacy of therapy of this aminoacidopathy. Twelve image-guided localized proton nuclear magnetic resonance spectroscopic studies were performed in seven subjects with PKU using pulse sequences optimized to detect the aromatic protons of Phe. Ten control studies were also performed using a 2.1-Tesla Bruker Biospec spectrometer. Plasma Phe was measured at the time of the spectroscopic examination in the PKU patients. A Phe signal was observed in all 12 studies performed on the group with PKU, and in five studies cerebral Phe concentrations were measured to be 480 to 780 mumol/g. Plasma Phe concentrations were 0.7 to 3.3 mM (10.8 to 54.8 mg/dL) in the subjects with PKU. Human cerebral Phe concentrations can be measured noninvasively using proton nuclear magnetic resonance spectroscopy. A simultaneous measure of Phe and several other cerebral metabolites is obtained with this innovative technology. Adaptations of this technique can be used to investigate PKU and other neurometabolic disorders with modifications of current clinical magnetic resonance imaging systems.
Asunto(s)
Química Encefálica , Espectroscopía de Resonancia Magnética , Fenilalanina/análisis , Adolescente , Adulto , Femenino , Humanos , Masculino , ProtonesRESUMEN
Chromosomal abnormalities account for a significant percentage of congenital malformations in the neonate. While some of the syndromes can be suspected on clinical grounds, the clinician will need to have a high index of suspicion based on the presence of multiple abnormalities that cannot be accounted for by other causes. Chromosome analysis should be performed promptly in these cases. Cultured lymphocytes are the standard preparation at present. However, new non-isotopic hybridization techniques are becoming available that allow analysis of interphase cells, and these may become more widely used as clinical experience with them is gained. Prognosis can usually be better defined once the chromosome analysis is complete. The information acquired may also be used to provide risk estimates for chromosomal abnormalities in future pregnancies of the parents of the affected infant and for other relatives. Empathetic counseling of the parents and family must be provided once the diagnosis is known. It must take into account the knowledge the chromosome analysis provides, be respectful of the parent's need for support, and be accurate as to prognosis of the condition diagnosed. When Down syndrome and Turner syndrome have been diagnosed, care must be taken to emphasize the positive aspects of the prognosis. When a chromosomal abnormality with an extremely poor prognosis is identified, support for withdrawal of medical intervention must be sensitively provided. The diagnosis and care of an infant with a chromosomal abnormality will challenge all of the pediatrician's diagnostic, therapeutic, and communication skills.
Asunto(s)
Aberraciones Cromosómicas , Trastornos de los Cromosomas , Adulto , Aberraciones Cromosómicas/diagnóstico , Aberraciones Cromosómicas/epidemiología , Aberraciones Cromosómicas/etiología , Aberraciones Cromosómicas/genética , Femenino , Reordenamiento Génico , Asesoramiento Genético , Humanos , Recién Nacido , Masculino , Fenotipo , Factores de Riesgo , Aberraciones Cromosómicas Sexuales/genética , TrisomíaRESUMEN
The inborn errors of metabolism must always be considered when a newborn presents with neurological distress, feeding difficulties, or a family history of neonatal or unexplained death. Clinical suspicion combined with prompt sophisticated laboratory evaluation is crucial if infants affected with this group of disorders are to be rescued.
Asunto(s)
Errores Innatos del Metabolismo , Errores Innatos del Metabolismo de los Aminoácidos , Errores Innatos del Metabolismo de los Carbohidratos , Servicios Médicos de Urgencia , Humanos , Lactante , Recién Nacido , Errores Innatos del Metabolismo Lipídico , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/terapiaRESUMEN
BACKGROUND: Dermatosparaxis is an autosomal recessive connective tissue disorder in animals that is caused by abnormal processing of type I procollagen and results in skin laxity and fragility. Only three humans with characteristic biochemical and electronmicroscopic findings have been recognized to date. OBSERVATIONS: We describe the clinical and electronmicroscopic findings in an affected boy who presented at birth with large full-thickness groin fissures, micrognathia, large fontanelles, umbilical hernia, and dental laminal cysts. He subsequently exhibited marked skin fragility, blue sclerae, joint laxity, increased bruisability, and growth retardation. The diagnosis of dermatosparaxis was made by electron-microscopic findings consisting of characteristic small, irregular, and circular collagen fibers in the skin. His phenotype is strikingly similar to two other reported children with the disorder, which is now classified in humans as Ehlers-Danlos VII-C. CONCLUSIONS: The newly recognized phenotype of Ehlers-Danlos VII-C is a distinct connective tissue disorder characterized by marked skin fragility and laxity, blue sclerae, increased bruisability, micrognathia, umbilical hernia, and growth retardation. A suspected clinical diagnosis can be confirmed by electron-microscopic and biochemical studies of connective tissue.
Asunto(s)
Síndrome de Ehlers-Danlos , Enfermedades de la Piel/congénito , Anomalías Múltiples , Colágeno/ultraestructura , Síndrome de Ehlers-Danlos/clasificación , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/patología , Humanos , Lactante , Masculino , Fenotipo , Piel/ultraestructura , Enfermedades de la Piel/clasificación , Enfermedades de la Piel/diagnóstico , Enfermedades de la Piel/patologíaRESUMEN
We describe a male twin with the smallest terminal deletion of chromosome 2q [46,XY,del(2)(q37.2)] reported to date. His deletion was confirmed by a fluorescence in situ hybridization study using a probe from the deleted region. Only 3 other cases with larger deletions including 2q37.2-->qter have been reported. Clinical manifestations our patient has in common with them include frontal bossing, long eyelashes, micrognathia, infantile hypotonia and developmental delay. His twin brother is physically and developmentally normal and chromosomes of the parents were normal. The mildness of the phenotype in this patient supports less stringent criteria for cytogenetic study of developmentally impaired individuals.
Asunto(s)
Aberraciones Cromosómicas/genética , Deleción Cromosómica , Cromosomas Humanos Par 2 , Adulto , Preescolar , Aberraciones Cromosómicas/fisiopatología , Bandeo Cromosómico , Trastornos de los Cromosomas , Femenino , Humanos , Hibridación in Situ , Masculino , FenotipoRESUMEN
Dermatosparaxis is a recessively inherited connective-tissue disorder that results from lack of the activity of type I procollagen N-proteinase, the enzyme that removes the amino-terminal propeptides from type I procollagen. Initially identified in cattle more than 20 years ago, the disorder was subsequently characterized in sheep, cats, and dogs. Affected animals have fragile skin, lax joints, and often die prematurely because of sepsis following avulsion of portions of skin. We recently identified two children with soft, lax, and fragile skin, which, when examined by transmission electron microscopy, contained the twisted, ribbon-like collagen fibrils characteristic of dermatosparaxis. Skin extracts from one child contained collagen precursors with amino-terminal extensions. Cultured fibroblasts from both children failed to cleave the amino-terminal propeptides from the pro alpha 1(I) and pro alpha 2(I) chains in type I procollagen molecules. Extracts of normal cells cleaved to collagen, the type I procollagen synthesized by cells from both children, demonstrating that the enzyme, not the substrate, was defective. These findings distinguish dermatosparaxis from Ehlers-Danlos syndrome type VII, which results from substrate mutations that prevent proteolytic processing of type I procollagen molecules.
Asunto(s)
Síndrome de Ehlers-Danlos/patología , Procolágeno/metabolismo , Aminoácidos/metabolismo , Células Cultivadas , Colágeno/biosíntesis , Colágeno/genética , Colágeno/aislamiento & purificación , Síndrome de Ehlers-Danlos/clasificación , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/metabolismo , Electroforesis en Gel de Poliacrilamida , Femenino , Fibroblastos/metabolismo , Prueba de Complementación Genética , Humanos , Hidrólisis , Lactante , Microscopía Electrónica , Procolágeno/genética , Procesamiento Postranscripcional del ARN , Piel/metabolismo , Piel/ultraestructuraRESUMEN
N-Acetyl-L-glutamate synthetase (NAG synthetase) is a mitochondrial matrix enzyme which catalyzes the synthesis of N-acetyl-Lglutamate (NAG), a physiologic activator of the urea cycle enzyme carbamylphosphate synthetase I. Deficiency of NAG synthetase in humans has been reported only three times previously. Two cases presented with uncontrolable neonatal hyperammonemia leading to death, while a third child presented with hyperammonemia and a neurodegenerative picture at 15 months of age after previously being healthy. We report here a new case of NAG synthetase deficiency who presented at 4 years, 10 months of age with an episode of hyperammonemia. Diagnosis was made at age 5 years, 6 months when a liver biopsy showed 9.7% of normal activity. Urine orotic acid was low, and total NAG content in liver was normal. Liver pathology revealed micro- and macrovesicular fat and mitochondria of irregular size and shape with intracristae crystallizations. NAG content in liver in patients with NAG synthetase deficiency has not previously been reported. Its normal value in the face of NAG synthetase deficiency suggests an abnormal localization of NAG to the cytoplasm and the likelihood of aberrant cytoplasmic synthesis of this compound. Additional physiologic implications of this speculative abnormal compartmentalization are discussed.
Asunto(s)
Acetiltransferasas/deficiencia , Glutamatos/metabolismo , Hígado/metabolismo , Aminoácidos/sangre , N-Acetiltransferasa de Aminoácidos , Amoníaco/sangre , Preescolar , Cristalización , Humanos , Hígado/patología , Masculino , Microscopía Electrónica , Mitocondrias Hepáticas/patología , Ácido Orótico/orinaRESUMEN
Screening newborn infants for inherited disorders has been effective in preventing mental retardation, growth failure, and death from several metabolic disorders for more than two decades. Technical advances have provided more screening tools for both genetic and nongenetic conditions, and in the coming decades these techniques will be used not only to screen newborns but to assess genetic risks in entire populations. The financial, legal, and ethical issues which these activities raise must influence the development of public policies in order to reap the benefits promised. The conference published here was designed to address these issues for health care practitioners, health policy planners, and public health professionals.
Asunto(s)
Pruebas Genéticas , Diagnóstico Prenatal , Femenino , Tamización de Portadores Genéticos , Enfermedades Genéticas Congénitas/diagnóstico , Humanos , Recién Nacido , EmbarazoRESUMEN
Newborn screening for inborn errors of metabolism is an established practice that has shown its value in preventing the morbidity, mortality, and mental retardation that ravage the child suffering from an inherited disorder of intermediary metabolism. The American Academy of Pediatrics has taken a strong stand supporting newborn screening for PKU and hypothyroidism for all newborns and has repeatedly stressed the need for such screening to be part of an integrated program that incorporates screening, diagnosis, management, and support. As we enter the 21st century, the challenges of maintaining excellence in existing programs, developing new screening tests, and assuring optimal follow-up and management must be met for all children.