RESUMEN
BACKGROUND: For urea cycle disorders (UCD), proportions and mortality of early onset (EO) patients, as well as outcome at one year of life show large variability. We aimed to integrate available evidence to create benchmarks for new diagnostic and therapeutic strategies. METHODS: Medline search for reports published between 1978 and Dec 22, 2014 was completed by hand search. Random effects meta-analysis was done for four UCDs, deficiency of carbamylphosphate synthetase 1 (CPS1D), male/female ornithine transcarbamylase (OTCDm/f), argininosuccinate synthetase (ASSD) and lyase (ASLD). Effects of publication year and geographic area were analysed by meta-regression. RESULTS: Twenty-four publications report onset time (n = 1542 patients), survival of EO (n = 665 patients) and outcome at one year of life (n = 172 patients). Proportions for EO manifestation (95% confidence interval) were: CPS1D = 0.75 (0.61;0.88); OTCDm = 0.52 (0.39;0.65); OTCDf = 0.07 (0.03;0.11); ASSD = 0.65 (0.57;0.73); ASLD = 0.60 (0.44;0.77); for surviving EO patients: CPS1D = 0.64 (0.50;0.79); OTCDm = 0.40 (0.16;0.64); OTCDf = 0.57 (0.29;0.85); ASSD = 0.67 (0.48;0.86); ASLD = 0.81 (0.68;0.94); and for normal outcome at one year for survivors: CPS1D = 0.20 (0.07;0.38); OTCDm = 0.15 (0.00;0.39); OTCDf no data; ASSD = 0.36 (0.13;0.60); ASLD = 0.36 (0.17;0.58). Between study variation was large. Year of publication had no effect. Studies from Europe showed lower survival rates than those from Japan or USA. CONCLUSIONS: UCDs, except for OTCDf, have high risks of EO disease manifestation and, except for ASLD, of neonatal death. No improvement of survival was observed over more than three decades. Geographic variation remains to be explained. This comprehensive description of the natural history of EO UCDs should be considered by scientists, clinicians, health policy makers and guideline developers.
Asunto(s)
Mortalidad Infantil , Trastornos Innatos del Ciclo de la Urea/mortalidad , Argininosuccinato Sintasa/metabolismo , Femenino , Humanos , Lactante , Liasas/metabolismo , Masculino , Estudios Observacionales como Asunto , Ornitina Carbamoiltransferasa/metabolismo , Trastornos Innatos del Ciclo de la Urea/metabolismoRESUMEN
BACKGROUND: Organic acidurias (OADs) and urea cycle disorders (UCDs) are inborn metabolic disorders with a risk for acute and chronic metabolic decompensation resulting in impairments of the central nervous system and other organ systems. So far, there is no systematic study of intellectual functioning, behavioural/emotional problems and health-related quality of life (HRQoL), and how these domains are connected. METHODS: Data of 152 patients with OADs (n = 100) and UCDs (n = 52) from the European Registry and Network of intoxication type Metabolic Diseases (E-IMD) using standardized instruments were compared with normative data. RESULTS: Behavioural/emotional problems are increased in OADs or UCDs patients by a factor of 2.5 (3.0), in female asymptomatic carriers of X-linked inherited UCD ornithine transcarbamylase deficiency (fasOTCD) by a factor of 1.5. All groups show similar patterns of behavioural/emotional problems, not different from epidemiological data. Mental disability (IQ ≤ 70) was found in 31% of OAD, 43% of UCD, but not in fasOTCD subjects. HRQoL was decreased in the physical domain, but in the normal range. Behavioural/emotional problems were significantly associated with intellectual functioning (OR = 6.24, 95%CI: 1.39-27.99), but HRQoL was independent from both variables. CONCLUSIONS: Patients with OADs and UCDs show increased frequencies of mental disability and behavioural/emotional problems. Profiles of behavioural/emotional problems were similar to epidemiological data. Intellectual disability and behavioural/emotional problems were strongly associated. Patients' HRQoL was in the normal range, possibly compensated by coping strategies of their families. Diagnostics and clinical care of OAD/UCD patients should be improved regarding behavioural/emotional, intellectual and quality of life aspects.
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Discapacidad Intelectual/etiología , Trastornos Mentales/etiología , Enfermedades Metabólicas/complicaciones , Errores Innatos del Metabolismo/complicaciones , Trastornos Innatos del Ciclo de la Urea/complicaciones , Preescolar , Emociones , Femenino , Humanos , Discapacidad Intelectual/metabolismo , Masculino , Trastornos Mentales/metabolismo , Enfermedades Metabólicas/metabolismo , Errores Innatos del Metabolismo/metabolismo , Enfermedad por Deficiencia de Ornitina Carbamoiltransferasa/complicaciones , Enfermedad por Deficiencia de Ornitina Carbamoiltransferasa/metabolismo , Calidad de Vida , Trastornos Innatos del Ciclo de la Urea/metabolismoRESUMEN
BACKGROUND: The clinical presentation of patients with organic acidurias (OAD) and urea cycle disorders (UCD) is variable; symptoms are often non-specific. AIMS/METHODS: To improve the knowledge about OAD and UCD the E-IMD consortium established a web-based patient registry. RESULTS: We registered 795 patients with OAD (n = 452) and UCD (n = 343), with ornithine transcarbamylase (OTC) deficiency (n = 196), glutaric aciduria type 1 (GA1; n = 150) and methylmalonic aciduria (MMA; n = 149) being the most frequent diseases. Overall, 548 patients (69 %) were symptomatic. The majority of them (n = 463) presented with acute metabolic crisis during (n = 220) or after the newborn period (n = 243) frequently demonstrating impaired consciousness, vomiting and/or muscular hypotonia. Neonatal onset of symptoms was most frequent in argininosuccinic synthetase and lyase deficiency and carbamylphosphate 1 synthetase deficiency, unexpectedly low in male OTC deficiency, and least frequently in GA1 and female OTC deficiency. For patients with MMA, propionic aciduria (PA) and OTC deficiency (male and female), hyperammonemia was more severe in metabolic crises during than after the newborn period, whereas metabolic acidosis tended to be more severe in MMA and PA patients with late onset of symptoms. Symptomatic patients without metabolic crises (n = 94) often presented with a movement disorder, mental retardation, epilepsy and psychiatric disorders (the latter in UCD only). CONCLUSIONS: The initial presentation varies widely in OAD and UCD patients. This is a challenge for rapid diagnosis and early start of treatment. Patients with a sepsis-like neonatal crisis and those with late-onset of symptoms are both at risk of delayed or missed diagnosis.
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Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Encefalopatías Metabólicas/diagnóstico , Glutaril-CoA Deshidrogenasa/deficiencia , Hiperamonemia/diagnóstico , Enfermedad por Deficiencia de Ornitina Carbamoiltransferasa/diagnóstico , Trastornos Innatos del Ciclo de la Urea/diagnóstico , Adolescente , Adulto , Anciano , Niño , Preescolar , Europa (Continente) , Femenino , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual , Masculino , Persona de Mediana Edad , Sistema de Registros , Vómitos , Adulto JovenRESUMEN
BACKGROUND: The disease course and long-term outcome of patients with organic acidurias (OAD) and urea cycle disorders (UCD) are incompletely understood. AIMS: To evaluate the complex clinical phenotype of OAD and UCD patients at different ages. RESULTS: Acquired microcephaly and movement disorders were common in OAD and UCD highlighting that the brain is the major organ involved in these diseases. Cardiomyopathy [methylmalonic (MMA) and propionic aciduria (PA)], prolonged QTc interval (PA), optic nerve atrophy [MMA, isovaleric aciduria (IVA)], pancytopenia (PA), and macrocephaly [glutaric aciduria type 1 (GA1)] were exclusively found in OAD patients, whereas hepatic involvement was more frequent in UCD patients, in particular in argininosuccinate lyase (ASL) deficiency. Chronic renal failure was often found in MMA, with highest frequency in mut(0) patients. Unexpectedly, chronic renal failure was also observed in adolescent and adult patients with GA1 and ASL deficiency. It had a similar frequency in patients with or without a movement disorder suggesting different pathophysiology. Thirteen patients (classic OAD: 3, UCD: 10) died during the study interval, ten of them during the initial metabolic crisis in the newborn period. Male patients with late-onset ornithine transcarbamylase deficiency were presumably overrepresented in the study population. CONCLUSIONS: Neurologic impairment is common in OAD and UCD, whereas the involvement of other organs (heart, liver, kidneys, eyes) follows a disease-specific pattern. The identification of unexpected chronic renal failure in GA1 and ASL deficiency emphasizes the importance of a systematic follow-up in patients with rare diseases.
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Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Aciduria Argininosuccínica/diagnóstico , Encefalopatías Metabólicas/diagnóstico , Glutaril-CoA Deshidrogenasa/deficiencia , Enfermedad por Deficiencia de Ornitina Carbamoiltransferasa/diagnóstico , Acidemia Propiónica/diagnóstico , Trastornos Innatos del Ciclo de la Urea/diagnóstico , Adolescente , Adulto , Anciano , Niño , Preescolar , Europa (Continente) , Femenino , Humanos , Lactante , Recién Nacido , Estimación de Kaplan-Meier , Fallo Renal Crónico/complicaciones , Hígado/metabolismo , Masculino , Persona de Mediana Edad , Tamizaje Neonatal , Fenotipo , Sistema de Registros , Adulto JovenRESUMEN
BACKGROUND: Newborn screening for inborn errors of metabolism is regarded as highly successful by health professionals. Little is known about parents' perspectives on child development and social impact on families. METHODS: Parents of 187 patients with metabolic disorders detected by newborn screening rated child development, perceived burdens on child and family, and future expectations on a questionnaire with standardized answers. Parental ratings were compared with standardized psychometric test results. Regression analysis was performed to identify factors associated with extent of perceived burden. RESULTS: In 26.2% of patients, parents perceived delays in global development and/or specific developmental domains (physical, social, intellectual, language). Parents expected normal future development in 95.7%, and an independent adult life for their child in 94.6%. Comparison with psychometric test results showed that parents of children with cognitive impairments tended to overrate their child's abilities. Mild/medium burden posed on the family (child) by the metabolic disorder was stated by 56.1% (48.9%) of parents, severe/very severe burden by 19.3% (8.6%). One third of families reported financial burden due to the metabolic disorder. Dietary treatment and diagnoses with risk for metabolic decompensation despite treatment were associated with higher perceived burden for the family. Disorders rated as potentially very burdensome by experts were not rated accordingly by parents, demonstrating different perspectives of professionals and parents. CONCLUSION: Although newborn screening leads to favourable physical and cognitive outcome, living with a metabolic disorder may cause considerable stress on patients and families, emphasizing the need for comprehensive multidisciplinary care including psychological and social support.
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Desarrollo Infantil/fisiología , Familia/psicología , Enfermedades Metabólicas/fisiopatología , Enfermedades Metabólicas/psicología , Padres/psicología , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Tamizaje Neonatal/métodos , Calidad de Vida , Apoyo Social , Encuestas y CuestionariosRESUMEN
BACKGROUND: Recurrent acute and life-threatening metabolic decompensations are thought to be the major cause of mortality and morbidity in patients with propionic acidemia (PA). Since metabolic decompensations in these patients usually develop gradually, there is considerable uncertainty about the beginning and when emergency treatment should be initiated. The major aim of this study was to evaluate the usefulness of biochemical parameters for improving decision-making on the start of emergency treatment. METHODS: We analysed data of 16 PA patients continuously followed in our centre. Metabolic decompensation was defined clinically by the occurrence of at least one of three alarming symptoms: vomiting, food refusal or impaired consciousness. Thirty-eight biochemical parameters were analysed. RESULTS: A total of 259 metabolic decompensations were documented and compared with 625 routine visits. Among the symptoms used to clinically define metabolic decompensations, vomiting was most frequent (87 %). In total, 19 biochemical parameters differentiated between metabolic decompensations and routine visits. Among them ammonia, acid-base balance and anion gap were most reliable to identify a metabolic decompensation, and to estimate its severity. A comparative analysis of patients with PA and methylmalonic acidemia during metabolic decompensation showed similar results. CONCLUSIONS: Ammonia, acid-base balance and anion gap are important biochemical parameters to identify an (impending) metabolic decompensation and to assess its severity in PA patients. The identified biochemical parameters should be integrated in an algorithm for clinical decision-making on emergency treatment and should be tested in a prospective trial.
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Toma de Decisiones , Tratamiento de Urgencia , Acidemia Propiónica/sangre , Acidemia Propiónica/terapia , Equilibrio Ácido-Base , Adolescente , Adulto , Errores Innatos del Metabolismo de los Aminoácidos/sangre , Amoníaco/química , Apetito , Niño , Preescolar , Técnicas de Apoyo para la Decisión , Humanos , Propionatos/química , Acidemia Propiónica/diagnóstico , Inconsciencia , Vómitos , Adulto JovenRESUMEN
BACKGROUND: In phenylketonuria presymptomatic treatment following newborn screening prevents severe mental and physical impairment. The reasons for subtle impairments of cerebral functions despite early treatment remain unclear. We assessed a broad spectrum of visual functions in early-treated patients with phenylketonuria and evaluated two hypotheses-the dopamine and the long-chain polyunsaturated fatty acids (LCPUFAs) depletion hypotheses. METHODS: Contrast sensitivity, colour vision, electroretinography, frequency doubling technology campimetry (FDT), and their relation with blood phenylalanine and docosahexaenoic acid levels were assessed in 36 patients with phenylketonuria and 18 age-matched healthy controls. RESULTS: Contrast sensitivity was significantly lower and total error scores in colour vision significantly higher in patients than controls. Electroretinography results differed significantly between patients and controls. We found a trend for the effect of phenylalanine-levels on contrast sensitivity and a significant effect on colour vision/FDT results. Docosahexaenoic acid levels in erythrocytes were not associated with visual functions. CONCLUSION: This is the first evaluation of visual functions in phenylketonuria using a comprehensive ophthalmological test battery. We found no evidence supporting the long-chain polyunsaturated fatty acids depletion hypothesis. However, the effect of phenylalanine-levels on visual functions suggests that imbalance between phenylalanine and tyrosine may affect retinal dopamine levels in phenylketonuria. This is supported by the similar patterns of visual functions in patients with phenylketonuria observed in our study and patients with Parkinson's disease.
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Dopamina/metabolismo , Ácidos Grasos Insaturados/metabolismo , Fenilcetonurias/fisiopatología , Visión Ocular , Adolescente , Adulto , Estudios de Casos y Controles , Visión de Colores , Sensibilidad de Contraste , Electrorretinografía , Femenino , Humanos , Masculino , Fenilcetonurias/metabolismo , Adulto JovenRESUMEN
Smith-Lemli-Opitz (SLOS), or RSH syndrome, is an autosomal recessive deficiency of 7-dehydrocholesterol reductase (DHCR7) resulting in an accumulation of 7- and 8-dehydrocholesterol (7- and 8-DHC) in tissues and body fluids. At birth patients have variable malformations of CNS, heart, kidney, genitalia, and limbs, which may be life-limiting. In later course, psychomotor and mental retardation and behavior abnormalities become evident. Prenatally SLOS can be suspected on the basis of malformations and intrauterine growth retardation (IUGR) in prenatal ultrasonography and reduced maternal free estriol in serum. The diagnosis is confirmed by sterol analysis in a chorionic villus biopsy or amniotic fluid (AF). In this study, we evaluated the predictive value of the above mentioned criteria in combination with family history by quantification of sterols in AF in pregnancies with either a family history, ultrasonographical abnormalities typical for SLOS, or reduced maternal serum unconjugated estriol (MSuE3). The relative frequency of SLOS in fetuses with an affected sibling was 0.23, as to be expected for an autosomal recessive disease. The probability for SLOS was <0.6% when neither an affected sib nor more than one typical SLOS malformation was present. For safety reasons and for cost-effectiveness we recommend careful evaluation of history, MSuE3, and clinical presentation before determining sterols in AF.
Asunto(s)
Síndrome de Smith-Lemli-Opitz/diagnóstico , Líquido Amniótico/química , Biomarcadores/sangre , Femenino , Humanos , Valor Predictivo de las Pruebas , Embarazo , Diagnóstico Prenatal , Síndrome de Smith-Lemli-Opitz/sangre , Síndrome de Smith-Lemli-Opitz/diagnóstico por imagen , Esteroles/sangre , Ultrasonografía PrenatalRESUMEN
BACKGROUND: Metabolic treatment in glutaric aciduria type I (GA-I) including a low lysine diet with lysine-free, tryptophan-reduced amino acid supplements (AAS), carnitine supplementation and early start of emergency treatment during putatively threatening episodes of intermittent febrile illness dramatically improves the outcome and thus has been recommended by an international guideline group (Kölker et al, J Inherit Metab Dis 30:5-22, 2007). However, possible affection of linear growth, weight gain and biochemical follow-up monitoring has not been studied systematically. METHODS: Thirty-three patients (n = 29 asymptomatic, n = 4 dystonic) with GA-I who have been identified by newborn screening in Germany from 1999 to 2009 were followed prospectively during the first six years of life. Dietary treatment protocols, anthropometrical and biochemical parameters were longitudinally evaluated. RESULTS: Mean daily intake as percentage of guideline recommendations was excellent for lysine (asymptomatic patients: 101 %; dystonic patients: 103 %), lysine-free, tryptophan-reduced AAS (108 %; 104 %), energy (106 %; 110 %), and carnitine (92 %; 102 %). Low lysine diet did not affect weight gain (mean SDS 0.05) but mildly impaired linear growth in asymptomatic patients (mean SDS -0.38), while dystonic patients showed significantly reduced weight gain (mean SDS -1.32) and a tendency towards linear growth retardation (mean SDS -1.03). Patients treated in accordance with recent recommendations did not show relevant abnormalities of routine biochemical follow-up parameters. INTERPRETATION: Low lysine diet promotes sufficient intake of essential nutrients and anthropometric development in asymptomatic children up to age 6 year, whereas individualized nutritional concepts are required for dystonic patients. Revised recommendations for biochemical monitoring might be required for asymptomatic patients.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/dietoterapia , Pesos y Medidas Corporales , Encefalopatías Metabólicas/dietoterapia , Alimentos Formulados , Glutaril-CoA Deshidrogenasa/deficiencia , Lisina/administración & dosificación , Errores Innatos del Metabolismo de los Aminoácidos/sangre , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Errores Innatos del Metabolismo de los Aminoácidos/fisiopatología , Antropometría , Biomarcadores/análisis , Biomarcadores/sangre , Encefalopatías Metabólicas/sangre , Encefalopatías Metabólicas/metabolismo , Encefalopatías Metabólicas/fisiopatología , Carnitina/administración & dosificación , Niño , Preescolar , Suplementos Dietéticos , Ingestión de Alimentos/fisiología , Femenino , Estudios de Seguimiento , Glutaril-CoA Deshidrogenasa/sangre , Glutaril-CoA Deshidrogenasa/metabolismo , Humanos , Lactante , Masculino , Monitoreo Fisiológico/métodosRESUMEN
The cerebral formation and entrapment of neurotoxic dicarboxylic metabolites (glutaryl-CoA, glutaric and 3-hydroxyglutaric acid) are considered to be important pathomechanisms of striatal injury in glutaric aciduria type I (GA-I). The quantitatively most important precursor of these metabolites is lysine. Recommended therapeutic interventions aim to reduce lysine oxidation (low lysine diet, emergency treatment to minimize catabolism) and to enhance physiologic detoxification of glutaryl-CoA via formation of glutarylcarnitine (carnitine supplementation). It has been recently shown in Gcdh(-/-) mice that cerebral lysine influx and oxidation can be modulated by arginine which competes with lysine for transport at the blood-brain barrier and the inner mitochondrial membrane [Sauer et al., Brain 134 (2011) 157-170]. Furthermore, short-term outcome of 12 children receiving arginine-fortified diet showed very promising results [Strauss et al., Mol. Genet. Metab. 104 (2011) 93-106]. Since lysine-free, arginine-fortified amino acid supplements (AAS) are commercially available and used in Germany for more than a decade, we evaluated the effect of arginine supplementation in a cohort of 34 neonatally diagnosed GA-I patients (median age, 7.43 years; cumulative follow-up period, 221.6 patient years) who received metabolic treatment according to a published guideline [Kölker et al., J. Inherit. Metab. Dis. 30 (2007) 5-22]. Patients used one of two AAS product lines during the first year of life, resulting in differences in arginine consumption [group 1 (Milupa Metabolics): mean=111 mg arginine/kg; group 2 (Nutricia): mean=145 mg arginine/kg; p<0.001]. However, in both groups the daily arginine intake was increased (mean, 137 mg/kg body weight) and the dietary lysine-to-arginine ratio was decreased (mean, 0.7) compared to infants receiving human milk and other natural foods only. All other dietary parameters were in the same range. Despite significantly different arginine intake, the plasma lysine-to-arginine ratio did not differ in both groups. Frequency of dystonia was low (group 1: 12.5%; group 2: 8%) compared with patients not being treated according to the guideline, and gross motor development was similar in both groups. In conclusion, the development of complementary dietary strategies exploiting transport competition between lysine and arginine for treatment of GA-I seems promising. More work is required to understand neuroprotective mechanisms of arginine, to develop dietary recommendations for arginine and to evaluate the usefulness of plasma monitoring for lysine and arginine levels as predictors of cerebral lysine influx.
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Errores Innatos del Metabolismo de los Aminoácidos/dietoterapia , Encefalopatías Metabólicas/dietoterapia , Suplementos Dietéticos , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Arginina/sangre , Arginina/metabolismo , Encéfalo/metabolismo , Encefalopatías Metabólicas/diagnóstico , Niño , Preescolar , Femenino , Glutaril-CoA Deshidrogenasa/deficiencia , Humanos , Lactante , Lisina/sangre , Lisina/metabolismo , Masculino , Resultado del TratamientoRESUMEN
Recurrent, life-threatening metabolic decompensations often occur in patients with methylmalonic aciduria (MMAuria). Our study evaluated (impending) metabolic decompensations in these patients aiming to identify the most frequent and reliable clinical and biochemical abnormalities that could be helpful for decision-making on when to start an emergency treatment. Seventy-six unscheduled and 179 regular visits of 10 patients with confirmed MMAuria continuously followed by our metabolic centre between 1975 and 2009 were analysed. The most frequent symptom of an impending acute metabolic decompensation was vomiting (90% of episodes), whereas symptoms of intercurrent infectious disease (29%) or other symptoms (such as food refusal and impaired consciousness) were found less often. Thirty-five biochemical parameters were included in the analysis. Among them, pathological changes of acid-base balance reflecting metabolic acidosis with partial respiratory compensation (decreased pH, pCO(2), standard bicarbonate, and base excess) and elevated ammonia were the most reliable biochemical parameters for the identification of a metabolic decompensation and the estimation of its severity. In contrast, analyses of organic acids, acylcarnitines and carnitine status were less discriminative. In conclusion, careful history taking and identification of suspicious symptoms in combination with a small number of rapidly available biochemical parameters are helpful to differentiate compensated metabolic condition and (impending) metabolic crisis and to decide when to start an emergency treatment.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Equilibrio Ácido-Base , Acidosis/sangre , Acidosis/diagnóstico , Acidosis/metabolismo , Adolescente , Adulto , Errores Innatos del Metabolismo de los Aminoácidos/sangre , Amoníaco/sangre , Bicarbonatos/metabolismo , Carnitina/análogos & derivados , Carnitina/metabolismo , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Masculino , Adulto JovenRESUMEN
In a survey conducted in 2010/2011 data from the 28 EU member states, four EU candidate states (Croatia, FYROM, Iceland, Turkey), three potential EU candidate states (Bosnia Herzegovina, Montenegro, Serbia), and two EFTA states (Norway and Switzerland) were collected. The status and function of newborn screening (NBS) programmes were investigated from the information to prospective parents and the public via confirmation of a positive screening result up to decisions on treatment. This article summarises the results from screening laboratory findings to start of treatment. In addition we asked about the existence of feedback loops reporting the conclusions of confirmation of screening results to the screening laboratory and communication of long-term outcome to diagnostic units and possibly existing central registries. Parallel to the description of actual practices of where, how and by whom the different steps of the programmes are executed, we also asked for the existence of guidelines or directives regulating the screening programmes, material to support information of parents about diagnoses and treatment and training facilities for professionals involved in the programmes. This survey gives a first comprehensive overview of the steps following a positive screening result in European NBS programmes. The 37 data sets reveal substantial variation of national screening panels, but also a lot of similarities. Analysis across all countries revealed that actual practice is often organised but not regulated by guidelines. Material to inform patients is available more often for explaining treatment (69 %) than explaining the necessity of confirmatory diagnostics (41 %). Training of professionals is rarely regulated by a guideline (2 %), but is offered for paediatricians (40 %) and dieticians (29 %) and only rarely for other professions (e.g. geneticists, clinical nurse specialists, psychologists). Registry-based evaluation of long-term outcome is as yet almost nonexistent (3 %).
Asunto(s)
Enfermedades del Recién Nacido/diagnóstico , Enfermedades del Recién Nacido/terapia , Tamizaje Neonatal/métodos , Tamizaje Neonatal/normas , Salud Pública/métodos , Salud Pública/normas , Comunicación , Recolección de Datos/métodos , Europa (Continente) , Unión Europea , Estudios de Seguimiento , Humanos , Recién Nacido , Tamizaje Neonatal/economía , Padres , Estudios Prospectivos , Control de Calidad , Encuestas y Cuestionarios , Terapéutica/economía , Terapéutica/métodos , Terapéutica/normas , TiempoRESUMEN
OBJECTIVE: To evaluate the effect of treatment according to current evidence-based recommendations on the neurological outcome of patients with glutaric aciduria type I (GA-I). METHODS: Fifty-two patients identified by newborn screening (NBS) in Germany from 1999 to 2009 were followed prospectively. Neurological outcome was assessed by the occurrence of an acute encephalopathic crisis and the severity of a movement disorder (MD) with predominant dystonia superimposing on axial hypotonia. Outcome was evaluated in relation to therapy and therapy-independent parameters. RESULTS: Outcome was best in GA-I patients who were treated in full accordance with treatment recommendations (n=37; 5% MD). Deviations from recommended basic metabolic treatment (low-lysine diet, carnitine) resulted in an intermediate outcome (n=9; 44% MD), whereas disregard of emergency treatment recommendations was associated with a poor outcome (n=6; 100% MD). Treatment regimens deviating from recommendations significantly increased the risk for MD (odds ratio [OR], 35; 95% confidence interval [CI], 5.88-208.39) and acute encephalopathic crises (OR, 51.32; 95% CI, 2.65-993.49). Supervision by a metabolic center improved the outcome (18% vs 57% MD; OR, 6.17; 95% CI, 1.15-33.11), whereas migrational background and biochemical phenotype (high versus low excretor status) had no significant effect. INTERPRETATION: Follow-up of neonatally diagnosed patients with GA-I in Germany clearly demonstrates that the inclusion of this rare disease in the NBS disease panel has significantly improved the neurological outcome of affected individuals. The establishment of and adherence to evidence-based treatment recommendations, and supervision by experienced metabolic centers helps to minimize the number of patients who do not benefit from NBS.
Asunto(s)
Adhesión a Directriz , Deficiencia Múltiple de Acil Coenzima A Deshidrogenasa/terapia , Guías de Práctica Clínica como Asunto , Niño , Preescolar , Medicina Basada en la Evidencia , Femenino , Estudios de Seguimiento , Alemania , Humanos , Lactante , Recién Nacido , Masculino , Tamizaje Neonatal , Resultado del TratamientoRESUMEN
BACKGROUND: In classical homocystinuria (HCU, MIM# 236200) due to the deficiency of cystathionine ß-synthase (EC 4.2.1.22) there is a clear evidence for the success of early treatment. The aim of this study was to develop and evaluate a two-tier strategy for HCU newborn screening. METHODS: We reevaluated data from our newborn screening programme for Qatar in a total number of 125,047 neonates including 30 confirmed HCU patients. Our hitherto existing screening strategy includes homocysteine (Hcy) measurements in every child, resulting in a unique dataset for evaluation of two-tier strategies. Reevaluation included methionine (Met) levels, Met to phenylalanine (Phe) ratio, and Hcy. Four HCU cases identified after database closure were also included in the evaluation. In addition, dried blood spot samples selected by Met values >P97 in the newborn screening programs in Austria, Australia, the Netherlands, and Taiwan were analyzed for Hcy. RESULTS: Met to Phe ratio was found to be more effective for first sieve than Met, sorting out nearly 90% of normal samples. Only 10% of the samples would have to be processed by second-tier measurement of Hcy in dried blood spots. As no patient with HCU was found neither in the samples investigated for HCU, nor by clinical diagnosis in the other countries, the generalization of our two-tier strategy could only be tested indirectly. CONCLUSION: The finally derived two-tier algorithm using Met to Phe ratio as first- and Hcy as second-tier requires 10% first-tier positives to be transferred to Hcy measurement, resulting in 100% sensitivity and specificity in HCU newborn screening.
RESUMEN
BACKGROUND: Patients with phenylketonuria have been reported to be deficient in long-chain polyunsaturated fatty acids (LCPUFAs). It has been postulated that good compliance with the dietary regimen negatively influences LCPUFA status. METHODS: In 36 patients with phenylketonuria and 18 age-matched healthy control subjects LCPUFA-levels in plasma phospholipids and cholesteryl esters, erythrocyte phosphatidylcholine and phosphatidylethanolamine were evaluated. RESULTS: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) levels did not differ significantly between patients and control subjects in plasma and erythrocyte fractions. There was a significant negative correlation between SDS (standard deviation) scores of DHA-levels in erythrocyte parameters from the respective age-matched control group and patients' concurrent and long-term phenylalanine levels for erythrocyte phosphatidylethanolamine and erythrocyte phosphatidylcholine. Patients with lower (higher) phenylalanine levels had positive (negative) DHA-SDS. CONCLUSION: In contrast to previous reports we did not find lower LCPUFA-levels in patients with phenylketonuria compared to age-matched healthy control subjects. Good dietary control was associated with better LCPUFA status.
Asunto(s)
Eritrocitos/metabolismo , Ácidos Grasos Insaturados/sangre , Fenilcetonurias/dietoterapia , Fenilcetonurias/metabolismo , Adolescente , Adulto , Niño , Ésteres del Colesterol/sangre , Ácidos Docosahexaenoicos/sangre , Ácido Eicosapentaenoico/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estado Nutricional , Fosfatidilcolinas/sangre , Fosfatidiletanolaminas/sangre , Fosfolípidos/sangre , Adulto JovenRESUMEN
BACKGROUND: Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is included in many newborn screening programmes worldwide. In addition to the prevalent mutation c.985A>G in the ACADM gene, potentially mild mutations like c.199T>C are frequently found in screening cohorts. There is ongoing discussion whether this mutation is associated with a clinical phenotype. METHODS: In 37 MCADD patients detected by newborn screening, biochemical phenotype (octanoylcarnitine (C8), ratios of C8 to acetylcarnitine (C2), decanoylcarnitine (C10) and dodecanoylcarnitine (C12) at screening and confirmation) and clinical phenotype (inpatient emergency treatment, metabolic decompensations, clinical assessments, psychometric tests) were assessed in relation to genotype. RESULTS: 16 patients were homozygous for c.985A>G (group 1), 11 compound heterozygous for c.199T>C and c.985A>G/another mutation (group 2) and 7 compound heterozygous for c.985A>G and mutations other than c.199T>C (group 3) and 3 carried neither c.985A>G nor c.199T>C but other known homozygous mutations (group 4). At screening C8/C2 and C8/C10, at confirmation C8/C2, C8/C10 and C8/C12 differed significantly between patients compound heterozygous for c.199T>C (group 2) and other genotypes. C8, C10 and C8/C2 at screening were strongly associated with time of sampling in groups 1 + 3 + 4, but not in group 2. Clinical phenotype did not differ between genotypes. Two patients compound heterozygous for c.199T>C and a severe mutation showed neonatal decompensation with hypoglycaemia. CONCLUSION: Biochemical phenotype differs between MCADD patients compound heterozygous for c.199T>C with a severe mutation and other genotypes. In patients detected by newborn screening, clinical phenotype does not differ between genotypes following uniform treatment recommendations. Neonatal decompensation can also occur in patients with the presumably mild mutation c.199T>C prior to diagnosis.
RESUMEN
BACKGROUND: Glutaric aciduria type I (GA-I) is an inherited metabolic disease due to deficiency of glutaryl-CoA dehydrogenase (GCDH). Cognitive functions are generally thought to be spared, but have not yet been studied in detail. METHODS: Thirty patients detected by newborn screening (n = 13), high-risk screening (n = 3) or targeted metabolic testing (n = 14) were studied for simple reaction time (SRT), continuous performance (CP), visual working memory (VWM), visual-motor coordination (Tracking) and visual search (VS). Dystonia (n = 13 patients) was categorized using the Barry-Albright-Dystonia Scale (BADS). Patients were compared with 196 healthy controls. Developmental functions of cognitive performances were analysed using a negative exponential function model. RESULTS: BADS scores correlated with speed tests but not with tests measuring stability or higher cognitive functions without time constraints. Developmental functions of GA-I patients significantly differed from controls for SRT and VS but not for VWM and showed obvious trends for CP and Tracking. Dystonic patients were slower in SRT and CP but reached their asymptote of performance similar to asymptomatic patients and controls in all tests. Asymptomatic patients did not differ from controls, except showing significantly better results in Tracking and a trend for slower reactions in visual search. Data across all age groups of patients and controls fitted well to a model of negative exponential development. CONCLUSIONS: Dystonic patients predominantly showed motor speed impairment, whereas performance improved with higher cognitive load. Patients without motor symptoms did not differ from controls. Developmental functions of cognitive performances were similar in patients and controls. Performance in tests with higher cognitive demand might be preserved in GA-I, even in patients with striatal degeneration.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/psicología , Encefalopatías Metabólicas/psicología , Trastornos del Conocimiento/psicología , Distonía/psicología , Glutaril-CoA Deshidrogenasa/deficiencia , Pruebas Neuropsicológicas , Adaptación Psicológica , Adolescente , Adulto , Niño , Conducta Infantil , Preescolar , Estudios Transversales , Procesamiento Automatizado de Datos , Femenino , Humanos , Recién Nacido , Masculino , Tamizaje Neonatal , Adulto JovenRESUMEN
Biochemical detection of inborn errors of creatine metabolism or transport relies on the analysis of three main metabolites in biological fluids: guanidinoacetate (GAA), creatine (CT) and creatinine (CTN). Unspecific clinical presentation of the diseases might be the cause that only few patients have been diagnosed so far. We describe a LC-MS/MS method allowing fast and reliable diagnosis by simultaneous quantification of GAA, CT and CTN in urine, plasma and cerebrospinal fluid (CSF) and established reference values for each material. For quantification deuterated stable isotopes of each analyte were used as internal standards. GAA, CT and CTN were separated by reversed-phase HPLC. The characterization was carried out by scanning the ions of each compound by negative ion tandem mass spectrometry. Butylation is needed to achieve sufficient signal intensity for GAA and CT but it is not useful for analyzing CTN. The assay is linear in a broad range of analyte concentrations usually found in urine, plasma and CSF. Comparison of the "traditional" cation-exchange chromatography and LC-MS/MS showed proportional differences but linear relationships between the two methods. The described method is characterized by high speed and linearity over large concentration ranges comparable to other published LC-MS methods but with higher sensitivity for GAA and CT. In addition, we present the largest reference group ever published for guanidino compounds in all relevant body fluids. Therefore this method is applicable for high-throughput approaches for diagnosis and follow-up of inborn errors of creatine metabolism and transport.