RESUMEN
BACKGROUND: As part of the German Collaborative Study on Phenylketonuria (PKU)/Hyperphenylalaninaemia (HPA) Study Protocol, a Blaskovics protein loading test (180 mg phenylalanine (phe) protein equivalent per kg body weight and day for 72 h) had been applied to 145 children at the age of 6 months. For investigating possible age-related changes of metabolic phenotype, 51 of them received a 2nd loading test at 5 years of age. METHODS: Besides the analysis of blood phe levels, acidic phe transamination metabolites were quantified in urine. RESULTS: Compared to the 6-month data, the mean blood phe level 72 h after start of loading (Phe72) was found to be decreased by 7% (P = 0.06), whereas the mean urinary excretion (per 1.73 m2 body surface and day) of 2-hydroxyphenylacetic acid was increased 1.9-fold (P < 0.01). Corresponding with these analytical data, the kinetic model constant k out of metabolic plus renal phe disposal was found increased 1.3-fold in mean (P < 0.01).In 3 of the 51 patients, Phe72 was very high at 6 months while in the medium range at 5 years, suggesting that catabolic states may mimic a more severe metabolic defect.The blood phe level response of mild PKU (type II) was assigned identically at both ages in 7/9 patients. Diverging results were (i) response type III (mild hyperphenylalaninaemia) at 6 months and type II at 5 years and (ii) type II at 6 months and type III at age 5. CONCLUSION: Renal elimination of OHPAA and phe tolerance increase significantly between the age of 6 months and 5 years, suggesting that, at least in childhood, formation and/or renal disposal of phe transamination metabolites may be major distal determinants of phe tolerance.
RESUMEN
BACKGROUND: As part of the German Collaborative Study of Children Treated for Phenylketonuria (PKU), a three-day protein loading test was applied to children at 6 months of age. This load elicits three principal types of blood phenylalanine (Phe) response, with types I and III clinically corresponding to classic PKU and mild hyperphenylalaninaemia not requiring diet (MHP), respectively. An intermediate type II, clinically corresponding to mild PKU, is characterized by early decline of blood Phe from above 1200 micromol/L down to levels between 600 and 1200 micromol/L at 72 h. AIMS: Unbiased classification and kinetic and molecular characterization of the intermediate Phe response; estimation of phenotypic variability of Phe disposal. METHOD: A kinetic model with zero-order protein synthesis and first-order rate of metabolic disposal of Phe is applied to 157 tests. RESULTS: A model of exponentially saturated activation describes the acceleration of Phe disposal from day 1 to 3 in the intermediate type of response. Eleven of 14 p.Y414C functional hemizygotes and two of three p.R261Q homozygotes manifested this kinetic type. The rate estimates of Phe metabolic disposal differ widely in patients with identical PAH genotype, yet are highly correlated with the Phe level at 72 h.
Asunto(s)
Técnicas y Procedimientos Diagnósticos , Fenilcetonurias/genética , Fenilcetonurias/metabolismo , Proteínas/farmacocinética , Proteínas/uso terapéutico , Análisis Mutacional de ADN , Frecuencia de los Genes , Genotipo , Semivida , Humanos , Lactante , Cinética , Modelos Biológicos , Fenotipo , Fenilalanina/sangre , Fenilalanina/metabolismo , Fenilalanina Hidroxilasa/genética , Fenilcetonurias/diagnósticoRESUMEN
Tetrahydrobiopterin (BH(4)) cofactor loading is a standard procedure to differentiate defects of BH(4) metabolism from phenylalanine hydroxylase (PAH) deficiency. BH(4) responsiveness also exists in PAH-deficient patients with high residual PAH activity. Unexpectedly, single cases with presumed nil residual PAH activity have been reported to be BH(4) responsive, too. BH(4) responsiveness has been defined either by a >or=30% reduction of blood Phe concentration after a single BH(4) dose or by a decline greater than the individual circadian Phe level variation. Since both methods have methodological disadvantages, we present a model of statistical process control (SPC) to assess BH(4) responsiveness. Phe levels in 17 adult PKU patients of three phenotypic groups off diet were compared without and with three different single oral dosages of BH(4) applied in a double-blind randomized cross-over design. Results are compared for >or=30% reduction and SPC. The effect of BH(4) by >or=30% reduction was significant for groups (p < 0.01) but not for dose (p = 0.064), with no interaction of group with dose (p = 0.24). SPC revealed significant effects for group (p < 0.01) and the interaction for group with dose (p < 0.05) but not for dose alone (p = 0.87). After one or more loadings, seven patients would be judged to be BH(4) responsive either by the 30% criterion or by the SPC model, but only three by both. Results for patients with identical PAH genotype were not very consistent within (for different BH(4) doses) and between the two models. We conclude that a comparison of protein loadings without and with BH(4) combined with a standardized procedure for data analysis and decision would increase the reliability of diagnostic results.
Asunto(s)
Biopterinas/análogos & derivados , Fenilalanina Hidroxilasa/genética , Fenilalanina/sangre , Fenilcetonurias/tratamiento farmacológico , Administración Oral , Adulto , Biopterinas/efectos adversos , Biopterinas/uso terapéutico , Estudios Cruzados , Dieta , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Masculino , Modelos Estadísticos , Fenilalanina Hidroxilasa/deficiencia , Fenilcetonurias/sangre , Fenilcetonurias/genética , Resultado del Tratamiento , Adulto JovenRESUMEN
In recent years, an increasing number of national guidelines on the treatment of phenylketonuria (PKU) have emerged. Most of these guidelines are dedicated to the care of children, while less attention is paid to the care of adults, although all guidelines underline the importance of diet for life. This review aims to summarize issues that need to be addressed within a guideline on the treatment of PKU, especially when care for patients beyond childhood is concerned. In this respect, it is of importance that adult patients, both willing and unwilling to be treated, need a guideline for care and follow-up. In PKU there is certainly a need for an improved unified guideline, especially after childhood, although many of the considerations in this article also apply to recommendations for treatment of children. Such a guideline will be a tool to improve treatment in PKU patients but should also include recommendations for collecting data for clinical and research purposes. Guideline development should also focus on nutritional, neuropsychological and psychosocial issues and not only on target plasma phenylalanine concentrations. In addition, guidelines must address not only what has to be done but also how it can be done, thereby improving concordance with the recommendations for treatment and management.
Asunto(s)
Fenilcetonurias/dietoterapia , Adulto , Barrera Hematoencefálica , Densidad Ósea , Niño , Dietoterapia/métodos , Guías como Asunto , Humanos , Imagen por Resonancia Magnética/métodos , Modelos Biológicos , Ciencias de la Nutrición , Fenilalanina/sangre , Fenilalanina/metabolismo , Fenilcetonurias/sangreRESUMEN
With the introduction of tandem mass spectrometry, newborn screening for disorders of propionate metabolism became widely available. However, there is controversy whether population screening for these disorders should be performed. The most widely used primary metabolite C(3) itself has a poor specificity or lacks 100% sensitivity for milder forms and/or defects of cobalamin metabolism. Strategies to improve specificity have included the calculation of metabolite ratios (e.g. C(3)/C(2)) or second-tier strategies with analysis of methylmalonic acid or 2-methylcitric acid from the primary screening specimen. We report the results of a new statistical approach to identify parameter combinations that allow for 100% sensitivity as well as increased specificity. The promising results of this alternative approach will have to be substantiated on larger data sets.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Ácido Metilmalónico/orina , Tamizaje Neonatal , Propionatos/metabolismo , Humanos , Recién Nacido , Sensibilidad y Especificidad , Espectrometría de Masas en TándemRESUMEN
Rare metabolic diseases are chronic, progressive, present frequently with a life-threatening course and may result in severe handicaps. They demand high diagnostic and therapeutic standards and efforts from physicians and patients. The challenge for society and health systems in dealing with patients affected by one of these diseases is to offer comprehensive service by a multi-professional team of specialists and evidence-based as well as economic (i.e. necessary, sufficient and effective) treatment. Patients and families should be treated in specialized metabolic centres guaranteeing continuous improvement of the scientific and clinical principles of treatment, standardized outcome evaluation, strict quality assurance as well as optimal psychosocial care and counselling. Networking of national and international metabolic centres seems imperative for clinical research in the field of rare metabolic diseases in order to provide adequate sample sizes and to yield substantial results.
Asunto(s)
Ensayos Clínicos como Asunto/tendencias , Redes Comunitarias/organización & administración , Difusión de la Información/métodos , Enfermedades Metabólicas/diagnóstico , Enfermedades Metabólicas/terapia , Enfermedades Raras/diagnóstico , Enfermedades Raras/terapia , Investigación Biomédica/tendencias , Atención a la Salud/organización & administración , Alemania , HumanosRESUMEN
In recent years several studies on tetrahydrobiopterin (BH4)-responsive phenylalanine hydroxylase (PAH) deficiency have been published. The molecular mechanisms of BH4 responsiveness are not conclusively understood, but there is evidence that BH4 responsiveness in hyperphenylalaninaemia (HPA) depends on the patient's genotype and residual PAH activity. As a BH4 preparation will soon obtain marketing approval as an alternative treatment for phenylketonuria (PKU), it is particularly important to evaluate this treatment and to define criteria to identify patients with a potential benefit from it. Most of the patients found to be BH4-responsive suffered from mild PKU or mild hyperphenylalaninaemia (MHP) and some of these would not be treated at all in many countries. Of patients with moderate and classic forms of PKU, only a few were classified as responders and the clinical significance of the effect size may be small.
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Biopterinas/análogos & derivados , Suplementos Dietéticos , Fenilalanina Hidroxilasa/deficiencia , Fenilcetonurias/diagnóstico , Fenilcetonurias/tratamiento farmacológico , Biopterinas/uso terapéutico , Genotipo , Humanos , Recién Nacido , Modelos Biológicos , Modelos Moleculares , Mutación , Tamizaje Neonatal/métodos , FenotipoRESUMEN
Smith-Lemli-Opitz syndrome (SLOS) is a malformation syndrome caused by deficiency of 7-dehydrocholesterol reductase catalysing the last step of cholesterol biosynthesis. This results in an accumulation of 7- and 8-dehydrocholesterol (7 + 8-DHC) and, in most patients, a deficiency of cholesterol. Current therapy consists of dietary cholesterol supplementation, which raises plasma cholesterol levels, but clinical effects have been reported in only a few patients. Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors were shown to reduce 7 + 8-DHC levels and increase cholesterol concentrations in two small trials with divergent clinical outcome. This retrolective study evaluates the effects of cholesterol only and of cholesterol plus the HMG-CoA reductase inhibitor simvastatin on plasma sterols in 39 SLOS patients and on anthropometric measures in 20 SLOS patients. Cholesterol as well as additional simvastatin decreased the plasma (7 + 8-DHC)/cholesterol ratio. However, the mechanism leading to the decreasing ratio was different. Whereas it was due to an increasing cholesterol concentration in the cholesterol-only cohort, a decreasing 7 + 8-DHC concentration was demonstrated in the cohort receiving additional simvastatin. We could not confirm a positive effect of simvastatin treatment on anthropometric measures or behaviour, as previously reported.
Asunto(s)
Colesterol/uso terapéutico , Simvastatina/uso terapéutico , Síndrome de Smith-Lemli-Opitz/tratamiento farmacológico , Niño , Colesterol/administración & dosificación , Estudios de Cohortes , Suplementos Dietéticos , Nutrición Enteral , Femenino , Genotipo , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Masculino , Síndrome de Smith-Lemli-Opitz/genéticaRESUMEN
Glutaryl-CoA dehydrogenase (GCDH) deficiency is an autosomal recessive disease with an estimated overall prevalence of 1 in 100 000 newborns. Biochemically, the disease is characterized by accumulation of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutarylcarnitine, which can be detected by gas chromatography-mass spectrometry of organic acids or tandem mass spectrometry of acylcarnitines. Clinically, the disease course is usually determined by acute encephalopathic crises precipitated by infectious diseases, immunizations, and surgery during infancy or childhood. The characteristic neurological sequel is acute striatal injury and, subsequently, dystonia. During the last three decades attempts have been made to establish and optimize therapy for GCDH deficiency. Maintenance treatment consisting of a diet combined with oral supplementation of L: -carnitine, and an intensified emergency treatment during acute episodes of intercurrent illness have been applied to the majority of patients. This treatment strategy has significantly reduced the frequency of acute encephalopathic crises in early-diagnosed patients. Therefore, GCDH deficiency is now considered to be a treatable condition. However, significant differences exist in the diagnostic procedure and management of affected patients so that there is a wide variation of the outcome, in particular of pre-symptomatically diagnosed patients. At this time of rapid expansion of neonatal screening for GCDH deficiency, the major aim of this guideline is to re-assess the common practice and to formulate recommendations for diagnosis and management of GCDH deficiency based on the best available evidence.
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Glutaril-CoA Deshidrogenasa/deficiencia , Glutaril-CoA Deshidrogenasa/genética , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/terapia , Niño , Preescolar , Femenino , Glutaril-CoA Deshidrogenasa/metabolismo , Humanos , Lactante , Recién Nacido , Espectrometría de Masas , Errores Innatos del Metabolismo/dietoterapia , Errores Innatos del Metabolismo/genética , Mutación , Tamizaje Neonatal , Fenotipo , RiesgoRESUMEN
Three decades after the first description of glutaryl-CoA dehydrogenase deficiency, major progress has been achieved in the prevention of acute striatal necrosis and neurological sequelae in affected children, if diagnosis is made early and treatment is started before manifestation of acute encephalopathic crises. However, all concepts for diagnostic work-up, monitoring, and treatment are solely experience-based, and 10-35% of early-diagnosed children do not or only incompletely benefit from the current management. They still develop neurological deterioration and sequelae despite early implementation of dietary treatment, carnitine supplementation and emergency treatment during acute intercurrent illnesses. International efforts should be made to move management of affected children from experience-based to evidence-based medicine. Major tools for this optimization are the establishment of an international patients' database, the implementation of an international prospective clinical study, and the development of international guidelines for diagnostic work-up, monitoring and therapy.
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Errores Innatos del Metabolismo de los Aminoácidos/terapia , Oxidorreductasas actuantes sobre Donantes de Grupo CH-CH/deficiencia , Errores Innatos del Metabolismo de los Aminoácidos/diagnóstico , Bases de Datos Factuales , Medicina Basada en la Evidencia , Glutaril-CoA Deshidrogenasa , Guías como Asunto , Humanos , Monitoreo FisiológicoRESUMEN
We report the results of tetrahydrobiopterin (BH4) loading tests in 10 German patients with mild phenylketonuria. A significant decline of phenylalanine values after application of BH4 was observed in all but one patients. Molecular genetic analyses revealed a range of different PAH gene mutations. Re-testing of one patient previously reported as non-responsive to BH4 loading showed a moderate response with a higher dose of BH4. Nevertheless, there appear to be kinetic differences in phenylalanine hydroxylation in patients with the same genotype. Non-responsiveness to 20 mg/kg BH4 was observed only in a single patient who was compound heterozygous for the novel mutation R176P (c.527G>C) and the common null-mutation P281L. In summary, our data are in line with recent reports indicating that BH4 sensitivity is a normal feature of most mild forms of PAH deficiency but may be influenced by other factors.
Asunto(s)
Biopterinas/análogos & derivados , Biopterinas/metabolismo , Fenilalanina Hidroxilasa/deficiencia , Fenilcetonurias/enzimología , Administración Oral , Sustitución de Aminoácidos/genética , Sustitución de Aminoácidos/fisiología , Biopterinas/administración & dosificación , Niño , Esquema de Medicación , Humanos , Lactante , Recién Nacido , Mutación Missense/genética , Tamizaje Neonatal , Fenilalanina/sangre , Fenilalanina Hidroxilasa/fisiología , Fenilcetonurias/sangre , Fenilcetonurias/metabolismoRESUMEN
Recently, BH(4)-responsive phenylalanine hydroxylase (PAH) deficiency was reported in patients with specific mutations in the PAH gene, and it was suggested that BH(4) responsiveness may be determined by the respective genotypes. We now report on three patients with PAH deficiency and the same genotype but different responses to standardized BH(4) loading. Our results suggest that BH(4) responsiveness in PAH deficiency is at least partly independent from PAH genotype.
Asunto(s)
Biopterinas/administración & dosificación , Fenilalanina Hidroxilasa/genética , Fenilcetonurias/genética , Sustitución de Aminoácidos , Biopterinas/análogos & derivados , Genotipo , Heterocigoto , Humanos , Recién Nacido , Mutación , Fenilalanina/sangre , Fenilalanina/efectos de los fármacos , Fenilalanina Hidroxilasa/deficiencia , Fenilcetonurias/enzimología , Pterinas/orinaRESUMEN
UNLABELLED: Phenylketonuria treatment policies vary not only between different countries worldwide, but also within one country. Recommendations and guidelines for phenylketonuria should deal with the following subjects: 1. What is the target age to start dietary phenylalanine restriction under newborn-screening conditions? 2. At which plasma phenylalanine concentration should phenylalanine restriction be initiated? 3. Which are the recommended plasma phenylalanine concentrations at different ages? 4. What is the recommended frequency of monitoring phenylalanine in plasma? Statements from the following countries are presented: Czech Republic, Denmark, France, Germany, Great Britain, Hungary, Ireland, Poland, Slovakia and the United States. CONCLUSION: Due to the lack of internationally accepted guidelines, management of phenylketonuria still varies between different countries. Our efforts should focus on the formulation of internationally acceptable and accepted recommendations for the treatment of patients with phenylketonuria at different ages.
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Fenilcetonurias/dietoterapia , Guías de Práctica Clínica como Asunto , Adolescente , Adulto , Envejecimiento/sangre , Niño , Preescolar , Recolección de Datos , Europa (Continente) , Humanos , Lactante , Recién Nacido , Fenilalanina/administración & dosificación , Fenilalanina/sangre , Fenilcetonurias/sangre , Factores de Tiempo , Estados UnidosRESUMEN
UNLABELLED: Designs, analyses and results of longitudinal studies of intelligence of patients treated early for phenylketonuria (PKU) are reviewed. All studies converge on the conclusion that after the age of 10 years, IQ development is stable for different degrees of dietary relaxation. On average, for each 300 mumol/l increase in blood phenylalanine (Phe) levels pre-school, IQ decreases by about half a standard deviation. Children with Phe levels below 400 mumol/l in early and middle childhood had the best outcomes which were near normal. PKU seems to suppress the global level of IQ without impairment of domain-specific competencies. For historical reasons there is no research on IQ development of early treated patients in middle or late adulthood, and it remains unclear whether older age groups might carry new risks. CONCLUSION: It is argued that control group designs, meta-analysis, and interdisciplinary studies combining psychology, neurology and neuropathology could increase the understanding of phenylketonuria as well as the scientific basis of its treatment.
Asunto(s)
Desarrollo Infantil , Inteligencia , Fenilcetonurias/psicología , Psicología Infantil , Adulto , Niño , Preescolar , Alemania , Humanos , Lactante , Fenilcetonurias/dietoterapia , Investigación , Factores de Tiempo , Reino Unido , Estados UnidosRESUMEN
UNLABELLED: Treatment of hyperphenylalaninaemias due to phenylalanine hydroxylase deficiency with a low phenylalanine (Phe) diet is highly successful in preventing neurological impairment and mental retardation. There is consensus that, for an optimal outcome, treatment should start as early as possible, and that strict blood Phe level control is of primary importance during the first years of life, but for adolescent and adult patients international treatment recommendations show a great variability. A working party of the German Working Group for Metabolic Diseases has evaluated research results on IQ data, speech development, behavioural problems, educational progress, neuropsychological results, electroencephalography, magnetic resonance imaging, and clinical neurology. Based on the actual knowledge, recommendations were formulated with regard to indication of treatment, differential diagnosis, and Phe level control during different age periods. The development of the early-and-strictly-treated patient in middle and late adulthood still remains to be investigated. Therefore, the recommendations should be regarded as provisional and subject to future research. Efficient treatment of phenylketonuria has to go beyond recommendations for blood Phe level control and must include adequate dietary training, medical as well as psychological counselling of the patient and his family, and a protocol for monitoring outcome. CONCLUSIONS: Early-and-strictly-treated patients with phenylketonuria show an almost normal development. During the first 10 years treatment should aim at blood Phenylalanine levels between 40 and 240 micromol/L. After the age of 10, blood phenylalanine level control can be gradually relaxed. For reasons of possible unknown late sequelae, all patients should be followed up life-long.
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Fenilalanina/sangre , Fenilcetonurias/prevención & control , Guías de Práctica Clínica como Asunto , Adolescente , Adulto , Evaluación Educacional , Electroencefalografía , Pruebas Genéticas , Alemania , Humanos , Pruebas de Inteligencia , Imagen por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Trastornos Mentales , Pruebas Neuropsicológicas , Fenilcetonurias/diagnóstico , Fenilcetonurias/terapia , Habla , Tomografía Computarizada de EmisiónRESUMEN
Phenylketonuria (PKU) and mild hyperphenylalaninemia (MHP) are allelic disorders caused by mutations in the gene encoding phenylalanine hydroxylase (PAH). Previous studies have suggested that the highly variable metabolic phenotypes of PAH deficiency correlate with PAH genotypes. We identified both causative mutations in 686 patients from seven European centers. On the basis of the phenotypic characteristics of 297 functionally hemizygous patients, 105 of the mutations were assigned to one of four arbitrary phenotype categories. We proposed and tested a simple model for correlation between genotype and phenotypic outcome. The observed phenotype matched the predicted phenotype in 79% of the cases, and in only 5 of 184 patients was the observed phenotype more than one category away from that expected. Among the seven contributing centers, the proportion of patients for whom the observed phenotype did not match the predicted phenotype was 4%-23% (P<.0001), suggesting that differences in methods used for mutation detection or phenotype classification may account for a considerable proportion of genotype-phenotype inconsistencies. Our data indicate that the PAH-mutation genotype is the main determinant of metabolic phenotype in most patients with PAH deficiency. In the present study, the classification of 105 PAH mutations may allow the prediction of the biochemical phenotype in >10,000 genotypes, which may be useful for the management of hyperphenylalaninemia in newborns.
Asunto(s)
Fenilalanina Hidroxilasa/genética , Alelos , Europa (Continente) , Genotipo , Humanos , Mutación/genética , Fenotipo , Fenilalanina/sangre , Fenilalanina Hidroxilasa/deficiencia , Fenilcetonurias/epidemiología , Fenilcetonurias/genéticaRESUMEN
Twenty-two French patients with early treated phenylketonuria (PKU) off diet (no reduced phenylalanine, Phe) since their 5th birthday, 23 German patients on diet (reduced Phe), and 21 healthy control subjects from childhood to adulthood matched for age, sex, and IQ were investigated for visuomotor reaction time, sustained attention, and visual stimulus scanning. Determinations were made whether 1) the three groups showed different developmental trends in their reaction times, 2) the threshold of a Phe blood level of 360 mumol/L formulated in recent recommendations can be regarded as safe, 3) test performances are related to the quality of dietary control in the same way for all age groups, and 4) long-term elevated Phe levels result in aggravating effects of increasing differences between patients on and off diet and healthy controls. Results revealed that developmental trends were similar in all treatment groups. Only children with a mean Phe level below 360 mumol/L performed as well as control subjects. Differences between treatment groups decreased in adulthood, and no aggravating effect could be observed. Mean performance of patients with mild PKU off diet was in the same range as performance of patients with classical or mild PKU on diet, calling into question the benefit of treating these patients. It is concluded that it is preferably safer to maintain Phe blood levels below 360 mumol/L at least during the first 10 y of life.