Evaluación del estado de salud en pacientes con fenilcetonuria / Assessment of the health status of patients with phenylketonuria

Introducción: la fenilcetonuria es el más conocido de todos los errores congénitos del metabolismo. Su detección precoz y una dieta baja en fenilalanina pueden prevenir el retraso mental en los pacientes. Objetivo: evaluar el impacto del programa de prevención precoz de fenilcetonuria en la provincia de Holguín, en el periodo de enero de 1986 a octubre de 2012. Métodos: se realizó un estudio descriptivo retrospectivo en los niños atendidos en la consulta de fenilcetonuria del Hospital Pediátrico de Holguín. El universo estuvo constituido por los 12 pacientes con el diagnóstico de fenilcetonuria. La información se obtuvo a través de las historias clínicas. Se evaluó el control metabólico mediante los valores de fenilalanina sérica registrados en las historias clínicas, el estado nutricional se valoró mediante las tasas de percentiles establecidas en Cuba y el coeficiente intelectual se analizó mediante test psicométricos. Resultados: el 66,6 por ciento(8 de los pacientes) presentó un control metabólico bueno, y 7 para un 58,3 por ciento un intelecto normal. De los pacientes diagnosticados antes de 1986, 3 presentan un retardo mental ligero (42,9 por ciento) y el 28,6 por ciento está incapacitado (2). El 100 por ciento de los diagnosticados por programa presentan un intelecto normal y 5 no presentan síntomas. Estudian 4 para un 80 por ciento. El 83,3 por ciento de los pacientes estudiados son eutróficos (10). Conclusiones: el programa de diagnóstico precoz ha permitido que el estado de salud de los pacientes fenilcetonúricos mejore en cuantía significativa, con una estabilidad en el control metabólico y una integración apreciable a la sociedad

Introduction: phenylketonuria is the most recognized congenital metabolic error. Its early detection and low phwnylalanine diet can prevent mental retardation in these patients. Objective: to evaluate the impact of the early phenylketonuria prevention program in Holguin province from January 1986 to October 2012. Methods: a retrospective descriptive study was made in children who were assisted at the phenylketonuria department of pediatric hospital in Holguin province. The universe of study was 12 patients diagnosed with phenylketonuria. The medical histories provided the necessary information. The metabolic control was evaluated through the serum phanylalanin figures recorded in the medical history, the nutritional status was assessed according to the percentile rates set in Cuba and the intellect coefficient was analyzed with psychometric tests. Results: in this group, 66.6 percent (8 patients) presented good metabolic control and 58.3 percent (7) showed normal intellect. Of the patients diagnosed with the disease before 1986, three (42.9 percent ) suffered mild mental retardation and two (28.6 percent) were disabled. All the patients diagnosed by this program showed normal intellect and 5 had no symptoms. Four were studying for 80 percent. Of the studied patients, 83.3 percent (10) were eutrophic. Conclusions: the early diagnosis program has allowed the significant improvement of the health status of the phenylketonuric patients, with stable metabolic control and noticeable integration to the society

Screening programme for phenylketonuria in the Gaza Strip: evaluation and recommendations.

Phenylketonruia (PKU) is an inherited metabolic disorder that results in progressive mental retardation. PKU is a paradigm of a disease that can be identified by proper screening of newborns and medical follow-up in order to prevent serious complications. The present study was designed to evaluate the Palestinian national screening programme for PKU in the Gaza Strip. Data about the screening of PKU in the Gaza Strip were obtained from the records of the healthcare centers of the Palestinian Ministry of Health (MOH) during the year 2000. In addition, PKU patients and families were interviewed. The results showed that the prevalence of PKU in the Gaza Strip varied considerably between the different regions with an overall prevalence of 6.35/100,000, while the maximum prevalence of 28.3/100,000 occurred in the rural areas. Coverage of PKU testing in the Gaza Strip is limited to about 35.3 per cent of the total newborns, who are delivered and receive health care at the government clinics. Among those newborns delivered at the government clinics, the percentage of PKU screening is about 87.8 per cent. However, PKU testing is not carried out at UNRWA clinics where about two-thirds of newborn deliveries take place. On average, 61 per cent of PKU testing is made in the infant's second week, ranging between 11 and 17 days, and the remaining (39 per cent) are tested thereafter. Approximately 60 per cent of PKU patients had consanguine parents (first cousins), while 7.7 per cent had no consanguinity. Only 43.1 per cent of PKU patients were fed on the specialized low phenylalanine milk. An inverse correlation was reported between the use of low phenylalanine milk and age. A total of 35.4 per cent of the PKU patients were regularly monitored by blood tests each month, 47.7 per cent had not been tested for the previous year. It was concluded that the PKU screening programme has to be improved, the screening methods should be reviewed, and the screening coverage should include all the newborns in the Gaza Strip.

Dietoterapia en errores innatos del metabolismo / Nutritional treatment of inborn errors of metabolism

Dependiendo del defecto enzimático, algunos errores innatos del metabolismo (EIM) responden satisfactoriamente a la manipulación de la dieta. Según la alteración metabólica, se han identificado siete formas de tratamiento nutricional, las que permiten reestablecer el balance metabólico. Una de ellas es a través de la reducción del sustrato acumulado causado por la deficiencia primaria de una enzima o por la inhibición secundaria de una de ellas. Un ejemplo ampliamente descrito en la literatura es la fenilquetonuria en la que se ha demostrado que gracias al diagnóstico neonatal temprano, seguido de un tratamiento basado en una dieta restringida en fenilalanina revierten su acumulación previniendo con ello el da¤o neurológico que la enfermedad causa al no ser tratada temprana y adecuadamente. Otra forma de tratamiento es la suplementación de una sustancia nutritiva en déficit debido al defecto metabólico, como ocurre en los defectos del ciclo de la urea, en los cuales donde la arginina debe entregarse como fármaco. Algunos EIM con defecto parcial de la enzima tienen la posibilidad de estimular vías alternas para detoxificar o evitar la síntesis de sustancias nocivas a través drogas o megadosis de vitaminas, un ejemplo es la homocistinuria donde la betaína y piridoxina reducen la producción de homocisteína. Otros defectos enzimáticos abren vías metabólicas alternas, las que generan metabolitos tóxicos, el tratamiento en estos casos, consiste en proporcionar cofactores o megadosis de vitaminas para formar complejos no tóxicos que sean excretados por vía urinaria. Es importante se¤alar que el diagnóstico precoz y el seguimiento estricto a largo plazo, permite que un ni¤o con un EIM se desarrolle normalmente.

Avaliação do programa de prevenção e promoção da saúde de fenilcetonúricos / Evaluation of the program for prevention and health promotion in phenylketonuria patients in Brazil

OBJETIVO: Avaliar os resultados de ações preventivas e de promoção à saúde institucionalizadas para crianças fenilcetonúricas. MÉTODOS: Foram avaliados os resultados alcançados pelo Programa de Triagem Neonatal, do Estado do Paraná, entre os fenilcetonúricos, no período de 1996 a 2001. Foram investigados dados socioeconômicos e aplicado instrumento de medição da função motora grossa para determinar as habilidades motoras de 32 crianças fenilcetonúricas com diagnóstico e tratamento precoces. Optou-se pela utilização do coeficiente de correlação de Pearson para verificar a relação entre a variável de interesse (escore motor) e as demais variáveis quantitativas (nível médio de fenilalanina pós-tratamento, escolaridade do pai e da mãe, idade da criança no início do tratamento e renda familiar). RESULTADOS: Dentre as crianças avaliadas, 93,7 por cento apresentaram desenvolvimento de acordo com os parâmetros de normalidade referenciados na literatura. O tratamento foi iniciado no primeiro mês em 71,9 por cento dos casos de fenilcetonúria. A pesquisa socioeconômica registrou 39,5 por cento de pais com instrução até o quarto ano escolar. Foi encontrada correlação significativa entre o escore motor da criança e a escolaridade dos pais (N=32), e entre o escore motor e a precocidade do tratamento (N=27). CONCLUSÕES: Os resultados evidenciaram a alta efetividade do programa avaliado. A baixa escolaridade dos pais e sua relação com o escore motor ressaltam a importância do apoio aos pais na dietoterapia. A relação encontrada entre o escore motor e o início do tratamento confirma a necessidade da adesão imediata ao programa. A inexistência na literatura de outros estudos de avaliação dificulta a generalização dos resultados.

[An eighteen-year study on phenylketonuria].

A study on phenylketonuria (PKU) has been carried out in China-Japan Friendship Hospital since 1984. The results revealed that: (1) Totally 603 patients with PKU were diagnosed and treated in the hospital from October 1984 to September 2002. Among which 136 cases were identified by neonatal screening and treated within 3 months. One hundred and ninety-five cases were treated when the children were 3-12 months of age. Another 272 PKU children were diagnosed when they were more than 1 year old. All of these late-treated cases had some signs and symptoms of PKU. Mental retardation was found in 467 cases and various patterns of seizures in 119 cases. After treatment with low-phenylalanine diet, the follow-up for early-treated patients revealed that their physical and mental developments were normal. In late-treated patients, abnormal behaviour was significantly improved and their developmental quotient were elevated. Prenatal gene diagnosis of PKU risk foetus in 22 PKU families was successfully performed. (2) Urinary pterins obtained from 369 HPA patients were measured by HPLC. Twenty two patients with BH4 deficiency have been recognized. Six single base mutations were detected in 18 unrelated northern Chinese BH4 deficiency families, and the mutations at nucleotides 259C-->T and 286G-->A were common mutations. Eighteen BH4 deficient patients were treated with BH4, L-dopa and 5-hydroxytryptophan, and the results were satisfactory. (3) The abnormal rate of EEG was high in untreated patients with PKU, mainly showing epileptiform discharges and partly showing background activity abnormality. The most frequent finding was patchy areas of increased signal intensity in white matter on MRI in the brain of PKU patients, while delayed myelination and brain agenesis were often detected. After dietary treatment, follow-ups with EEG and MRI revealed that the abnormalities were decreased significantly. (4) The relationship between genotype and intellectual phenotype was examined in 29 late-treated patients with classical PKU. It was found that the genotype of 22 patients were compatible with intellectual phenotype and not well matched in 7 cases. The result indicate that the genotype was well matched with intellectual phenotype in classical PKU patients.

Newborn PKU screening in Turkey: at present and organization for future.

At present, pkenylketonuria screening is a national child health program in Turkey which is carried out collaboratively by the Ministry of Health and three University Children's Hospitals in Ankara, Istanbul and Izmir. Since 1986 the number of cities included in the screening program has gradually increased, now and it covers all the metropolises the country. A total of 383 babies were found with persistent hyperphenylalaninemia (1:4,172) among 1,605,582 babies screened by the Guthrie test at the Hacettepe Screening Center in Ankara. By taking into account pretreatment phenylalanine levels and phenlyalanine tolerances at five years of age, the numbers of classical and mild-moderate phenylketonuria and mild hyperphenylalaninemia cases were 216, 102 and 58, respectively. The major problems encountered in the screening program and in management of the detected cases were unsatisfactory sample collection, early discharge from maternity hospitals, difficulties in reaching some detected cases, and noncompliance with dietary therapy due to illiterate parents or to lack of social insurance. To screen and treat all newborns for phenylketonuria and to include at least hypothyroidism in the screening program, there is a need for a more disciplinary intersectoral approach than exists at present.

Prepregnancy testing for single-gene disorders by polar body analysis.

Preventive measures for single-gene disorders are currently based on carrier screening in pregnancy and prenatal diagnosis. Although this has been extremely effective for preventing new cases of common inherited conditions, the major limitation is still termination of 25% of wanted pregnancies following detection of affected fetuses. To overcome this important problem, we developed a method for prepregnancy genetic testing that involves DNA analysis of the first and second polar bodies, which are extruded during maturation and fertilization of oocytes. We offered this option to 28 couples at risk for having children with single-gene disorders. Fifty clinical cycles were performed from these patients for the following conditions: 20 for cystic fibrosis, 18 for thalassemia, 6 for sickle cell disease, 2 each for Gaucher disease and LCHAD (long-chain 3-hydroxyacyl-COA dehydrogenase deficiency), and 1 each for hemophilia B and phenylketonuria. Oocytes obtained from these patients using in vitro fertilization procedures (IVF) were tested by a sequential multiplex nested PCR analysis of the first and second polar body to detect the gene involved simultaneously with linked polymorphic markers. A total of 191 of 399 oocytes with predicted genotype were mutation free and preselected for fertilization and transfer. In all but three cycles, one to three unaffected embryos with predicted unaffected genotypes were transferred, resulting in 20 pregnancies, from which 19 healthy children have been born. The follow-up analysis of embryos resulting from oocytes with predicted affected genotype, confirmed the diagnosis in 97% of cases, demonstrating the reliability of prepregnancy diagnosis of single-gene defects by polar body analysis.

[Programs of systematic screening in neonatology. Pharmaco-economic aspects]. / Les programmes de dépistage systématique en néonatologie. Aspects pharmaco-économiques.

Systematic neonatal screening offers many advantages for the patients, its family and the community. The Genetic center of the University Hospital of Liège provides neonatal screening for the following diseases: phenylketonuria, congenital hypothyroidy, cystic fibrosis, alpha-1-antitrypsin, adrenal hyperplasia and biotinidase deficiency. On economical grounds, it is clear that the organisation of neonatal screening costs less to the community than the cost of the disease if diagnosis is made too late as to allow an alleviation, or even a total recovery, of the symptomatology.

Neonatal screening: current trends and quality control in the United Kingdom.

Neonatal screening for phenylketonuria (PKU) and congenital hypothyroidism (CHT) is universal across the UK using heel prick blood collected at 6-14 days of age. Additional programmes for sickle cell disorders, cystic fibrosis, Duchenne muscular dystrophy and galactosaemia are provided in some areas. The number of inherited metabolic disorders (IMDs) has greatly increased since the introduction of PKU screening, and there have been major advances in treatment, e.g. organ transplantation, drug therapy. Recent developments in technology have expanded the possibilities for screening using the heel prick blood specimen, particularly the application of tandem mass spectrometry. There is a case for introducing tandem mass spectrometry, limited to clearly defined diseases where specificity is adequate and there are satisfactory diagnostic tests. Any change in newborn screening to a much broader group of disorders must be carefully introduced and monitored preferably as a pilot study. A key component of a laboratory screening service is quality control. There are well established UK programmes for PKU and CHT. Consideration of the needs for other disorders is now an important priority.

[The routine sampling procedure for PKU should be changed. Venous puncture is less painful than heel lancing]. / Praxis vid PKU-provtagning bör ändras. Venpunktion gör mindre ont än hälstick.

All newborns in Sweden are screened for phenylketonuria (PKU), among other things, blood usually being sampled by heel lancing. Because it is unnecessarily painful, however, this form of sampling in newborns has recently been questioned. There is reason to recommend sampling from a dorsal hand vein as the method of choice for PKU screening purposes.

[Maternal hyperphenylalaninemia in a population of healty Czech women. 18 years' experience with mass screening, diet therapy and metabolic monitoring]. / Materské hyperfenylalaninémie v ceské populaci zdravých tehotných zen. 18leté zkusenosti s fakultativním screeningem, dietní lécbou a metabolickým sledováním.

BACKGROUND: Elevated phenylalanine levels in maternal blood (hyperphenylalaninaemia) during pregnancy damages the developing foetal tissues. Early detection of pregnant women with hyperphenylalaninaemia and adherence to a low phenylalanine diet already before conception and throughout pregnancy can prevent this damage. The objective of the investigation are results achieved screening and strict monitoring of low phenylalanine dietetic treatment in detected pregnant women of the Prague population. METHODS AND RESULTS: 186 350 healthy women of the Prague population were examined by the chromatographic screening test in a venous blood sample during their first visit in a maternity welfare centre and 22 positive cases were detected (incidence 1:8470). In 86% mild, persistent or benign forms of phenylketonuria were involved. Nineteen patients were treated by a low phenylalanine diet and the phenylalanine tolerance was monitored as well as the nitrogen balance, amino acids in serum and urine, protein markers, trace elements, vitamins, lipids, the body mass index-BMI, changes of body weight after introduction of the dietetic treatment and treatment during pregnancy. A significant increase of the phenylalanine tolerance by 20 to 200% was found, mostly in the second half of pregnancy and reduced values of serum and urinary selenium. The decrease of body weight when the diet was introduced and the increment during pregnancy correlated with the BMI value. In the other investigated parameters no significant deviations were found. CONCLUSION: Fifteen healthy children with normal psychomotor development delivered by 12 mothers with hyperphenylalaninaemia provide evidence of the effectiveness of prenatal screening for hyperphenylalaninaemia during pregnancy.

[20-year national screening for phenylketonuria in The Netherlands. National Guidance Commission PKU]. / Twintig jaar landelijke screening op fenylketonurie in Nederland. Landelijke Begeleidingscommissie PKU.

OBJECTIVE: Evaluation of the Dutch national screening programme for phenylketonuria (PKU). DESIGN: Descriptive. SETTING: Nationwide. METHODS: Data on the screening were obtained from the laboratories, from the registration offices of vaccination and screening results and from the paediatricians to whom infants with positive screening values were referred, during the period from September 1st, 1974 to December 31st, 1993. RESULTS: During the study period 3,481,738 infants were screened in the Netherlands (99.4% of all live births). The sensitivity of the programme was 98%, the specificity 99.99% and the positive predictive value 50%. The prevalence of PKU varied considerably between regions, e.g. from 1:33,600 in Zuid-Holland to 1:8,250 in Limburg (average in the Netherlands 1:18,000). The percentage of patients treated before the age of 22 days was 84% in the period from 1974 to 1988 and 95% in the period from 1989 to 1993 (p = 0.04). Birth weight in patients with PKU was 141 g (95% confidence interval: 66-216) less than the expected birth weight in the Netherlands. Furthermore, a slight growth retardation occurred in the first three years of life in early treated patients. The percentage of patients following special education was twice as high as in the general population (p < 0.001). CONCLUSION: The screening procedure for PKU is functioning at a high level. Despite early treatment development of patients with PKU is slightly below normal.

Nutritional therapy for pregnant women with a metabolic disorder.

Nutritional therapy is essential for a normal reproductive outcome in phenylketonuric women. In homocystinuria, fetal outcome is good in women whose disorder is responsive to vitamin B6 therapy and is poor in women whose disorder is unresponsive to therapy. Pregnancy in galactosemia is rare because of the almost universal ovarian dysfunction present in female patients with this disorder. Transplantation of the fertilized ovum is a promising possibility for these women. In women with MSUD, there has been only one case of pregnancy reported to date.

[Screening of newborn infants in Norway for severe metabolic disease]. / Screening av nyfødte i Norge for alvorlig metabolsk sykdom.

The objective of neonatal screening for phenylketonuria and congenital hypothyroidism is early diagnosis and initiation of treatment to prevent brain damage and mental retardation. We present the results of the Norwegian national neonatal screening programme for phenylketonuria and congenital hypothyroidism. Screening for phenylketonuria based on serum phenylalanine determinations started in 1967 and covered the whole country in 1978. National screening for congenital hypothyroidism started in 1979. One hundred children with phenylketonuria and 280 children with a strong indication of congenital hypothyroidism have been detected up to 1 October 1994. Screening-related challenges and principles of treatment are discussed.

[Neonatal screening for metabolic diseases--a task without priority in the Norwegian health policy?]. / Neonatal screening for metabolske sykdommer--en helsepolitisk uprioritert oppgave i Norge?

The Norwegian national screening programme for early diagnosis of phenylketonuria and congenital hypothyroidism was established in 1978-79. The organization and implementation of the programme is based on a marginal cost policy profile and has kept almost the same structure throughout the period of national neonatal screening. We focus on practical measures aimed at increasing the quality of the programme, and suggest a health political reconsideration of public preference and financial support for neonatal screening in Norway.

Responsabilidad médico-legal de los obstetras / Responsability medicolegal of obstetrician

Deberes y derechos de los obstetras. Sus responsabilidades: presupuestos, prueba, sujeto pasivo, eximentes. Situaciones particulares: embarazo, aborto, cesárea, esterilización. Apéndice legal: Ley 17132, Ley 23413, Ley 23674, Ley 24540, Código de Etica de la Confederación Médica Argentina