Psychomotor retardation and intermitent convulsions for 8 months in an infant / 中国当代儿科杂志

This study reports a boy with psychomotor retardation and epilepsy due to maternal phenylketonuria (PKU). The boy was admitted at the age of 20 months because of psychomotor retardation and epilepsy. He had seizures from the age of 1 year. His development quotient was 43. He presented with microcephaly, normal skin and hair color. Brain MRI scan showed mild cerebral white matter demyelination, broadening bilateral lateral ventricle and foramen magnum stricture. Chromosome karyotype, urine organic acids, blood amino acids and acylcarnitines were normal. His mother had mental retardation from her childhood. She presented with learning difficulties and yellow hair. Her premarriage health examinations were normal. She married a healthy man at age of 26 years. When she visited us at 28 years old, PKU was found by markedly elevated blood phenylalanine (916.54 μmol/L vs normal range 20-120 μmol/L). On her phenylalanine hydroxylase (PAH) gene, a homozygous mutations c.611A>G (p.Y204C) was identified, which confirmed the diagnosis of PAH-deficient PKU. Her child carries a heterozygous mutation c.611A>G with normal blood phenylalanine. Her husband had no any mutation on PAH. It is concluded that family investigation is very important for the etiological diagnosis of the children with mental retardation and epilepsy. Carefully clinical and metabolic survey should be performed for the parents with mental problems to identify parental diseases-associated child brain damage, such as maternal PKU.

Síndrome de fenilquetonuria materna, un nuevo desafío para Chile / Maternal phenylketonuria syndrome, a new challenge for Chile

Phenylquetonuria (PKU) is a hereditary disease, caused by the deficiency or absence of the enzyme phenylalanine hydroxylase, which produces an abnormal conversion of phenylalanine (Phe) to tyrosine. If PKU is not diagnosed and treated during the neonatal period, blood accumulation of Phe causes neurological damage. Chile has a neonatal screening program for PKU and congenital hypothyroidism since 1992; this program has diagnosed 162 PKU patients in Chile, which are being followed-up in INTA, Universidad de Chile. Nowadays, there are 20 PKU patients in adolescence, so we face a new challenge such as maternal PKU syndrome. This syndrome refers to the teratogenic effect of Phe in a pregnant PKU female. The most frequent anomalies are intrauterine growth retardation, microcephaly, global development retardation and congenital heart defects. Their occurrence is directly related to maternal Phe during pregnancy. In order to assure a normal pregnancy and to prevent this syndrome, levels of Phe in blood should be kept between 2 and 6 mgldl prior to conception and throughout pregnancy. Considering this challenge, INTA has proposed a strict protocol of follow-up to improve the compliance to nutritional therapy and prevent maternal PKU syndrome.

La fenilquetonuria (PKU) es una patología hereditaria, producida por la deficiencia o ausencia de la enzima fenilalanina hidroxilasa, lo que impide la metabolización normal de la fenilalanina (FA) a tirosina. La acumulación de fenilalanina en la sangre ocasiona daño neurológico si no es diagnosticada y tratada desde el periodo neonatal. Desde 1992 Chile tiene un programa de pesquisa neonatal de PKU e hipotiroidismo congénito, lo que ha permitido diagnosticar 162 casos con PKU, los que mantienen un seguimiento integral en el INTA, de la Universidad de Chile. Actualmente hay 20 PKU en etapa de adolescencia, por lo que nos enfrentamos a un nuevo desafío, el síndrome de PKU materna. Este síndrome se refiere al efecto teratogénico de la FA en una embarazada con PKU. Las alteraciones más características son el retraso del crecimiento intrauterino, la microcefalia, el retraso global del desarrollo y los defectos cardiacos congénitos. La presencia de estas alteraciones está directamente relacionada con los niveles de FA de la madre durante el embarazo. Para asegurar un embarazo normal y prevenir este síndrome se recomienda la mantención de niveles de FA entre 2 y 6 mg/dl, desde el período preconcepcional y durante todo el embarazo. El INTA considerando este desafío, ha propuesto un protocolo de seguimiento estricto preconcepcional y durante el embarazo con el objetivo de favorecer la adherencia al tratamiento nutricional y prevenir el síndrome de PKU materna.

Enzymatic preparation of low-phenylalanine Formula derived from skim milk hydrolysate for phenyl ketonuric patients

Phenylketonuria [PKU] is one of the most common inborn errors of amino acids metabolism. WHO guidelines introduced in 1979 and revised 1988 for breast-feeding infants with PKU included a formula containing low amounts of phenylalanine as a part of dietary prescription. Mental retardation can be prevented if PKU is diagnosed in the 1 st three weeks of life and diet therapy started straightaway throughout life and especially in the hyper phenylalaninemic mothers before conception and during pregnancy. The aim of the present study was to synthesize a low-phenylalanine formula suitable to be taken by PKU children, adolescents and the hyperphenylalaninemic mothers. This formula should be of high biological value, taken safely by those patients and to be of low cost. The formula was prepared from skim milk hydrolysate using two proteolytic enzymes. The first was the immobilized purified papain enzyme and the second was the modified protease XXIII prepared from Aspergillus oryzae. The skim milk hydrolysate was adsorbed on barium sulphate or activated carbon for removing phenylalanine. They were applied separately for the purpose of debittering and nutritional value comparison. This skim milk hydrolysate had been supplemented with the amino acids tryptophan, tyrosine, methionine and valine. Beside the comprehensive amino acids analysis [Especially for the free amino acids], this formula was then analyzed for protein, fat, lactose and ash contents as well as microbiological and biological testing on mice. Hyperphenylalaninemia was induced in BALB/c mice model then changes in blood phenylalanine level and weight were scored during the periods of mutagenesis as well as the treatment period compared with the control group. The amino acids analysis showed that phenylalanine was 0.71gm/100 gram protein in the skim milk hydrolysate compared to 3.26gm amino acid/100 gram protein in the skim milk. The level of free phenylalanine decreased from 6.34% [In the skim milk] to 0% after adsorption to barium sulphate and compared to 3.41% after adsorption to activated carbon. The formula adsorbed on barium sulphate, although it is more preserving to the nutritional composition; yet, it is less effective in the debittering effect than that adsorbed on activated carbon. This formula, in addition to being of high nutritional value, it is not expensive since it is obtained from skim milk hydrolysate. From the present study, it could be concluded that: The synthesized low-phenylalanine formula was effective in supplying most of the needed dietary intakes for conditions of hyperphenylalaninemia. The use of the immobilized purified Papain and modified protease XXIII from Aspergillus oryzae in enzymatic hydrolysis of skim milk has been proved to be effective in hydrolysis and emulsification

A case of two sisters births from mother with phenylketonuria lacking mental retardation / 소아과

In this untreated classic phenylketonuria (PKU) case, mental retardation is severe; however, there have been individuals-like the mother of this case who have escaped mental retardation and all the other potential sequelae of phenylketonuria, despite having high blood phenylalanine levels, and very poor dietary control. It appears that they have nearly normal brain phenylalanine levels despite high blood phenylalanine (Phe) levels. A number of studies have now demonstrated considerable variability in blood vs. brain phenylalanine levels in phenylketonuria patients. Outcome of phenylketonuria appears to be related to brain phenylalanine levels. We report a case of "undiagnosed" maternal phenylketonuria syndrome. A female infant had low birth weight (2,400 g) with microcephaly. We examined her family and discovered that her mother was an undiagnosed phenylketonuria patient with a borderline intelligence quotient (IQ). The infant's sister, six years old, was diagnosed with phenylketonuria at the age of four years was mentally retarded and had received an operation for cleft lip and palate. the sister had also had a low birth weight (2,300 g). Her sister and mother were compound heterozygotes (mother: R243Q/Y325X; sister: Y325X/P407S). The infant and father were heterozygous carriers (baby: R243Q/-; father: P407S/-).

Fenilcetonúria materna: relato de caso / Maternal phenylketonuria: a case report

A fenilcetonúria materna é uma aminoacidopatia caracterizada por níveis elevados de fenilalanina plasmática na gestante, o que pode provocar anormalidades no desenvolvimento do feto, condição que se denomina síndrome de fenilcetonúria materna. Deve ser diagnosticada laboratorialmente, uma vez que as manifestações clínicas são inespecíficas. Relatamos um caso de paciente secundigesta, com antecedente pessoal de retardo do desenvolvimento cognitivo, sem antecedentes patológicos obstétricos, com diagnóstico laboratorial de hiperfenilalaninemia na atual gestação, sendo tratada com dieta específica. O recém-nato, nascido a termo, não apresentou alterações físicas ou defeitos congênitos confirmados. A gestação anterior, na qual não houve diagnóstico e controle da fenilcetonúria, resultou em criança com séria deficiência psicomotora confirmada, além de microcefalia e distúrbios auditivos e da fala. Com o conhecimento dos efeitos da hiperfenilalaninemia materna sobre o feto, tornam-se essenciais o diagnóstico e a instituição precoce do tratamento durante a gravidez em pacientes com suspeita clínica de fenilcetonúria. No caso aqui descrito, houve benefícios materno-fetais do tratamento dietoterápico oferecido, reforçando a importância da identificação de mulheres fenilcetonúricas em idade reprodutiva.

Síndrome de fenilcetonuria materna / Maternal phenylketonuria syndrome

El síndrome de fenilcetonuria materna es una embriopatía que ocurre en hijos de madres fenilalaninémicas que no han recibido tratamiento dietético adecuado preconcepcional ni durante la gestación. El presente articulo expone la semiología, fisiopatología de este síndrome y posibles mecanismos del daño intraútero que provoca. Define las mujeres en riesgo y explica la conducta a seguir con ellas para prevenir la ocurrencia de embriopatía por fenilcetonuria materna en la descendencia. Se enfatiza en el estricto control metabólico desde que la futura madre planifica su gestación y durante todo el embarazo como única opción terapéutica eficaz. Se reafirma el papel protagónico de la atención primaria de salud en la prevención de la embriopatía por fenilcetonuria materna. Las fenilcetonúricas que arriban a la edad reproductiva deben ser clasificadas de riesgo preconcepcional y recibir una amplia información que les permita reconocer las probabilidades que tiene de desarrollar una embriopatía, planificar adecuadamente su embarazo y asumir la necesidad de llevar una dieta restrictiva. Se deben buscar activamente las hiperfenilalaninémicas benignas para que previa dispensarización reciban seguimiento bioquímico y del neurodesarrollo, con énfasis en las hembras que alcanzan la edad reproductiva

Enfermedades heredometabólicas y embarazo / Hereditary metabolic diseases and pregnancy

El contar con la posibilidad diagnóstica y tratamiento efectivo para algunas variantes de enfermedades heredometabólicas ha propiciado el reconocimiento de una importante población femenina adulta portadora de ellas. Existe una importante relación entre varias enfermedades heredometabólicas y el deseo de un embarazo que debe tenerse en cuenta durante la atención prenatal y perinatal. En este artículo se realizó una revisión de las enfermedades heredometabólicas y sus consecuencias sobre el embarazo y su producto. Se resaltó la posibilidad de diagnóstico prenatal ecográfico de malformaciones fetales que hacen sospechar el diagnóstico en este período, así como la posibilidad de algunas enfermedades heredometabólicas de ser tratadas prenatalmente. Se alertó de las graves complicaciones que sobre la gestación y el puerperio (síndrome HELLP) producen algunas enfermedades heredometabólicas del feto. Se sugirió que mujeres portadoras de ciertas enfermedades heredometabólicas como la homocistinuria y la fenilcetonuria, sean aconsejadas del riesgo incrementado de complicaciones de la gestación y del daño fetal intraútero que produce su enfermedad. Especial relevancia se le ofreció a la fenilcetonuria, en la cual con un tratamiento dietético restrictivo preconcepcional y durante la gestación se logra prevenir la embriofetopatía característica de esta entidad

Medición de TSH, T4 y Phe en muestras de sangre del cordón umbilical en papel de filtro: impacto en el tamizaje neonatal / Measurements of TSH, T4 and Phe in samples of umbilical cord blood on filter paper: impact on neonatal screening

En este momento existe consenso en que el hipotiroidismo congénito y la fenilcetonuria constituyen modelos teóricos prácticos ideales en el tamizaje neonatal. La tendencia actual en el mundo es la salida temprana de las maternidades debido a razones socioeconómicas, lo cual guía, sin duda, a la implementación de estos programas en sangre del cordón umbilical. Se evaluaron los niveles de T4 total, TSH y Phe en muestras de sangre del cordón umbilical de 458 recién nacidos, colectadas en papel de filtro S&S 2992, utilizando ultramicroensayos fluorescentes. La distribución de frecuencias para las concentraciones de TSH mostró un valor medio de 1,7 mUl/l; el 98 por ciento de las muestras tuvieron concentraciones en el rango de 0-10 mUl/l, el 1,7 por ciento entre 10-20 mUl/l y una muestra con valor mayor de 20 mUl/l; para T4 el valor medio de concentración fue de 177,2 nmol/l; el 90,2 por ciento tuvo valores entre 116-370 nmol/l, el 9,6 por ciento entre 60-116 nmol/l y una muestra con un valor menor de 60 nmol/l. Para Phe, el valor promedio fue de 4,6 µmol/l (0,7mg/dl), el 80,3 por ciento entre 0-60 µmol/l (0-1 mg/dl), el 19,2 por ciento entre 60-120 µmol/l (1-2 mg/dl) y 2 muestras con valor mayor de 120 µmol/l ( 2 mg/dl). Los resultados obtenidos demuestran que es factible el empleo de muestras en sangre del cordón para el diagnóstico precoz de hipotiroidismo congénito, no así en el caso de la Phe donde los niveles detectados fueron muy bajos por lo que no garantiza total efectividad en el diagnóstico de fenilcetonuria

Importância do diagnóstico e tratamento da fenilcetonúria / Diagnoses and treatment of phenylketonuria

A fenilcetonúria (PKU) é o mais comum dos erros congênitos do metabolismo de aminoácidos. Resulta da deficiência da fenilalanina hidroxilase, enzima que catalisa a conversäo de fenilalanina em tirosina. A introduçäo de uma dieta com baixo teor de fenilalanina deve ter início nos primeiros meses de vida, de preferência no primeiro mês, para evitar o retardo mental, manifestaçäo clínica mais severa da doença. Foi elaborada revisäo sobre essa temática, que aborda desde a PKU clássica até a hiperfenilalaninemia branda, incluindo relato sobre a PKU maternal e os efeitos da exposiçäo do útero a altos níveis de fenilalanina sobre o feto