Strict Low-phenylalanine Diet Research Articles

Neurological manifestations in adults with phenylketonuria: new cases and review of the literature.

Phenylketonuria (PKU) is a rare autosomal recessive disease characterised by high plasma phenylalanine levels inducing, if untreated, serious neurological manifestations in children but also, rarely, in adults who stopped their diet. The objective of the study was to describe the neurological manifestations observed in adults with PKU. We analysed cases reported in French reference centres for inborn errors of metabolism and cases already reported in the literature. We report 8 new cases of neurological manifestations and 22 cases in the literature, which occurred in adult PKU patients, associated with chronic or rapid increase of phenylalanine levels, mostly when strict low-phenylalanine diet was stopped early in life. Neurological symptoms consisted in cerebellar ataxia, tremor, brisk reflexes, visual loss, sensory manifestations, and/or headaches. Visual loss was more frequent in the new cases (4/8) of the present series than in the literature (4/22). These neurological complications were associated with leucopathy on brain magnetic resonance imaging (27/29). The start of a low-phenylalanine diet improved or fully reversed neurological manifestations, even in patients with late diagnosis during adulthood. Neurological manifestations can complicate PKU in adult patients with elevated phenylalanine levels, after long or short period of diet discontinuation. Neurologists should be aware of this diagnosis, and measure phenylalaninemia in case of neurological symptoms associated with non-specific leucopathy on brain MRI. PKU patients should be systematically encouraged to continue their diet and their medical follow-up to avoid neurological complications.

Vitamin/mineral and micronutrient status in patients with classical phenylketonuria

Strict low-phenylalanine diet is associated with an increased risk of developing micronutrient deficiencies in patients with phenylketonuria (PKU). The primary objective of this single-center, case-control study was to assess the nutritional parameters of patients with PKU on strict low-phenylalanine diet without vitamin and mineral supplementation compared to a healthy control group. Secondary objective was to identify the adequacy of vitamin/mineral supplementation in phenylalanine-free (Phe-free) amino acid formulas. A total of 112 age- and sex-matched patients with PKU and 36 controls who did not take vitamin or mineral supplementation at least for the last 6 months were enrolled in the study. Biochemical and hematological markers including hemoglobin, serum vitamin B12, folic acid, iron, ferritin, transferrin saturation, copper, prealbumin, albumin, total protein, phosphorus, calcium, 25-hydroxy vitamin D, zinc, vitamin A and vitamin E levels were screened from fasting morning blood samples. One hundred and twelve patients with classical PKU (53 females, 47.3%) and 36 healthy controls (18 females, 50.0%) were enrolled in the study. The mean age of patients with PKU was 136.8±82.1 months (18-377). Median serum vitamin B12 level of patients with PKU was found to be higher than the control group (p=0.002). Vitamin B12 deficiency was 15.2% and 30.6% in patients with PKU and healthy controls, respectively (p=0.040). Mean serum folic acid level was higher in patients with PKU than the control group (p<0.0001). In 55.4% of patients with PKU, and 2.8% of the control group, serum folic acid level was above the reference range (p<0.0001). The frequency of ferritin and prealbumin values above the reference range was found to be higher in patients with PKU compared to the control group (44.4% vs 16.9%, p=0.001; 38.8% vs 22.1%, p=0.020, respectively). 25-Hydroxy vitamin D deficiency was detected in 53.6% and 47.2% of patients with PKU and the control group, respectively. Mean serum copper level was higher in the well-controlled (114.3±26.7μg/dL) group than the poorly controlled group (101.0±29.1μg/dL) (p=0.022). Phe-free amino acid formulas provide adequate vitamin A and zinc levels in patients with PKU, and result in excess folic acid, vitamin B12, copper and vitamin E values that are higher than required levels. Our results demonstrate a high percentage of vitamin D deficiency in patients with classical PKU and also in healthy controls in Turkey.

Phenylketonuria

Phenylketonuria remains one of the most common inborn errors in the United Kingdom. It is detected on the newborn heel-prick screening sample allowing early treatment with a strict low phenylalanine diet supplemented with artificial amino acids, and appropriate vitamin and minerals. Although the long-term prognosis is good, there is an increasing body of evidence highlighting subtle problems in neuropsychological function with slower reaction times and poorer executive function than peers. White matter changes clearly seen on brain magnetic resonance imaging may have some relationship to these neuropsychological difficulties but their significance is not clearly understood. The diet, although successful, is difficult to follow lifelong and with its attendant risks of nutritional deficiencies needs careful specialist management. In view of these challenges new treatments such as sapropterin (a tetrahydrobiopterin analogue) and large neutral amino acids are currently being used in phenylketonuria and a human trial has started using ammonia lyase as enzyme replacement therapy. Maternal phenylketonuria syndrome remains a risk for those who conceive whilst blood phenylalanine is elevated and females must be counselled early in childhood to avoid this risk.

La maladie de Hartnup est liée à des mutations du gène SLC6A19 qui code pour un transporteur d’acides aminés analogue de B”AT1

Phenylketonuria remains one of the most common inborn errors in the United Kingdom. It is detected on the newborn heel-prick screening sample allowing early treatment with a strict low phenylalanine diet supplemented with artificial amino acids, and appropriate vitamin and minerals. Although the long-term prognosis is good, there is an increasing body of evidence highlighting subtle problems in neuropsychological function with slower reaction times and poorer executive function than peers. White matter changes clearly seen on brain magnetic resonance imaging may have some relationship to these neuropsychological difficulties but their significance is not clearly understood. The diet, although successful, is difficult to follow lifelong and with its attendant risks of nutritional deficiencies needs careful specialist management. In view of these challenges new treatments such as sapropterin (a tetrahydrobiopterin analogue) and large neutral amino acids are currently being used in phenylketonuria and a human trial has started using ammonia lyase as enzyme replacement therapy. Maternal phenylketonuria syndrome remains a risk for those who conceive whilst blood phenylalanine is elevated and females must be counselled early in childhood to avoid this risk.

Abnormal feeding behaviours in phenylketonuria

The strict low phenylalanine diet used in the treatment of phenylketonuria (PKU) may adversely affect feeding behaviour and nutritional status in PKU children. The feeding behaviour of 15 unselected PKU children (12 girls, 3 boys) aged 1–5 years (mean age 3 years) was studied. Each child was matched with an unrelated age‐ and sex‐matched non‐PKU control child. All the PKU children were on a strict low phenylalanine diet. The mothers of all the children completed a validated feeding assessment questionnaire examining maternal perceptions of the incidence and type of feeding problems, feeding behaviour and parental management. A scored video recording of each child eating a midday meal was made, and mothers recorded a 3‐day dietary assessment. Mothers of PKU children perceived their children to have more feeding problems than the mothers of the control children. They said that they were more likely to have a poor appetite (P&lt;0.05), and have more gastrointestinal symptoms (P&lt;0.05). The PKU group were more likely to be given their midday meal separately from the rest of the family (PKU group 67%, control group 20%; P&lt;0.05), were less likely to start their meal without prompting (P&lt;0.005) and received less parental feeding directed verbalization (P&lt;0.05). Although there was no significant difference in energy intake between the two groups, the PKU group had a significantly lower weight z score than the control group: median (range) weight for age, PKU group z score −0.81 (−2.23 to 2.21); control group 0.65 (−0.81 to 1.83) (P&lt;0.05), but no differences were noted for height z score. This study is the first to report on the extent of feeding difficulties in young PKU children. An awareness of the consequences of rigid diet therapy should prove helpful in improving management strategies.

Magnetic resonance imaging in phenylketonuria: Reversal of cerebral white matter change

Objectives: To investigate the extent to which the abnormalities in cerebral white matter in adolescents and adults with phenylketonuria (PKU) are reversible. Method: Magnetic resonance imaging (MRI) of the brain was repeated in 41 patients with PKU (age range, 14 to 49 years) after an interval (median, 9 months; range, 3 to 12 months) of dietary intervention. Scans were scored according to the extent of the white matter involvement. After an initial MRI, five patients returned to a strict low-phenylalanine diet with amino acid supplement; 21 patients started a low-protein diet (1 gm/kg) with amino acid supplement; and 15 patients made no dietary alteration. Results: Scans improved in all five patients who returned to a strict low-phenylalanine diet, in 5 of the 21 patients on the low-protein diet plus amino acid supplement, and in 4 of the 15 patients who made no dietary change. There was a significant association between change in the MRI findings and in the blood phenylalanine concentration (Pearson correlation: r = 0.55; p <0.0002) and between change in the MRI and in the phenylalanine level at the time of the second scan ( r = 0.58; p <0.0001). Improvement was seen primarily in those in whom phenylalanine levels were reduced to less than 900 μmol/L. There was no obvious change in MRI score after 3 weeks of strict phenylalanine restriction for the two adults who underwent serial scanning. Conclusion: The MRI changes in PKU are at least partially reversible by lowering the blood phenylalanine concentration. (J P EDIATR 1995;127:251-5)

Fetal damage due to maternal phenylketonuria: Effects of dietary treatment and maternal phenylalanine concentrations around the time of conception

In 94 infants born to women with PKU, birth weight and head circumference were inversely and linearly related to the mothers' phenylalanine concentrations close to conception; with each 200 mumols/L rise in phenylalanine concentrations, birth weight fell by 98 g and head circumference by 0.46 cm. This relationship was highly significant and appeared to be the same whether or not the mother received a low phenylalanine diet. Even in the 28 infants whose mothers conceived on a strict low phenylalanine diet, birth weights and head circumferences, corrected for sex and gestation, were a little below the population norms (3421 g and 34.7 cm compared with 3600 g and 35.2 cm respectively) although the differences were not statistically significant. Optimal fetal growth occurred only in infants whose mothers had phenylalanine concentrations close to the normal range at conception. Dietary treatment started after conception did not appear to confer any benefit.

Impact of medical genetics concerning phenylketonuria: accomplishments, status and practical future possibilities.

Millions of newborn infants are screened for phenylketonuria (PKU) to prevent the inherited metabolic error by dietary treatment. For some PKU patients a relaxed low-phenylalanine diet will be lifelong. PKU-women must return to a strict low-phenylalanine diet before conception and during pregnancy to insure the delivery of a normal child. Two mutations that account for 60% of the PKU genes in Denmark are established and oligonucleotide probing enables carrier detection and genetic counselling. Primary hepatocytes can be successfully cultured and transformed with phenylalanine hydroxylase cDNA and somatic gene therapy of PKU may be a future possibility.

Timing of strict diet in relation to fetal damage in maternal phenylketonuria. An international collaborative study by the MRC/DHSS Phenylketonuria Register.

64 infants born to women with phenylketonuria (PKU) were grouped according to the mother's dietary treatment in pregnancy. 17 infants, whose mothers were receiving a strict low phenylalanine diet and had blood phenylalanine concentrations below 600 mumol/l at the time of conception, had normal birthweights and head circumferences and no malformations. In the 29 infants whose mothers were receiving either a relaxed diet or a normal diet at conception but who started a strict diet at some time during pregnancy, birthweights and head circumferences were below those in healthy infants and there was an excess of malformations; the findings closely resembled those for the 18 infants whose mothers received no treatment during pregnancy. The birthweights and head circumferences of the 64 infants were inversely related to the maternal phenylalanine concentrations around the time of conception. Only a strict diet started before conception is likely to prevent fetal damage.

PREVENTING FETAL DAMAGE IN MOTHERS WITH PKU.

It is well known that pregnant women with phenylketonuria (PKU) who do not follow a restricted diet often give birth to impaired infants. In contrast, women who adhere to a strict low-phenylalanine diet can deliver normal infants. But how soon after conception must the diet begin in order to protect the …