Family Social Status and Dietary Adherence of Patients with Phenylketonuria

Objective

There are several problems associated to the management of patients with phenylketonuria (PKU). Social status could be one of the affecting factors on dietary adherence in these patients. The aim of this study was to evaluate family social status and dietary adherence of PKU patients in Iranian population.

Methods

In a cross-sectional study, we studied 105 Iranian PKU patients (born 1984 to 2010), treated and followed at Mofid Children''s Hospital, Tehran. Social status was defined by number of children in family, number of affected children in family, maternal and paternal education, marital and employment status of the parents. Age at diagnosis and duration of treatment were also recorded. Mean plasma phenylalanine level was considered as a sign of dietary adherence in PKU patients and was calculated considering the phenylalanine measurements throughout at least one year.

Findings

Mean plasma phenylalanine concentration was 5.9±3.6 mg/dl in patients <12 years old and 13.1±3.9 mg/dl in patients >12 years old. Blood phenylalanine concentrations in 47.6% of patients were in normal age-related reference range. There was a significant association between divorced and unemployed parents, and higher levels of blood phenylalanine concentration (P=0.02 and P=0.03 respectively). There was a significant positive correlation between number of affected children in the family (r=0.43, P<0.001), age at diagnosis (r=0.2, P=0.03), treatment duration (r=0.7, P=<0.001) and blood phenylalanine concentrations. There was no significant relation between parental education, family size and dietary adherence.

Conclusion

Social status affects dietary adherence to some extent. We suggest exploring care-givers dietary knowledge as the next step to improve dietary compliance in these patients.     

Biochemical control,genetic analysis and magnetic resonance imaging in patients with phenylketonuria

Thirteen patients with phenylketonuria, detected by neonatal screening and started on diet within 16 days of age, were investigated between 10 and 18 years of age by magnetic resonance imaging (MRI) of the brain. Biochemical control was assessed from: (1) the life time blood phenylalanine (Phe) control (as determined from (a) the mean yearly exposure to Phe; (b) the accumulated time for each patient that Phe was <120 mol/l; (c)>400 mol/l; (d)>800 mol/l; and (e)>1200 mol/l); and (2) the blood Phe control over the 5 years prior to imaging (assessed for each patient by the mean yearly Phe exposure over that period). In all patients the phenylalanine hydroxylase gene locus was studied using restriction fragment length polymorphism haplotypes and mutant genes were screened for a variety of specific mutations which have been reported in other European populations or in populations of north European descent. Two patients had significant abnormalities of cerebral white matter. Although both showed poor biochemical control this did not reach statistical significance when compared to those with normal imaging. DNA haplotype patterns could be assigned to 11 patients and mutant genes were identified in 12. One patient with abnormal imaging and 4 patients without abnormalities had mutations on both chromosomes identified. In these 5 patients there was significant correlation between their genotype and biochemical control. Mutations resulting in residual in vitro enzyme activity were associated with normal imaging.     

Maternal phenylketonuria syndrome in cousins caused by mild,unrecognized phenylketonuria in their mothers homozygous for the phenylalanine hydroxylase Arg-261-Gln mutation

Intrauterine growth retardation, microcephaly, and developmental delay in two first cousins lead to the recognition of phenylketonuria (PKU) in their mothers, 24- and 23 year-old sisters with blood phenylalanine concentrations of approx. 1.2 mmol/l who had never been treated and had no overt mental retardation. Both mothers were shown to be homozygous for a point mutation leading to an Arg-to-Gln substitution at codon 261 of the phenylalanine hydroxylase gene, a mutation which has been recently identified and tentatively associated with a mild variant of PKU. Our observation suggests that homozygosity for the Arg-261-Gln mutation can indeed result in mild PKU with little or perhaps no mental retardation, but also indicates that in such women, who may go unrecognized if not screened for, blood phenylalanine is elevated enough to cause the maternal PKU syndrome in their offspring.     

北京市20年新生儿疾病筛查回顾性分析

目的分析北京市1989—2009年新生儿先天性甲状腺功能减退症（CH）和苯丙酮尿症（PKU）的筛查结果,为进一步提高新生儿疾病筛查的管理水平及干预措施提供依据。方法 采集出生72h后、正常哺乳的新生儿足跟血于特定滤纸上,进行CH及PKU筛查。PKU筛查检测指标为血苯丙氨酸（Phe）浓度,分别采用细菌抑制法（1989—2003年）和荧光法（2004—2009年）;CH筛查检测指标为血促甲状腺激素（TSH）水平,分别采用放免法（1989—2003年）及时间分辨荧光免疫分析法（DELFIA）（2003—2009年）。结果 1989—2009年,北京市共筛查新生儿1745998名,筛查率由1989年的14.01%提高到2009年98.16%,可疑患儿复诊率由1991年的65.85%提高到2009年的92.18%,共确诊CH482例,发病率1：3622;PKU192例,发病率1：9094。结论 新生儿疾病筛查是包括管理、筛查、随访、诊治、评估、教育等多个环节的系统服务工程,各部门的协调配合是提高筛查管理质量的有效措施,完善的新生儿疾病筛查工作可有效降低残疾儿的发生。     

Mental and motor development and psychosocial adjustment of Chinese children with phenylketonuria

Aim: This study was designed to evaluate mental and motor development, psychosocial adjustment (temperament and behavioural problems) in children with phenylketonuria (PKU). Methods: Twenty‐eight Chinese children aged from three to 36 months with early‐treated PKU were evaluated by Bayley Scales of Infant Development (BSID), Peabody Developmental Motor Scale (PDMS‐II), Toddler Temperament Questionnaire (TTQ) and Achenbach's Child Behavior Checklist (CBCL). The related factors, including blood phenylalanine (Phe) levels, and the socio‐economic status (SES) of the children's family were also explored. Results: In comparison with healthy control, early‐treated PKU children showed no delay in the mental and motor development. However, they presented higher levels on four of the nine temperamental dimensions (higher level in activity, more intense in reaction, more negative mood and more distraction). They also had more behavioural problems in depression, aggression and destructibility. A lower Phe level and a higher SES of children's family showed a positive effect on development index, temperamental characteristics and behavioural problems. Conclusion: Early‐treated PKU children were normal in the mental and motor development. However, they presented higher level on four of the nine temperamental dimensions and had more behavioural problems. Paediatric control combined with psycho‐counselling was suggested for young PKU children.     

Postnatal depression mediates the relationship between infant and maternal sleep disruption and family dysfunction

Background

Previous research has linked family sleep disruption and dysfunction in children; however, the mechanism is unknown.

Aims

This study examined whether maternal sleep and postnatal depression (PND) mediate the relationship between infant sleep disruption and family dysfunction.

Study design and participants

Mothers of infants aged 12 months old (N = 111; 48% male) completed infant and parent sleep surveys, the Edinburgh Postnatal Depression Scale and the Family Assessment Device.

Results

Poor infant sleep was related to poor maternal sleep, which was associated with higher PND and higher level of family dysfunction.

Conclusions

Results are consistent with the proposition that identification of both infant and maternal sleep problems during infancy can be relevant to reduction of PND and improved family functioning.     

Assessment of maternal anxiety following neonatal screening and investigation for occult spinal dysraphism

The objective was to determine maternal anxiety and attitudes associated with a programme of neonatal screening and investigation for occult spinal dysraphism. Questionnaires were completed after diagnostic investigation (time 1) and 6 months later (time 2) by 83 mothers of babies with possible markers of occult spinal dysraphism who were normal on spinal ultrasound. Outcome measures were: attitudes to the programme; maternal adjustment and attitudes to the baby; the State-Trait Anxiety Inventory. Fifty-four other postnatal mothers formed the comparison group for maternal adjustment. No significant differences were found between investigation group (time 1) and comparisons on measures of maternal adjustment. Anxious mothers gave more negative responses to some maternal adjustment items but not to attitudes to the programme. Mean state anxiety at time 1 (33.66) and time 2 (33.69) and mean trait anxiety (36.23) were not higher than in mothers of normal babies. It can be concluded that a programme of investigation for neonatal abnormalities that pays attention to detail need not cause excessive maternal anxiety. However, some mothers remain anxious even after receiving normal results. Anxiety can be assessed during appraisal of a new investigation programme, but refinements are needed.     

Galactose metabolites in blood from neonates with and without hypergalactosaemia detected by mass screening

Concentrations of galactose (Gal) in plasma and galactose metabolites in red blood cells (RBC) were determined in 18 normal neonates and 249 others with hypergalactosaemia according to the Paigen method. Normal neonatal values for plasma Gal, RBC galactose-1-phosphate (Gal-1-P), RBC uridine diphosphate glucose (UDP-Glc), and RBC uridine diphosphate galactose (UDP-Gal) were 0.96 ± 0.71 mg/dl, 1.69 ± 1.45 mg/dl of packed RBC, 1.00 ± 0.45 mg/dl of packed RBC, and 1.44 ± 0.45 mg/dl of packed RBC, respectively. The UDP-Gal concentration was higher and the UDP-Glc concentration lower than previously reported in normal children. Of the 249 cases with excessive Gal in whole blood, 23 showed high Gal concentrations in plasma; among these, four portacaval shunts and one case of congenital biliary atresia were diagnosed. In subjects homozygous or heterozygous for UDP-Gal-4 epimerase deficiency, concentrations of UDP-Gal and Gal-1-P were elevated only in RBC, corresponding to restriction of the metabolic abnormality to these cells. Most cases of hypergalactosaemia detected by the Paigen method have large excesses of Gal-1-P in RBC. Although a specific diagnosis based solely on blood Gal metabolites is difficult, individual concentrations reflect underlying conditions to some extent. Conclusion In neonates, uridine diphosphate galactose concentrations were higher and uridine diphosphate glucose concentrations were lower than previously reported paediatric values. Patients with high plasma galactose concentrations should be investigated by hepatic imaging. Received: 21 March 2000 / Accepted: 18 May 2000     

Growth of patients with congenital hypothyroidism detected by neonatal screening in Japan

BACKGROUND: The growth of patients with congenital hypothyroidism detected by neonatal screening in Japan was investigated. The data investigated were obtained from Medical Aid Program for Chronic Pediatric Diseases of Specified Categories registered in 2002. METHOD: The present study included 2341 patients (1030 male, 1311 female) registered as having congenital hypothyroidism. To investigate the growth of these patients, their heights plotted on cross-sectional growth charts for boys and girls, their bodyweights expressed as percentage of bodyweight for height and the frequency distribution of percentage of bodyweight for height were assessed. RESULTS: Cross-sectional growth charts of both male and female patients showed that the heights of the majority of the patients with congenital hypothyroidism were within +/-2SD. Approximately half of the patients with heights below -2SD, had some complications. The mean percentages of ideal bodyweights for height were 103.0 +/- 12.9% for both sexes (+/-SD, n = 2033), 103.3 +/- 12.7% for boys, and 102.7 +/- 12.9% for girls. The frequency distribution of percentage of bodyweight showed no tendency of shifting to either ends in comparison with normal distribution curve. CONCLUSION: Patients with congenital hypothyroidism detected by neonatal screening had normal growth in general, suggesting that the neonatal screening system is being performed efficiently from detection to treatment of the disease in Japan. However, it remains unclear whether some uncomplicated patients with a height below -2 SD are sufficiently treated or not. Close observation of these patients may be needed.     

Final height and pubertal growth in Japanese patients with congenital hypothyroidism detected by neonatal screening

Aim: To investigate the final adult heights and pubertal growth patterns in Japanese patients with congenital hypothyroidism (CH) detected by neonatal screening. Methods: A retrospective chart review was conducted of female patients >15 y of age (n = 18) and male patients >18 y of age (n = 9), who were detected by neonatal screening and kept on continuous thyroid hormone replacement therapy. Final height standard deviation scores (FHSDS) and target height standard deviation scores (THSDS) were determined. Parameters characterizing the pubertal growth process (such as age at onset of pubertal growth spurt and age at peak pubertal growth) were obtained from each patient's growth rate chart. Menarchial age was determined in each female patient by reviewing the medical record. The impact on FHSDS of the etiology of CH, the severity of CH, the time of initiation of therapy and the adequacy of treatment during the first year of life was assessed. Results: All patients had received initial thyroid hormone treatment no later than 50 d of age, and had reached their final height. The mean FHSDS for female and male patients were +0.17 ± 0.99 and -0.03 ± 0.99, respectively. The mean FHSDS-THSDS for female and male patients was +0.09 ± 0.77 and -0.19 ± 0.53, respectively. No difference was seen in pubertal growth parameters for either gender compared with that of the reference population, except for a greater peak height velocity and pubertal height gain in male patients. The mean menarchial age was identical to that of the reference population. No significant relationship was found between the FHSDS and any of the factors investigated.

Conclusion: The adult height of patients with CH detected by neonatal screening was equivalent to that of the reference population and their target height. As long as early intervention and satisfactory management are ensured, severe CH does not appear to reduce final adult height.     

Low iron stores in infants and children with treated phenylketonuria: A population at risk for iron-deficiency anaemia and associated cognitive deficits

A retrospective study of 53 patients with phenylketonuria (PKU), whose disease was managed with a low-phenylalanine diet, revealed a high incidence of iron depletion (as reflected by subnormal serum ferritin concentrations). Serum ferritin concentrations under 10 g/l were found in one out of six infants aged 5–12 months. Concentrations under 16 g/l were found in 16 of 22 children aged 1–3 years and in 11 of 25 children aged 4–12 years. Dietary iron, estimated from prescribed intakes of medical foods, exceeded the Canadian recommended nutrient intake, suggesting that low stores of iron may be secondary to reduced bioavailability and absorption of iron. These findings suggest that the current dietary management of PKU is associated with an increased risk for low iron stores. Investigators have reported an association in young children between iron-deficiency anaemia and both cognitive and motor disturbances. Children with PKU, already at risk of neurological damage because of phenylalanine neurotoxicity, may be at increased risk as a result of iron depletion. Serum ferritin as well as haemoglobin concentration should be monitored, along with plasma phenylalanine and tyrosine, to ensure optimum treatment of affected children.     

Hypergalactosaemia in a patient with portal-hepatic venous and hepatic arterio-venous shunts detected by neonatal screening

Hypergalactosaemia was discovered in a newborn girl during routine metabolic screening. Hereditary enzyme deficiency was ruled out. She had multiple hepatic haemangiomas with portal-hepatic venous and hepatic arterio-venous shunts. Since she showed signs of high-output heart failure due to the arterio-venous shunt, hepatic artery embolization was performed at age 3 months. A galactose tolerance test was performed before and after embolization and when the haemangioma no longer appeared on ultrasonography. Even after embolization, the level of blood galactose was abnormally elevated in the galactose tolerance test, but the blood galactose was eliminated more rapidly than before embolization. When the hepatic haemangioma was no longer detected by ultrasonography, the peak galactose level decreased. We surmise that the hypergalactosaemia was due to these shunts. In cases of hypergalactosaemia of unknown cause; liver haemangioma with portal-hepatic venous shunting should be considered as a possible cause. If a hepatic arteriovenous shunt also exists, this may contribute to the effect of the portosystemic shunting.     

An asymptomatic infant with isolated 3-methylcrotonyl-coenzyme A carboxylase deficiency detected by newborn screening for maple syrup urine disease

We describe an asymptomatic male infant with isolated 3-methylcrotonyl-coenzyme A carboxylase deficiency who came to medical attention by newborn mass screening due to elevated blood leucine. The diagnosis was made by abnormal urinary organic acids at 20 days of age and was confirmed by assay of the carboxylase activities in cultured skin fibroblasts. Conclusion More attention should be paid to slight elevations of leucine levels in newborn mass screening. Urinary organic acid analysis should be performed in conspicuous cases. Received: 9 October 1996 / Received in revised form and accepted: 18 February 1997     

Sjögren's syndrome with membranous glomerulonephritis detected by urine screening of schoolchildren

A case of Sjögren's syndrome with glomerulonephritis is presented. The patient was a 13 year old male with hematuria and proteinuria discovered by urine screening of school children. Evaluation showed no evidence of any associated connective tissue disease. Kidney biopsy was consistent with membranous glomerulonephritis. Sjögren's syndrome with membranous glomerulonephritis is rare and the patient was the youngest case in the literature.     

Control of congenital infection with Toxoplasma gondii by neonatal screening based on detection of specific immunoglobulin M antibodies eluted from phenylketonuria filter-paper blood-spot samples

Two ongoing neonatal screening programmes for congenital infection with Toxoplasma gondii are presented. The New England Newborn Screening Programme has included congenital toxoplasmosis since 1986. The test is based on detection of Toxoplasma-speci fi c immunoglobulin M (IgM) antibodies eluted from the phenylketonuria (PKU) card. The seroprevalence of Toxoplasma IgG antibodies is at present about 13% and the birth prevalence of congenital toxoplasmosis approximately 1 per 10000 liveborn children. The Danish national neonatal screening programme was expanded to include congenital toxoplasmosis from 1 January 1999. The test is also based on detection of Toxoplasma-speci fi c IgM antibodies eluted from PKU cards. The seroprevalence of Toxoplasma IgG antibodies in pregnant women is around 25% and the birth prevalence about 1 per 3000 liveborn children. The birth prevalence of congenital Toxoplasma infection is within the range of other congenital disorders included in different screening programmes. Neonatal screening is feasible in areas with a low risk of congenital infection where prenatal screening will not be applicable.     

Follow up study on children with dyslipidaemia detected by mass screening at 18 months of age: effect of 12 months dietary treatment

The present study was done to evaluate the effect of short-term dietary therapy on 148 dyslipidaemic children (24 familial hypercholesterolaemia, 105 non-familial hypercholesterolaemia and 19 hypertriglyceridaemia), detected by mass screening in children at 18 months of age. In the model diet used for treatment, 15% of the total calories were obtained from protein, 27% from fat and 57% from carbohydrate. Cholesterol intake was set at <200 mg/day and the ratio of polyunsaturated to saturated fatty acid (P/S ratio) was 1.2. When compared to the composition of the diet ingested by the dyslipidaemic children, only the P/S ratio changed from 0.7 to 1.2. During 12 months treatment, levels of total cholesterol, low density lipoproteins cholesterol and apoB decreased by 10%–15% in children with familial and non-familial hypercholesterolaemia. There was no significant change in the levels of high density lipoproteins. In 19 children with hypertriglyceridaemia, the intake of carbohydrate was limited to 55% of the total calories consumed and after 12 months of treatment, triglyceride levels reverted to normal. Throughout the study period, apprimately 70% of the children on this dietary therapy were seen in our clinics every 3–6 months and physical development was within normal ranges. These results, taken together, indicate that dietary therapy can be effective for correcting dyslipidaemia, even in young children.     

Clinical features and outcome of eight infants with intrahepatic porto-venous shunts detected in neonatal screening for galactosaemia

Of 18 newborn infants found to have persistent galactosaemia and without enzyme deficiencies, intrahepatic porto-venous (P-V) shunts were the cause in 8 cases. We retrospectively analysed the clinical and biochemical features of the eight infants. Four patients received prednisolone, one of whom with heart failure owing to arteriovenous shunts also underwent hepatic arterial embolization. The other four patients were merely observed without receiving drug therapy. Regardless of treatment, the P-V shunts disappeared in five infants before the age of 1 y and persisted in three others. All infants showed mild or moderate abnormalities in liver function tests. None exhibited hyperammonemia or neuropsychiatric symptoms related to the shunts. The data indicated that the prognosis of infants with intrahepatic P-V shunts is generally good. In the absence of complications related to the P-V shunts, no treatment other than galactose elimination diet is indicated.     

Hypothalamo-pituitary hypothyroidism detected by neonatal screening for congenital hypothyroidism using measurement of thyroid-stimulating hormone and thyroxine

The optimal strategy in neonatal screening for congenital hypothyroidism is still a subject of controversy. In Kanagawa Prefecture in Japan, simultaneous thyroid-stimulating hormone (TSH) and T4/fT4 determination has been used, while the results of our program may provide valuable information. Cumulative findings were analysed to determine the type and frequency of thyroid disorders in infants detected by simultaneous TSH and T4/fT4 determination, and the TSH and T4/fT4 screening strategy was validated. A total of 1284130 neonates were screened between October 1979 and September 1997 and infants followed because of low T4/fT4 without elevated TSH (T4 < 51.5 nmol/L or fT4 < 9 pmol/L and TSH < 15 mU/L) were retrospectively analysed. The first survey was carried out within 6 mo of birth and the second in 1998; 258 infants were diagnosed with congenital hypothyroidism at the first medical evaluation, 15 of them with hypothalamo-pituitary hypothyroidism. However, in the second survey, only 8 children were confirmed as having hypothalamo-pituitary hypothyroidism, therefore the incidence detected by the present strategy was 1/160516. Of 8 children with hypothalamo-pituitary hypothyroidism, mental retardation was prevented in 3 owing to early treatment. CONCLUSIONS: Simultaneous measurement of TSH and T4/fT4 is a useful strategy for detecting hypothalamo-pituitary hypothyroidism, but more studies are needed to show the cost-benefits of using this strategy.