Clinical onset and course, response to treatment and outcome in 24 patients with the cblE or cblG remethylation defect complemented by genetic and in vitro enzyme study data.

BACKGROUND: The cobalamin E (cblE) (MTRR, methionine synthase reductase) and cobalamin G (cblG) (MTR, methionine synthase) defects are rare inborn errors of cobalamin metabolism leading to impairment of the remethylation of homocysteine to methionine. METHODS: Information on clinical and laboratory data at initial full assessment and during the course of the disease, treatment, outcome and quality of life was obtained in a survey-based, retrospective study from physicians caring for patients with the CblE or CblG defect. In addition, data on enzyme studies in cultured skin fibroblasts and mutations in the MTRR and MTR gene were analysed. RESULTS: In 11 cblE and 13 cblG patients, failure to thrive, feeding problems, delayed milestones, muscular hypotonia, cognitive impairment and macrocytic anaemia were the most frequent symptoms. Delay in diagnosis depended on age at first symptom and clinical pattern at presentation and correlated significantly with impaired communication abilities at follow-up. Eighteen/22 patients presented with brain atrophy or white matter disease. Biochemical response to treatment with variable combinations of betaine, cobalamin, folate was significant. The overall course was considered improving (n = 8) or stable (n = 15) in 96% of patients, however the average number of CNS symptoms per patient increased significantly over time and 16 of 23 patients were classified as developmentally delayed or severely handicapped. In vitro enzyme analysis data showed no correlation with outcome. Predominantly private mutations were detected and no genotype- phenotype correlations evident. CONCLUSIONS: The majority of patients with the cblE and cblG defect show limited clinical response to treatment and have neurocognitive impairment.

A severe form of non-classic Pompe's disease with normal creatinine kinase level.

A 24-month-old boy was referred to our pediatric intensive care unit because of difficulty in weaning from artificial ventilation. He had 2 bronchopneumonia attacks in 2 months; the diagnosis of Pompe's disease was confirmed by low glucosidase activity in lymphocytes and cultured fibroblasts without abnormality in the serum creatine kinase level. Our patient's creatine kinase levels were permanently normal. To the best of our knowledge, our Pompe's case is the first in the literature who has normal creatinine kinase levels despite earlier onset and rapidly progressive disease.

Dihydropyrimidine dehydrogenase deficiency caused by a novel genomic deletion c.505_513del of DPYD.

Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disorder of the pyrimidine degradation pathway. In a patient presenting with convulsions, psychomotor retardation and Reye like syndrome, strongly elevated levels of uracil and thymine were detected in urine. No DPD activity could be detected in peripheral blood mononuclear cells. Analysis of the gene encoding DPD (DPYD) showed that the patient was homozygous for a novel c.505_513del (p.169_171del) mutation in exon 6 of DPYD.

A study on neonatal factors and eruption time of primary teeth.

OBJECTIVE: The purpose of this study was to determine the time of the eruption of the first primary tooth (FPT) in infants and to assess the effects of neonatal factors on the timing of the eruption. BASIC RESEARCH DESIGN: The dental and medical records of healthy infants were reviewed to gather data on birth weight (BW), gestational age (GA), prenatal history, and the time of the eruption of the FPT. Additionally, the mothers of these infants were asked to identify their smoking habits and/or caffeine consumption during pregnancy through face-to-face interviews. The resulting data were statistically analysed with the Student's t, Tukey, and Pearson correlation tests. RESULTS: The mean eruption times (MET) for girls and boys were 7.25 +/- 2.47 and 7.07 +/- 1.66 months respectively (p > 0.05). The MET of the FPT in infants with a GA of less than 34 weeks, 34 to 37 weeks, or over 37 weeks were 8.0 +/- 2.0, 8.29 +/- 2.97, 6.93 +/- 1.87 months, respectively. The MET in infants with a BW of 1500 to 2500g was 8.28 +/- 2.28 months, while the MET for the infants with a BW of over 2500g was 6.99 +/- 1.94 (p = 0.014). CONCLUSION: A significant difference was found in the METs of infants with low and normal BWs. No significant differences were observed in the MET as related to other neonatal factors.

Prediction of outcome in isolated methylmalonic acidurias: combined use of clinical and biochemical parameters.

Objectives Isolated methylmalonic acidurias (MMAurias) are caused by deficiency of methylmalonyl-CoA mutase or by defects in the synthesis of its cofactor 5'-deoxyadenosylcobalamin. The aim of this study was to evaluate which parameters best predicted the long-term outcome. Methods Standardized questionnaires were sent to 20 European metabolic centres asking for age at diagnosis, birth decade, diagnostic work-up, cobalamin responsiveness, enzymatic subgroup (mut(0), mut(-), cblA, cblB) and different aspects of long-term outcome. Results 273 patients were included. Neonatal onset of the disease was associated with increased mortality rate, high frequency of developmental delay, and severe handicap. Cobalamin non-responsive patients with neonatal onset born in the 1970s and 1980s had a particularly poor outcome. A more favourable outcome was found in patients with late onset of symptoms, especially when cobalamin responsive or classified as mut(-). Prevention of neonatal crises in pre-symptomatically diagnosed newborns was identified as a protective factor concerning handicap. Chronic renal failure manifested earlier in mut(0) patients than in other enzymatic subgroups. Conclusion Outcome in MMAurias is best predicted by the enzymatic subgroup, cobalamin responsiveness, age at onset and birth decade. The prognosis is still unfavourable in patients with neonatal metabolic crises and non-responsiveness to cobalamin, in particular mut(0) patients.

Diagnostic work-up and management of patients with isolated methylmalonic acidurias in European metabolic centres.

The long-term outcome of patients with methylmalonic aciduria (MMA) is still uncertain due to a high frequency of complications such as chronic renal failure and metabolic stroke. The understanding of this disease is hampered by a huge variation in the management of these patients. The major aim of this study was to evaluate the current practice in different European metabolic centres. A standardized questionnaire was sent to 20 metabolic centres asking for standard procedures for confirmation of diagnosis, testing cobalamin responsiveness, dietary treatment, pharmacotherapy, and biochemical and clinical monitoring. Sixteen of 20 metabolic centres (80%) returned questionnaires on 183 patients: 89 of the patients were classified as mut(0), 36 as mut(-), 13 as cblA, 7 as cblB, and 38 as cblA/B. (1) Confirmation of diagnosis: All centres investigate enzyme activity by propionate fixation in fibroblasts; six centres also perform mutation analysis. (2) Cobalamin response: Ten centres follow standardized protocols showing large variations. A reliable exclusion of nonspecific effects has not yet been achieved by these protocols. (3) Long-term treatment: In cobalamin-responsive patients, most centres use hydroxocobalamin (1-14 mg/week i.m. or 5-20 mg/week orally), while two centres use cyanocobalamin. All cobalamin-nonresponsive patients and most cobalamin-responsive patients are supplemented with L: -carnitine (50-100 mg/kg per day). Fourteen centres use intestinal decontamination by antibiotic therapy. Most centres follow D-A-CH (n = 6) or Dewey (n = 4) recommendations for protein requirements. Fourteen centres regularly use precursor-free amino acid supplements. Standardized monitoring protocols are available in seven centres, again showing high variability.

Updated growth curves for Turkish children aged 15 days to 60 months.

BACKGROUND: Growth reference values are useful in paediatric health care as a health indicator. Secular changes in height for age values are also known to affect the timing of puberty and brain weight. Different populations may be at different stages of this secular trend. It is, therefore, necessary to periodically update the growth reference values for each population to identify these changes. The aim of this study was to update the growth reference values for Turkish infants and young children. METHODS: Background information and height/length, weight and head circumference measurements on a sample of 2391 boys and 2102 girls were obtained from Well Child Clinic Records. The LMS method was used for the analyses. The percentage of exclusive breastfeeding was 62% at 4 months and 26.6% at 6 months. The continuation rate of breastfeeding at 12 months was 62.5%. RESULTS: Comparison with previous Turkish data showed an increase in height of 0.9 cm for boys and 1.1 cm for girls at age 5 years. The increase in weight was 0.220 kg in girls, while a decrease of 0.160 kg was noted in boys. Comparison with the 2000 US and Swedish values indicated that population differences may exist in pre-pubertal years. CONCLUSION: This study provides an enhanced instrument to evaluate the growth of Turkish infants and young children.

Breast feeding in organic acidaemias.

Breast feeding has been recommended for the dietary treatment of infants with organic acidaemias, but studies documenting clinical experience are still very few. Nine infants, diagnosed with methylmalonic acidaemia (n = 4), propionic acidaemia (n = 1), isovaleric acidaemia (n = 2) and glutaric acidaemia type I (n = 2) were breast fed after diagnosis. The age of the patients was 28.9+/- 13.4 months (mean +/- SD) (range 10-57 months). Eight patients were diagnosed with clinical symptoms and one because of an affected sibling. After the control of acute metabolic problems, an initial period with a measured volume of expressed breast milk was continued with on-demand breast feeding with the addition of a special essential amino acid mixture and energy supplements. Breast feeding was well tolerated in seven infants with good growth, metabolic control and neurological outcome. The duration of breast feeding was 12.3+/- 7.4 months (mean +/- SD) (range 4-24 months) in these patients. Breast feeding was terminated in the patient with propionic acidaemia because of two acute metabolic episodes requiring hospitalization, and could not be continued in one of the patients with isovaleric acidaemia owing to shortage of breast milk. A decrease in the frequency of infections, acute metabolic episodes and hospital admissions was observed in breast-fed infants. Breast feeding of infants with organic acidaemias is feasible with close monitoring of clinical parameters such as growth, development and biochemistry, including amino acids, organic acids and ammonia.

Haemophilus influenzae type b carriage among 3- to 24-month-old Turkish children.

There are few studies from developing countries on the epidemiology of Haemophilus influenzae (Hib) infections among infants and children. We set out to determine the prevalence of oropharyngeal Hib colonization among Turkish children younger than two years of age and to identify antimicrobial resistance among the isolates. A cross-sectional study was conducted on 818 healthy children and oropharyngeal secretions were sampled. The carriage rate of Hib was found to be 7.2% and this increased significantly with age. Carriage of Hib among 3- to 6-month-old children (3.5%) was higher than expected and was significantly higher among children who were passive smokers (P=0.04). Logistic regression analysis showed that breastfeeding status was the sole significant factor for colonization (OR 2.2, 95% CI 1.26-3.82). Antimicrobial susceptibility tests on 56 isolates of H. influenzae showed that 51.8% and 21.4% were resistant to trimethoprim-sulphamethoxazole and ampicillin respectively. Other notable resistances were to cefalexin (10.7%) and chloramphenicol (3.6%); no isolates were resistant to ceftriaxone.

Hyperchylomicronaemia due to lipoprotein lipase deficiency as a cause of false-positive newborn screening for biotinidase deficiency.

Two cases of molecular genetically proven lipoprotein lipase deficiency are reported. Both patients were detected owing to a false-positive neonatal screening test for biotinidase deficiency. We conclude that both the fluorimetric and the colorimetric screening tests for biotinidase deficiency used with dried blood samples are affected by severe hyperchylomicronaemia and that, most probably, severe plasma turbidity interferes with the assay.

Consanguineous 3-methylcrotonyl-CoA carboxylase deficiency: early-onset necrotizing encephalopathy with lethal outcome.

A patient with a severe neonatal variant of 3-methylcrotonyl-CoA carboxylase (MCC) deficiency is reported. The first child of healthy consanguineous Turkish parents presented on the second day of life with dehydration, cyanosis, no sucking, generalized muscular hypotonia, encephalopathy, respiratory depression requiring mechanic ventilation, macrocephaly, severe acidosis and hypoglycaemia. Elevated C5-OH-carnitine in dried blood spot by tandem MS and elevated urinary excretion of 3-hydroxyisovaleric acid and 3-methylcrotonylglycine suggested MCC deficiency, confirmed by enzyme analysis in cultured fibroblasts. Cerebral ultrasonography and cranial CT findings revealed progressive changes such as disseminated encephalomalacia, cystic changes, ventricular dilatation and cerebral atrophy. Treatment with high-dose biotin and protein-restricted diet was ineffective and the patient died at the age of 33 days with progressive neurological deterioration. Mutation analysis revealed a homozygous mutation in the splice acceptor site of intron 15 in the MCC beta-subunit. Early-onset severe necrotizing encephalopathy should be included in the differential diagnosis of isolated MCC deficiency.

Asymptomatic adults and older siblings with biotinidase deficiency ascertained by family studies of index cases.

We report 32 biotinidase-deficient patients detected by family studies in the index cases. The study group consisted of 10 mothers, 4 fathers and 18 siblings. There were 17 individuals (3 mothers, 4 fathers and 10 siblings) with profound biotinidase deficiency (BD) (< 10% of mean normal activity) and 15 (7 mothers and 8 siblings) with partial BD (10-30% of mean normal activity). In the profound BD group, only three siblings were symptomatic. Dermatitis, microcephaly, developmental delay and convulsions were observed. The patients with partial BD did not have any clinical symptoms except one sibling with borderline IQ score. None of the parents was symptomatic. Family investigation of patients with BD is very important for the detection of asymptomatic patients who are at risk of exhibiting symptoms at any age. Careful evaluation of these untreated individuals with BD is important to obtain additional information about the natural history of this disorder and may provide clues to phenotype-genotype relationships and treatment regimes.

Hyperhydroxyprolinaemia detected in newborn screening with tandem mass spectrometry.

Hydroxyproline has the same integer molecular weight as leucine and isoleucine and is quantified with these by tandem mass spectrometry. An infant was diagnosed with hyperhydroxyprolinaemia following further evaluation of an elevated "leucine" level in newborn screening by tandem mass spectrometry.

Ten steps for successful breast-feeding: assessment of hospital performance, its determinants and planning for improvement.

This paper discusses results from a project which aims to document the maternity hospital practices in istanbul within the context of Ten Steps for Successful Breastfeeding. Instruments developed for use in hospital level implementation of the WHO/UNICEF baby friendly hospital initiative were used in five hospitals (two public and three private). No hospital was implementing all Ten Steps. A core hospital team on lactation management and a sufficient number of health personnel skillful in breastfeeding counselling and adequate delivery room conditions are required to implement the Ten Steps. It is very difficult to provide these conditions in public hospitals with an excessive patient load. On the other hand, the fee for service system and the policy of changing practices according to the wishes of the clients can also become barriers to successful breastfeeding, as may occur in some private hospitals.

Female health workers: an obstetric risk group.

OBJECTIVE: The aim of the study was to gather information about the pregnancies of female health workers and to compare them with those of another group of working women with different working conditions, namely bank workers, METHODS: Using a cross-sectional comparative design, physicians (184), nurses (197) and bank-workers (192) were interviewed about their previous pregnancies and working conditions during those pregnancies. RESULTS: The majority of physicians (70.6%) and nurses (81.2%) had night work during their pregnancies and two-thirds of them continued this work until the last month of pregnancy, even though they have a legal right not to work during the night after the 7th month of pregnancy. Health workers had shorter maternity leaves than bank workers (P < 0.001) and complained more about the negative attitudes of managers and colleagues during their pregnancy (P < 0.001). Health workers had more preterm deliveries (P < 0.05) compared with bank workers, and nurses had more low birth weight babies compared with bank workers (P < 0.05). CONCLUSION: There is a need for a change in the climate in hospitals in terms of the working conditions of pregnant health staff and the attitudes towards them.

Carbohydrate malabsorption in acute diarrhea.

A group of 245 well nourished infants with acute diarrhea were screened for carbohydrate malabsorption by evaluating stool pH and reducing substances in the stools. Carbohydrate malabsorption was diagnosed in 28 cases (11%). Clinical features of carbohydrate intolerance were present in only one case. The duration of diarrhea after admission ranged from 1 to 13 days (mean 3.9 days). An oral lactose tolerance test was consistent with lactase deficiency in 32% of all cases. Thin layer chromatography showed many carbohydrates including monosaccharides in the stools, indicating that the defect in intestinal absorption was not specific for lactose.

Who lives with whom in Istanbul?

PIP: An analysis of household characteristics in Istanbul, Turkey, is presented using 1985 census data. Comparisons are made with 1907 household statistics. The importance of migration to the city for household characteristics is noted, and the living arrangements of migrants are compared for 1907 and 1985.^ieng

Paraprofessional women as health care facilitators in mother and child health.

The aim of the study was to compare the performance of midwives with that of lady home visitors (LHV; paraprofessionals). The project area was divided into six according to the population map. One midwife or one LHV was assigned to each visiting area. Home visits were carried out to identify and offer guidance on family planning (FP), antenatal care, well-child control, immunizations and other mother and child health related issues to those at high risk. Criteria taken for evaluation were the numbers of pregnant women identified in the last trimester; pregnant women receiving antenatal care; deliveries attended by a health care provider; modern FP users; continuation rate of the new users; pregnancy rate in new users; immunization status of children; well-child visits of the children. No significant differences were found in these health measurements between areas visited by LHV and areas visited by midwives. Response rates to the invitation was also similar in both areas. An important observation was the good performance of the LHV in communicating with the families. Women with limited school attainment from the community can be used effectively and efficiently in community health services.