[Standardization of the Kent Infant Development Scale: implications for primary care pediatricians]. / Normalización de la Escala de Desarrollo Infantil de Kent. Implicaciones para la práctica pediátrica ambulatoria.

OBJECTIVE: The purpose of this study was the standardization of an infant assessment protocol based on behavioral observations of Spanish parents. The Kent Infant Development (KIDS) scale was translated into Spanish and named "Escala de Desarrollo Infantil de Kent" (EDIK). PATIENTS AND METHODS: The EDIK normative data were collected from the parents of 662 healthy infants (ages 1 to 15 months) in pediatric clinics. Infants born more than 2 weeks premature or who had serious physical or neurological illness were not included. RESULTS: EDIK raw scores of Spanish infants were converted to developmental ages by comparing them with the number of behaviors for each age group in the normative sample. We obtained the mean score and standard deviation for the full scale and different domains (cognitive, motor, social, language, and self-help). CONCLUSIONS: This study shows that EDIK is sensitive to differences in ages and a good instrument that allows one to make a classification between normal infants or those at risk. It should prove useful in developmental pediatric practice.

Twenty-year outcome analysis of genetic screening programs for Tay-Sachs and beta-thalassemia disease carriers in high schools.

Programs for education, screening, and counseling of senior-high-school students, in populations at high risk for Tay-Sachs and beta-thalassemia diseases, have existed for >20 years in Montreal. Four process and outcome variables are reported here: (i) voluntary participation rates in the high-school cohort; (ii) uptake rates for the screening test; (iii) origin of carrier couples seeking the prenatal diagnosis option in the programs; and (iv) change in incidence of the two diseases. Between 1972 and 1992, we screened 14,844 Ashkenazi-Jewish students, identified 521 HexA-deficient carriers (frequency 1:28), reached 89% of the demographic cohort in the educational component of the program, and achieved 67% voluntary participation in the subsequent screening phase. The corresponding data for the beta-thalassemia program are 25,274 students (mainly of Mediterranean origin) representing 67% of the cohort with 61% voluntary participation in the screening phase (693 carriers; frequency 1:36). From demographic data, we deduce that virtually all the carriers identified in the high-school screening program remembered their status, had their partner tested if they did not already know they were a carrier couple, and took up the options for reproductive counseling/prenatal diagnosis. In Montreal, the current origin of all couples using prenatal diagnosis for Tay-Sachs and beta-thalassemia diseases is the corresponding genetic screening/testing program, whereas, at the beginning of the programs, it was always because there was a history of an affected person in the family. Incidence of the two diseases has fallen by 90%-95% over 20 years; the rare new cases are born (with two exceptions) outside the target communities or to nonscreened couples.

[A new method for evaluating psychomotor development based on information from parents. The Spanish version of the Kent Infant Development Scale]. / Nuevo método de evaluación del desarrollo psicomotor basado en la información de los padres. Versión española de la Kent Infant Development Scale.

OBJECTIVE: The purpose of this dissertation research was to design, standardize and validate the Spanish version of the Kent Infant Development Scale (KIDS). PATIENTS AND METHODS: This questionnaire is based on information obtained from the parents. It was translated into Spanish and named "Escala de Desarrollo Infantil de Kent" (EDIK). The EDIK normative data were collected from the parents of 662 healthy infants (ages 1 to 15 months) in pediatric clinics in Catalonia (Spain). RESULTS: Test-retest reliability (r = 0.99; p < 0.001), interjudge reliability (r = 0.98; p < 0.001) and internal consistency (Cronbach alpha = 0.9947) were determined. An "r' of 0.96 was obtained when EDIK scores were compared to their estimated developmental ages obtained from the Denver Developmental Scale. The correlation of the infants' chronological age and their EDIK was 0.96 (p < 0.001). CONCLUSIONS: The high reliability and validity correlation coefficients demonstrate the sound psychometric properties of the EDIK. It appears to be a useful and acceptable instrument in measuring the developmental status of infants by using the reports of their parents.

What young people think and do when the option for cystic fibrosis carrier testing is available.

We report findings in phase II of a pilot study of cystic fibrosis (CF) carrier screening/testing by mutation analysis. Phase I has been reported elsewhere. Eligible participants in phase II (n = 815) were students (15 to 17 years of age) in public high schools. An educational component (exchange of information and discussion about common genetic disorders including CF) preceded, by one week or more, voluntary participation in the screening component which required a blood sample. The uptake rate for screening was 42%. Nine carriers (2pq = 0.0260) were identified, all with the delta F508 mutation; students were also tested for G551D, G542X, W1282X, and -549-mutations, but no carriers of these alleles were found. Carriers had positive views of the education and testing experiences. Persons identified as 'non-carriers' were also surveyed (n = 135, response rate 41%). As in phase I, the majority (83%) again understood that a negative DNA test had not excluded them from possible carrier status. Students who participated in the informational component but were not screened served here as controls in the follow up survey (n = 208, response rate 53%). Their views were similar to those of the screened non-carriers, and similar also to those held by students, adults, pregnant women, couples, and CF relatives in other communities.

Prospective analysis and classification of patients with cystinuria identified in a newborn screening program.

Patients who inherit mutant cystinuria genes excrete high concentrations of cystine, ornithine, arginine, and lysine in the urine. At least three variants of cystinuria can be distinguished in heterozygotes. To determine whether certain combinations of mutant genes are more disadvantageous than others, we analyzed amino acid excretion in families of 17 probands with cystinuria identified by the Quebec neonatal screening program. Parents of the probands were classified into the three known phenotypes by calculating the sum of cystine, ornithine, arginine, and lysine excretion. Although parents of type I/I homozygotes excreted amounts of cystine in the normal range, their offspring excreted significantly greater amounts of urinary cystine than did children who have type I/III genetic compounds. This observation suggests that types I and III cystinuria mutations might involve two distinct genetic loci. Children with type I/I homozygous cystinuria often excrete cystine at levels greater than the theoretic solubility limit and may be at greatest risk for nephrolithiasis. We outline an approach to monitoring children with cystinuria who come to medical attention before formation of cystine stones.

Methylmalonic acidemia with a severe chemical but benign clinical phenotype.

A 5-year-old boy of West African origin had methylmalonic acidemia with a mut- enzyme phenotype, no clinical response to hydroxycobalamin, and metabolite measurements indicative of the severe form of mutase deficiency. His development, both mental and physical, was satisfactory and he had no episodes of metabolic decompensation. The explanation for the neurotoxic effects and metabolic decompensation in typical methylmalonic acidemia and the (allelic) genotype that explains this patient's phenotype are uncertain.

'Celtic' phenylketonuria chromosomes found? Evidence in two regions of Quebec Province.

We analyzed mutations, RFLP haplotypes (H), and a VNTR polymorphism at the phenylalanine hydroxylase locus (PAH) in 12 French-Canadian patients with phenylketonuria (PKU) from the eastern region of Quebec province and 13 non-French-Canadian PKU patients from the Montreal region. There were 10 different mutation/H/VNTR haplotype combinations on the 50 PKU chromosomes: one set of 5 and another of 8 accounted for 88 and 77% of these chromosomes in the French-Canadian and non-French-Canadian patients, respectively. The differences in PKU haplotypes between the two groups of probands reflect the different histories of the two populations. Three PKU haplotype combinations were shared by the two groups: IVS12nt1:H-3:VNTR-8, I65T:H-9:VNTR-8, and R408W:H-1:VNTR-8. The IVS12nt1 mutation (18% of the total sample) is prevalent in northern Europeans. The I65T-H-9 and R408W:H-1 haplotypes have seldom been reported in Europeans but when encountered tend to be found in northwestern regions. The R408W mutation is usually on H-2 in Europeans. In Quebec the R408W:H-1 and I65T:H-9 haplotypes accounted for 20% of PKU chromosomes, clustered in two geographic regions, and in every family where they occurred an Irish or Scottish ('Celtic') ancestor could be inferred. We propose that I65T:H-9:VNTR-8 and R408W:H-1:VNTR-8 chromosomes are markers for a diaspora of 'Celtic' descendants. Our findings predict the distributions of these unusual PKU haplotypes in contemporary Europeans.

Newborn screening for sickle cell and other hemoglobinopathies: a Canadian pilot study.

We estimated incidence of HbS disease in Quebec. It is approximately 9 cases per 100,000 births (equivalent to the incidence of the hyperphenylalanemias). Accordingly, we performed a voluntary pilot study in 9 self-identified ethnic groups; 3528 families were counselled about the relevance of newborn screening for hemoglobinopathies; and 2779 cord blood samples were collected (participation rate, 78.7%) and analyzed for Hemoglobin S and other hemoglobin variants by cellulose acetate electrophoresis. There were 95 (3.42%) positive tests on the initial (cord blood) samples, of which only 40 could be confirmed because of low participation in follow-up. We identified 8 false-positive tests; 7 had been classified initially as alpha-thalassemia trait and one as HbC heterozygosity on the first test. The relative frequency of hemoglobinopathy genes (confirmed) was: 52.5% HbS; 22.5% alpha-thalassemia; 22.5% other mutation; all but one patient with sickle cell disease were heterozygotes; the majority (71%) of HbS genes were accounted for by the 7% of screened newborns who were Black; a further 24% of the HbS genes were accounted for by 7% with Central American ancestry. Record linkage of the findings in heterozygotes for use later in life is an unsolved problem. Seventy five first-degree relatives of the 48 probands were screened in follow-up studies (64% of parents participated); 5 couples at risk for having a future child with a hemoglobinopathy were identified. Attitudes toward follow-up varied among the ethnic groups. The single family with an affected newborn (sickle cell anemia) was counselled effectively; the infant received penicillin prophylaxis.(ABSTRACT TRUNCATED AT 250 WORDS)

Hereditary tyrosinaemia type II in a consanguineous Ashkenazi Jewish family: intrafamilial variation in phenotype; absence of parental phenotype effects on the fetus.

We describe an Ashkenazi Jewish family in which two adults, offspring of consanguineous parents, have persistent hypertyrosinaemia (770-1110 mumol/L; normal less than 110 mumol/L). The metabolic disorder in this family is apparently due to hepatic cytosolic tyrosine aminotransferase deficiency (hereditary tyrosinaemia, type II; McKusick, 276600), because it is associated with the oculocutaneous manifestations of Richner-Hanhart syndrome. The association of this syndrome with hereditary tyrosinaemia type II is presumed to be constant. It is not in this family. The affected female sib (age 41 years) has hypertyrosinaemia and oculocutaneous signs; the brother (age 39 years) has hypertyrosinemia but no oculocutaneous disease. Both sibs have two children; none has signs of a metabolic fetopathy. Maternal hypertyrosinaemia and maternal hyperphenylalaninaemia evidently constitute different risk factors for the fetus. Paternal hypertyrosinaemia is apparently not a risk to male infertility.

Specificity and sensitivity of hexosaminidase assays and DNA analysis for the detection of Tay-Sachs disease gene carriers among Ashkenazic Jews.

Tay-Sachs disease (TSD), a neurodegenerative disorder resulting from a deficiency of the lysosomal enzyme hexosaminidase A (HexA), clusters in Ashkenazic Jews. Population-based screening programs to detect carriers of TSD genes by means of HexA assays have been active since the 1970s. The recent characterization of 3 mutations in the HEXA gene (in exon 7, exon 11, and intron 12), which account for over 90% of HEXA mutations in Ashkenazim, appeared to offer better options for screening and diagnosis. The relative frequencies of the three mutations in Montreal are similar to those reported in four other North American populations. We compared enzyme and DNA analyses to determine specificity and sensitivity of each test when the other was used as the confirmatory procedure. Neither procedure has a sensitivity of 1.0. Maximum sensitivity and specificity were achieved by using both tests together. The findings here are likely to apply to most cases where the variant screened enzyme phenotype can result from more than one mutation.

Maple syrup urine disease: interrelations between branched-chain amino-, oxo- and hydroxyacids; implications for treatment; associations with CNS dysmyelination.

Four patients with classical maple syrup urine disease were treated for up to 5885 days per patient with a relaxed protocol allowing branched-chain amino acid levels in plasma to rise about 5 times the normal mean value. The patients have had satisfactory development and lifestyle. They spent 318 days in hospital during 19,937 aggregate treatment days. Plasma levels of leucine and the corresponding 2-oxo acid were shown to be elevated disproportionately relative to the other branched-chain metabolites. Levels of isoleucine and valine were lower than those of leucine apparently because of runout into alternative metabolite pools, namely the R metabolites for isoleucine and the hydroxyacid for valine. The chronic accumulation of branched-chain 2-oxo acid(s) in our patients was associated with chronic dysmyelinating changes in CNS visible by imaging. Another patient with a thiamine-responsive variant of maple syrup urine disease had five acute crises incurring 29 days in hospital in a total of 6910 treatment days. However, she did not have chronic metabolic dyshomeostasis (her average plasma amino acid values were normal) and she had no evidence of dysmyelination. A relaxed treatment protocol for patients with maple syrup urine disease may benefit them in quality of life, but it apparently exacts a cost in metabolic control and CNS pathology.

Optimization of cosolvent concentration and excipient composition in a topical corticosteroid solution.

Physicochemical factors involved in the development of a topical solution of a novel corticosteroid, tipredane (1), are described. A cosolvent system consisting of polyethylene glycol 400 (PEG 400), propylene glycol, and water was used to dissolve the concentration (0.1% w/w) of 1 required for the formulation. The solvent mixture was also nonirritating to the skin. Buffering agent, antioxidant, and metal-chelating agent were required to stabilize the drug. Solubilities of hydrophilic and lipophilic excipients were ensured by careful adjustment of their concentrations, as well as that of PEG 400. Two formulations, one containing potassium citrate and the other tromethamine as the buffering agents, were identified. Upon storage, sodium metabisulfite, an antioxidant used in the formulation, oxidized to form K2SO4 in the formulation containing potassium citrate. Potassium citrate decreased the solubility and resulted in the precipitation of K2SO4 by exerting a common ion effect. Lowering of the concentrations of potassium citrate, sodium metabisulfite, and PEG 400 ensured the solubility of K2SO4 formed. There was no such precipitation of K2SO4 in the formulation buffered with tromethamine, thus indicating that tromethamine is a good buffering agent in cosolvent systems.

Prospective ascertainment of complete and partial serum biotinidase deficiency in the newborn.

We screened 163,000 newborn filter-paper blood samples for serum biotinidase deficiency (McKusick 25326) and found 15 probands: three had complete deficiency (incidence 18.4 cases per million live births, 95% confidence interval 4-54 cases per million); the others had partial deficiency. The positive predictive value of the test for either form of biotinidase deficiency was 9.86%. We found seasonal variation in biotinidase activity in filter-paper blood samples. The cost per test was Can.$0.27 (1987 dollar value) and per case of complete deficiency ascertained, $15,500. Family studies indicated that complete serum biotinidase deficiency is a homozygous phenotype and partial deficiency is the heterozygous form. Homozygous cases were treated with biotin and have shown no clinical manifestations (55 patient-months of observation). None of the heterozygotes (n = 42, age 3 months - 62 years) has clinical manifestations. The number of heterozygotes found by screening was much less than predicted probably because the screening test detects mainly the samples with very low (outlier) biotinidase activity. The variant allele(s) for biotinidase deficiency was more common in French Canadians than in other ethnic groups in Quebec; there was no evidence of regional clustering or founder effect.

Hyperphenylalaninemia due to deficiency of 6-pyruvoyl tetrahydropterin synthase. Unusual gene dosage effect in heterozygotes.

We have identified deficient biopterin synthesis in four probands and one sib with persistent postnatal hyperphenylalaninemia. The metabolic findings were associated with a benign clinical presentation and normal biopterin level in cerebrospinal fluid in the newborn period, indicating the peripheral (hepatic) form of this autosomal recessive phenotype. Impaired development was apparent at 3 months in one proband not treated early. Treatment with oral tetrahydropterin restored adequate phenylalanine hydroxylase activity; it also maintained or improved CNS function. The deficient enzyme in these subjects is 6-pyruvoyl tetrahydropterin synthase (PTS). Erythrocyte activity of PTS in homozygotes (or compound heterozygotes) is less than 10% of normal. Heterozygotes have 20%-50% of normal PTS activity (enzyme phenotype), a finding compatible with a range of gene dosage effects, some abnormal. The metabolic phenotype in heterozygotes (urine biopterin excretion) did not correlate with erythrocyte PTS activity. The complex relationship between erythrocyte PTS activity, and biopterin synthesis in these families indicates genetic heterogeneity at the PTS locus.