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PubMed2006

Methylmalonic and propionic aciduria.

Methylmalonic and propionic aciduria (PA) are the most frequent forms of branched-chain organic acidurias. These autosomal recessive disorders result from deficient activity of methylmalonyl-CoA mutase and propionyl-CoA carboxylase, respectively. Clinically, acute or chronic neurologic signs are caused by the accumulation of toxic compounds proximal to the metabolic block. Phenotype varies from severe neonatal-onset forms with high mortality and poor outcome to milder forms with a later onset. In both cases the clinical course is dominated by the risk of relapses of life-threatening episodes of metabolic decompensation and of severe organ failure. Despite improvement of treatment, the overall outcome remains disappointing with no major differences between the two diseases. The diagnosis is based on the presence of characteristic compounds in body fluids as detected by organic acid analysis in urine and acylcarnitine profile in blood. Therapy is based on low-protein high-energy diet, carnitine supplementation, and metronidazole. Some patients with methylmalonic aciduria (MMA) respond to pharmacological doses of vitamin B12. Given the poor long-term prognosis, liver transplantation has been recently attempted as an alternative therapy to conventional medical treatment to cure the underlying metabolic defect. Nevertheless, the overall experience to date does not clearly demonstrate its effectiveness in preventing further deterioration or improving survival and quality of life. The recent implementation of neonatal screening by electrospray tandem mass spectrometry has decreased early mortality and improved the short-term outcome, without changing the detection rate of both diseases in the screening population compared to clinically detected cases. However, the limited number of patients and the short duration of their follow-up do not yet permit drawing final conclusions on its effect on the long-term outcome of methylmalonic and propionic acidemia.

Humans↗
PubMed2006

A common mutation in the CBS gene explains a high incidence of homocystinuria in the Qatari population.

We report the results of a study carried out to delineate genetic and epidemiological aspects of homocystinuria in the Qatari population. Sixty-four patients with homocystinuria (37 males, 27 females, age 1 to 29 years) from 31 nuclear families were ascertained over a period of more than four years. The incidence of homocystinuria in Qatar was calculated to be > or =1:3000, the highest in the world known so far. All patients in whom data were available were vitamin B6-nonresponsive. Molecular studies were performed in all patients. All 53 patients from tribe M and all three patients from tribe K were homozygous for the mutation c.1006C>T (p.R336C) in the CBS gene, with an additional seven patients resulting from mixed marriages between tribe M and tribe K. A single patient from tribe S was homozygous for mutation c.700G>A (p.D234N) in the CBS gene. Both mutations have been previously reported but involve hypermutable CpG dinculeotides and may be recurrent mutations in the Qatari population. The results of this study illustrate a strong founder effect causing a high prevalence of an autosomal recessive disease in a highly consanguineous Arabian population. Molecular neonatal screening may be suitable for early detection of homocystinuria in this population.

Adolescent↗
PubMed2002

The epidemiology of mental retardation: challenges and opportunities in the new millennium.

There are a number of problems and challenges in relating the science of epidemiology to mental retardation (MR). These relate to how MR is defined and classified and how these definitions may change over time. These as well as other differences in ascertainment sources and methods need to be considered when comparing MR prevalence over time and place. On the other hand, advances in technology also provide new and efficient methods of data collection both by data linkage and by use of web-based methods to study rare diseases. While prevalence studies have not been individually reviewed, we have examined the range of data including recent studies relating to how prevalence differs according to age, gender, social class and ethnicity. Some problems with available etiological classification systems have been identified. Recent etiological studies, most of which use different classification systems, have been reviewed and explanations have been postulated to account for differences in results. Individual risk factors for MR are considered whilst the option of considering a population as opposed to a high risk strategy to MR prevention is raised. This might well involve improving the social milieu surrounding the occurrence of individual risk factors. The impact of biotechnological advances such as antenatal and neonatal screening and assisted reproduction on MR are discussed. The issue of how inequalities in access to technology may impact on case identification and even have the potential to further widen inequalities is raised. The importance of extending the use of epidemiological tools to study the social, health and economic burden of MR is also emphasized. However, in order to apply to MR the "prevention-intervention-research" cycle, which surely underpins all epidemiology, it is vital to ensure that the methodological challenges we raise are adequately addressed.

Adolescent↗
PubMed1994

Rocking and pacifiers: two comforting interventions for heelstick pain.

The effects of behavioral interventions in reducing the stress of infant pain are not well documented. Two comfort interventions, rocking and pacifiers, were compared with routine care administered to 60 newborn infants randomly assigned to the three conditions following a neonatal screening heelstick. Heart rate, state of arousal, and crying were recorded continuously. Both pacifiers and rocking reduced crying, but pacifiers predominantly produced sleep states and rocking predominantly produced alert states. Pacifiers reduced heart rate levels significantly more than did rocking. Thus, newborns clearly benefit from both comforting methods. Several mechanisms are proposed to account for these findings.

Bloodletting↗
PubMed2005

Prenatal diagnosis of sickle syndromes in India: dilemmas in counselling.

OBJECTIVES: The sickle gene is prevalent in the scheduled caste and tribal populations in India. The clinical presentation of sickle cell disease is extremely variable, and there are no neonatal screening programmes. This is the first report on prenatal diagnosis of sickle syndromes in 85 couples at risk (sickle cell anemia-69; sickle thalassemia-16) from different regions in India. Most of the couples were from a low socioeconomic group and their decisions were entirely dependent on the local counselling given. We have evaluated the acceptability of prenatal diagnosis and the dilemmas faced in counselling these families. METHODS: Chorion villus sampling was done in the first trimester and DNA analysis using reverse dot blot hybridization or restriction enzyme digestion with Dde1 in 65 cases. Cordocentesis was done in the second trimester and fetal blood analyses by automated HPLC in 20 cases who came late. RESULTS: 32.9% of couples came prospectively for diagnosis. 23.5% of fetuses were affected (sickle cell anemia-18, sickle thalassemia-2). The beta-thalassemia mutation in both cases was IVS 1-5(G->C). All the couples with an unfavourable diagnosis opted for termination of pregnancy. CONCLUSION: Sickle cell anemia has a relatively benign clinical course in some tribal groups in India. This raises a dilemma whether we are justified in advising prenatal diagnosis in all such cases.

Anemia, Sickle Cell↗
PubMed2004

Reduction in prevalence of chronic Pseudomonas aeruginosa infection at a regional pediatric cystic fibrosis center.

Various management strategies were introduced at the Leeds Regional Cystic Fibrosis (CF) Unit in an attempt to reduce the prevalence of chronic Pseudomonas aeruginosa respiratory infection, previously thought to be inevitable in most children with CF. These included neonatal screening (1975), regular microbiological monitoring (1975), early antibiotic treatment of first isolations of P. aeruginosa (1985), intensive intravenous antibiotic treatment where nebulized antibiotics failed to eradicate P. aeruginosa (1988), and separate clinics for patients chronically infected with P. aeruginosa and uninfected patients (1991). The aim of this study was to assess the impact of these interventions. All 232 patients receiving full-time care at the Leeds Paediatric CF Centre during the period January 1990-December 2000 were categorized into four groups: never grown P. aeruginosa; free of P. aeruginosa for at least 1 year; intermittent grower of P. aeruginosa with </=50% of months with samples positive for P. aeruginosa over the previous 12 months; and chronic P. aeruginosa infection with >50% of months with samples positive for P. aeruginosa over the previous 12 months. The yearly prevalence of patients having chronic P. aeruginosa infection fell significantly during the study, from 24.5% in 1990 to 18.1% in 2000 (P < 0.05), despite an increase in mean age of patients from 7.73 to 9.42 years. The number of patients aged less than 11 years who had chronic P. aeruginosa infection fell from 23.8% in January 1990 to only 4.3% by December 2000. The annual incidence and mean age of first acquisition of P. aeruginosa did not alter significantly. In conclusion, antipseudomonal management strategies were associated with both reduced prevalence, and an increase in the mean age of onset of chronic P. aeruginosa infection.

Adolescent↗
PubMed2001

A phenylalanine hydroxylase amino acid polymorphism with implications for molecular diagnostics.

Mutations in the gene encoding phenylalanine hydroxylase (PAH, EC 1.14.16.1) are associated with various degrees of hyperphenylalaninemia, including classical phenylketonuria (PKU). We examined the PAH gene in a Brazilian PKU family of African origin and identified three missense variants, R252W (c.754C --> T), K274E (c.820A --> G), and I318T (c.953T --> C), the two latter of which were transmitted in cis. Expression analyses in two different in vitro systems showed that I318T is associated with profoundly decreased enzyme activity, whereas the enzyme activity of K274E is indistinguishable from that of the wild-type protein. Detailed kinetic analyses of PAH expressed in E. coli showed that the K274E mutant protein has kinetic properties similar to that of the wild-type protein. Population studies have suggested that the K274E variant occurs on approximately 4% of African-American PAH alleles, whereas the neonatal screening incidence of PKU among African Americans is only 1:100,000. This is to our knowledge the first demonstration of a PAH missense variant with no apparent association to PAH deficiency. Awareness of this common variant may be helpful to laboratories that perform molecular diagnosis of PAH deficiency in populations of African origin.

Alleles↗
PubMedDate not supplied

Tetrahydrobiopterin deficiencies without hyperphenylalaninemia: diagnosis and genetics of dopa-responsive dystonia and sepiapterin reductase deficiency.

DOPA responsive dystonia (DRD) and sepiapterin reductase (SR) deficiency are inherited disorders of tetrahydrobiopterin (BH4) metabolism characterized by the signs and symptoms related to monoamine neurotransmitter deficiency. In contrast to classical forms of BH4 deficiency DRD and SR deficiency present without hyperphenylalaninemia and thus cannot be detected by the neonatal screening for phenylketonuria (PKU). While DRD is mostly caused by autosomal dominant mutations in the GTP cyclohydrolase I gene (GCH1), SR deficiency is an autosomal recessive disease. The most important biochemical investigations for the diagnosis of these neurological diseases includes CSF investigations for neurotransmitter metabolites and pterins as well as neopterin and biopterin production in cytokine-stimulated fibroblasts. Discovery of SR deficiency opened new insights into alternative pathways of the cofactor BH4 via carbonyl, aldose, and dihydrofolate reductases. As a consequence of the low dihydrofolate reductase activity in the brain, dihydrobiopterin intermediate accumulates and inhibits tyrosine and tryptophan hydroxylases and uncouples nitric oxide synthase (nNOS), leading to neurotransmitter deficiency and possibly also to neuronal cell death.

Alcohol Oxidoreductases↗
PubMedDate not supplied

Compliance in a screening program for neuroblastoma.

BACKGROUND: The Quebec Screening Program for neuroblastoma was undertaken to determine if routine screening of infants for neuroblastoma would decrease the mortality rate from this cancer. All 476,603 children born in Quebec during a 5-year period (1989 to 1994) were offered this screening at ages 3 weeks and 6 months. Through various strategies, an attempt was made to attain the highest level of voluntary compliance possible. METHODS: Each screening consisted of the analysis of the catecholamine metabolites vanillylmandelic acid and homovanillic acid on a dry, urine-saturated filter paper mailed to a central laboratory by the parents. The strategies employed to optimize compliance consisted of increasing the awareness of the parents, health professionals, and the public about neuroblastoma and the screening program. RESULTS: The population responded well to this public health measure, with a 91% compliance rate at 3 weeks and a 74% compliance rate at 6 months. CONCLUSIONS: A well-informed population accustomed to voluntary screening for metabolic disease in infants responds well to screening for cancer.

Female↗
PubMed1990

Hearing screening in health examination services for young children at health centers in Japan.

The infant hearing screening program (IHSP) was devised for the early discovery of severe to profound hearing impairments in children. The program has been planned for use in the ordinary health examination services (with a follow-up program) for young children in health centers. The IHSP consists of a three-part test battery: a high-risk register for deafness, a developmental test of auditory function, and an auditory behavioral test. From 1977 to 1983, 22,443 young children were screened in four health centers in Osaka City. Ten of these children were identified as having serious hearing loss. Five of these 10 children were below 11 months of age. The incidence of children with severe to profound hearing impairment was inferred to be approximately 0.04% in the general population of young children. Certain problems occurred in the IHSP, and included a high level of over-referrals. However, the IHSP was considered to be a useful screening method for the early detection of severe hearing impairments when used in general health check-ups in health centers.

Child Health Services↗
PubMed1996

Apparent higher frequency of phenylketonuria in the Mexican state of Jalisco.

The geographic origin of Mexican patients with phenylketonuria (PKU) in Mexico City and in southern California was studied. Compared to patients with other metabolic disorders, patients with PKU were significantly more likely to have originated from the Los Altos region of the state of Jalisco and its environs. The incidence of PKU among mentally retarded students attending special education schools was found to be significantly higher in Jalisco (particularly the Los Altos region) than in the neighboring state of Guanajuato (1.09% vs 0.3%). These results strongly suggest a "population of origin" effect, the mutant allele(s) having been introduced by the Spanish ancestors of the current population. Our findings also support the addition of PKU to the neonatal screening program for this region of Mexico.

Child↗
PubMed1984

Ethnic distribution of phenylketonuria in the north German population.

Results of neonatal screening for phenylketonuria (PKU) suggest a west-east gradient of PKU gene frequency in central Europe. In order to test the hypothesis that the unexpectedly high prevalence of PKU in northwestern Germany (northern region of the FRG) is due to the migration of Germans from eastern regions of prewar Germany in the decade after World War II, grandparental origin was determined in a group of 87 pediatric PKU patients and in a control group of 210 children. Grandparents of east German origin were significantly more frequent among the PKU patients. The observed frequency distribution of grandparental subgroups was described by a theoretical distribution in order to obtain a likely set of values for the ratio between the frequency of the PKU gene in the autochthonous populations of prewar northeastern and northwestern Germany. The most likely value for the PKU gene frequency ratio was 1.37, which indicates that the prevalence for PKU in prewar northeastern Germany was almost twice as high as in the autochthonous population of the northwest.

Ethnicity↗
PubMed1981

Red cell phosphoglucomutase (PGM)-deficiency: hereditary defect of the PGM1-locus.

Reduced phosphoglucomutase (PGM) activity (approximately 25% of normal) was found in erythrocytes from a healthy newborn infant. The PGM activity was also diminished (approximately 50% of normal) in the erythrocytes of the parents. No PGM1 isoenzymes were found in the erythrocytes of the propositus, as demonstrated by the starch gel electrophoresis. Both parents showed a normal distribution of the PGM1 isoenzymes. We propose a heterozygous state in the parents for a gene determining the activity of the PGM1 isoenzymes and that no activity of the PGM1 isoenzyme could be detected in erythrocytes of the propositus because of his homozygous state. In neonatal screening for galactosaemia red cell PGM deficiency gives false positive results, as does glucose-6-phosphate dehydrogenase deficiency.

Diagnosis, Differential↗
PubMed1986

"Inborn errors of metabolism" and "chemical individuality", two ideas of Sir Archibald Garrod briefly revisited 50 years after his death.

Two ideas of Sir A. Garrod, "chemical individuality" (1902) and "inborn errors of metabolism" (1908) have proved fundamental for the development of medical knowledge. The latter idea was more fortunate than the former which, however has been extremely heuristic. On the other hand the two ideas are not entirely independent of each other: in fact, a third Garrodian concept, "inborn factors in disease", represents a significant link between them. "Inborn errors of metabolism" revived the laws of genetics and opened the way to interpretation of the molecular diseases with all their inherent practical modern implications (neonatal screening, prenatal diagnosis, and in perspective, genetic engineering). "Chemical individuality" still constitutes a valid premise for knowledge of biological individuality (in other words, the "biological ego") fundamentally programmed for conservation of self and for continuous discrimination of self versus non-self.

Adult↗
PubMed1987

Phenylketonuria in Kuwait and Arab countries.

Seven cases of phenylketonuria including a pair of siblings were detected among 451 institutionalized mentally retarded individuals in Kuwait. A further 13 cases from eight Arab families of different nationalities were ascertained among referral cases. The occurrence of phenylketonuria in Kuwait and other Arab countries is discussed in view of the high consanguinity rate and large family size. Our findings stress the need for neonatal screening.

Adolescent↗
PubMed1995

Tyrosinaemia--treatment and outcome.

Tyrosinaemia type I is, untreated, a fatal disease: in the acute form from liver failure, in the chronic form often from hepatocellular carcinoma. Acute neurological crisis is also a cause of death. Traditionally the treatment has been with diet, but for a decade liver transplantation has been the ultimate treatment. The continuous production of the pathological metabolites in the kidneys after transplantation appears to be without significance. Introduction of the enzyme inhibitor NTBC in the treatment of tyrosinaemia has reduced the need for liver transplants. Neonatal screening may be justified as efficient treatment has become available. The complex phenotype of lethal albino mice, with severe alterations in gene expression, has been shown to be caused by fumarylacetoacetase deficiency. Prolonged hypoglycaemia in otherwise adequately treated tyrosinaemia patients may result from depressed expression of genes coding for enzymes in gluconeogenesis, as seen in the mouse model. Self-induced genetic correction in liver tissue that occurs in many tyrosinaemia patients may reduce the risk of liver failure in some patients.

Amino Acid Metabolism, Inborn Errors↗
PubMed1995

Pre- and postnatal diagnosis of peroxisomal disorders using stable-isotope dilution gas chromatography--mass spectrometry.

Quantitative analysis of the following peroxisomal metabolites is reported: very long-chain fatty acids (VLCFA), pipecolic acid, bile acid intermediates, phytanic and pristanic acid, in plasma, urine, cerebrospinal fluid (CSF), blood spots collected at neonatal screening and amniotic fluid. An overview is given of the concentrations of these metabolites in body fluids from control subjects and all patients investigated so far in this laboratory. The method of choice is gas chromatography -- mass spectrometry (GC-MS) with electron capture detection, combined with the use of stable-isotope-labelled internal standards.

Amniotic Fluid↗
PubMed1991

Polymorphic DNA haplotypes at the phenylalanine hydroxylase locus and their relation to phenotype in Swedish phenylketonuria families.

The genetic heterogeneity at the phenylalanine hydroxylase (PAH) locus was studied in 88 families including 93 of the 105 children with phenylketonuria (PKU) or hyperphenylalaninemia (HPA) detected through the Swedish neonatal screening program from 1966 to the end of 1986. Haplotypes based on eight restriction fragment length polymorphisms (RFLPs) at the PAH locus could be constructed for 132 normal and 136 mutant alleles. The normal alleles were of 27 different RFLP haplotypes, 9 of which have not been described previously, but there was a dominance of a few haplotypes common to many European populations. The distribution of mutant alleles was significantly different from that in neighboring countries, even though over 90% of all mutant alleles were confined to six RFLP haplotypes, also prevalent in other European populations. Allele-specific oligonucleotide hybridization analysis for the Arg408 to Trp408 mutation and for the G to A splicing mutation in intron 12 showed exceptions to the previously reported linkage of these mutations to mutant haplotypes 2 and 3, respectively. Correlation of mutant alleles with clinical phenotypes pointed to the presence of at least two different mutations associated with each of six haplotypes. We argue that PKU/HPA in the Swedish population may be caused by at least 13 different mutations in addition to the 4 already identified. The theoretical informativity of RFLP analysis in heterozygote detection and prenatal diagnosis in PKU/HPA families was estimated at approximately 85%. Carrier detection could, in effect, be accomplished for 88% of the 56 healthy siblings in the families studied.

Alleles↗