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Presentation, diagnosis, and treatment of the disorders of monoamine neurotransmitter metabolism.
For many years, all of the described cases of monoamine neurotransmitter deficiency were associated with hyperphenylalaninemia that was generally detected at neonatal screening. It is now clear that inherited deficiency of monoamines often occurs in the absence of hyperphenylalaninemia and that the normal battery of screening tests used to investigate individuals with suspected metabolic disease will not detect these cases. Diagnosis in this situation must rely heavily on clinical suspicion. This article, therefore, describes the presentation and clinical symptoms that result from defective monoamine neurotransmission; outlines therapeutic approaches; and explains how cerebrospinal fluid profiles of monoamine metabolites, their precursors, and the cofactor required for monoamine synthesis can be used to pinpoint the exact site of the metabolic lesion.
Heel lancing in term new-born infants: an evaluation of pain by frequency domain analysis of heart rate variability.
The aim of the investigation was to assess pain by frequency domain analysis of heart rate variability (HRV) during a routine heel lancing procedure in term new-born infants. Beat-to-beat heart rate (HR) was recorded in 23 healthy new-born infants on the maternity ward during blood sampling for neonatal screening. A sham heel prick prior to the sharp lancing procedure was performed randomly in half of the infants. Spectral analysis of HRV was assessed for each of the following sequences: (1) baseline (2) sham heel prick (3) sharp heel prick and (4) squeezing the heel for blood sampling. The response to the sham prick did not differ significantly from the sharp prick. Compared with the baseline, sharp lancing gave rise to minor increases in HR and variability in the low frequency band of the spectral analysis. A clear stress response was provoked when the heel was squeezed for blood sampling, indicated by an increased HR and a decreased spectral power in the high frequency band (i.e. lower vagal tone). The different stress responses during the lancing and the squeezing of the heel were clearly illustrated when principal component analysis was applied and the vectors for the changes in HR and spectral pattern were indicated. In conclusion, the squeezing of the heel is the most stressful event during the heel prick procedure.
Nutritional challenges of infants with cystic fibrosis.
Nutrition plays an essential role in the management of cystic fibrosis (CF), particularly in infants with their high energy requirement due to rapid growth. Most infants are already malnourished at the time of clinical diagnosis due to an energy imbalance with increased losses and needs not compensated by energy intake. Even in very young asymptomatic CF patients diagnosed by neonatal screening programs, nutritional deficits can be detected in a high proportion of infants, since about half of all CF patients have evidence of pancreatic insufficiency at the time of birth. This review provides recommendations for assessment of the nutritional status at diagnosis and nutritional management including supplementation with pancreatic enzymes during the first year of life.
Clinical, fluorine-18 labeled 2-fluoro-2-deoxyglucose positron emission tomography of the brain, MR spectroscopy, and therapeutic attempts in methylenetetrahydrofolate reductase deficiency.
The cases of three infants, two Saudi and one Bahraini, with methylenetetrahydrofolate reductase (MTHFR) deficiency are reported. They presented in the neonatal period with lethargy, poor feeding, hypotonia, and frequent apneas. Tandem mass spectrometry (MS/MS) of a blood spot indicated very low methionine level and of urine revealed high homocysteine. The diagnosis was confirmed by demonstrating severe deficiency of MTHFR in the cultured skin fibroblast. All patients were treated with folinic acid, vitamin B12, betaine, and methionine, with good initial response to the therapy. In two patients, the diagnosis was late and their disease was severe, resulting in neurological crippling. However, in the third patient, who was diagnosed and treated early, the current neurological status is normal. In her case, at 1 month of age, the brain FDG PET scan documented very faint cerebral and cerebellar cortical activities. After 5 months of intensive therapy, that included 200-600 mg/kg per day methionine, she had a dramatic clinical and biochemical recovery as well as a parallel improvement in FDG PET. Brain MR spectroscopy indicated normal neuronal glial and myelin markers for her age. We conclude that the functional changes confirmed by the FDG PET study were better correlated with the clinical course of the patient and adequately monitored the response to therapy. This disease warrants early detection through neonatal screening program, since the beneficial effect of early administration of adequate therapy with combined use of betaine and a high dose of methionine is rewarding and may be the treatment of choice for MTHFR deficiency.
BH4-sensitive hyperphenylalaninemia: new case and review of literature.
We report a patient with BH(4)-sensitive phenylketonuria. In neonatal screening, phenylalanine levels above 10 mg/dl were detected. In the tetrahydrobiopterin- (BH(4)) loading test, phenylalanine concentrations in serum fell significantly. Dihydropteridine reductase activity in blood, pterines, and neurotransmitters in cerebrospinal fluid, as well as pterines in urine were all normal. Mutation analysis revealed compound-heterozygosity for the mutations R408W and K320N. Under BH(4)-supplementation without a specific phenylalanine-reduced diet, phenylalanine-concentrations are in the therapeutic range and our patient developed normally.
[A familial case with generalized resistance to thyroid hormones].
BACKGROUND: The syndrome of generalized resistance to thyroid hormones is more frequent than was thought. CASE REPORTS: A 13-year old girl was examined for her short stature. Evaluation of her thyroid function showed increased levels of IT3 and IT4 and normal value of TSH; she also had mosaic Turner's syndrome. Her cousin was rapidly diagnosed as suffering from the same syndrome because of moderately high thyrotropic levels found during neonatal screening; this syndrome was confirmed by molecular biology tests. Five generations of this family were identified as being affected with a pattern indicating autosomal dominant inheritance. CONCLUSION: The clinical manifestations of familial generalized resistance to thyroid hormones vary but this syndrome is easy to biologically confirm. The importance of diagnosing affected children as early as possible should be emphasized, as in such cases their development must be closely monitored particularly where their growth and neurodevelopment are concerned.
Paediatric hip--ultrasound screening for developmental dysplasia of the hip: a review.
This paper will try to deal with the following questions: Which is the correct screening model for the developmental dysplasia of the hip (DDH)? What is the clinical significance of "sonographic" DDH? Can overtreatment produced by ultrasound (US) screening cause a waste of resources and eventually morbidity? We reviewed the literature since January, 1996 through December, 2000. To compare our experience with the literature, we analysed the results of the US examinations of the hip performed in our Institute. Over 4 years of US screening 11326 infants (22652 hips), aged 3 days to 4 months, were examined consecutively. Sonographic hip findings were abnormal in 531 infants (4.7%). The screening showed 381 subjects (3.36% of the population) with a type IIa hip (bilateral or unilateral); 65% of these infants were normal at follow up and only 35% worsened. On the whole we treated 282 infants (2.5%). No open reduction was performed. Avascular necrosis appeared in 2/282 treated cases (1.06%). We support the routine generalised US screening of neonatal hips. The excess of doubtful cases and, consequently, of the extra referrals may be limited, and the overtreatment decreased to the lowest rates reported by optimisation of everyone's approach.
Simultaneous measurement of phenylalanine and tyrosine in phenylketonuric plasma and dried blood by high-performance liquid chromatography.
Phenylketonuria (PKU) is a disorder characterized by an interruption in the conversion of phenylalanine to tyrosine, a reaction catalyzed by phenylalanine hydroxylase (PAH). Animal models of PKU used in this study were induced by daily subcutaneous injections of pups with alpha-methylphenylalanine plus phenylalanine in utero and postnatally from day 4 to day 14. Dry blood and plasma were utilized to measure phenylalanine concentration in PKU rats. The results indicated that the concentration of phenylalanine is higher and more stable in plasma than dry blood. Precolumn derivatization of dried blood and plasma free amino acids were conducted with phenylisothiocyanate (PITC). The phenylthiocarbamyl (PTC) derivatives were separated on a reversed-phase C-18 column (15 cm x 4.6 mm). A gradient high-performance liquid chromatography method with two eluents, 0.1 M sodium acetate buffer and 100% acetonitrile was developed to facilitate the separation of nine amino acids within 11 min. Tyrosine and phenylalanine eluted the column at 5.4 and 9.4 min, respectively. This method provides a quick and reliable technique for neonatal screening.
Effect of age at thyroid stimulating hormone normalization on postural control in children with congenital hypothyroidism.
Neonatal screening programmes allow early treatment to limit the consequences of congenital hypothyroidism on maturation of the central nervous system, and on psychomotor and educational outcome. Consequences of age at thyroid stimulating hormone (TSH) normalization on postural control were evaluated in 17 children with congenital hypothyroidism (14 females, three males; median age 12 years 1 month, range 7 to 14 years) and in 11 control individuals (eight females, three males: median age 10 years 6 months, range 8 to 14 years). Children with congenital hypothyroidism were split into two groups according to time of TSH normalization: before (group 1) or after (group 2) 3 months of age. Posturography (static and dynamic tests), educational (school performance), and psychomotor (WISC and revised Bruininks Oseretsky tests) evaluations were carried out. Group 2 results showed significant abnormalities in postural, educational, and psychomotor aptitudes in comparison with group 1 and control children (stability, Bruininks-Oseretsky, school performance: p < or = 0.05 or p < or = 0.01). Early TSH normalization is necessary to allow for normal development of the neurosensorial afferent pathways (vestibular, proprioceptive) and of central integration (cerebellum, vestibular nuclei).
Subclinical visual impairment in phenylketonuria. A neurophysiological study (VEP-P) with clinical, biochemical, and neuroradiological (MRI) correlations.
During detailed visual function testing, pattern-reversal visual evoked potentials (VEP), generated by different spatial frequencies (3 c/d, 1 c/d and 0.6 c/d) and visual contrasts (100% and 10%) were recorded in 21 adolescent and young adult phenylketonuric (PKU) patients (11 females and 10 males; mean age 14.8 years, range 9-22.8) on and off diet. In 14 of the 21 patients, disease had been detected at neonatal screening and in 7 later. Ten age-matched healthy subjects acted as controls. Recordings in more than 40% of eyes in the whole group and 30% of eyes in the screening subgroup showed a prolonged P100 latency. All visual pattern stimuli elicited a significantly longer P100 latency in PKU patients than in controls. VEP latencies to 3 c/d, 1 c/d and 1 c/d with 10% contrast--but not to 0.6 c/d--were longer in patients off diet than in patients on diet. No differences were found between VEP latencies in early- and later-detected subjects. To study the link between biochemical variables and VEP latencies, we envisaged either a linear relationship between recent exposure to phenylalanine (Phe) and VEP abnormalities or a threshold model considering phenylalanine (Phe) concentrations among the factors influencing VEP latencies. The correlation analysis detected an association between plasma Phe concentrations and abnormal VEP latencies, predicting that plasma Phe concentrations > 901 mumol/L would prolong VEP latencies to 1 c/d; concentrations > 879 mumol/L would prolong latencies to 3 c/d; and concentrations > 898 mumol/L would prolong latencies to 1 c/d with 10% contrast.
Glutaric aciduria type I: from clinical, biochemical and molecular diversity to successful therapy.
The biochemical hallmark of glutaric aciduria type I (GA I) due to glutaryl-CoA dehydrogenase deficiency is the accumulation of glutaric acid, and to a lesser degree of 3-hydroxyglutaric and glutaconic acids. Abnormal metabolites vary from gross organic aciduria to only slightly or intermittently elevated or even normal excretion of glutaric acid, making the diagnosis sometimes difficult. Close to 100 pathogenic mutations have been identified in the gene encoding glutaryl-CoA dehydrogenase. Specific mutations correlate with low or no excretion of glutaric acid, but there appears to be no correlation between genotype and clinical phenotype. GA I causes unique age- and location-specific neuropathological sequelae. Starting in the second half of gestation, maturation of the frontal and temporal cortex is hindered, leading to the characteristic appearance of frontotemporal atrophy. Between 6 and 18 months of age, relatively mild neurological symptoms may become exacerbated by fever or a catabolic state in the course of common infections or routine immunizations, by fasts required for surgery, or by minor head injuries. Putamen and caudate are destroyed, resulting in a permanent movement disorder that is similar to cerebral palsy and ranges from extreme hypotonia to choreoathetosis to rigidity with spasticity. Recently, the underlying pathophysiology could be delineated to an environmentally triggered age- and location-specific overstimulation of the NMDA 2B receptor subtype. Current therapy prevents brain degeneration in more than 90% of affected infants who are treated prospectively. Without treatment, more than 90% of affected children will develop severe neurological disabilities. Recognition of this disorder before the brain has been injured is essential to treatment. GA I may be recognized in routine neonatal screening performed with tandem mass spectrometry by an elevation of glutarylcarnitine. Where this is not done, timely diagnosis depends on the recognition of relatively nonspecific physical findings such as hypotonia, irritability, macrocephaly, on the detection of suggestive abnormalities in neuroimaging and on quantitative urinary organic acid analysis by gas chromatography--mass spectrometry.
Applications of mass spectrometry in the study of inborn errors of metabolism.
During the twentieth century, and particularly in its last decade, there have been major advances in mass spectrometry (MS). As a result, MS remains one of the most powerful tools for the investigation of genetic metabolic disease. Analysis of organic acids by gas chromatography-mass spectrometry (GC-MS) and analysis of acylcarnitines by tandem mass spectrometry are still leading to the discovery of new disorders. Tandem mass spectrometry is increasingly being used for neonatal screening. New methods for lipid analysis have opened up the fields of inborn errors of cholesterol synthesis, of bile acid synthesis and ofleukotriene synthesis. The latest developments in MS allow it to be used for determination of the amino acid sequence and posttranslational modifications of proteins. There are still some major hurdles to be overcome, but soon it should be possible to detect mutant proteins directly rather than by cDNA or genomic DNA analysis. Measurement of which proteins are overexpressed and underexpressed ('proteomics') should provide further information on the pathogenesis of complications of inborn errors, e.g. hepatic cirrhosis. The use of stable isotopes in conjunction with MS allows us to probe metabolic pathways. As an example, evidence is presented to support the contention that vitamin E and its oxidation product are catabolized by peroxisomal beta-oxidation. Mass spectrometry also has a major role in monitoring new forms of treatment for inborn errors.
Autism and phenylketonuria.
Phenylketonuria (PKU) has been also reported in children with infantile autism (IA); however, the frequency of this association is variably reported. Patients with various forms of hyperphenylalaninemia (HPA) were evaluated applying two methods: the Autism Diagnostic Interview-Revised (ADI-R) and the Childhood Autism Rating Scale (CARS). A total of 243 patients were investigated, 97 with classical PKU, 62 identified by neonatal screening, and 35 late diagnosed. None out of 62 patients with classic PKU diagnosed early met criteria for autism. In the group of 35 patients diagnosed late, two boys (5.71%) ages 16 and 13 years fulfilled the diagnostic criteria for autism. The present study confirms that classical PKU is one of the causes of autism, but the prevalence seems to be very low.
The incidence of cystic fibrosis in Scotland calculated from heterozygote frequencies.
The incidence of cystic fibrosis (CF) has previously been calculated from epidemiological surveys and from neonatal screening. With the cloning of the CF gene it has become possible to derive incidence figures from heterozygote frequencies, provided that the distribution of mutant alleles among healthy carriers is the same as among affected people. We have estimated the allele frequencies for four CF mutations, AF508, G551D, G542X and R117H, in 14360 unselected women undergoing antenatal heterozygote screening. The proportion of R117H, an allele of known mild effect, was much greater for heterozygotes than for homozygotes. The incidence of CF was therefore calculated from the heterozygote frequencies of AF508, G551D and G542X in a larger cohort of 27 161 successively screened women. The point estimate for the incidence of CF in the Scottish population was 1 in 1984, with 95% confidence intervals of 1 in 1692 to 1 in 2336.
Screening for GALC to make neonatal diagnosis and initial neonatal stem cell treatment with umbilical cord blood.
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Molecular genetic basis and prevalence of glycogen storage disease type IIIA in the Faroe Islands.
Glycogen storage disease type IIIA (GSD IIIA) is caused by mutations of the amyloglucosidase gene (AGL). For most populations, none of the AGL mutations described to date is particularly frequent. In this paper, we report that six children with GSD IIIA from the Faroe Islands were found to be homozygous for the novel nonsense mutation c.1222C>T (R408X) of the AGL gene. This mutation is easily detected by restriction enzyme digest with NsiI after mismatch PCR. Investigating five intragenic polymorphisms, we could show that this mutation was always associated with the same haplotype. The c.1222C>T mutation could be detected on two chromosomes of another 50 unselected GSD IIIA patients of other European or North American origin which means that this mutation plays a minor role worldwide. From the fact that we are currently aware of a total of 14 GSD IIIA cases in the Faroese population of 45 000, the observed prevalence is 1 : 3100. While the novel AGL mutation c.1222C>T was not detectable among 198 German newborns, nine out of 272 children from the Faroese neonatal screening program were found to be heterozygous for this mutation. Thus, the calculated prevalence is 1 : 3600 (95% CI 1:700-1:6400). We conclude that due to a founder effect, the Faroe Islands have the highest prevalence of GSD IIIA world-wide. The detection of the molecular defect has facilitated the diagnosis and has offered the opportunity for prenatal diagnosis in this patient group.
Complete virilization in congenital adrenal hyperplasia: clinical course, medical management and disease-related complications.
OBJECTIVE: In girls with congenital adrenal hyperplasia (CAH), genital ambiguity usually leads to a rapid neonatal diagnosis. Rarely, CAH causes complete virilization and male sex assignment with a delayed diagnosis. After being confronted with very specific problems in two of such patients, we collected data of patients with CAH and complete virilization in a nationwide study to delineate specific problems of these rare patients in order to improve their management. DESIGN AND PATIENTS: Through the German Working Group of Paediatric Endocrinology (Arbeitsgemeinschaft Pädiatrische Endokrinologie, APE), questionnaires were sent to all members caring for patients with CAH and complete virilization in their endocrine clinics. Data from 16 patients from 10 paediatric endocrine centres were assessed by questionnaire. RESULTS: The following problems have been encountered. (1) Sex assignment/gender identity: initially all patients had a male sex assignment. Six patients were diagnosed during the first month of life. Five were reassigned to female sex immediately, one at the age of 19 months. Except in one girl demonstrating some tomboyish behaviour, gender role behaviour in these patients did not differ from unaffected girls. Ten patients were diagnosed late at 3.4--7 years of age. In seven patients with a late diagnosis, male sex assignment was maintained; one of them expressed some concerns about living as a male. In three patients late sex reversal was performed, gender identity is very poor in one and new sex assignment is currently under consideration. (2) SURGERY: irrespective of the sex assigned, all patients had between one and three surgical procedures, including clitoris reduction and (repeated) vaginoplasties in patients with female sex assignment. Hysterectomy and ovarectomy were performed in patients with male sex assignment. (3) Short stature: patients with a late diagnosis of CAH had extremely advanced bone ages of +6.3 to +9.5 years, leading to severely reduced final height of 137 to 150 cm in adult patients. Patients tended to follow height percentiles of genetic females. One pubertal patient was suicidal due to short stature. (4) Central precocious puberty (CPP): prolonged exposition to adrenal androgens led to CPP in one patient. He was treated with GnRH analogues until gonadectomy. CONCLUSIONS: Patients with CAH and complete virilization have a high risk of being diagnosed late. There are major problems and uncertainties of the patients' families and the treating physicians concerning gender assignment. Gender identity is disturbed in some patients. In addition, multiple surgical procedures are necessary and short stature as well as central precocious puberty might be important to avoid late sequelae. While some surgical interventions are probably unavoidable, most of these issues could be resolved with an early diagnosis. Thus, especially for these patients, a neonatal screening programme for CAH would be of paramount importance.