Screening For Metabolic Diseases Research Articles

Metabolic newborn screening: between past and future

The introduction of new technologies such as tandem mass spectrometry (MS/MS) has lead to a major revolution in newborn screening for metabolic diseases: from “a test for a disease” (i.e. Guthrie test) to “a test for many diseases”. On a single drop of blood it is now possible to analyze and quantify various metabolites, not only acylcarnitines and amino acids, but also adenosine and 2′-deoxyadenosine (for the detection of ADA-SCID) and lysosomal enzymes. Therefore a great potential can be seen in near future for the diagnosis of diseases for which there may be a specific and effective therapy.

Term of pregnancy and mode of delivery: the neonatologist's point of view

The introduction of new technologies such as tandem mass spectrometry (MS/MS) has lead to a major revolution in newborn screening for metabolic diseases: from “a test for a disease” (i.e. Guthrie test) to “a test for many diseases”. On a single drop of blood it is now possible to analyze and quantify various metabolites, not only acylcarnitines and amino acids, but also adenosine and 2′-deoxyadenosine (for the detection of ADA-SCID) and lysosomal enzymes. Therefore a great potential can be seen in near future for the diagnosis of diseases for which there may be a specific and effective therapy.

Cystathionine Β-Synthase Deficiency, Turner Syndrome and İmmune Hydrops Fetalis in a Newborn: A Rare Coincidence

Cystathionine β-synthase (CBS) deficiency is a rare inborn error of amino acid metabolism affecting energy supply at the cellular level. Neonatal screening allows early presymptomatic diagnosis and better outcome, by preventing the complications like thrombotic disease. Here we present a female newborn baby with immune hydrops fetalis and mosaic Turner syndrome who has incidentally been early diagnosed with CBS deficiency upon detection of increased methionine on serum amino acid chromatography. The patient was unresponsive to pridoxine treatment which was compatible with p.S349N mutation detected on both alleles of cystathionine β-synthase gene. We would like to stress the point that CBS deficiency can be diagnosed by screening even in the setting of exchange transfusions and amino acid paper chromotography is a cheap and valuable metabolic screening tool in experienced hands. Since routine newborn screening for many metabolic diseases is currently not practiced in Turkey, all newborns born to families in which previous siblings had died due to unknown cause should be evaluated by amino acid paper chromotography and by other conventional metabolic tests when necessary.

Screening criteria: the need to deal with new developments and ethical issues in newborn metabolic screening

Newborn metabolic screening is the most widespread application of screening technology and provides the most comprehensive application of genetics in health services, where the Guthrie blood spot cards allow screening for metabolic diseases in close to 100 % of all newborn babies. Despite over 40 years of use and significant benefits to well in excess of 100,000 children worldwide, there is remarkably little consensus in what conditions should be screened for and response to new advances in medicine relating to programme expansion. In this article, the international criteria for newborn metabolic screening are considered, and we propose that these criteria are poorly developed in relation to the baby, its family and society as a whole. Additionally, the ethical issues that should inform the application of screening criteria are often not developed to a level where a consensus might easily be achieved. We also consider that when family interests are factored in to the decision-making process, they have a significant influence in determining the list of diseases in the panel, with countries or states incorporating family and societal values being the most responsive. Based on our analysis, we propose that decision criteria for metabolic screening in the newborn period should be adapted to specifically include parent and family interests, community values, patients’ rights, duties of government and healthcare providers, and ethical arguments for action in the face of uncertainty.

Second-tier test for quantification of underivatized amino acids in dry blood spot for metabolic diseases in newborn screening

The quantitative analysis of amino acids (AAs) in single dry blood spot (DBS) samples is an important issue for metabolic diseases as a second-tier test in newborn screening. An analytical method for quantifying underivatized AAs in DBS was developed by using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The sample preparation in this method is simple and ion-pairing agent is not used in the mobile phase that could avoid ion suppression, which happens in mass spectrometry and avoids damage to the column. Through chromatographic separation, some isomeric compounds could be identified and quantified, which cannot be solved through only appropriate multiple reactions monitoring transitions by MS/MS. The concentrations of the different AAs were determined using non-deuterated internal standard. All calibration curves showed excellent linearity within test ranges. For most of the amino acids the accuracy of extraction recovery was between 85.3 and 115 %, and the precision of relative standard deviation was <7.0 %. The 35 AAs could be identified in DBS specimens by the developed LC-MS/MS method in 17-19 min, and eventually 24 AAs in DBS were quantified. The results of the present study prove that this method as a second-tier test in newborn screening for metabolic diseases could be performed by the quantification of free AAs in DBS using the LC-MS/MS method. The assay has advantages of high sensitive, specific, and inexpensive merits because non-deuterated internal standard and acetic acid instead of ion-pairing agent in mobile phase are used in this protocol.

Prevalence of Metabolic Syndrome in Patients with Psoriasis: A Population-Based Study in the United Kingdom

Increasing epidemiological evidence suggests independent associations between psoriasis and cardiovascular and metabolic disease. Our objective was to test the hypothesis that directly-assessed psoriasis severity relates to the prevalence of metabolic syndrome and its components.Population-based, cross-sectional study using computerized medical records from The Health Improvement Network Study population included individuals aged 45-65 years with psoriasis and practice-matched controls. Psoriasis diagnosis and extent were determined using provider-based questionnaires. Metabolic syndrome was defined using National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III criteria.44,715 individuals were included: 4,065 with psoriasis and 40,650 controls. 2,044 participants had mild psoriasis (≤2% body surface area (BSA)), 1,377 had moderate (3-10% BSA), and 475 had severe psoriasis (>10% BSA). Psoriasis was associated with metabolic syndrome, adjusted odds ratio (OR) 1.41 (95% CI 1.31-1.51), varying in a “dose-response” manner, from mild (adj. OR 1.22, 95% CI 1.11-1.35) to severe psoriasis (adj. OR 1.98, 95% CI 1.62-2.43).Psoriasis is associated with metabolic syndrome and the association increases with increasing disease severity. Furthermore, associations with obesity, hypertriglyceridemia and hyperglycemia increase with increasing disease severity independent of other metabolic syndrome components. These findings suggest that screening for metabolic disease should be considered for psoriasis, especially when extensive.

P-1250 - Is this really schizofrenia?

Introduction A 34 year old man was referred to our unit for psychiatric evaluation. His psychomotor development was normal until the age of 12, when he started showing progressive loss of cognitive skills and finalized motor activity. Symptoms rapidly worsened and by the age of 20 his language and motor skills were severly compromised. Starting at age 17 he had been treated with both 1st and 2nd generation antipsychotics which did not lead to any changes in symptoms. Family history was negative for psychotic or neurological disorders. The mother had alcohol abuse disorder and the younger sister was diagnosed with generalized anxiety disorder. Method At the time of our evaluation patient was receiving 10 mg of Olanzapine. He was vigilant and passively cooperative to examination; he displayed physical immobility, waxy flexibilitas, stereotyped behaviour, camptocormia, echolalia, blunted affect and automatic and repetitive behaviour. Thought content was difficult to evaluate but he denied hallucinations or delusional thoughts. Results BP was normal, as well as brain MRI and PET. Screening for Wilson's disease, metabolic diseases and fragile X Syndrome were negatve. DAT scan was also performed and showed no abnormalities. Medication withdrawal didn’t lead to any changes in his status. Conclusions The patient's symtoms fulfill the criteria for drug resistant Catatonic Schizophrenia. However the early onset of symptoms, the rapid deterioration of cognitive abilities, the early and extensive motor imparment and the complete resistance to drug treatment make this an interesting case for discussion about differential diagnosis.

Nonpharmacologic Treatment of Chronic Graft-versus-Host Disease in Children and Adolescents

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for many children with life-threatening diseases. One of the most significant long-term complications of transplantation is chronic graft-versus-host disease (cGVHD). Although the rates of cGVHD after HSCT are lower in the pediatric population than in adults, cGVHD remains a significant cause of morbidity and mortality. Medicines used to prevent and treat cGVHD remain unsatisfactory, with protracted use of immune suppression necessary and high rates of first-line treatment failure. Efforts to improve salvage treatment are urgently required. Nonpharmacologic strategies attempt to modulate the cellular inflammation response and possibly allow reduction or cessation of immunosuppressive drugs. Mesenchymal stromal cells (MSC) have been shown invitro to mediate a wide variety of immune responses. MSC have been used in the prophylaxis of acute GVHD (aGVHD) and for the treatment of established steroid refractory aGVHD and, more recently, in the management of cGVHD. Extracorporeal photochemotherapy (ECP) has shown promising efficacy in graft-versus-host disease, and may allow a significant reduction in the use of systemic steroids and other immunosuppressants, reducing long-term morbidity and mortality. The accumulated experience shows ECP to be well tolerated, with no clinically significant side effects.

Pulmonary Hypertension Presenting With Apnea, Cyanosis, and Failure to Thrive in a Young Child

Pulmonary Hypertension Presenting With Apnea, Cyanosis, and Failure to Thrive in a Young Child

Hallazgos clínicos y genéticos en pacientes con deficiencia de biotinidasa detectados en el cribado neonatal o selectivo de sordera o de enfermedades metabólicas hereditarias

Background and objetive To evaluate clinical, biochemical and genetic findings of two series of patients with biotinidase deficiency. Patients and method Fifteen cases detected through newborn screening and six through selective screening for hearing loss or metabolic disease. Results No patient detected by neonatal screening had symptoms and only one case with partial biotinidase activity developed myoclonic seizures that resolved with biotin. More common mutations found among this group were p.D444H and the double mutation [p.D444H;p.A171T]. However, neurological and hearing manifestations predominated among the six symptomatic cases and mutations p.L32fs, p.G34fs, p.T401I, p.D444H, p.T532 M and the novel one p.L466fs were identified. Patients with profound biotinidase deficiency and/or clinical signs were treated with pharmacological doses of biotin (10-30 mg daily). Conclusion Biotinidase deficiency must be included in the newborn screening programmes in order to begin early treatment even in partial forms. Different mutations found in both series of patients suggest that routine genetic procedure of the BTD gene by direct sequencing might be useful to assign patients to the partial or profound form of the disease.

Parents' Experiences of Expanded Newborn Screening Evaluations

Abnormal results of newborn screening for common metabolic diseases are known to create substantial distress for parents. We explored parents' perceptions during diagnostic evaluations for newer disorders that are less well understood. Thirty families completed 48 open-ended interviews before and/or after parents received confirmatory test results for their infants. Qualitative content analysis was used to analyze the data. Parents were shocked by the notification of the abnormal test result. Their urgent and often frustrating searches for information dominated the early phase of the screening process. Treatment center personnel were mainly informative and reassuring, but waiting for results exacerbated parents' distress. Equivocal results from diagnostic testing created uncertainties for parents regarding their infants' long-term health. After counseling, some parents reported inaccurate ideas about the disorders despite exposure to large amounts of information. Regardless of the challenges and anxieties of the evaluation, nearly every parent thought newborn screening was an important program for infant health. The evaluation of a newborn for an abnormal screening result was highly stressful for parents. To help reduce parents' distress, improvements in communications and clinical services are needed. Recommendations of useful Internet sites and discussions of this information may benefit parents. Tailoring counseling to meet the needs of culturally and educationally diverse families is needed. Families and infants with equivocal results are a new group of patients who merit comprehensive clinical follow-up.

Efficacy and outcome of expanded newborn screening for metabolic diseases--report of 10 years from South-West Germany.

BackgroundNational newborn screening programmes based on tandem-mass spectrometry (MS/MS) and other newborn screening (NBS) technologies show a substantial variation in number and types of disorders included in the screening panel. Once established, these methods offer the opportunity to extend newborn screening panels without significant investment and cost. However, systematic evaluations of newborn screening programmes are rare, most often only describing parts of the whole process from taking blood samples to long-term evaluation of outcome.MethodsIn a prospective single screening centre observational study 373 cases with confirmed diagnosis of a metabolic disorder from a total cohort of 1,084,195 neonates screened in one newborn screening laboratory between January 1, 1999, and June 30, 2009 and subsequently treated and monitored in five specialised centres for inborn errors of metabolism were examined. Process times for taking screening samples, obtaining results, initiating diagnostic confirmation and starting treatment as well as the outcome variables metabolic decompensations, clinical status, and intellectual development at a mean age of 3.3 years were evaluated.ResultsOptimal outcome is achieved especially for the large subgroup of patients with medium-chain acyl-CoA dehydrogenase deficiency. Kaplan-Meier-analysis revealed disorder related patterns of decompensation. Urea cycle disorders, organic acid disorders, and amino acid disorders show an early high and continuous risk, medium-chain acyl-CoA dehydrogenase deficiency a continuous but much lower risk for decompensation, other fatty acid oxidation disorders an intermediate risk increasing towards the end of the first year. Clinical symptoms seem inevitable in a small subgroup of patients with very early disease onset. Later decompensation can not be completely prevented despite pre-symptomatic start of treatment. Metabolic decompensation does not necessarily result in impairment of intellectual development, but there is a definite association between the two.ConclusionsPhysical and cognitive outcome in patients with presymptomatic diagnosis of metabolic disorders included in the current German screening panel is equally good as in phenylketonuria, used as a gold standard for NBS. Extended NBS entails many different interrelated variables which need to be carefully evaluated and optimized. More reports from different parts of the world are needed to allow a comprehensive assessment of the likely benefits, harms and costs in different populations.

Screening for Insulin Resistance and Cardiovascular Risk in Collegiate Football Linemen

To investigate the relationship between fitness, obesity, and the risk factors of type 2 diabetes and cardiovascular disease in obese-classified [by body mass index (BMI) > 30 kg/m] collegiate football linemen and male students of similar age and BMI. Cross-sectional observational study. Institutional university based. Two groups of volunteer students. Thirty collegiate football linemen and 10 sedentary age-matched and size-matched peers. Status as lineman or sedentary student. Height, weight, blood pressure, and body fat percent (BF%) were measured for each subject. Fasting blood draw was used to determine glucose, insulin, cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides. The athlete group had lower mean (SD) BF% [21.8 (3.89) vs control 27.1 (7.07); P = 0.01], despite no significant difference in age, weight, height, or BMI. The athlete group had lower systolic blood pressure [135.6 (13.29) mm Hg vs 148.1 (13.77); P = 0.015] and at-risk LDL (10% vs 40%; P = 0.05). The groups did not differ significantly in other measures. Body fat percent (before and after adjusting for BMI) was significantly correlated with every risk factor except glucose, whereas BMI was only significantly correlated with blood pressure and insulin. Collegiate football linemen with elevated BMI have select risk factors, particularly blood pressure and LDL cholesterol that improved over sedentary peers. However, concerning risk factor profiles of linemen warrant standard age-appropriate and size-appropriate screening for cardiovascular and metabolic disease. Body fat percent more strongly correlated with risk factors than with BMI and may be the stronger tool for estimating risk in this population.

Potassium-aggravated muscle stiffness in 12 cats

12 European shorthair cats (6 males and 6 females; age range, 2 months to 3 years) from 1 household were evaluated for clinical signs of recurrent and progressive muscle spasticity. Genetic relationships among the cats were suspected but were not known. Physical examination of all cats revealed a thin to mildly emaciated body condition and signs of suppurative rhinitis. Results of neurologic evaluations revealed no abnormalities in any cats at rest, but exercise- and stress-induced episodes of muscle spasticity were observed. Results of hematologic (7/12 cats) and CSF (4) analysis, diagnostic imaging (including radiography [7] and magnetic resonance imaging [4]), electromyography (4), motor nerve conduction tests (4), screening for metabolic storage diseases (4), provocation tests via exercise in a cold (4°C [39.2°F]) environment (7), and gross pathological and histologic examination (5) revealed no abnormalities that could potentially explain the clinical signs. However, consumption of a potassium-enriched diet resulted in severe aggravation of clinical signs in 7 of 7 cats, leading to a diagnosis of potassium-aggravated muscle stiffness. 5 cats were euthanized after initial examination because of poor physical condition and severe clinical signs. Spasticity in the 7 remaining cats was improved during a 6-week follow-up period as they reduced their own activity. Further investigation and treatment were declined. Channelopathies are rarely recognized diseases in domestic animals. In addition to conventional diagnostic evaluation methods, provocation tests in a clinical environment can be used in the assessment of channelopathies.

Type 1 diabetes and perinatal factors in Catalonia (Spain)*

To identify perinatal risk factors associated with the development of type 1 diabetes. The research was designed as a retrospective study of cases and controls. Catalan Register of Diabetes and the Register of Newborn Screening for Metabolic Diseases were the data sources used in this study. The variables studied include sex, birth weight, age of onset of type 1 diabetes, maternal age at delivery, type of delivery, and type of feeding at birth. Anthropometric growth patterns of Carrascosa have been used to classify birth weight as small for gestational age: weight <10th percentile; appropriate for gestational age: weight ≥10th percentile and ≤90th percentile; and large for gestational age (LGA): weight >90th percentile. Statistical analysis was carried out using bivariate analysis (chi-squared test), and odds ratios and 95% confidence intervals were predicted. A total of 1530 infants were analyzed (306 type 1 diabetes cases, 1224 control subjects). A significantly greater percentage of LGA babies were observed among diabetics (16.3% compared with 11.3% of the control group). The risk of having type 1 diabetes in children who were LGA was 1.45 times greater than that shown in children with normal and low birth weight. Only being born LGA was significantly associated with developing type 1 diabetes.

1159 The Diagnostic Accuracy of Biochemical Measurements in Screening for Metabolic Bone Disease in Preterm Infants: A Systematic Review

1159 The Diagnostic Accuracy of Biochemical Measurements in Screening for Metabolic Bone Disease in Preterm Infants: A Systematic Review

1155 Screening and Treatment Strategies for Metabolic Bone Disease in Preterm Infants: Results of a National Questionnaire Survey in the Netherlands

1155 Screening and Treatment Strategies for Metabolic Bone Disease in Preterm Infants: Results of a National Questionnaire Survey in the Netherlands

Screening for the inherited metabolic diseases in infants with cholestasis and changing pattern of diagnosis

Objective To investigate the changing pattern of diagnosis of infantile cholestasis after screening the inherited metabolic diseases in infants with cholestasis. Methods Infants under 12 months with cholestasis were identified retrospectively from hospital records from Jan. 1996 to Dec. 2007. The data were retrieved from the medical records and analyzed by focusing particularly on the changing etiology of cholestasis and inherited metabolic diseases in these infants after performing routine screening and diagnostic procedures. Results Among 421 infants identified as having cholestasis during 12-years study period, the common causes of infantile cholestasis were cytomegalovirus (CMV) infection (36. 11% ), bile duct hypoplasia or congenital biliary atresia (31.59%), metabolic disease (8.08%), miscellaneous (10.69%), and unknown ( 13.54% ). The proportion of infants with metabolic diseases after screening increased 16 folds compared with before screening( 15.76% vs 0. 92% ,P<0. 01 ), whereas the proportion of infants with unknown cause decreased from 17.43% to 9.36% (P<0.05). There was no significant change in the proportions of CMV infection, congenital biliary atresia, and miscellaneous causes. The major metabolic diseases of 34 infants included citrin deficiency (41. 18% ) and tyrosinemia (23.53%), followed by galactosemia and progressive familial intrahepatic cholestasis (8. 82% )etc. Conclusions Inherited metabolic disease has become an important cause of infantile cholestasis, which is mainly due to citrin deficiency. Therefore, it is necessary to set a routing screening of citrin deficiency in infants with cholestasis. Key words: Infant, cholestasis; Cytomegalovirus; Inherited metabolic disease; Citrin deficiency

High Prevalence of Low-Trauma Fracture in Chronic Pancreatitis

Chronic pancreatitis (CP) is associated with risk factors that may negatively impact bone and mineral metabolism. The important clinical end point of osteoporosis is "low-trauma" fracture. The purpose of this study was to examine the prevalence of "low-trauma" fracture in patients with CP, compared with fracture rates in "high-risk" gastrointestinal (GI) illnesses, for which metabolic bone disease screening guidelines are in place. This is a retrospective cohort database study examining patients with CP and "high-risk" GI illnesses seen at a single tertiary care center. Time points ranged between 31 July 1998 and 31 July 2008. The main outcome measure was "low-trauma" fracture prevalence using specific International Classification of Diseases, Ninth Revision, Clinical Modification fracture codes. A total of 3,192 CP patients and 1,461,207 non-CP patients were included in the study. The fracture prevalence (patients with fracture per total patients) was as follows: controls, 1.1% (16,208/1,436,699); Crohn's disease, 3.0% (182/6057); CP, 4.8% (154/3192); cirrhosis, 4.8% (805/16,658); celiac disease, 5.0% (74/1480); and postgastrectomy, 5.4% (17/313). Prevalence for each group was statistically greater than controls (P<0.001). CP fracture prevalence was greater than controls (P<0.001) and Crohn's disease (P<0.001), and comparable with the remaining "high-risk" GI illness groups (P>0.05). The odds of fracture (odds ratio (OR), 95% confidence interval (CI)) compared with controls, adjusted for age, gender, and race was: CP 2.4 (2.1, 2.9); Crohn's disease 1.7 (1.5, 2.0); gastrectomy 2.5 (1.5, 4.1); cirrhosis 2.6 (2.4, 2.7); and celiac disease 2.7 (2.1, 3.4). The odds of fracture for each disease group were statistically greater than controls (P<0.0001). The prevalence of low-trauma fracture in CP patients is comparable with or higher than that of "high-risk" GI illnesses, for which osteoporosis screening guidelines exist.

Choréo-acanthocytose sans acanthocytes

Introduction Chorea-acanthocytosis (ChAc) is one of the neuroacanthocytosis syndromes which form a group of disorders characterized by the association of neurological abnormalities and spiculated red blood cells called acanthocytes. ChAc patients exhibit involuntary movements, psychiatric abnormalities and progressive cognitive deterioration. We report a case of ChAc in which blood smears failed to demonstrate acanthocytes. Case report A 26-year-old man presented since two years with hyperkinetic movements. The family history was non contributive, parents were consanguineous. Neurological examination revealed choreatic hyperkinesia and dystonia, predominant in the orofacial region. Mild cognitive decline and behavior abnormalities were noted with repetitive activities. Brain MRI showed striatal atrophy. Molecular testing for Huntington's disease was negative. Routine biological screening was normal except for elevated CPK and LDH. Copper and ceruloplasmin blood levels were normal, as well as purine metabolism and lipoproteins. Further screening for metabolic diseases showed no significant abnormality. Expression of Kell antigens was normal. In several blood smears no acanthocytes were seen. Electromyographic studies showed slight neuropathic changes. Despite the absence of acanthocytes, chorein western blot was performed on blood samples which revealed an absent or markedly reduced level of chorein in erythrocyte membranes. A mutation of the ChAc gene was thus likely so the diagnosis of ChAc was retained. Genetic studies for VPS13A are pending. Discussion ChAc is an autosomal recessive disorder due to mutations of the VPS13A gene coding for chorein. Absence or late appearance of acanthocytes in ChAc has been described in a few case reports. In conclusion ChAc is a rare disorder in which the presence of acanthocytes is not mandatory. In case of doubt, chorein western blot can be useful.