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1.
J Inherit Metab Dis ; 42(3): 398-406, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30706953

RESUMO

Biogenic amines synthesis in phenylketonuria (PKU) patients with high phenylalanine (Phe) concentration is thought to be impaired due to inhibition of tyrosine and tryptophan hydroxylases and competition with amino acids at the blood-brain barrier. Dopamine and serotonin deficits might explain brain damage and progressive neuropsychiatric impairment in adult PKU patients. Ten early treated adult PKU patients (mean age 38.2 years) and 15 age-matched controls entered the study. Plasma and cerebrospinal fluid (CSF) Phe, 5-hydroxyindoleacetic acid (5-HIAA), 5-hydroxytryptophan (5-HTP), 3,4-dihydroxy-l-phenylalanine (l-DOPA) and homovanillic acid (HVA) were analyzed. Voxel-based morphometry statistical nonparametric mapping was used to test the age-corrected correlation between gray matter atrophy and CSF biogenic amines levels. 5-HIAA and 5-HTP were significantly reduced in PKU patients compared to controls. Significant negative correlations were found between CSF 5-HIAA, HVA, and 5-HTP and Phe levels. A decrease in 5-HIAA and 5-HTP concentrations correlated with precuneus and frontal atrophy, respectively. Lower HVA levels correlated with occipital atrophy. Biogenic amines deficits correlate with specific brain atrophy patterns in adult PKU patients, in line with serotonin and dopamine projections. These findings may support a more rigorous Phe control in adult PKU to prevent neurotransmitter depletion and accelerated brain damage due to aging.

2.
J Inherit Metab Dis ; 42(1): 128-139, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30740731

RESUMO

PURPOSE: To assess how the current practice of newborn screening (NBS) for homocystinurias compares with published recommendations. METHODS: Twenty-two of 32 NBS programmes from 18 countries screened for at least one form of homocystinuria. Centres provided pseudonymised NBS data from patients with cystathionine beta-synthase deficiency (CBSD, n = 19), methionine adenosyltransferase I/III deficiency (MATI/IIID, n = 28), combined remethylation disorder (cRMD, n = 56) and isolated remethylation disorder (iRMD), including methylenetetrahydrofolate reductase deficiency (MTHFRD) (n = 8). Markers and decision limits were converted to multiples of the median (MoM) to allow comparison between centres. RESULTS: NBS programmes, algorithms and decision limits varied considerably. Only nine centres used the recommended second-tier marker total homocysteine (tHcy). The median decision limits of all centres were ≥ 2.35 for high and ≤ 0.44 MoM for low methionine, ≥ 1.95 for high and ≤ 0.47 MoM for low methionine/phenylalanine, ≥ 2.54 for high propionylcarnitine and ≥ 2.78 MoM for propionylcarnitine/acetylcarnitine. These decision limits alone had a 100%, 100%, 86% and 84% sensitivity for the detection of CBSD, MATI/IIID, iRMD and cRMD, respectively, but failed to detect six individuals with cRMD. To enhance sensitivity and decrease second-tier testing costs, we further adapted these decision limits using the data of 15 000 healthy newborns. CONCLUSIONS: Due to the favorable outcome of early treated patients, NBS for homocystinurias is recommended. To improve NBS, decision limits should be revised considering the population median. Relevant markers should be combined; use of the postanalytical tools offered by the CLIR project (Collaborative Laboratory Integrated Reports, which considers, for example, birth weight and gestational age) is recommended. tHcy and methylmalonic acid should be implemented as second-tier markers.

3.
Orphanet J Rare Dis ; 13(1): 149, 2018 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-30157945

RESUMO

BACKGROUND: Phenylketonuria (PKU) is often considered as the classical example of a genetic disorder in which severe symptoms can nowadays successfully be prevented by early diagnosis and treatment. In contrast, untreated or late-treated PKU is known to result in severe intellectual disability, seizures, and behavioral disturbances. Rarely, however, untreated or late-diagnosed PKU patients with high plasma phenylalanine concentrations have been reported to escape from intellectual disability. The present study aimed to review published cases of such PKU patients. METHODS: To this purpose, we conducted a literature search in PubMed and EMBASE up to 8th of September 2017 to identify cases with 1) PKU diagnosis and start of treatment after 7 years of age; 2) untreated plasma phenylalanine concentrations ≥1200 µmol/l; and 3) IQ ≥80. Literature search, checking reference lists, selection of articles, and extraction of data were performed by two independent researchers. RESULTS: In total, we identified 59 published cases of patients with late-diagnosed PKU and unexpected favorable outcome who met the inclusion criteria. Although all investigated patients had intellectual functioning within the normal range, at least 19 showed other neurological, psychological, and/or behavioral symptoms. CONCLUSIONS: Based on the present findings, the classical symptomatology of untreated or late-treated PKU may need to be rewritten, not only in the sense that intellectual dysfunction is not obligatory, but also in the sense that intellectual functioning does not (re)present the full picture of brain damage due to high plasma phenylalanine concentrations. Further identification of such patients and additional analyses are necessary to better understand these differences between PKU patients.

4.
Mol Genet Metab Rep ; 15: 106-109, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30023298

RESUMO

Incidence for the branched-chain intoxication-type disorders, maple syrup urine disease, propionic acidemia and methlymalonic aciduria is dependent on the population screened. Here newborn screening results from three world regions, state screening laboratories in the United States, a region in Germany and Kuwait provides new incidence numbers. Maple syrup urine disease incidence in the United States was calculated to be 1: 220219, in South-West Germany 1: 119573 (Germany nationwide 1:177978), and in Kuwait 1: 59426. Incidence of propionic acidemia alone is calculated to be 1: 242741 in the United States, 1: 284450 in South-West Germany (Germany nationwide 1:202617) and 1:59426 in Kuwait. Incidence of isolated methylmalonic aciduria alone is 1:69354 in the United States, 1:568901 in South-West Germany (Germany nationwide 1:159199) and 1: 19809 in Kuwait. In the United States several newborn screening laboratories combine their results for propionic acidemia and methylmalonic aciduria, and also include combined remethylation disorders in the respective category, resulting in an incidence of 1:50709. Combined evaluation of methylmalonic aciduria, propionic aciduria and combined remethylation disorders results in a similar incidence for Germany of 1:67539. This evaluation of newborn screening incidences reflects some population differences for three intoxication-type metabolic disorders. However, different sample sizes of the populations screened over different time periods, and differences in case definitions for methylmalonic acidurias have to be considered when interpreting these data.

5.
World J Pediatr ; 14(5): 470-481, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29948967

RESUMO

BACKGROUND: Newborn screening (NBS) in Germany currently includes 15 target disorders. Recent diagnostic improvements suggest an extension of the screening panel. METHODS: Since August 2016, a prospective study evaluating 26 additional target disorders (25 metabolic disorders and vitamin B12-deficiency) in addition to the German screening panel is performed at the Newborn Screening Center Heidelberg. First-tier results from tandem-MS screening are complemented by second-tier strategies for 15 of the additional target disorders. NBS results of seven patients diagnosed symptomatically with one of the additional target disorders by selective screening since August 2016 are retrospectively evaluated. RESULTS: Over a 13-month period, 68,418 children participated in the study. Second-tier analyses were performed in 5.4% of samples. Only 59 (0.1%) of study participants had abnormal screening results for one of the additional target disorders. Target disorders from the study panel were confirmed in 12 children: 1 3-hydroxy-3-methylglutaryl coenzyme A (CoA)-lyase deficiency, 1 citrullinemia type I, 1 multiple acyl-CoA dehydrogenase-deficiency, 1 methylenetetrahydrofolate reductase-deficiency, and 8 children with maternal vitamin B12-deficiency. In addition, six of seven patients diagnosed symptomatically outside the study with one of the target disorders would have been identified by the study strategy in their NBS sample. CONCLUSIONS: Within 13 months, the study "Newborn Screening 2020" identified additional 12 children with treatable conditions while only marginally increasing the recall rate by 0.1%. Maternal vitamin B12-deficiency was the most frequent finding. Even more children could benefit from screening for the additional target disorders by extending the NBS panel for Germany and/or other countries.

6.
Int Ophthalmol ; 38(2): 429-441, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28243830

RESUMO

PURPOSE: To compare stage of visual field loss (VFL) and age at diagnosis between patients with different types of glaucoma with regard to glaucoma screening and driving ability. METHODS: In a cross-sectional study of 1988 consecutive patients with different types of glaucoma VFL at diagnosis and age at diagnosis were assessed. Patients with binocular advanced or severe VFL were classified unable, patients with no VFL in one eye and VFL I-V (Aulhorn classification) in the other eye able, all other constellations questionably able to drive. RESULTS: There were significant differences in age at diagnosis between different glaucomas and between patients with different stages of VFL at diagnosis. Age-related assessment of VFL at diagnosis in normal tension glaucoma (NTG) compared to primary open-angle glaucoma (POAG) showed that NTG is not a disease of the elderly but a disease with late diagnosis at severe VFL. In POAG a solely age-related glaucoma screening, e.g. from the age of 50 years, does not sufficiently lead to diagnosis at an early stage of the disease. In POAG solely based on binocular VFL 11.5% of patients were judged unable, 29.2% questionably able to drive, in NTG 19.6%/43.1%, pigmentary glaucoma 16%/22%, pseudoexfoliation glaucoma 9.1%/16.7%, and in primary angle-closure glaucoma 14.6%/30%. CONCLUSIONS: Depending on type of glaucoma more than 50% of patients require counselling regarding safe driving as part of clinical care. A disease-specific, age-related perimetric examination considering additional risk factors like family history of glaucoma is essential for early detection of glaucoma and road safety.


Assuntos
Condução de Veículo , Glaucoma/diagnóstico , Programas de Rastreamento/métodos , Campos Visuais/fisiologia , Adulto , Idade de Início , Idoso , Estudos Transversais , Feminino , Glaucoma/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade
7.
J Glaucoma ; 26(10): 940-946, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28991151

RESUMO

PURPOSE: Prospective evaluation of family history (FH) of glaucoma and FH of optic disc drusen (ODD) in patients with sonographically confirmed ODD. PATIENTS AND METHODS: A total of 87 patients with ODD interviewed all their first-degree and second-degree relatives using a detailed questionnaire on whether an ophthalmologist had diagnosed or excluded glaucoma or ocular hypertension (OH). Using a second questionnaire, 62 of these patients also provided information about ODD in their FH. Control groups for FH of glaucoma consisted of 2170 patients with glaucoma or OH evaluated with the same methods and identical questions for FH of glaucoma in a previous study, and of 176 healthy individuals without glaucoma or ODD who were interviewed on family history of glaucoma. RESULTS: Glaucoma in FH was significantly more frequent in patients with ODD with an incidence of 20.7% compared with healthy controls with an incidence of 2.8%, and half as frequent as in glaucoma patients with an incidence of 40%. ODD in FH were found in 9.7% of patients with ODD. CONCLUSIONS: As there is a high frequency of family history of glaucoma in patients with ODD, evaluation of FH of ODD and FH of glaucoma is essential in patients with ODD. Glaucoma in FH of ODD patients requires intraocular pressure monitoring and whenever deemed beneficial timely initiation of intraocular pressure-lowering therapy.


Assuntos
Glaucoma/epidemiologia , Drusas do Disco Óptico/epidemiologia , Adulto , Feminino , Glaucoma/fisiopatologia , Humanos , Incidência , Pressão Intraocular , Masculino , Pessoa de Meia-Idade , Hipertensão Ocular/fisiopatologia , Estudos Prospectivos , Inquéritos e Questionários , Tonometria Ocular
8.
PLoS One ; 12(9): e0184897, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28915261

RESUMO

BACKGROUND AND AIMS: Increased propionylcarnitine levels in newborn screening are indicative for a group of potentially severe disorders including propionic acidemia (PA), methylmalonic acidemias and combined remethylation disorders (MMACBL). This alteration is relatively non-specific, resulting in the necessity of confirmation and differential diagnosis in subsequent tests. Thus, we aimed to develop a multiplex approach for concurrent determination of 3-hydroxypropionic acid, methylmalonic acid and methylcitric acid from the same dried blood spot (DBS) as in primary screening (second-tier test). We also set out to validate the method using newborn and follow-up samples of patients with confirmed PA or MMACBL. METHODS: The assay was developed using liquid chromatography-tandem mass spectrometry and clinically validated with retrospective analysis of DBS samples from PA or MMACBL patients. RESULTS: Reliable determination of all three analytes in DBSs was achieved following simple and fast (<20 min) sample preparation without laborious derivatization or any additional pipetting steps. The method clearly distinguished the pathological and normal samples and differentiated between PA and MMACBL in all stored newborn specimens. Methylcitric acid was elevated in all PA samples; 3-hydroxypropionic acid was also high in most cases. Methylmalonic acid was increased in all MMACBL specimens; mostly together with methylcitric acid. CONCLUSIONS: A liquid chromatography-tandem mass spectrometry assay allowing simultaneous determination of the biomarkers 3-hydroxypropionic acid, methylmalonic acid and methylcitric acid in DBSs has been developed. The assay can use the same specimen as in primary screening (second-tier test) which may reduce the need for repeated blood sampling. The presented preliminary findings suggest that this method can reliably differentiate patients with PA and MMACBL in newborn screening. The validated assay is being evaluated prospectively in a pilot project for extension of the German newborn screening panel (?Newborn screening 2020"; Newborn Screening Center, University Hospital Heidelberg).


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/sangue , Citratos/sangue , Teste em Amostras de Sangue Seco/métodos , Ácido Láctico/análogos & derivados , Programas de Rastreamento/métodos , Ácido Metilmalônico/sangue , Acidemia Propiônica/sangue , Cromatografia Líquida/métodos , Feminino , Humanos , Recém-Nascido , Ácido Láctico/sangue , Masculino , Espectrometria de Massas/métodos
9.
Orphanet J Rare Dis ; 12(1): 47, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28274234

RESUMO

BACKGROUND: Sapropterin dihydrochloride, a synthetic formulation of BH4, the cofactor for phenylalanine hydroxylase (PAH, EC 1.14.16.1), was initially approved in Europe only for patients ≥4 years with BH4-responsive phenylketonuria. The aim of the SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®) trial was to assess the efficacy (improvement in daily phenylalanine tolerance, neuromotor development and growth parameters), safety and pharmacokinetics of sapropterin dihydrochloride in children <4 years. RESULTS: In total, 109 male or female children <4 years with confirmed BH4-responsive phenylketonuria or mild hyperphenylalaninemia and good adherence to dietary treatment were screened. 56 patients were randomly assigned (1:1) to 10 mg/kg/day oral sapropterin plus a phenylalanine-restricted diet or to only a phenylalanine-restricted diet for 26 weeks (27 to the sapropterin and diet group and 29 to the diet-only group; intention-to-treat population). Of these, 52 patients with ≥1 pharmacokinetic sample were included in the pharmacokinetic analysis, and 54 patients were included in the safety analysis. At week 26 in the sapropterin plus diet group, mean phenylalanine tolerance was 30.5 (95% confidence interval 18.7-42.3) mg/kg/day higher than in the diet-only group (p < 0.001). The safety profile of sapropterin, measured monthly, was acceptable and consistent with that seen in studies of older children. Using non-linear mixed effect modelling, a one-compartment model with flip-flop pharmacokinetic behaviour, in which the effect of weight was substantial, best described the pharmacokinetic profile. Patients in both groups had normal neuromotor development and stable growth parameters. CONCLUSIONS: The addition of sapropterin to a phenylalanine-restricted diet was well tolerated and led to a significant improvement in phenylalanine tolerance in children <4 years with BH4-responsive phenylketonuria or mild hyperphenylalaninemia. The pharmacokinetic model favours once per day dosing with adjustment for weight. Based on the SPARK trial results, sapropterin has received EU approval to treat patients <4 years with BH4-responsive phenylketonuria. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01376908 . Registered June 17, 2011.


Assuntos
Biopterina/análogos & derivados , Fenilcetonúrias/dietoterapia , Fenilcetonúrias/tratamento farmacológico , Algoritmos , Biopterina/administração & dosagem , Biopterina/metabolismo , Biopterina/uso terapêutico , Pré-Escolar , Dieta/métodos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Fenilalanina/administração & dosagem , Fenilalanina/sangue , Fenilalanina Hidroxilase/metabolismo , Fenilcetonúrias/sangue
10.
World J Pediatr ; 13(2): 136-143, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28101774

RESUMO

BACKGROUND: Newborn screening is a precondition for early diagnosis and successful treatment of remethylation disorders and classical homocystinuria (cystathionine-ß-synthase deficiency). Newborn screening for classical homocystinuria using total homocysteine measurement in dried blood spots has been very successfully performed for many years for newborns from Qatar. METHODS: A new optimized newborn screening strategy for remethylation disorders and homocystinuria was developed and evaluated for newborns from Qatar using total homocysteine measurement as first-tier and methionine, methionine-phenylalanine-ratio and propionylcarnitine as second-tiers. Proposed cut-offs were also retrospectively evaluated in newborn screening samples of 12 patients with remethylation disorders and vitamin B12 deficiency from Qatar and Germany. RESULTS: Over a 12 months period, the proposed strategy led to a decrease in the recall rate in homocysteine screening for Qatar from 1.09% to 0.68%, while allowing for additional systematic inclusion of remethylation disorders and vitamin B12 deficiency into the screening panel for Qatar. In the evaluated period the applied strategy would have detected all patients with classical homocystinuria identified by the previous strategy and in addition 5 children with maternal nutritional vitamin B12 deficiency and one patient with an isolated remethylation disorder. Additional retrospective evaluation of newborn screening samples of 12 patients from Germany and Qatar with remethlyation disorders or vitamin B12 deficiency showed that all of these patients would have been detected by the cut-offs used in the proposed new strategy. In addition, an adapted strategy for Germany using methionine, methionine-phenylalanine-ratio and propionylcarnitine as first-tier, and homocysteine as a second-tier test was also positively evaluated retrospectively. CONCLUSIONS: The proposed strategy for samples from Qatar allows inclusion of remethylation disorders and vitamin B12 deficiency in the screening panel, while lowering the recall rate. An adapted second-tier strategy is presented for screening in Germany and will be prospectively evaluated over the next years in a pilot project named "Newborn Screening 2020".


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Homocistinúria/diagnóstico , Triagem Neonatal/métodos , Deficiência de Vitamina B 12/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/sangue , Erros Inatos do Metabolismo dos Aminoácidos/epidemiologia , Estudos de Coortes , Feminino , Alemanha/epidemiologia , Homocistinúria/sangue , Homocistinúria/epidemiologia , Humanos , Incidência , Recém-Nascido , Masculino , Projetos Piloto , Catar/epidemiologia , Estudos Retrospectivos , Medição de Risco , Deficiência de Vitamina B 12/sangue , Deficiência de Vitamina B 12/epidemiologia
11.
JIMD Rep ; 32: 87-94, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27325427

RESUMO

BACKGROUND: In classical homocystinuria (HCU, MIM# 236200) due to the deficiency of cystathionine ß-synthase (EC 4.2.1.22) there is a clear evidence for the success of early treatment. The aim of this study was to develop and evaluate a two-tier strategy for HCU newborn screening. METHODS: We reevaluated data from our newborn screening programme for Qatar in a total number of 125,047 neonates including 30 confirmed HCU patients. Our hitherto existing screening strategy includes homocysteine (Hcy) measurements in every child, resulting in a unique dataset for evaluation of two-tier strategies. Reevaluation included methionine (Met) levels, Met to phenylalanine (Phe) ratio, and Hcy. Four HCU cases identified after database closure were also included in the evaluation. In addition, dried blood spot samples selected by Met values >P97 in the newborn screening programs in Austria, Australia, the Netherlands, and Taiwan were analyzed for Hcy. RESULTS: Met to Phe ratio was found to be more effective for first sieve than Met, sorting out nearly 90% of normal samples. Only 10% of the samples would have to be processed by second-tier measurement of Hcy in dried blood spots. As no patient with HCU was found neither in the samples investigated for HCU, nor by clinical diagnosis in the other countries, the generalization of our two-tier strategy could only be tested indirectly. CONCLUSION: The finally derived two-tier algorithm using Met to Phe ratio as first- and Hcy as second-tier requires 10% first-tier positives to be transferred to Hcy measurement, resulting in 100% sensitivity and specificity in HCU newborn screening.

12.
Artigo em Inglês | MEDLINE | ID: mdl-27269713

RESUMO

BACKGROUND: Patients with phenylketonuria have been reported to be deficient in long-chain polyunsaturated fatty acids (LCPUFAs). It has been postulated that good compliance with the dietary regimen negatively influences LCPUFA status. METHODS: In 36 patients with phenylketonuria and 18 age-matched healthy control subjects LCPUFA-levels in plasma phospholipids and cholesteryl esters, erythrocyte phosphatidylcholine and phosphatidylethanolamine were evaluated. RESULTS: Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) levels did not differ significantly between patients and control subjects in plasma and erythrocyte fractions. There was a significant negative correlation between SDS (standard deviation) scores of DHA-levels in erythrocyte parameters from the respective age-matched control group and patients' concurrent and long-term phenylalanine levels for erythrocyte phosphatidylethanolamine and erythrocyte phosphatidylcholine. Patients with lower (higher) phenylalanine levels had positive (negative) DHA-SDS. CONCLUSION: In contrast to previous reports we did not find lower LCPUFA-levels in patients with phenylketonuria compared to age-matched healthy control subjects. Good dietary control was associated with better LCPUFA status.


Assuntos
Eritrócitos/metabolismo , Ácidos Graxos Insaturados/sangue , Fenilcetonúrias/dietoterapia , Fenilcetonúrias/metabolismo , Adolescente , Adulto , Criança , Ésteres do Colesterol/sangue , Ácidos Docosa-Hexaenoicos/sangue , Ácido Eicosapentaenoico/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Fosfatidilcolinas/sangue , Fosfatidiletanolaminas/sangue , Fosfolipídeos/sangue , Adulto Jovem
13.
J Inherit Metab Dis ; 39(5): 625-632, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27139199

RESUMO

BACKGROUND: Hydroxyprolinemia is an inborn error of amino acid degradation that is considered a non-disease. Known for more than 50 years, its genetic cause and prevalence have remained unclear. In MS/MS newborn screening, the mass spectrum of hydroxyproline cannot be differentiated from isoleucine and leucine causing false positive newborn screening test results for maple syrup urine disease (MSUD). METHODS: We studied two siblings with hydroxyprolinemia via exome sequencing and confirmed the candidate gene in five further individuals with hydroxyprolinemia, who were all characterized biochemically and clinically. The prevalence was calculated based on the number of individuals with hydroxyprolinemia detected via MS/MS newborn screening at our centre from 2003 to 2014. RESULTS: In six cases, we identified homozygous or compound heterozygous mutations in PRODH2 as the underlying genetic cause of hydroxyprolinemia. One individual was heterozygous for a deletion in PRODH2 and had an intermittent biochemical phenotype with partial normalization of hydroxyproline concentrations. In one further individual with persistent hydroxyprolinemia no mutation in PRODH2 was found, raising the possibility of another defect of hydroxyproline degradation yet to be identified as the underlying cause of hydroxyprolinemia. Plasma hydroxyproline concentrations were clearly elevated in all individuals with biallelic mutations in PRODH2. All studied individuals remained asymptomatic, giving further evidence that hydroxyprolinemia is a benign condition. The estimated prevalence of hydroxyprolinemia in Germany is about one in 47,300 newborns. CONCLUSION: Our results establish mutations in PRODH2 as a cause of human hydroxyprolinemia via impaired dehydrogenation of hydroxyproline to delta1-pyroline-3-hydroxy-5-carboxylic acid, and we suggest PRODH2 be renamed HYPDH. Hydroxyprolinemia is an autosomal-recessively inherited benign condition. It is a frequent cause of false positive screening results for MSUD, the prevalence being about 2.5 times higher than that of MSUD.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/etiologia , Erros Inatos do Metabolismo dos Aminoácidos/genética , Mutação/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/deficiência , Criança , Pré-Escolar , Feminino , Alemanha , Heterozigoto , Homozigoto , Humanos , Hidroxiprolina/genética , Lactente , Recém-Nascido , Masculino , Doença da Urina de Xarope de Bordo/etiologia , Doença da Urina de Xarope de Bordo/genética , Triagem Neonatal/métodos , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Fenótipo , Prevalência , Prolina Oxidase/genética
14.
Ann Hematol ; 95(3): 397-402, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26658910

RESUMO

Children with sickle cell disease (SCD) benefit from newborn screening, because life-threatening complications can be prevented by pre-symptomatic diagnosis. In Germany, the immigration of people from endemic countries is steadily growing. Comprehensive data about the epidemiology and prevalence of SCD in Germany are however lacking, and SCD is not included in the national newborn screening program. We provide data on the prevalence of SCD in a population from both urban and rural areas in Southwest Germany. Anonymized dried blood spots from 37,838 unselected newborns were analyzed by allele-specific PCR for the HbS mutation. Samples tested positive were subjected to Sanger sequencing of the entire ß-globin coding sequence firstly to validate the screening and secondly to identify compound heterozygous SCD patients with other mutations of the ß-globin gene. We identified 83 carriers of the sickle cell trait, three compound heterozygous SCD patients (two with sickle cell-ß-thalassemia, one with sickle cell-Hb Tianshui) but no homozygous SCD patients. The novel molecular method and strategy for newborn screening for SCD presented here compares favorably in terms of sensitivity (1.0 for homozygous HbS, 0.996 for heterozygous HbS), specificity (0.996), practicability, and costs with conventional biochemical screening. Our results demonstrate a significant prevalence of SCD of approximately 1:12,000 in an unselected urban and rural population in Southwest Germany. Together with previously published even higher results from exclusively urban populations in Berlin and Hamburg, our data provide the basis for the decision on a newborn screening program for SCD in Germany.


Assuntos
Anemia Falciforme/diagnóstico , Anemia Falciforme/epidemiologia , Triagem Neonatal/métodos , Anemia Falciforme/genética , Estudos de Coortes , Teste em Amostras de Sangue Seco/métodos , Feminino , Alemanha/epidemiologia , Humanos , Recém-Nascido , Masculino , Prevalência , Traço Falciforme/diagnóstico , Traço Falciforme/epidemiologia , Traço Falciforme/genética
15.
JIMD Rep ; 23: 101-12, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25940036

RESUMO

BACKGROUND: Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is included in many newborn screening programmes worldwide. In addition to the prevalent mutation c.985A>G in the ACADM gene, potentially mild mutations like c.199T>C are frequently found in screening cohorts. There is ongoing discussion whether this mutation is associated with a clinical phenotype. METHODS: In 37 MCADD patients detected by newborn screening, biochemical phenotype (octanoylcarnitine (C8), ratios of C8 to acetylcarnitine (C2), decanoylcarnitine (C10) and dodecanoylcarnitine (C12) at screening and confirmation) and clinical phenotype (inpatient emergency treatment, metabolic decompensations, clinical assessments, psychometric tests) were assessed in relation to genotype. RESULTS: 16 patients were homozygous for c.985A>G (group 1), 11 compound heterozygous for c.199T>C and c.985A>G/another mutation (group 2) and 7 compound heterozygous for c.985A>G and mutations other than c.199T>C (group 3) and 3 carried neither c.985A>G nor c.199T>C but other known homozygous mutations (group 4). At screening C8/C2 and C8/C10, at confirmation C8/C2, C8/C10 and C8/C12 differed significantly between patients compound heterozygous for c.199T>C (group 2) and other genotypes. C8, C10 and C8/C2 at screening were strongly associated with time of sampling in groups 1 + 3 + 4, but not in group 2. Clinical phenotype did not differ between genotypes. Two patients compound heterozygous for c.199T>C and a severe mutation showed neonatal decompensation with hypoglycaemia. CONCLUSION: Biochemical phenotype differs between MCADD patients compound heterozygous for c.199T>C with a severe mutation and other genotypes. In patients detected by newborn screening, clinical phenotype does not differ between genotypes following uniform treatment recommendations. Neonatal decompensation can also occur in patients with the presumably mild mutation c.199T>C prior to diagnosis.

17.
Invest Ophthalmol Vis Sci ; 56(13): 7999-8007, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26720447

RESUMO

PURPOSE: To evaluate frequency of migraine, vasospasm (VS), family history (FH) of migraine, and family history of glaucoma (FHG) in different types of glaucoma in relation to age and stage of visual field loss (VFL) at diagnosis. METHODS: A total of 2170 patients with glaucoma or ocular hypertension (OH) were interviewed by using standardized questions concerning FHG, age at diagnosis, and potential risk factors, including migraine and VS. Of 2027 patients providing information on migraine, 1244 had primary open-angle glaucoma (POAG), 140 normal tension glaucoma (NTG), 49 pigmentary glaucoma, 64 pseudoexfoliation glaucoma (PEX), 138 OH, and 218 primary angle closure glaucoma (PACG). RESULTS: Of all patients, 13.7% reported migraine, 19.0% VS, 30.8% FH of migraine, and 40.3% FHG. Patients with FHG had a significantly higher frequency of migraine than patients without FHG (15.7% vs. 12.3%, P = 0.02). Migraine was significantly more frequent in NTG (21.4%) than POAG (13.1%; P = 0.01), PEX (7.8%; P = 0.02), and PACG (10.1%; P = 0.004). Compared to patients with POAG, patients with NTG had a 63.5% higher age-corrected probability for migraine (P = 0.007). There was no evidence for migraine or VS being prognostic factors regarding the extent of VFL at diagnosis. Migraine and VS were significantly more frequent in females. CONCLUSIONS: The higher frequency of migraine and VS in females could contribute to the female preponderance in NTG. Our findings suggest an association of NTG and migraine and a common, possibly polygenetic, vascular etiology of these two diseases both with familial predisposition.


Assuntos
Glaucoma/etiologia , Transtornos de Enxaqueca/complicações , Hipertensão Ocular/etiologia , Vasoespasmo Intracraniano/complicações , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Fatores Sexuais , Transtornos da Visão/etiologia , Campos Visuais/fisiologia
18.
J Inherit Metab Dis ; 37(2): 189-95, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23949009

RESUMO

BACKGROUND: Newborn screening for inborn errors of metabolism is regarded as highly successful by health professionals. Little is known about parents' perspectives on child development and social impact on families. METHODS: Parents of 187 patients with metabolic disorders detected by newborn screening rated child development, perceived burdens on child and family, and future expectations on a questionnaire with standardized answers. Parental ratings were compared with standardized psychometric test results. Regression analysis was performed to identify factors associated with extent of perceived burden. RESULTS: In 26.2% of patients, parents perceived delays in global development and/or specific developmental domains (physical, social, intellectual, language). Parents expected normal future development in 95.7%, and an independent adult life for their child in 94.6%. Comparison with psychometric test results showed that parents of children with cognitive impairments tended to overrate their child's abilities. Mild/medium burden posed on the family (child) by the metabolic disorder was stated by 56.1% (48.9%) of parents, severe/very severe burden by 19.3% (8.6%). One third of families reported financial burden due to the metabolic disorder. Dietary treatment and diagnoses with risk for metabolic decompensation despite treatment were associated with higher perceived burden for the family. Disorders rated as potentially very burdensome by experts were not rated accordingly by parents, demonstrating different perspectives of professionals and parents. CONCLUSION: Although newborn screening leads to favourable physical and cognitive outcome, living with a metabolic disorder may cause considerable stress on patients and families, emphasizing the need for comprehensive multidisciplinary care including psychological and social support.


Assuntos
Desenvolvimento Infantil/fisiologia , Família/psicologia , Doenças Metabólicas/fisiopatologia , Doenças Metabólicas/psicologia , Pais/psicologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Triagem Neonatal/métodos , Qualidade de Vida , Apoio Social , Inquéritos e Questionários
19.
Invest Ophthalmol Vis Sci ; 55(1): 259-64, 2014 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-24327611

RESUMO

PURPOSE: To evaluate in different types of glaucoma frequency of family history of glaucoma (FHG), age at diagnosis, glaucoma risk in relatives, and acceptance rate of genetic glaucoma tests. To assess stage of visual field loss (VFL) in relation to FHG. METHODS: Using standardized questions whether an ophthalmologist had found or excluded glaucoma or ocular hypertension (OH), 2170 patients with glaucoma or OH interviewed all their first and second degree relatives. One thousand three hundred thirty-eight patients had POAG, 233 primary angle closure glaucoma (PACG), 148 OH, 153 normal tension glaucoma (NTG), 50 pigmentary glaucoma (PG), and 66 pseudoexfoliation glaucoma (PEX). RESULTS: Frequency of FHG was 40% in POAG, without significant differences compared with NTG (P = 0.08), OH (P = 0.5), PACG (P = 0.4), and PG (P = 0.6). There were significant differences in age at diagnosis between the glaucomas (smallest between group P < 0.0001). Patients with FHG were significantly younger at diagnosis than patients without FHG in all types of glaucoma (all P values ≤ 0.03), except NTG and PEX. Patients' siblings and mothers had the highest detection probability for glaucoma in POAG and OH. There was no significant relation between stage of VFL and FHG in POAG (P = 0.6). Sixty-eight percent of patients would participate in genetic glaucoma tests. CONCLUSIONS: There is a similarly high genetic disposition in all types of glaucoma. Disease risk was especially high in mothers and siblings. In patients with FHG, knowledge of genetic disposition of the glaucomas may have led to earlier diagnosis. This highlights the need for glaucoma awareness campaigns.


Assuntos
Predisposição Genética para Doença , Glaucoma/epidemiologia , Programas de Rastreamento , Vigilância da População/métodos , Adulto , Idoso , Feminino , Alemanha/epidemiologia , Glaucoma/genética , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco
20.
Mol Genet Metab ; 108(1): 1-7, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23219290

RESUMO

BACKGROUND: In phenylketonuria presymptomatic treatment following newborn screening prevents severe mental and physical impairment. The reasons for subtle impairments of cerebral functions despite early treatment remain unclear. We assessed a broad spectrum of visual functions in early-treated patients with phenylketonuria and evaluated two hypotheses-the dopamine and the long-chain polyunsaturated fatty acids (LCPUFAs) depletion hypotheses. METHODS: Contrast sensitivity, colour vision, electroretinography, frequency doubling technology campimetry (FDT), and their relation with blood phenylalanine and docosahexaenoic acid levels were assessed in 36 patients with phenylketonuria and 18 age-matched healthy controls. RESULTS: Contrast sensitivity was significantly lower and total error scores in colour vision significantly higher in patients than controls. Electroretinography results differed significantly between patients and controls. We found a trend for the effect of phenylalanine-levels on contrast sensitivity and a significant effect on colour vision/FDT results. Docosahexaenoic acid levels in erythrocytes were not associated with visual functions. CONCLUSION: This is the first evaluation of visual functions in phenylketonuria using a comprehensive ophthalmological test battery. We found no evidence supporting the long-chain polyunsaturated fatty acids depletion hypothesis. However, the effect of phenylalanine-levels on visual functions suggests that imbalance between phenylalanine and tyrosine may affect retinal dopamine levels in phenylketonuria. This is supported by the similar patterns of visual functions in patients with phenylketonuria observed in our study and patients with Parkinson's disease.


Assuntos
Dopamina/metabolismo , Ácidos Graxos Insaturados/metabolismo , Fenilcetonúrias/fisiopatologia , Visão Ocular , Adolescente , Adulto , Estudos de Casos e Controles , Visão de Cores , Sensibilidades de Contraste , Eletrorretinografia , Feminino , Humanos , Masculino , Fenilcetonúrias/metabolismo , Adulto Jovem
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