Zusammenfassung Hintergrund In der Neonatologie sind peripher eingeführte zentrale Katheter ein häufiger Zugangsweg zur parenteralen Ernährung und Verabreichung von Medikamenten und Flüssigkeit. Die Vorteile stehen den Risiken wie Infektion, Thrombose und Fehllage gegenüber. Fragestellung Welche Charakteristika und klinischen Zeichen weisen auf das Vorliegen einer katheterassoziierten Thrombose hin? Material und Methoden In einer retrospektiven Betrachung aus dem Zeitraum 2010–2016 wurden alle Fälle von katheterassoziierten Thrombosen untersucht. Identifiziert wurden 10 Frühgeborene, deren Indikation zur Katheteranlage, Zugangsweg, Lage der Katheterspitze, Liegedauer, klinische Symptome und Krankheitsverlauf analysiert wurden. Ergebnisse Bei 10 Frühgeborenen mit einem Gestationsalter von 23 + 4 bis 34 + 5 SSW wurden 11 Thromboseereignisse beobachtet. Zehn der 11 Thromboseereignisse betrafen die V. cava inferior nach Katheteranlage an der unteren Extremität. Die Indikation zur Katheteranlage waren parenterale Ernährung und chirurgische Eingriffe. Bei 9 Patienten traten perinatale Komplikationen auf. Bei allen Patienten bestand während der Liegedauer der Katheter der Verdacht auf eine Infektion. Das Auftreten der Thrombose wurde nach 3 bis 27 Tagen sonographisch dokumentiert. In 8 Thromboseereignissen war eine Thrombozytopenie, in 4 Fällen eine Beinschwellung auffällig. Diskussion Das Patientenkollektiv zeigt Gemeinsamkeiten im klinischen Verlauf und bei den Symptomen, welche auf das Vorliegen einer Thrombose deuten. Auffällig ist außerdem, dass die meisten Thromboseereignisse das Stromgebiet der V. cava inferior betrafen.

Background In neonatology peripherally inserted central catheters are a frequently used access route for parenteral nutrition and for the administration of drugs and fluids. The advantages are offset by the risks, such as infection, thrombosis and malpositioning. Objective Which characteristics and clinical signs indicate the presence of catheter-associated thrombosis? Material and methods In a retrospective study all cases of catheter-associated thrombosis from 2010 to 2016 were analyzed and 10 premature infants were identified. Data on indications for catheter placement, access route, position of the catheter tip, length of stay, clinical symptoms and course of disease were collected. Results In 10 preterm infants with a gestational age of 23 + 4-34 + 5 weeks 11 thrombotic events were observed. Out of 11 thrombotic events 10 occurred in the inferior vena cava. Indications for catheter placement were parenteral nutrition and surgical interventions. Perinatal complications had occurred in 9 patients. All patients were suspected to have an infection while the catheters were in place. The occurrence of thrombosis was documented after 3-27 days by ultrasound. In 8 thrombotic events thrombocytopenia was conspicuous, in 4 cases leg swelling led to the diagnosis. Discussion In our patients, similarities in the clinical course and in the symptoms indicated the presence of thrombosis. Interestingly, most thrombotic events occurred in the inferior vena cava.

Der nicht-immunologische Hydrops fetalis (NIHF) ist definiert als eine pathologische Flüssigkeitsansammlung in ≥2 fetalen Kompartimenten ohne nachweisbare maternale Antikörper gegen fetale Erythrozyten. Beim NIHF handelt es sich um ein unspezifisches Symptom und das Endstadium einer Vielzahl möglicher Erkrankungen. Trotz der enormen Fortschritte in der pränatalen Diagnostik zur Früherkennung von fetalen Pathologien und der postnatalen Ursachenforschung bleibt die zugrunde liegende Ätiologie in vielen Fällen ungeklärt. Somit stellt die Untersuchung der Ätiologie des NIHF den Schwerpunkt unserer Analyse dar.

Die therapeutische Hypothermie (TH) verbessert bei Neugeborenen mit hypoxisch-ischämischer Enzephalopathie (HIE) das langfristige Outcome. Die TH ist daher seit ca. 10 Jahren Bestandteil der klinischen Routine und sollte zur Anwendung kommen, wenn bei reifen Neugeborenen Hinweise für eine perinatale Asphyxie und Zeichen einer moderaten oder schweren HIE vorliegen.

Background and aims After the implementation of a local treatment protocol at our NICU, we aimed to systematically evaluate if intubation for apnea of prematurity was avoided by doxapram. We asked, if frequency and severity of apneas were affected and if side effects occurred. Methods We prospectively analysed all premature infants < 30 weeks treated according to a standardised protocol during 10/2010 to 04/2013. Doxapram was given only, if otherwise intubation had been necessary. We registered the number of apneas, bradycardias, and desaturations, pCO2 and side effects an hour before, at the start of, and during 48 h after onset of treatment. Results 21 of 66 (31.8%) infants (mean gestational age 25.5 weeks, mean birth weight 705 g) were treated during 2½ years. All of them had been treated with caffeine and CPAP before doxapram was applied. In 13 of 67 (19%) therapy courses, infants were intubated because of persistent apnea during 48 h of doxapram treatment. The frequency of apneas (2.7 vs. 0.2), bradycardias <80/min (1.0 vs. 0.2), and desaturations <80% (3.4 vs. 1.1) per hour decreased. Therapy was ceased in 5 cases because of side effects (gastrointestinal disturbances, seizure, extreme myoclonia). Conclusions Intubation was avoided in a large proportion of cases. In addition, frequency and severity of apneas diminished. Thus, doxapram seems to be effective. However, in face of side effects and lack of long term outcome data, it should be used with caution. Randomised studies are needed to achieve more information about efficacy and safety.

Clinical GeneticsVolume 83, Issue 4 p. 395-396 LETTERS TO THE EDITOR Successful long-term enzyme replacement therapy in a young adult with Fabry disease C Kampmann, Corresponding Author C Kampmann Section of Lysosomal Storage Diseases and Cardiology, Center for Diseases in Childhood and Adolescence, University Medical Center Mainz, Mainz, Germany Correspondence Prof. Dr C. Kampmann Zentrum für Kinder- und Jugendmedizin Universitätsmedizin Mainz Langenbeckstr. 1 D-55131 Mainz, Germany Tel.: +49 6131 177328 fax: +49 6131 17477328 e-mail: [email protected]Search for more papers by this authorG Kalkum, G Kalkum Section of Lysosomal Storage Diseases and Cardiology, Center for Diseases in Childhood and Adolescence, University Medical Center Mainz, Mainz, GermanySearch for more papers by this authorM Beck, M Beck Section of Lysosomal Storage Diseases and Cardiology, Center for Diseases in Childhood and Adolescence, University Medical Center Mainz, Mainz, GermanySearch for more papers by this authorC Whybra, C Whybra Section of Lysosomal Storage Diseases and Cardiology, Center for Diseases in Childhood and Adolescence, University Medical Center Mainz, Mainz, GermanySearch for more papers by this author C Kampmann, Corresponding Author C Kampmann Section of Lysosomal Storage Diseases and Cardiology, Center for Diseases in Childhood and Adolescence, University Medical Center Mainz, Mainz, Germany Correspondence Prof. Dr C. Kampmann Zentrum für Kinder- und Jugendmedizin Universitätsmedizin Mainz Langenbeckstr. 1 D-55131 Mainz, Germany Tel.: +49 6131 177328 fax: +49 6131 17477328 e-mail: [email protected]Search for more papers by this authorG Kalkum, G Kalkum Section of Lysosomal Storage Diseases and Cardiology, Center for Diseases in Childhood and Adolescence, University Medical Center Mainz, Mainz, GermanySearch for more papers by this authorM Beck, M Beck Section of Lysosomal Storage Diseases and Cardiology, Center for Diseases in Childhood and Adolescence, University Medical Center Mainz, Mainz, GermanySearch for more papers by this authorC Whybra, C Whybra Section of Lysosomal Storage Diseases and Cardiology, Center for Diseases in Childhood and Adolescence, University Medical Center Mainz, Mainz, GermanySearch for more papers by this author First published: 19 April 2013 https://doi.org/10.1111/j.1399-0004.2012.01916.xCitations: 5Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1Mehta A, Ricci R, Widmer U et al. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin Invest 2004: 34: 236–242. 10.1111/j.1365-2362.2004.01309.x CASPubMedWeb of Science®Google Scholar 2Mehta A, Beck M, Elliott P et al. Enzyme replacement therapy with agalsidase alfa in patients with Fabry's disease: an analysis of registry data. Lancet 2009: 374: 1986–1996. 10.1016/S0140-6736(09)61493-8 CASPubMedWeb of Science®Google Scholar 3Banikazemi M, Bultas J, Waldek S et al. Agalsidase-beta therapy for advanced Fabry disease: a randomized trial. Ann Intern Med 2007: 146: 77–86. 10.7326/0003-4819-146-2-200701160-00148 PubMedWeb of Science®Google Scholar 4Kampmann C, Linhart A, Baehner F et al. Onset and progression of the Anderson-Fabry disease related cardiomyopathy. Int J Cardiol 2008: 130: 367–373. 10.1016/j.ijcard.2008.03.007 PubMedWeb of Science®Google Scholar 5Utsumi K, Yamamoto N, Kase R et al. High incidence of thrombosis in Fabry's disease. Intern Med 1997: 36: 327–329. 10.2169/internalmedicine.36.327 CASPubMedWeb of Science®Google Scholar Citing Literature Volume83, Issue4April 2013Pages 395-396 ReferencesRelatedInformation

Background Although non immunological hydrops fetalis (NIHF) is a very rare disorder, the disturbance accounts for a disproportionate share (3%) of overall mortality in the perinatal period. Lysosomal storage disorders (LSD) are only exceptionally considered to be the cause of NIHF. The reported incidence is about 1%. On the other hand, in about 18% of all cases, NIHF is classified as idiopathic. Patients and methods We report four cases of transient NIHF due to LSD and reviewed the literature for LSD associated with NIHF. Results At present, 12 different LSD are described to be associated with NIHF. The majority of reported patients already had a family history of NIHF, which had not been investigated. A diagnostic approach to the fetus with NIHF due to suspected LSD is suggested. Conclusions Extensive and thorough investigation of the etiology of NIHF is obligatory. In particular, LSD should be considered in idiopathic NIHF. Enzymatic studies in chorionic villous samples or amniotic cultured cells, once the most common conditions associated with NIHF have been ruled out, should be performed. We assume that the incidence of LSD in NIHF is significantly higher than the estimated 1% reported in previous studies. This is important for genetic counseling, as there is at first, a high risk of recurrence and, secondly, the availability of enzyme replacement therapy for an increasing number of LSD.

Fallbeschreibung einer pränatal diagnostizierten fetalen Mucolipidose Typ II (I cell Disease) mit entsprechenden sonographischen Befunden. Review der bestehenden Literatur.

The original 40-question Fabry-specific Paediatric Health and Pain Questionnaire (FPHPQ) was developed to understand and assess the symptoms in Fabry Disease (FD) patients as no validated instrument existed. The objective of this study was to evaluate the psychometric properties of the FPHPQ. FPHPQ data were collected from the FOS, a registry sponsored by Shire HGT for patients with FD who were treatment naive or receiving enzyme replacement therapy with agalsidase alfa. Descriptive statistics and exploratory factor analysis were conducted to assess the item performance and to explore the underlying constructs. Reliability, validity, and responsiveness were also examined. Eighty-seven children (aged 4-18 years) from 8 different countries completed the questionnaire. From descriptive statistics and EFA, 23 items in three subscales emerged: Pain associated with heat or exertion; pain associated with cold; abdominal pain and fatigue. Internal consistency reliability for all three subscales was good (Cronbach alpha ≥ 0.84) and high for all age groups (4-7, 8-12, 13-18 years). Test-retest reliability was high for all three subscales (intraclass correlation coefficient ≥ 0.74). Construct validity was demonstrated by moderate correlation with the Brief Pain Inventory (BPI), KINDL, and EQ-5D. Known group validity showed that all subscales were able to discriminate between mild and moderate FD severity as classified by the FOS MSSI (Mainz Severity Score Index). The FPHPQ heat and exertion subscale was responsive to change in symptoms between responders and non-responders as defined by change in EQ-5D index scores between Visits 1 and 2. Preliminary analyses indicate that the measurement properties of FPHPQ are valid and reliable for assessing patient-reported symptoms of FD. The questionnaire could be a useful tool for clinicians to understand the progression of disease and monitor treatment effects. FPHPQ will be further validated and refined as the FOS database is continuously adding more patients.

AIM:To assess the effects of enzyme replacement therapy (ERT) in children with Fabry disease.METHODS:Safety and efficacy of ERT with agalsidase alfa, 0.2 mg/kg infused over 40 minutes every 2 weeks for 23 weeks, were studied in a multicentre open-label trial in nine boys and four girls. Median age at the start of the study was 11.0 years (range 3.5-18 years).RESULTS:Fifty-four adverse events were reported in 11 patients. No serious adverse events related to ERT were reported. Twelve of the 54 adverse events were considered possibly or probably related to ERT. Infusion reactions (8 mild, 3 moderate) occurred in four boys, in seven infusions. One boy developed IgG antibodies, although he continued to make good clinical progress. At the end of the study, two of the four boys and the one girl on regular pain medication at baseline had stopped taking analgesics. Brief Pain Inventory (BPI) scores decreased in most patients by week 12 and were sustained until the end of the study. This change was greater in the boys, who had higher (worse) BPI scores at baseline. Pain-related quality of life (QoL) scores also decreased during the study. Plasma globotriaosylceramide concentrations and urinary globotriaosylceramide:sphingomyelin ratios decreased after 12 and 23 weeks of therapy, particularly in the boys. Increases in sweat volume were recorded in three out of five of the boys and in one of two girls tested after 23 weeks of treatment.CONCLUSION:ERT with agalsidase alfa in children with Fabry disease is well tolerated and, in the short term, appears to decrease pain and to improve pain-related QoL.

Aim: Fabry disease (Fabry) is a rare X‐linked disorder caused by a deficiency of the lysosomal enzyme α‐galactosidase A. The progressive accumulation of the major substrate, globotriaosylceramide, leads to renal dysfunction and hypertrophic cardiomyopathy, which are reported to become apparent in the third decade. This study was performed to determine if signs of cardiac manifestations of Fabry are seen in younger Fabry patients.

SummaryObjectives:Fabry disease is a multisystem disorder with phenotypic heterogeneity only partially explained by genotype. Elevated interleukin‐6 (IL‐6) plasma levels and C‐reactive protein (CRP) serum levels are associated with increased risk and worse outcome of ischaemic events, a serious prognostic sign in Fabry disease.Methods:56 patients (34 hemizygous males, 22 females; 5 children) were studied. A promoter polymorphism −174G > C of the IL‐6 gene associated with serum IL‐6 levels was compared with the Mainz Severity Score Index (MSSI) in patients with Fabry disease. CRP levels and polymorphism 1059 G > C were evaluated as markers of inflammation to ascertain the possibility of an inflammatory mechanism of IL‐6. Nonparametric ANOVA, Fisher's exact, Bonferroni, and Hardy–Weinberg (HW) statistics were used.Results:Mean age of adults = 42 (range 26–58) years; 29 patients received enzyme therapy (ERT). Mean total MSSI = 26.7 (range 14.2–39.2) points, i.e. moderate disease, but females were lower (total 23.4 ± 12.6 vs 32.2 ± 13.6). Controls but not patients were in HW equilibrium. Significant correlation existed between all sub‐scores of the MSSI and IL‐6 genotypes in females but only with three MSSI sub‐scores for males. The IL‐6 C/C genotype was significantly correlated with the neurological, general and total MSSI sub‐scores, generally twofold higher. There were no statistically significant correlations with CRP levels/polymorphisms and MSSI sub‐scores nor with IL‐6 polymorphisms. CRP levels decreased after ERT in patients with IL‐6 G/G or G/C genotypes but increased in patients with C/C (p = 0.003).Conclusions:The prevalence of the IL‐6 C allele significantly influences MSSI, i.e. clinical severity, especially in females. This is unrelated to IL‐6 as a pro‐inflammatory marker as demonstrated by lack of correlations with CRP levels and genotypes. IL‐6 −174 polymorphic C allele may be a prognostic marker in Fabry disease, especially in females.

Aim: To assess the effects of enzyme replacement therapy (ERT) in children with Fabry disease.

Fabry disease (FD) is a lysosomal storage disorder that is associated with marked cerebrovascular disease. Conventional MRI shows a progressive load of white matter lesions (WMLs) due to cerebral vasculopathy in the course of FD. To quantify brain structural changes in clinically affected male and female patients with FD we performed a prospective Diffusion-Tensor Imaging (DTI) study in 27 adult Fabry patients (13m, 14f) and 21 age-matched controls (12 m, 9f). Global Mean Diffusivity (MD) was increased in FD (P = 0.003) whereas global Fractional Anisotropy (FA) did not differ significantly between FD and controls. Even FD patients without significant WMLs (9m, 9f) showed increased global MD (P = 0.004). Regions of interest with significant MD elevations were located in the frontal, parietal and temporal white matter. No differences of thalamic and hippocampal DTI measurements could be detected between FD and controls. DTI parameters did not differ between male and female patients. The data provide the first evidence of a pattern of marked structural brain tissue alterations in adult FD male and female patients even without WMLs. DTI seems to be an appropriate diagnostic tool to quantify brain tissue integrity in FD. Moreover, this method could be favorable for longitudinal assessment of brain structure alterations in FD, and for monitoring the cerebral effects of enzyme replacement therapy.

AIM:Left ventricular (LV) hypertrophy is a common feature in Fabry disease-related progressive infiltrative hypertrophic cardiomyopathy and affects both men and women, but at different ages. To date, however, little is known about the role of right ventricular (RV) function in Fabry disease. Therefore, this study aimed to investigate the extent of RV involvement in patients with Fabry disease. METHODS:Echocardiographic examination of the right and left ventricle was carried out in 129 patients (80 women and 49 men) with Fabry disease. RESULTS:RV hypertrophy was present in 46 patients (35.7%). Of these patients, 13 showed signs of severely depressed right systolic function (tricuspid annulus movement < 10 mm and a prolonged RV pre-ejection period/pulmonary ejection time ratio) and six patients showed additional severe depression of parameters of diastolic function (pseudo-normal or restrictive RV filling pattems). Those patients with RV hypertrophy and severely compromised systolic and diastolic function had the highest LV masses (92 +/- 11.7 g/m(2.7)). CONCLUSION:RV involvement is common in Fabry disease and ultimately progresses to severe systolic and diastolic RV dysfunction. These findings might explain why patients with preserved LV function can develop clinical features such as reduced exercise capacity, organomegaly and lymphoedema.

In order to estimate the cumulative incidence rates of the mucopolysaccharidoses (MPS) in Germany, a retrospective epidemiological survey covering the period between 1980 and 1995 was implemented. Multiple ascertainment sources were used to identify affected patients. A prevalence of approximately 0.69 cases per 100,000 births was obtained for MPS I (Hurler phenotype). Within the study period, 4 patients with Hurler/Scheie phenotype and 7 cases with Scheie disease were detected. The cumulative incidence for MPS II (Hunter syndrome) was estimated as 0.64 cases per 100,000 births (1.3 cases per 100,000 male live births); that for MPS III (Sanfilippo syndrome types A, B and C) as 1.57 cases in 100,000 births; that for MPS IV A (Morquio syndrome) as 0.38 cases in 100,000; and that for MPS VI (Maroteaux-Lamy syndrome) as 0.23 cases per 100,000 births. Two cases of MPS IVB (beta-galactosidase deficiency) have been identified, but no patients with MPS VII or MPS IX. A relatively high number of patients with MPS IIIB, MPS IVA and MPS VI were of Turkish origin. The crude rate for all types of mucopolysaccharidoses is approximately 3.53 cases in 100,000 live births. The cumulative incidence pattern of MPS in Germany was compared with the corresponding rates among other industrial nations obtained from recent literature: the crude cumulative rates for all types of mucopolysaccharidoses (3.4-4.5 in 100,000 live births) were similar among all published populations; however, different frequencies of the various forms of MPS were observed.