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Abstract Introduction In 2009 the European Commission called for National action plans (NAP) to improve the care for persons with rare diseases. Germany set up a NAP in 2013 suggesting a three-tiered structure of co-operating centers (CC), centers of excellence (CE) and reference centers (CR). Since then CEs and CRs were organized in the framework of university hospitals. However, realization of CCs taking into account the requirements of the NAP has been slow. We therefore set-up a 12-months program to initiate co-operation and to support the development of structured CCs. Methods Our center invited 3000 physicians from Berlin and/or Brandenburg to participate. They were chosen either due to already referring patients with rare metabolic diseases to the center, residing in a neighborhood with diverse ethnic background, known to have a high prevalence for specific metabolic diseases, or working as a medical sub-specialist (gastroenterology, hematology, rheumatology) with a high probability to diagnose a rare metabolic disease. The center offered co-operation contracts, administrative and structured medical support, privileged access to the center for physicians and their patients, as well as a program of continuous medical education (CME) over a period of 12 months. Results Between 0.1 to 0.5% (mean 0.2%) of the invited physicians participated in CME meetings. None of them was interested in setting up a co-operating center. The physicians were interested in broadening their knowledge about rare diseases, but less so in direct care for these patients and not at all in fulfilling the requirements of the NAP. Conclusions The requirements of the NAP for CC are thought of as unrealistic due to their demands on structural re-organization, quality measurements and additional work-load for outpatient-care. Especially so, with respect for the low number of patients profiting from these efforts and the lack of re-imbursement. We suggest a reconsideration of the German NAP.

Abstract Background Pompe disease (PD) is an autosomal recessive, lysosomal storage disease due to a mutation of the acid α-glucosidase (GAA) gene. In adult patients, PD is characterized by slowly progressive limb-girdle and trunk myopathy and restrictive respiratory insufficiency. Enzyme replacement therapy (ERT) is available, improving or stabilizing muscle-function in some and slowing deterioration in other patients. Unfortunately, there is no biomarker available to indicate therapeutic efficacy and/or disease activity. Whole body MRI depicts all skeletal muscles demonstrating foci of atrophic muscles, i.e., late and irreversible pathological changes. Any method indicating the localizations of increased muscle glycogen storage, muscle inflammation and/or degradation could possibly help identifying newly afflicted tissue and may be of prognostic value. We therefore investigated 2-deoxy-2-[18]fluoro-D-glucose (FDG) PET, a biomarker for glucose-metabolism, as a tool to evaluate disease activity and prognosis in PD. Methods In a pilot study, we investigated four patients by FDG dynamic PET/CT while on ERT. One patient had FDG-PET/CT twice, before and after 12 months on ERT. Dynamic FDG-PET/CT quantifies the metabolic rate of glucose utilisation in mg/ml/min. MRI was performed in parallel with pelvic and thigh muscles semi-quantitatively scored for atrophy and disease-activity. Results None of the muscles analysed showed a focally increased FDG-uptake. Thus, quantification of muscle glucose metabolism could not be calculated. However, increased FDG-uptake, i.e., increased glucose utilisation, was observed in the respiratory muscles of one patient with severe, restrictive respiratory failure. In contrast, specific MRI sequences showed oedematous as well as atrophic muscle areas in PD. Conclusions Our pilot study demonstrates that FDG-uptake does not correlate with glycogen storage in vivo. In contrast, MRI is an excellent tool to demonstrate the extent of muscle involvement. Specific MRI sequences may even demonstrate early changes possibly allowing prognostic predictions or localization of early stages of PD.

This paper outlines the present status of medical therapy of acromegaly. Indications for permanent postoperative treatment, postirradiation treamtent to bridge the interval until remission as well as primary medical therapy are elaborated. Therapeutic efficacy of the different available drugs—somatostatin receptor ligands (SRLs), dopamine agonists, and the GH antagonist Pegvisomant—is discussed, as are the indications for and efficacy of their respective combinations. Information on their mechanism of action, and some pharmakokinetic data are included. Special emphasis is given to the difficulties to define remission criteria of acromegaly due to technical assay problems. An algorithm for medical therapy in acromegaly is provided.

OBJECTIVE: Acromegalic patients have increased lipolysis and decreased fat mass as well as reduced insulin sensitivity and glucose intolerance. During somatostatin analog therapy, these changes persist despite GH suppression, but they are now due to drug-induced suppression of insulin secretion. By contrast, during pegvisomant (PEG) therapy, GH no longer stimulates lipolysis due to the blockade of its receptor, while insulin action is unabated. Hence, both insulin sensitivity and fat mass, including intra-abdominal fat, should increase. We therefore studied intra-abdominal fat and insulin resistance in acromegalic patients after a 3-month octreotide-washout period, i.e., during untreated acromegaly, and during PEG treatment. METHODS: Five acromegalic patients, not controlled on octreotide (OCT) therapy, were studied after 3-month OCT washout and 6-month PEG therapy. Insulin sensitivity was determined by homeostatic model assessment value and hyperinsulinemic, normoglycemic clamp. Subcutaneous and intra-abdominal fat were measured by electron beam computed tomography. RESULTS: During PEG therapy, all the patients had normal, age-adjusted IGF-I concentrations. Compared with washout, insulin sensitivity (HOMA and M value) was not significantly different. However, intra-abdominal fat mass increased significantly during therapy (median (range) cm2: 112 (84–480) and 172 (112–524) respectively, P<0.05), while subcutaneous fat was not significantly different. Low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides remained unchanged. CONCLUSIONS: During PEG therapy of acromegalic patients, intra-abdominal fat increases. Visceral obesity is a risk factor for cardiovascular disease. Hence, confirmation and further studies in a larger cohort of acromegalic patients on PEG treatment are warranted. [ABSTRACT FROM AUTHOR]

Aims: No data is available about the significance of cardiovascular magnetic resonance (CMR) derived vascular distensibility (VD) and vessel wall ratio (VWR) for risk stratification in patients with type 2 diabetes mellitus (T2DM). Therefore, this study aimed to investigate the effects of T2DM on VD and VWR using CMR in both central and peripheral territories., Methods: Thirty-one T2DM-patients and nine controls underwent CMR. Angulation of the aorta, the common carotid, and the coronary arteries was performed to obtain cross-sectional vessel areas., Results: In T2DM the Carotid-VWR and the Aortic-VWR correlated significantly. Mean values of Carotid-VWR and Aortic-VWR were significantly higher in T2DM than in controls. Coronary-VD was significantly lower in T2DM than in controls. No significant difference in Carotid-VD or Aortic-VD in T2DM vs. controls, respectively, could be observed. In a subgroup of thirteen T2DM patients with coronary artery disease (CAD), Coronary-VD was significantly lower and Aortic-VWR was significantly higher compared to T2DM patients without CAD., Conclusion: CMR allows a simultaneous evaluation of the structure and function of three important vascular territories to detect vascular remodeling in T2DM., Competing Interests: SK received support from the DZHK (German Center for Cardiovascular Research), Partner Site Berlin. SK was supported by Philips Healthcare. This work was partially funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - SFB-1470 - B06. CS is an employee of Philips Healthcare. PD owns stock of Bayer and Siemens., (AJCD Copyright © 2023.)

To prevent maternal phenylketonuria (PKU) syndrome low phenylalanine concentrations (target range, 120-360 μmol/L) during pregnancy are recommended for women with PKU. We evaluated the feasibility and effectiveness of current recommendations and identified factors influencing maternal metabolic control and children's outcome. Retrospective study of first successfully completed pregnancies of 85 women with PKU from 12 German centers using historical data and interviews with the women. Children's outcome was evaluated by standardized IQ tests and parental rating of child behavior. Seventy-four percent (63/85) of women started treatment before conception, 64% (54/85) reached the phenylalanine target range before conception. Pregnancy planning resulted in earlier achievement of the phenylalanine target (18 weeks before conception planned vs. 11 weeks of gestation unplanned, p < 0.001) and lower plasma phenylalanine concentrations during pregnancy, particularly in the first trimester (0-7 weeks of gestation: 247 μmol/L planned vs. 467 μmol/L unplanned, p < 0.0001; 8-12 weeks of gestation: 235 μmol/L planned vs. 414 μmol/L unplanned, p < 0.001). Preconceptual dietary training increased the success rate of achieving the phenylalanine target before conception compared to women without training (19 weeks before conception vs. 9 weeks of gestation, p < 0.001). The majority (93%) of children had normal IQ (mean 103, median age 7.3 years); however, IQ decreased with increasing phenylalanine concentration during pregnancy. Good metabolic control during pregnancy is the prerequisite to prevent maternal PKU syndrome in the offspring. This can be achieved by timely provision of detailed information, preconceptual dietary training, and careful planning of pregnancy., (© 2022 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Background Phenylketonuria is the most common inborn error of amino acid metabolism, where oxidative stress and collateral metabolic abnormalities are likely to cause cardiac structural and functional modifications. We aim herein to characterize the cardiac phenotype of adult subjects with phenylketonuria using advanced cardiac imaging. Methods and Results Thirty-nine adult patients with phenylketonuria (age, 30.5±8.7 years; 10-year mean phenylalanine concentration, 924±330 µmol/L) and 39 age- and sex-matched healthy controls were investigated. Participants underwent a comprehensive cardiac magnetic resonance and echocardiography examination. Ten-year mean plasma levels of phenylalanine and tyrosine were used to quantify disease activity and adherence to treatment. Patients with phenylketonuria had thinner left ventricular walls (septal end-diastolic thickness, 7.0±17 versus 8.8±1.7 mm [ P <0.001]; lateral thickness, 6.1±1.4 versus 6.8±1.2 mm [ P =0.004]), more dilated left ventricular cavity (end-diastolic volume, 87±14 versus 80±14 mL/m 2 [ P =0.0178]; end-systolic volume, 36±9 versus 29±8 mL/m 2 [ P <0.001]), lower ejection fraction (59±6% versus 64±6% [ P <0.001]), reduced systolic deformation (global circumferential strain, -29.9±4.2 % versus -32.2±5.0 % [ P =0.027]), and lower left ventricular mass (38.2±7.9 versus 47.8±11.0 g/m 2 [ P <0.001]). T1 native values were decreased (936±53 versus 996±26 ms [ P <0.001]), with particular low values in patients with phenylalanine >1200 µmol/L (909±48 ms). Both mean phenylalanine ( P =0.013) and tyrosine ( P =0.035) levels were independently correlated with T1; and in a multiple regression model, higher phenylalanine levels and higher left ventricular mass associate with lower T1. Conclusions Cardiac phenotype of adult patients with phenylketonuria reveals some traits of an early-stage cardiomyopathy. Regular cardiology follow-up, tighter therapeutic control, and prophylaxis of cardiovascular risk factors, in particular dyslipidemia, are recommended.

Aims: Pompe disease is caused by pathogenic mutations in the alpha 1,4-glucosidase (GAA) gene and in patients with late onset Pome disease (LOPD), genotype-phenotype correlations are unpredictable. Skeletal muscle pathology includes glycogen accumulation and altered autophagy of various degrees. A correlation of the muscle morphology with clinical features and the genetic background in GAA may contribute to the understanding of the phenotypic variability., Methods: Muscle biopsies taken before enzyme replacement therapy were analysed from 53 patients with LOPD. On resin sections, glycogen accumulation, fibrosis, autophagic vacuoles and the degree of muscle damage (morphology-score) were analysed and the results were compared with clinical findings. Additional autophagy markers microtubule-associated protein 1A/1B-light chain 3, p62 and Bcl2-associated athanogene 3 were analysed on cryosections from 22 LOPD biopsies., Results: The myopathology showed a high variability with, in most patients, a moderate glycogen accumulation and a low morphology-score. High morphology-scores were associated with increased fibrosis and autophagy highlighting the role of autophagy in severe stages of skeletal muscle damage. The morphology-score did not correlate with the patient's age at biopsy, disease duration, nor with the residual GAA enzyme activity or creatine-kinase levels. In 37 patients with LOPD, genetic analysis identified the most frequent mutation, c.-32-13T>G, in 95%, most commonly in combination with c.525delT (19%). No significant correlation was found between the different GAA genotypes and muscle morphology type., Conclusions: Muscle morphology in LOPD patients shows a high variability with, in most cases, moderate pathology. Increased pathology is associated with more fibrosis and autophagy., (© 2019 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

Background: Neuroendocrine neoplasia (NEN) are rare and heterogenous tumours. Few data exist on the impact of surgical therapy., Materials and Methods: This is a retrospective analysis of prospectively collected data of gastroenteropancreatic NEN in the German NET-Registry (1999-2012). It focuses on patients without distant metastases (limited disease, LD, stage I-IIIB)., Results: Data of 2239 patients with NEN were recorded. Median age was 59 years, the gender ratio was 1:1.3 (f:m). A total of 986 patients (44%) had LD, and the 5-year survival rate (5 years) was 77% for all and 90% for patients with LD. A total of 1635 patients (73%) received a surgical therapy (1st to 6th line); the 5 and 10 ysr were 83/65% after and 59/35% without surgery for all patients (p < .001). The resection margins in the LD patients were 76%, 16%, and 3% for R0, R1 and R2, respectively. The 10 ysr was 84%, 59% and 42% for R0, R1 and R2 resections, respectively (p = .021 R0/R1, p < .001 R0/R2). The R0 resection rate was 75% for G1/G2 NET and 67% for G3 NEC., Conclusion: The rate of complete tumour resection (R0) in LD is independent of tumour grading, and R0 resection is the key determinant of long-term survival, as demonstrated by the 10 ysr. of 84%. All NEN patients with limited disease should be considered for operation, if possible, as the best 10-year survival is shown after an R0 resection.

Background: Only few data on dietary management of adult phenylketonuria (PKU) patients are published., Objectives: This study aimed to assess living situation, dietary practices, and health conditions of early-treated adult PKU patients., Methods: A total of 183 early-treated PKU patients ≥18 years from 8 German metabolic centers received access to an online survey, containing 91 questions on sociodemographic data, dietary habits, and health conditions., Results: 144/183 patients (66% females) completed the questionnaire. Compared with German population, the proportion of single-person households was higher (22 vs. 47%), the rate of childbirth was lower (1.34 vs. 0.4%), but educational and professional status did not differ. 82% of the patients adhered to a low-protein diet, 45% consumed modified low-protein food almost daily, and 84% took amino acid mixtures regularly. 48% of the patients never interrupted diet, and 14% stopped diet permanently. 69% of the patients reported to feel better with diet, and 91% considered their quality of life at least as good. The prevalence of depressive symptoms was high (29%) and correlated significantly to phenylalanine blood concentrations (p = 0.046). However, depressive symptoms were only mild in the majority of patients., Conclusion: This group of early-treated adult German PKU patients is socially well integrated, reveals a surprisingly high adherence to diet and amino acid intake, and considers the restrictions of diet to their daily life as low., (© 2020 S. Karger AG, Basel.)

Background: Patients with Phenylketonuria (PKU) are exposed to multiple cardiovascular risk factors, but the clinical significance of these abnormalities is yet unknown. The purpose of this study was to characterize the cardiovascular phenotype in adult patients with PKU by clinical and dietary data, measurements of biochemical markers, and non-invasive examination of vascular functions., Results: Twenty-three adult patients with PKU (age: 18-47 y; 30.8 ± 8.4 y) and 28 healthy controls (age: 18-47 y; 30.1 ± 9.1 y) were included in this study. PKU patients had significantly higher systolic and diastolic blood pressure, increased resting heart rate and a higher body mass index. Total cholesterol and non-HDL cholesterol levels were significantly increased in PKU patients, whereas plasma levels of HDL cholesterol and its subfraction HDL2 (but not HDL3) were significantly decreased. The inflammatory markers C-reactive protein and serum amyloid A protein and the serum oxidative stress marker malondialdehyde were significantly higher in patients with PKU. Venous occlusion plethysmography showed marked reduction in post-ischemic blood flow and the carotid to femoral pulse wave velocity was significantly increased demonstrating endothelial dysfunction and increased vascular stiffness., Conclusions: This study shows that the cardiovascular phenotype of adult PKU patients is characterized by an accumulation of traditional cardiovascular risk factors, high levels of inflammatory and oxidative stress markers, endothelial dysfunction and vascular stiffness. These data indicate the need for early cardiovascular risk reduction in patients with PKU.

Objective: Growth hormone (GH) deficiency is related to increased cardiovascular mortality. We studied clinical status, concentration of amino-terminal-pro B-type natriuretic-peptide (NT-proBNP) and echocardiographic parameters during long-term GH replacement (GH-R)., Methods: Fifty-one patients (29 females), 45.9 ± 11.3 years (mean ± s.d.), median follow-up 36.2 months, echocardiography and laboratory determinations initially and at 12-months intervals., Results: At the last follow-up (last observation carried forward) (LFU (LOCF)) insulin-like growth-factor-1 standard deviation score (IGF-1 SDS) was ±1 in 92% of the patients. The median NT-proBNP declined significantly and stabilized (-40.5%) at LFU (LOCF) due to patients with a basal NT-proBNP >125 ng/L (indicative of heart failure). The basal NT-proBNP and the final IGF-1 SDS were significant predictors of the NT-proBNP at LFU (LOCF). Initially left ventricular enddiastolic diameter (LVEDD), left ventricular posterior wall diameter (LVPWD) and ejection fraction (EF) were normal, while interventricular septum diameter (IVSD) and left ventricular mass index (LVMi) were slightly increased. LVPWD and IVSD had significantly declined by year three. The LVMi was moderately to severely abnormal in 37.3 and 52.0% of patients initially and at LFU (LOCF). At LFU (LOCF) LVMi and IGF-1 were significantly correlated in the 14 male patients of this subgroup., Conclusion: Long-term GH-R of GHD positively affected ISVD and LVPWD. In a subgroup of patients with severe GHD, LVMi increased concomitantly to the decline in NT-proBNP and this was positively correlated to the final IGF-1 concentration. Whether this observation indicates a positive development in a structurally altered heart muscle (reversal of adverse remodelling) or poses a future risk for heart failure needs further follow-up.

Introduction: In 2009 the European Commission called for National action plans (NAP) to improve the care for persons with rare diseases. Germany set up a NAP in 2013 suggesting a three-tiered structure of co-operating centers (CC), centers of excellence (CE) and reference centers (CR). Since then CEs and CRs were organized in the framework of university hospitals. However, realization of CCs taking into account the requirements of the NAP has been slow. We therefore set-up a 12-months program to initiate co-operation and to support the development of structured CCs., Methods: Our center invited 3000 physicians from Berlin and/or Brandenburg to participate. They were chosen either due to already referring patients with rare metabolic diseases to the center, residing in a neighborhood with diverse ethnic background, known to have a high prevalence for specific metabolic diseases, or working as a medical sub-specialist (gastroenterology, hematology, rheumatology) with a high probability to diagnose a rare metabolic disease. The center offered co-operation contracts, administrative and structured medical support, privileged access to the center for physicians and their patients, as well as a program of continuous medical education (CME) over a period of 12 months., Results: Between 0.1 to 0.5% (mean 0.2%) of the invited physicians participated in CME meetings. None of them was interested in setting up a co-operating center. The physicians were interested in broadening their knowledge about rare diseases, but less so in direct care for these patients and not at all in fulfilling the requirements of the NAP., Conclusions: The requirements of the NAP for CC are thought of as unrealistic due to their demands on structural re-organization, quality measurements and additional work-load for outpatient-care. Especially so, with respect for the low number of patients profiting from these efforts and the lack of re-imbursement. We suggest a reconsideration of the German NAP.