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Background: Acid sphingomyelinase deficiency (ASMD) is a rare, progressive, potentially fatal lysosomal storage disease that exhibits a broad spectrum of clinical phenotypes. There is a need to expand the knowledge of disease mortality and morbidity in Germany because of limited information on survival analysis in patients with chronic ASMD (type B or type A/B)., Methods: This observational, multicentre, retrospective cohort study was conducted using medical records of patients with the first symptom onset/diagnosis of ASMD type B or type A/B between 1st January 1990 and 31st July 2021 from four German medical centres. Eligible medical records were abstracted to collect data on demographic characteristics, medical history, hospitalisation, mortality, and causes of death from disease onset to the last follow-up/death. Survival outcomes were estimated using the Kaplan-Meier analysis. Standardised mortality ratio (SMR) was also explored., Results: This study included 33 chart records of patients with ASMD type B (n = 24) and type A/B (n = 9), with a median (interquartile range [IQR]) age of 8.0 [3.0-20.0] years and 1.0 [1.0-2.0] years, respectively, at diagnosis. The commonly reported manifestations were related to spleen (100.0%), liver (93.9%), and respiratory (77.4%) abnormalities. Nine deaths were reported at a median [IQR] age of 17.0 [5.0-25.0] years, with 66.7% of overall patients deceased at less than 18 years of age; the median [IQR] age at death for patients with ASMD type B (n = 4) and type A/B (n = 5) was 31.0 [11.0-55.0] and 9.0 [4.0-18.0] years, respectively. All deaths were ASMD-related and primarily caused by liver or respiratory failures or severe progressive neurodegeneration (two patients with ASMD type A/B). The median (95% confidence interval [CI]) overall survival age since birth was 45.4 (17.5-65.0) years. Additionally, an SMR [95% CI] analysis (21.6 [9.8-38.0]) showed that age-specific deaths in the ASMD population were 21.6 times more frequent than that in the general German population., Conclusions: This study highlights considerable morbidity and mortality associated with ASMD type B and type A/B in Germany. It further emphasises the importance of effective therapy for chronic ASMD to reduce disease complications., (© 2024. The Author(s).)

Background: Lysosomal Storage Diseases (LSD) are rare and multisytemic diseases which are caused by lysosomal enzyme deficiencies leading into accumulation of waste products due to an interruption in the decomposition process. Due to the low prevalence and therefore limited disease awareness as well as the fact that LSD patients present with unspecific symptoms the final diagnosis is often made after a long delay. The aim of this German-wide survey was to characterize the period between onset of symptoms and final diagnosis regarding e.g. self-perceived health, symptom burden and false diagnoses for patients with selected LSDs (Fabry disease (FD), Gaucher disease (GD) and Mucopolysaccharidosis type II (MPS II)., Methods: The study was conducted as a telephone based cross-sectional survey. All patients living in Germany with a confirmed diagnosis of FD, GD or MPS II were eligible to participate. The questionnaire was provided in advance in order to enable the participants to prepare for the interview. Only descriptive analyses were carried out. Single analyses were not carried out for all three patient groups due low case numbers., Results: Of the overall population, 39 patients have been diagnosed with FD, 19 with GD and 11 with MPS II with the majority of patients being index patients. The majority of FD patients reported their current health status as "satisfactory" or better (79.5%). Self-perceived health status was observed to be at least stable or improving for the majority of FD patients compared to the year prior to diagnosis. The most frequently reported symptoms for patients with FD were paraesthesias (51.3%), whereas patients with GD reported a tendency for bleeding, blue spots or coagulation disorder (63.2%) as well as hepatomegaly and/or splenomegaly (63.2%) as the most commonly appearing symptoms. The number of patients reporting misdiagnoses was n = 5 (13.5%) for patients with FD and n = 5 (27.8%) for patients with GD. The median duration of the diagnostic delay was 21.0 years for FD, 20.0 years for GD and 2.0 years for MPS II., Conclusions: This study showed that self-perceived status of health for patients might improve once the final correct diagnoses has been made and specific treatment was available. Furthermore, it was observed that diagnostic delay is still high in Germany for a relevant proportion of affected patients. Further challenges in the future will still be to increase awareness for these diseases across the entire healthcare sector to minimize the diagnostic delay., Competing Interests: Eugen Mengel received consulting fees and speakers honoraria from Sanofi Genzyme, Alexion, Orphazyme and Prevail. Eugen Mengel also received honoraria from Shire Deutschland GmbH to contribute his clinical expertise to this study. Jens Gaedeke has received honoraria from Amicus Therapeutics, Novartis, Sanofi, Roche. Jens Gaedeke also received honoraria from Shire Deutschland GmbH to contribute his clinical expertise to this study. Jörg Reinke received honoraria from BioMarin Pharmaceutical Inc., Genzyme, and Actelion. Jörg Reinke also received honoraria from Shire Deutschland GmbH to contribute his clinical expertise to this study. Holger Gothe is employed by IGES Institut GmbH; Simon Krupka and Christoph Ohlmeier were employed by IGES Institut GmbH at the time the study was performed. IGES Institut GmbH received funding from Shire Deutschland GmbH for the execution of the study and manuscript preparation. Anja Lachmann is employed by Shire Deutschland GmbH. These commercial affiliations do not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

Objective: To assess clinical features and general health status of adult patients with mucopolysaccharidosis (MPS) VI., Methods: This report includes the clinical history of patients older than 18 years with slowly progressing MPS VI and the retrospective analysis of the outcomes of available data collected between September 2003 and October 2008 at the Center of Pediatric and Adolescent Medicine, University Medical Center, Johannes Gutenberg-University of Mainz, Germany. Variables included were urinary glycosaminoglycan (uGAG) level, mutation analysis, body height, forced vital capacity (FVC), 6-minute walk test, echocardiographic findings, the need for craniocervical decompression surgery, orthopaedic findings and ophthalmological assessments., Results: The analysis included nine patients with MPS VI aged 19-29 years. The median age at diagnosis was 12 (range 6-20) years. At the time of the assessment (median age 25 years), median uGAG was 29 (range 15-149) μg/mg creatinine and median height 152 (range 136-161) cm. All patients had a FVC below standard values, seven showed reduced endurance in the 6-minute-walk test, all had valve changes with valve replacement in three, two underwent craniocervical decompression surgery, two underwent carpal tunnel surgery, five had ear/nose/throat (ENT) interventions, seven had hip pain/dysplasia, seven had corneal clouding and two were visually impaired., Conclusions: Although patients with slowly progressing MPS VI are a heterogeneous group showing disease manifestations in several organs, they seem to have some typical characteristics in common. Despite the attenuated clinical course, many of these patients show severe morbidity. Therefore, early diagnosis and proper follow-up and treatment are essential.

Background: Pompe disease (Glycogen storage disease type II, GSD II, acid alpha-glucosidase deficiency, acid maltase deficiency, OMIM # 232300) is an autosomal-recessive lysosomal storage disorder due to a deficiency of acid alpha-glucosidase (GAA, acid maltase, EC 3.2.1.20, Swiss-Prot P10253). Clinical manifestations are dominated by progressive weakness of skeletal muscle throughout the clinical spectrum. In addition, the classic infantile form is characterised by hypertrophic cardiomyopathy., Methods: In a cross-sectional single-centre study we clinically assessed 3 patients with classic infantile Pompe disease and 39 patients with non-classic presentations, measured their acid alpha-glucosidase activities and analysed their GAA genes., Results: Classic infantile patients had nearly absent residual enzyme activities and a typical clinical course with hypertrophic cardiomyopathy until the beginning of therapy. The disease manifestations in non-classic patients were heterogeneous. There was a broad variability in the decline of locomotive and respiratory function. The age of onset ranged from birth to late adulthood and correlated with enzyme activities. Molecular analysis revealed as many as 33 different mutations, 14 of which are novel. All classic infantile patients had two severe mutations. The most common mutation in the non-classic group was c.-32-13T>G. It was associated with a milder course in this subgroup., Conclusions: Disease manifestation strongly correlates with the nature of the GAA mutations, while the variable progression in non-classic Pompe disease is likely to be explained by yet unknown modifying factors. This study provides the first comprehensive dataset on the clinical course and the mutational spectrum of Pompe disease in Germany.

Background: National 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., Methods: In 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., Results: Optimal 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., Conclusions: Physical 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.

Background: Gaucher's disease is the autosomally recessively inherited deficiency of the lysosomal enzyme glucocerebrosidase. Increasing storage of glucocerebrosides leads to a multisystem disease, the prevalence of which is about 1:40,000 in central Europe and up to 1:2,000 in some other countries (e.g. Israel). The acute and chronic neuronopathic forms of the disease (formerly defined as Gaucher types 2 and 3) account for only 5 to 10% of all Gaucher patients in Central Europe and Germany and are thus less frequent than the non-neuronopathic disease (formerly defined as Gaucher type 1). Gaucher's disease is usually associated with spleno- and hepatomegaly, fatigue, skeletal complications, and several corresponding hematological and laboratory abnormalities. In 5 to 10% of the patients there are also central nervous symptoms such as myoclonic seizures, oculomotoric apraxia and a slight mental retardation., Methods: Four specialized centers care for more than 2/3 of all German Gaucher patients today. These centers present their consensus recommendations for state-of-the-art diagnosis and treatment of Gaucher's disease., Results: Recent epidemiological data indicate that only 10 to 20% of all Gaucher patients are correctly diagnosed (and treated) in Germany. The diagnosis today can be done in all patients by noninvasive methods, i.e. determination of the glucocerebrosidase activity in peripheral leukocytes and of the genetic defect. The current enzyme replacement therapy with glucocerebrosidase has proven effective to improve and often normalize hematological abnormalities, hepatosplenomegaly, skeletal complications and quality of life, provided that the therapy is started early and is given at adequate dosages., Conclusion: In view of the availability of an effective therapy, efforts should be made to increase the awareness of Gaucher's disease in differential diagnosis, to help to diagnose the disease with noninvasive techniques at early stages, and to provide practical guidelines for adequate treatment.