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Contains fulltext : 295915.pdf (Publisher’s version ) (Open Access), BACKGROUND/OBJECTIVES: The timely diagnosis of inherited metabolic disorders (IMD) is essential for initiating treatment, prognostication and genetic testing of relatives. Recognition of IMD in adults is difficult, because phenotypes are different from those in children and influenced by symptoms from acquired conditions. This systematic literature review aims to answer the following questions: (1) What is the diagnostic yield of exome/genome sequencing (ES/GS) for IMD in adults with unsolved phenotypes? (2) What characteristics do adult patients diagnosed with IMD through ES/GS have? METHODS: A systematic search was conducted using the following search terms (simplified): "Whole exome sequencing (WES)," "Whole genome sequencing (WGS)," "IMD," "diagnostics" and the 1,450 known metabolic genes derived from ICIMD. Data from 695 articles, including 27,702 patients, were analyzed using two different methods. First, the diagnostic yield for IMD in patients presenting with a similar phenotype was calculated. Secondly, the characteristics of patients diagnosed with IMD through ES/GS in adulthood were established. RESULTS: The diagnostic yield of ES and/or GS for adult patients presenting with unexplained neurological symptoms is 11% and for those presenting with dyslipidemia, diabetes, auditory and cardiovascular symptoms 10, 9, 8 and 7%, respectively. IMD patients diagnosed in adulthood (n = 1,426), most frequently portray neurological symptoms (65%), specifically extrapyramidal/cerebellar symptoms (57%), intellectual disability/dementia/psychiatric symptoms (41%), pyramidal tract symptoms/myelopathy (37%), peripheral neuropathy (18%), and epileptic seizures (16%). The second most frequently observed symptoms were ophthalmological (21%). In 47% of the IMD diagnosed patients, symptoms from multiple organ systems were reported. On average, adult patients are diagnosed 15 years after first presenting symptoms. Disease-related abnormalities in metabolites in plasma, urine or

Item does not contain fulltext, BACKGROUND: Newborn screening (NBS) programmes identify a wide range of disease phenotypes, which raises the question whether early identification and treatment is beneficial for all. This study aims to answer this question for primary carnitine deficiency (PCD) taking into account that NBS for PCD identifies newborns with PCD and also until then undiagnosed mothers. METHODS: We investigated clinical, genetic (variants in SLC22A5 gene) and functional (carnitine transport activity in fibroblasts) characteristics of all referred individuals through NBS (newborns and mothers) and clinically diagnosed patients with PCD (not through NBS). Disease phenotype in newborns was predicted using data from PCD mothers and cases published in literature with identical SLC22A5 variants. RESULTS: PCD was confirmed in 19/131 referred newborns, 37/82 referred mothers and 5 clinically diagnosed patients. Severe symptoms were observed in all clinically diagnosed patients, 1 newborn and none of the mothers identified by NBS. PCD was classified as severe in all 5 clinically diagnosed patients, 3/19 newborns and 1/37 mothers; as benign in 8/19 newborns and 36/37 mothers and as unknown in 8/19 newborns. Carnitine transport activity completely separated severe phenotype from benign phenotype (median (range): 4.0% (3.5-5.0)] vs 26% (9.5-42.5), respectively). CONCLUSION: The majority of mothers and a significant proportion of newborns with PCD identified through NBS are likely to remain asymptomatic without early treatment. Conversely, a small proportion of newborns with predicted severe PCD could greatly benefit from early treatment. Genetic variants and carnitine transport activity can be used to distinguish between these groups.

Dietary or nutritional management strategies are the cornerstone of treatment for many inborn errors of metabolism (IEMs). Though a vital part of standard of care, the products prescribed for this are often not formally registered as medication. Instead, they are regulated as food or as food supplements, impacting the level of oversight as well as reimbursed policies. This scoping literature review explores the European regulatory framework relevant to these products and its implications for current clinical practice. Searches of electronic databases (PubMed, InfoCuria) were carried out, supplemented by articles identified by experts, from reference lists, relevant guidelines and case-law by the European Court of Justice. In the European Union (EU), nutritional therapy products are regulated as food supplements, food for special medical purposes (FSMPs) or medication. The requirements and level of oversight increase for each of these categories. Relying on lesser-regulated food products to treat IEMs raises concerns regarding product quality, safety, reimbursement and patient access. In order to ascertain whether a nutritional therapy product functions as medication and thus could be classified as such, we developed a flowchart to assess treatment characteristics (benefit, pharmacological attributes, and safety) with a case-based approach. Evaluating nutritional therapy products might reveal a justifiable need for a pharmaceutical product. A flowchart can facilitate systematically distinguishing products that function medication-like in the management of IEMs. Subsequently, finding and implementing appropriate solutions for these products might help improve the quality, safety and accessibility including reimbursement of treatment for IEMs.

Contains fulltext : 282561.pdf (Publisher’s version ) (Open Access), Exome sequencing (ES) in the clinical setting of inborn metabolic diseases (IMDs) has created tremendous improvement in achieving an accurate and timely molecular diagnosis for a greater number of patients, but it still leaves the majority of patients without a diagnosis. In parallel, (personalized) treatment strategies are increasingly available, but this requires the availability of a molecular diagnosis. IMDs comprise an expanding field with the ongoing identification of novel disease genes and the recognition of multiple inheritance patterns, mosaicism, variable penetrance, and expressivity for known disease genes. The analysis of trio ES is preferred over singleton ES as information on the allelic origin (paternal, maternal, "de novo") reduces the number of variants that require interpretation. All ES data and interpretation strategies should be exploited including CNV and mitochondrial DNA analysis. The constant advancements in available techniques and knowledge necessitate the close exchange of clinicians and molecular geneticists about genotypes and phenotypes, as well as knowledge of the challenges and pitfalls of ES to initiate proper further diagnostic steps. Functional analyses (transcriptomics, proteomics, and metabolomics) can be applied to characterize and validate the impact of identified variants, or to guide the genomic search for a diagnosis in unsolved cases. Future diagnostic techniques (genome sequencing [GS], optical genome mapping, long-read sequencing, and epigenetic profiling) will further enhance the diagnostic yield. We provide an overview of the challenges and limitations inherent to ES followed by an outline of solutions and a clinical checklist, focused on establishing a diagnosis to eventually achieve (personalized) treatment.

Background: Enzyme replacement therapy (ERT) slows disease progression of Fabry disease (FD), especially when initiated before the onset of irreversible organ damage. However, with the clinically asymptomatic progression of renal, cardiac and cerebral disease manifestations spanning decades, optimal timing of ERT initiation remains unclear. Methods: In this cross-sectional retrospective study, seven male FD patients with a classical disease phenotype (cFD) who started treatment with agalsidase-beta in childhood were evaluated after 10 years of treatment (median age at evaluation 24 years, range 14–26). Cardiac imaging (echocardiography and MRI), electrophysiological and biochemical data of these patients were compared to those of untreated male cFD patients (n = 23, median age 22 years, range 13–27). Results: Albuminuria was less common and less severe in treated patients (albumin to creatinine ratio, ACR 0–8.8 mg/mmol, median 0.4) compared to untreated patients (ACR 0–248 mg/mmol, median 3.7, p = 0.02). The treated group had a lower left ventricular mass, measured using echocardiography (median 80 g/m2 versus 94 g/m2, p = 0.02) and MRI (median 53 g/m2 versus 68 g/m2, p = 0.02). Myocardial fibrosis was absent in all included patients. eGFR was normal in all treated patients whereas 7/23 (30%) of untreated patients had abnormal eGFR. Cerebral manifestations did not differ. Conclusions: Start of treatment with ERT before age 16, in male cFD patients is associated with reduced occurrence of renal and cardiac manifestations of FD, as assessed by intermediate endpoints. Confirmation that this approach delays or even prevents renal failure and cardiac events requires another decade of follow-up.

Background: A subset of patients with phenylketonuria benefit from treatment with tetrahydrobiopterin (BH 4), although there is no consensus on the definition of BH 4 responsiveness. The aim of this study therefore was to gain insight into the definitions of long-term BH 4 responsiveness being used around the world. Methods: We performed a web-based survey targeting healthcare professionals involved in the treatment of PKU patients. Data were analysed according to geographical region (Europe, USA/Canada, other). Results: We analysed 166 responses. Long-term BH 4 responsiveness was commonly defined using natural protein tolerance (95.6%), improvement of metabolic control (73.5%) and increase in quality of life (48.2%). When a specific value for a reduction in phenylalanine concentrations was reported (n = 89), 30% and 20% were most frequently used as cut-off values (76% and 19% of respondents, respectively). When a specific relative increase in natural protein tolerance was used to define long-term BH 4 responsiveness (n = 71), respondents most commonly reported cut-off values of 30% and 100% (28% of respondents in both cases). Respondents from USA/Canada (n = 50) generally used less strict cut-off values compared to Europe (n = 96). Furthermore, respondents working within the same center answered differently. Conclusion: The results of this study suggest a very heterogeneous situation on the topic of defining long-term BH 4 responsiveness, not only at a worldwide level but also within centers. Developing a strong evidence- and consensus-based definition would improve the quality of BH 4 treatment.

Objective: This study describes the influence of sex and disease phenotype on the occurrence of cardiac events in Fabry disease (FD). Methods: Cardiac events from birth to last visit (median age 50 years) were recorded for 213 patients with FD. Patients were categorised as follows: men with classical FD (n=57), men with non-classical FD (n=26), women with classical FD (n=98) and women with non-classical FD (n=32), based on the presence of classical FD symptoms, family history (men and women), biomarkers and residual enzyme activity (men). Event rates per 1000 patient-years after the age of 15 years and median event-free survival (EVS) age were presented. Influence of disease phenotype, sex and their interaction was studied using Firth's penalised Cox regression. Results: The event rates of major cardiovascular events (combined endpoint cardiovascular death (CVD), heart failure (HF) hospitalisation, sustained ventricular arrhythmias (SVAs) and myocardial infarction) were 11.0 (95% CI 6.6 to 17.3) in men with classical FD (EVS 55 years), 4.4 (95% CI 2.5 to 7.1) in wo

The hips are frequently involved in inheritable diseases which affect the bones. The clinical and radiological presentation of these diseases may be very similar to common hip disorders as developmental dysplasia of the hip, osteoarthritis and avascular necrosis, so the diagnosis may be easily overlooked and treatment may be suboptimal. Mucopolysaccharidosis (MPS) and Mucolipidosis (ML II and III) are lysosomal storage disorders with multisystemic involvement. Characteristic skeletal abnormalities, known as dysostosis multiplex, are common in MPS and ML and originate from intra-lysosomal storage of glycosaminoglycans in cells of the cartilage, bones and ligaments. The hip joint is severely affected in MPS and ML. Hip pathology results in limitations in mobility and pain from young age, and negatively affects quality of life. In order to better understand the underlying process that causes hip disease in MPS and ML, this review first describes the normal physiological (embryonic) hip joint development, including the interplay between the acetabulum and the femoral head. In the second part the factors contributing to altered hip morphology and function in MPS and ML are discussed, such as abnormal development of the pelvic- and femoral bones (which results in altered biomechanical forces) and inflammation. In the last part of this review therapeutic options and future perspectives are addressed.

Background: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD. Methods and findings: A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial. Conclusion: This consensus will help to shape the future of clinical trials in

Urea cycle disorders (UCDs) are a group of rare inherited metabolic diseases causing hyperammonemic encephalopathy. Despite intensive dietary and pharmacological therapy, outcome is poor in a subset of UCD patients. Reducing ammonia production by changing faecal microbiome in UCD is an attractive treatment approach. We compared faecal microbiome composition of 10 UCD patients, 10 healthy control subjects and 10 phenylketonuria (PKU) patients. PKU patients on a low protein diet were included to differentiate between the effect of a low protein diet and the UCD itself on microbial composition. Participants were asked to collect a faecal sample and to fill out a 24 h dietary journal. DNA was extracted from faecal material, taxonomy was assigned and microbiome data was analyzed, with a focus on microbiota involved in ammonia metabolism. In this study we show an altered faecal microbiome in UCD patients, different from both PKU and healthy controls. UCD patients on dietary and pharmacological treatment had a less diverse faecal microbiome, and the faecal microbiome of PKU patients on a protein restricted diet with amino acid supplementation showed reduced richness compared to healthy adults without a specific diet. The differences in the microbiome composition of UCD patients compared to healthy controls were in part related to lactulose use. Other genomic process encodings involved in ammonia metabolism, did not seem to differ. Since manipulation of the microbiome is possible, this could be a potential treatment modality. We propose as a first next step, to study the impact of these faecal microbiome alterations on metabolic stability. Take home message: The faecal microbiome of UCD patients was less diverse compared to PKU patients and even more compared to healthy controls.

This case illustrates the importance of multidisciplinary counselling and management of pregnancies in women with complex medical conditions, especially concerning women with cognitive impairment. We present a woman with hyperinsulinism/hyperammonaemia (HI/HA) syndrome. This syndrome is characterised by recurrent episodes of hypoglycaemia and elevated ammonia levels, which are potentially harmful to both the patient and a developing fetus. We describe a successful multidisciplinary approach during the pregnancy of a mentally challenged patient with HI/HA syndrome. This case illustrates the importance of personalised counselling during the preconception period and emphasises to include all disciplines involved in the medical and daily care of such a patient. In our case, the extensive multidisciplinary care during the preconception period, pregnancy, delivery and postpartum period resulted in a good maternal and neonatal outcome.

Evidence for effectiveness of newborn screening (NBS) for propionic acidemia (PA) and isolated methylmalonic acidemia (MMA) is scarce. Prior to implementation in the Netherlands, we aim to estimate the expected health gain of NBS for PA and MMA. In this national retrospective cohort study, the clinical course of 76/83 Dutch PA and MMA patients, diagnosed between January 1979 and July 2019, was evaluated. Five clinical outcome parameters were defined: adverse outcome of the first symptomatic phase, frequency of acute metabolic decompensations (AMD), cognitive function, mitochondrial complications, and treatment-related complications. Outcomes of patients identified by family testing were compared with the outcomes of their index siblings. An adverse outcome due to the first symptomatic phase was recorded in 46% of the clinically diagnosed patients. Outcome of the first symptomatic phase was similar in 5/9 sibling pairs and better in 4/9 pairs. Based on the day of diagnosis of the clinically diagnosed patients and sibling pair analysis, a preliminary estimated reduction of adverse outcome due to the first symptomatic phase from 46% to 36%-38% was calculated. Among the sibling pairs, AMD frequency, cognitive function, mitochondrial, and treatment-related complications were comparable. These results suggest that the health gain of NBS for PA and MMA in overall outcome may be limited, as only a modest decrease of adverse outcomes due to the first symptomatic phase is expected. With current clinical practice, no reduced AMD frequency, improved cognitive function, or reduced frequency of mitochondrial or treatment-related complications can be expected.