Treatments for lysosomal storage disorders

Abstract There are over 70 human diseases that are caused by defects in various aspects of lysosomal function. Until 20 years ago, the only specific therapy available for lysosomal storage disorders was allogeneic haemopoietic stem cell transplantation. Over the last two decades, there has been remarkable progress and there are now licensed treatments for seven of these diseases. In some cases, a choice of agents is available. For selected enzyme-deficiency disordes, ERT (enzyme-replacement therapy) has proved to be highly effective. In other cases, ERT has been less impressive, and it seems that it is not possible to efficiently deliver recombinant enzyme to all tissues. These difficulties have led to the development of other small-moleculebased therapies, and a drug for SRT (substrate-reduction therapy) is now licensed and potential chaperone molecules for ERT are in the late stages of clinical development. Nonetheless, there is still significant unmet clinical need, particularly when it comes to treating LSDs which affect the brain. LSDs have led the way in the development of treatment for genetic disorders, and it seems likely that there will be further therapeutic innovations in the future

SLC37A4-CDG : mislocalization of the glucose-6-phosphate transporter to the Golgi causes a new congenital disorder of glycosylation

Loss-of-function of the glucose-6-phosphate transporter is caused by biallelic mutations in SLC37A4 and leads to glycogen storage disease Ib. Here we describe a second disease caused by a single dominant mutation in the same gene. The mutation abolishes the ER retention signal of the transporter and generates a weak Golgi retention signal. Intracellular mislocalization of the transporter leads to a congenital disorder of glycosylation instead of glycogen storage disease

Role of serum N-terminal pro-brain natriuretic peptide measurement in diagnosis of cardiac involvement in patients with anderson-fabry disease

Enzyme replacement therapy has the potential to delay or reverse adverse cardiac remodeling in Anderson-Fabry disease (AFD); however, the current indications for enzyme replacement therapy rely on detecting relatively advanced features of the disease. We aimed to determine the relation between the serum N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration and cardiac abnormalities in patients with AFD. We hypothesized that it might help to detect early disease. NT-proBNP was measured under at rest conditions in 117 patients with AFD (age 48 ± 15 years, 46.2% men). All patients underwent clinical evaluation with electrocardiography and echocardiography. The median NT-proBNP concentration was 24 pmol/L (range <5 to 6,059). Of the 117 patients, 67 (57%) had elevated, age-corrected, NT-proBNP levels. In the 56 patients (48%) with normal echocardiographic findings, the NT-proBNP levels were greater than the age-predicted cutoffs in 10 of 25 patients with abnormal electrocardiographic findings and 3 of 31 patients with normal electrocardiographic findings (p <0.05). On multiple regression analysis, age, creatinine, left atrial volume index, E/Ea, and the presence of abnormal electrocardiographic findings were independently associated with log NT-proBNP (R(2) = 0.67, p <0.05). In conclusion, NT-proBNP concentrations were elevated in patients with AFD and early cardiac involvement, suggesting its measurement could assist in decisions regarding the timing of enzyme replacement therapy

TOPCAT and Gaia

TOPCAT, and its command line counterpart STILTS, are powerful tools for working with large source catalogues. ESA's Gaia mission, most recently with its second data release, is producing source catalogues of unprecedented quality for more than a billion sources. This paper presents some examples of how TOPCAT and STILTS can be used for analysis of Gaia data.Comment: 4 pages, 2 figures; to appear in the Proceedings of ADASS 2018, Astronomical Society of the Pacific (ASP) Conference Serie

In-depth phenotyping for clinical stratification of Gaucher disease.

BackgroundThe Gaucher Investigative Therapy Evaluation is a national clinical cohort of 250 patients aged 5-87 years with Gaucher disease in the United Kingdom-an ultra-rare genetic disorder. To inform clinical decision-making and improve pathophysiological understanding, we characterized the course of Gaucher disease and explored the influence of costly innovative medication and other interventions. Retrospective and prospective clinical, laboratory and radiological information including molecular analysis of the GBA1 gene and comprising > 2500 variables were collected systematically into a relational database with banking of collated biological samples in a central bioresource. Data for deep phenotyping and life-quality evaluation, including skeletal, visceral, haematological and neurological manifestations were recorded for a median of 17.3 years; the skeletal and neurological manifestations are the main focus of this study.ResultsAt baseline, 223 of the 250 patients were classified as type 1 Gaucher disease. Skeletal manifestations occurred in most patients in the cohort (131 of 201 specifically reported bone pain). Symptomatic osteonecrosis and fragility fractures occurred respectively in 76 and 37 of all 250 patients and the first osseous events occurred significantly earlier in those with neuronopathic disease. Intensive phenotyping in a subgroup of 40 patients originally considered to have only systemic features, revealed neurological involvement in 18: two had Parkinson disease and 16 had clinical signs compatible with neuronopathic Gaucher disease-indicating a greater than expected prevalence of neurological features. Analysis of longitudinal real-world data enabled Gaucher disease to be stratified with respect to advanced therapies and splenectomy. Splenectomy was associated with an increased hazard of fragility fractures, in addition to osteonecrosis and orthopaedic surgery; there were marked gender differences in fracture risk over time since splenectomy. Skeletal disease was a heavy burden of illness, especially where access to specific therapy was delayed and in patients requiring orthopaedic surgery.ConclusionGaucher disease has been explored using real-world data obtained in an era of therapeutic transformation. Introduction of advanced therapies and repeated longitudinal measures enabled this heterogeneous condition to be stratified into obvious clinical endotypes. The study reveals diverse and changing phenotypic manifestations with systemic, skeletal and neurological disease as inter-related sources of disability

Natural history of epilepsy in argininosuccinic aciduria provides new insights into pathophysiology: A retrospective international study

OBJECTIVE: Argininosuccinate lyase (ASL) is integral to the urea cycle, which enables nitrogen wasting and biosynthesis of arginine, a precursor of nitric oxide. Inherited ASL deficiency causes argininosuccinic aciduria, the second most common urea cycle defect and an inherited model of systemic nitric oxide deficiency. Patients present with developmental delay, epilepsy, and movement disorder. Here we aim to characterize epilepsy, a common and neurodebilitating comorbidity in argininosuccinic aciduria. METHODS: We conducted a retrospective study in seven tertiary metabolic centers in the UK, Italy, and Canada from 2020 to 2022, to assess the phenotype of epilepsy in argininosuccinic aciduria and correlate it with clinical, biochemical, radiological, and electroencephalographic data. RESULTS: Thirty-seven patients, 1-31 years of age, were included. Twenty-two patients (60%) presented with epilepsy. The median age at epilepsy onset was 24 months. Generalized tonic-clonic and focal seizures were most common in early-onset patients, whereas atypical absences were predominant in late-onset patients. Seventeen patients (77%) required antiseizure medications and six (27%) had pharmacoresistant epilepsy. Patients with epilepsy presented with a severe neurodebilitating disease with higher rates of speech delay (p = .04) and autism spectrum disorders (p = .01) and more frequent arginine supplementation (p = .01) compared to patients without epilepsy. Neonatal seizures were not associated with a higher risk of developing epilepsy. Biomarkers of ureagenesis did not differ between epileptic and non-epileptic patients. Epilepsy onset in early infancy (p = .05) and electroencephalographic background asymmetry (p = .0007) were significant predictors of partially controlled or refractory epilepsy. SIGNIFICANCE: Epilepsy in argininosuccinic aciduria is frequent, polymorphic, and associated with more frequent neurodevelopmental comorbidities. We identified prognostic factors for pharmacoresistance in epilepsy. This study does not support defective ureagenesis as prominent in the pathophysiology of epilepsy but suggests a role of central dopamine deficiency. A role of arginine in epileptogenesis was not supported and warrants further studies to assess the potential arginine neurotoxicity in argininosuccinic aciduria

Anticipated effects of burosumab treatment on long-term clinical sequelae in XLH: expert perspectives

X-linked hypophosphatemia (XLH) is a rare, progressive, genetic disease with multisystem impact that typically begins to manifest in early childhood. Two treatment options exist: oral phosphate in combination with active vitamin D (“conventional therapy”) and a fully human monoclonal anti-FGF23 antibody, burosumab. The clinical benefit of conventional therapy in adults is limited, and poor tolerance and complications are common. Burosumab was first approved as a treatment for XLH in 2018 and its disease-modifying benefits in clinical trials in children suggest burosumab treatment could also alter the disease course in adults. Without long-term clinical data on multiple XLH-related sequelae available, the results of an elicitation exercise are reported, in which eight global experts in XLH posited how long-term treatment with burosumab is anticipated to impact the life course of clinical sequelae in adults with XLH. Based on their clinical experiences, the available evidence and their disease understanding, the experts agreed that some long-term benefits of using burosumab are likely in adults with XLH even if they have a misaligned skeleton from childhood. Burosumab treatment is anticipated to reduce the incidence of fractures and halt the progression of clinical sequelae associated with conventional therapy. While the trajectories for established dental abscesses are not expected to improve with burosumab treatment, dental abscess development may be prevented. Starting treatment with burosumab in childhood to increase the likelihood of an aligned skeleton and continuation into and throughout adulthood to maintain euphosphatemia may optimize patient outcomes, although future real-world investigation is required to support this hypothesis