Search

Purpose: Following the publication of 5-year agalsidase alfa enzyme replacement therapy (ERT) outcomes data from the Fabry Outcome Survey (FOS), 10-year data were analyzed. Patients and methods: FOS (ClinicalTrials.gov identifier: NCT03289065) data (April 2001 to August 2018) were retrospectively analyzed. Estimated glomerular filtration rate (eGFR) and left ventricular mass indexed to height (LVMI) were analyzed after treatment start (baseline) for patients with ≥3 measurements, including baseline and year 10. Results: Median (range) age (years) of the evaluable treated renal cohort at treatment start was 48.8 (17.9–67.3) for females (n=62), 34.4 (18.0–66.8) for males (n=90). With eGFR ≥60 mL/min/1.73 m2 at baseline, mean (95% CI) rate of eGFR change (eGFR/year) over 10 years was relatively stable in females (n=52; −0.55 [−1.12, +0.01]) and slightly declined in males (n=79; −1.99 [−2.45, −1.54]). With impaired kidney function (eGFR 48 g/m2.7 in females, >50 g/m2.7 in males) at baseline, mean (95% CI) LVMI/year slightly increased over 10 years in females (n=18; +1.51 [+0.91, +2.12]) and males (n=14; +0.87 (+0.19, +1.55). Without LVH at baseline, mean (95% CI) LVMI/year was stable in females (n=16; +0.52 [−0.13, +1.17]) and males (n=21; +0.57 [+0.02, +1.13]) over 10 years. Conclusion: Agalsidase alfa-treated patients with 10-year FOS data and preserved kidney function and/or normal LVMI at baseline remained largely stable; those with decreased kidney function or LVH at baseline experienced modest declines in renal function and/or increases in LVMI.

McArdle disease is a disorder of muscle glycogen metabolism caused by mutations in the PYGM gene, encoding for the muscle-specific isoform of glycogen phosphorylase (M-GP). The activity of this enzyme is completely lost in patients' muscle biopsies, when measured with a standard biochemical test which, does not allow to determine M-GP protein levels. We aimed to determine M-GP protein levels in the muscle of McArdle patients, by studying biopsies of 40 patients harboring a broad spectrum of PYGM mutations and 22 controls. Lack of M-GP protein was found in muscle in the vast majority (95%) of patients, irrespective of the PYGM genotype, including those carrying missense mutations, with few exceptions. M-GP protein biosynthesis is not being produced by PYGM mutations inducing premature termination codons (PTC), neither by most PYGM missense mutations. These findings explain the lack of PYGM genotype-phenotype correlation and have important implications for the design of molecular-based therapeutic approaches.

More than 600 human disorders afflict the nervous system. Of these, neurodegenerative diseases are usually characterised by onset in late adulthood, progressive clinical course, and neuronal loss with regional specificity in the central nervous system. They include Alzheimer's disease and other less frequent dementias, brain cancer, degenerative nerve diseases, encephalitis, epilepsy, genetic brain disorders, head and brain malformations, hydrocephalus, stroke, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS or Lou Gehrig's Disease), Huntington's disease, and Prion diseases, among others. Neurodegeneration usually affects, but is not limited to, the cerebral cortex, intracranial white matter, basal ganglia, thalamus, hypothalamus, brain stem, and cerebellum. Although the majority of neurodegenerative diseases are sporadic, Mendelian inheritance is well documented. Intriguingly, the clinical presentations and neuropathological findings in inherited neurodegenerative forms are often indistinguishable from those of sporadic cases, suggesting that converging genomic signatures and pathophysiologic mechanisms underlie both hereditary and sporadic neurodegenerative diseases. Unfortunately, effective therapies for these diseases are scarce to non-existent. In this chapter, we highlight the clinical and genetic features associated with the rare inherited forms of neurodegenerative diseases, including ataxias, multiple system atrophy, spastic paraplegias, Parkinson's disease, dementias, motor neuron diseases, and rare metabolic disorders.

The variability of both phenotypic and genotypic expression in mitochondrial diseases makes clinical diagnosis difficult, which is essential to establish therapy, aid in genetic counselling or for performing prenatal diagnosis. We have therefore proposed a strategy to help determine correct diagnosis of these alterations, in an attempt to rationalize the number of tests and, whenever possible, avoid tissue biopsy and minimize the size of the biopsy when indicated.Based on mitochondrial metabolism and molecular bases, as well as their alterations, a preliminary metabolic examination is carried out including at least one study of cytoplasmatic (lactate/pyruvate) and mitochondrial oxide reduction (hydroxibutirate/acetoacetate) in basal conditions or, if required, following glucose overload or an effort test. Metabolic study, in addition to clinical exploration, are the screening tests used to determine the need for tissue biopsy in which biochemical (pyruvate dehydrogenase, free and total carnitine, beta oxidation enzymes and respiratory chain complexes), genetic (mitochondrial DNA or nuclear alterations) and histologic tests are carried out to confirm diagnosis.a) Metabolic exploration may discard mitochondrial disease and many cases, avoid the use of an invasive procedure such as tissue biopsy. b) Biochemical study of tissue biopsy is the only useful key in the confirming of the diagnosis when no mitochondrial and/or nuclear DNA are observed.

Agalsidase alfa; Cardiovascular outcomes; Renal outcomes Agalsidasa alfa; Resultados cardiovasculares; Resultados renales Agalsidasa alfa; Resultats cardiovasculars; Resultats renals Background Patient registries provide long-term, real-world evidence that aids the understanding of the natural history and progression of disease, and the effects of treatment on large patient populations with rare diseases. The year 2021 marks the 20th anniversary of the Fabry Outcome Survey (FOS), an international, multicenter, observational registry (NCT03289065). The primary aims of FOS are to broaden the understanding of Fabry disease (FD), an X-linked lysosomal storage disorder, and to improve the clinical management of affected patients. Here, we review the history of FOS and the analyses and publications disseminated from the registry, and we discuss the contributions FOS studies have made in understanding FD. Results FOS was initiated in April 2001 and, as of January 2021, 4484 patients with a confirmed diagnosis and patient informed consent have been enrolled from 144 centers across 26 countries. Data from FOS have been published in nearly 60 manuscripts on a wide variety of topics relevant to FD. Analyses of FOS data have investigated the long-term effectiveness and safety of enzyme replacement therapy (ERT) with agalsidase alfa and its effects on morbidity and mortality, as well as the benefits of prompt and early treatment with agalsidase alfa on the progression of cardiomyopathy and the decline in renal function associated with FD. Based on analyses of FOS data, ERT with agalsidase alfa has also been shown to improve additional signs and symptoms of FD experienced by patients. FOS data analyses have provided a better understanding of the natural history of FD and the specific populations of women, children, and the elderly, and have provided practical tools for the study of FD. FOS has also provided methodology and criteria for assessing disease severity which contributed to the continuous development of medical practice in FD and has largely improved our understanding of the challenges and needs of long-term data collection in rare diseases, aiding in future rare disease real-world evidence studies. Conclusion FOS over the last 20 years has substantially increased the scientific knowledge around improved patient management of FD and continues to expand our understanding of this rare disease. FOS is funded by Takeda Pharmaceuticals International AG, which also assisted in analyzing the data and preparing the manuscript. Takeda Development Center Americas, Inc. provided funding to Excel Medical Affairs for support in writing and editing this manuscript.

Traducció RAN; Transcripció antisentit; Moduladors fenotípics Traducción RAN; Transcripción antisentido; Moduladores fenotípicos RAN translation; Antisense transcription; Phenotypic modulators Myotonic Dystrophy type 1 (DM1) is a muscular dystrophy with a multi-systemic nature. It was one of the first diseases in which repeat associated non-ATG (RAN) translation was described in 2011, but has not been further explored since. In order to enhance our knowledge of RAN translation in DM1, we decided to study the presence of DM1 antisense (DM1-AS) transcripts (the origin of the polyglutamine (polyGln) RAN protein) using RT-PCR and FISH, and that of RAN translation via immunoblotting and immunofluorescence in distinct DM1 primary cell cultures, e.g., myoblasts, skin fibroblasts and lymphoblastoids, from ten patients. DM1-AS transcripts were found in all DM1 cells, with a lower expression in patients compared to controls. Antisense RNA foci were found in the nuclei and cytoplasm of a subset of DM1 cells. The polyGln RAN protein was undetectable in all three cell types with both approaches. Immunoblots revealed a 42 kD polyGln containing protein, which was most likely the TATA-box-binding protein. Immunofluorescence revealed a cytoplasmic aggregate, which co-localized with the Golgi apparatus. Taken together, DM1-AS transcript levels were lower in patients compared to controls and a small portion of the transcripts included the expanded repeat. However, RAN translation was not present in patient-derived DM1 cells, or was in undetectable quantities for the available methods. The research of G. Nogales-Gadea and A. Ramos-Fransi is funded by Instituto de Salud Carlos III (grant numbers PI15/01756 and PI18/00713) and co-financed by Fondos FEDER. G. Nogales-Gadea is supported by a Miguel Servet research contract (ISCIII CD14/00032, ISCIII CPII19/00021, and FEDER) and by a Trampoline Grant #21108 from AFM Telethon. E. Koehorst is funded by the La Caixa Foundation (ID 100010434), fellowship code LCF/BQ/IN18/11660019, cofunded by the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 713673. The research of M. Suelves is funded by Ministerio de Ciencia e Innovación (grant number PID2020-118730RB-I00) and co-financed by Fondos FEDER. J. Núñez-Manchón is funded by Instituto de Salud Carlos III I-PFIS fellowship (grant number IFI20/00022). G. Lucente is supported by a Rio Hortega contract (ISCIII CM16/00016 and FEDER). J. Chojnacki is supported by European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 793830. The work of A.P. Gómez-Escribano and R.P. Vázquez-Manrique is funded by the ISCIII (CPII16/00004, PI17/00011 and PI20/00114) and the Fundación Ramón Areces (CIVP19S8119). This work was supported by the CERCA program/ Government of Catalonia. The funding bodies had no role in the design of the study and the collection, analysis, and interpretation of data.

In the present study the use of extracellular vesicles (EVs) as vehicles for therapeutic enzymes in lysosomal storage disorders was explored. EVs were isolated from mammalian cells overexpressing alpha‐galactosidase A (GLA) or N‐sulfoglucosamine sulfohydrolase (SGSH) enzymes, defective in Fabry and Sanfilippo A diseases, respectively. Direct purification of EVs from cell supernatants was found to be a simple and efficient method to obtain highly active GLA and SGSH proteins, even after EV lyophilization. Likewise, EVs carrying GLA (EV‐GLA) were rapidly uptaken and reached the lysosomes in cellular models of Fabry disease, restoring lysosomal functionality much more efficiently than the recombinant enzyme in clinical use. In vivo, EVs were well tolerated and distributed among all main organs, including the brain. DiR‐labelled EVs were localized in brain parenchyma 1 h after intra‐arterial (internal carotid artery) or intravenous (tail vein) administrations. Moreover, a single intravenous administration of EV‐GLA was able to reduce globotriaosylceramide (Gb3) substrate levels in clinically relevant tissues, such kidneys and brain. Overall, our results demonstrate that EVs from cells overexpressing lysosomal enzymes act as natural protein delivery systems, improving the activity and the efficacy of the recombinant proteins and facilitating their access to organs neglected by conventional enzyme replacement therapies., This study has been supported by ISCIII (PI18_00871 co‐founded by Fondo Europeo de Desarrollo Regional (FEDER)), and CIBER‐BBN (EXPLORE) granted to IA. Different CIBER‐BBN units of ICTS ‘NANBIOSIS’ have participated in this work (https://www.nanbiosis.es/platform-units/), more specifically the U1/Protein Production Platform for protein purification, Unit 6 for NTA analysis and TFF purification and U20/FVPR for in vivo assays.

Biomarcadores; Fenotipo clásico; Enfermedad de Fabry Biomarkers; Classic phenotype; Fabry disease Biomarcadors; Fenotip clàssic; Malaltia de Fabry Fabry disease (FD) is a lysosomal storage disorder caused by deficient alpha-galactosidase A activity in the lysosome due to mutations in the GLA gene, resulting in gradual accumulation of globotriaosylceramide and other derivatives in different tissues. Substrate accumulation promotes different pathogenic mechanisms in which several mediators could be implicated, inducing multiorgan lesions, mainly in the kidney, heart and nervous system, resulting in clinical manifestations of the disease. Enzyme replacement therapy was shown to delay disease progression, mainly if initiated early. However, a diagnosis in the early stages represents a clinical challenge, especially in patients with a non-classic phenotype, which prompts the search for biomarkers that help detect and predict the evolution of the disease. We have reviewed the mediators involved in different pathogenic mechanisms that were studied as potential biomarkers and can be easily incorporated into clinical practice. Some accumulation biomarkers seem to be useful to detect non-classic forms of the disease and could even improve diagnosis of female patients. The combination of such biomarkers with some response biomarkers, may be useful for early detection of organ injury. The incorporation of some biomarkers into clinical practice may increase the capacity of detection compared to that currently obtained with the established diagnostic markers and provide more information on the progression and prognosis of the disease. The research has not received any external funding.

Background Mucopolysaccharidosis (MPS) IVA or Morquio A syndrome is a progressive and disabling disease characterized by a deficiency of the enzyme N-acetylgalactosamine-6-sulphate sulphatase. Its clinical presentation is very heterogeneous and poorly understood in adults. The aim of this study was to describe the clinical manifestations of MPS IVA in adult patients in Spain and to assess their health-related quality of life (HRQoL). Results Thirty-three patients from nine reference centres participated in the study. The median age was 32 (interquartile range [IQR]: 20.5–40.5) years. The phenotype was classical in 54.5% of patients, intermediate in 33.3% of patients, and non-classical in 12.1% of patients. The most common clinical manifestation was bone dysplasia, with a median height of 118 (IQR: 106–136) cm. Other frequent clinical manifestations were hearing loss (75.7%), ligamentous laxity (72.7%), odontoid dysplasia (69.7%), limb deformities that required orthopaedic aids (mainly hip dysplasia and genu valgus) (63.6%), and corneal clouding (60.6%). In addition, 36.0% of patients had obstructive sleep apnoea/hypopnoea syndrome and 33.3% needed non-invasive ventilation. Cervical surgery and varisation osteotomy were the most common surgical interventions (36.4% each). Almost 80% of patients had mobility problems and 36.4% used a wheelchair at all times. Furthermore, 87.9% needed help with self-care, 33.3% were fully dependent, and 78.8% had some degree of pain. HRQoL according to the health assessment questionnaire was 1.43 (IQR: 1.03–2.00) in patients with the non-classical phenotype, but 2.5 (IQR: 1.68–3.00) in those with the classical phenotype. Seven patients were initiated on enzyme replacement therapy (ERT), but two of them were lost to follow-up. Lung function improved in four patients and slightly worsened in one patient. The distance achieved in the six-minute walk test increased in the four patients who could perform it. HRQoL was better in patients treated with elosulfase alfa, with a median (IQR) of 1.75 (1.25–2.34) versus 2.25 (1.62–3.00) in patients not treated with ERT. Conclusions The study provides real-world data on patients with MPS IVA. Limited mobility, difficulties with self-care, dependence, and pain were common, together with poor HRQoL. The severity and heterogeneity of clinical manifestations require the combined efforts of multidisciplinary teams.

Agalsidasa alfa; Teràpia de reemplaçament enzimàtic; Malaltia de Fabry Agalsidasa alfa; Terapia de reemplazo de enzimas; Enfermedad de Fabry Agalsidase alfa; Enzyme replacement therapy; Fabry disease Purpose: Following the publication of 5-year agalsidase alfa enzyme replacement therapy (ERT) outcomes data from the Fabry Outcome Survey (FOS), 10-year data were analyzed. Patients and methods: FOS (ClinicalTrials.gov identifier: NCT03289065) data (April 2001 to August 2018) were retrospectively analyzed. Estimated glomerular filtration rate (eGFR) and left ventricular mass indexed to height (LVMI) were analyzed after treatment start (baseline) for patients with ≥3 measurements, including baseline and year 10. Results: Median (range) age (years) of the evaluable treated renal cohort at treatment start was 48.8 (17.9–67.3) for females (n=62), 34.4 (18.0–66.8) for males (n=90). With eGFR ≥60 mL/min/1.73 m2 at baseline, mean (95% CI) rate of eGFR change (eGFR/year) over 10 years was relatively stable in females (n=52; −0.55 [−1.12, +0.01]) and slightly declined in males (n=79; −1.99 [−2.45, −1.54]). With impaired kidney function (eGFR 48 g/m2.7 in females, >50 g/m2.7 in males) at baseline, mean (95% CI) LVMI/year slightly increased over 10 years in females (n=18; +1.51 [+0.91, +2.12]) and males (n=14; +0.87 (+0.19, +1.55). Without LVH at baseline, mean (95% CI) LVMI/year was stable in females (n=16; +0.52 [−0.13, +1.17]) and males (n=21; +0.57 [+0.02, +1.13]) over 10 years. Conclusion: Agalsidase alfa-treated patients with 10-year FOS data and preserved kidney function and/or normal LVMI at baseline remained largely stable; those with decreased kidney function or LVH at baseline experienced modest declines in renal function and/or increases in LVMI. The Fabry Outcome Survey is sponsored by Shire Human Genetic Therapies, Inc., a member of the Takeda group of companies. Shire International GmbH, a member of the Takeda group of companies, provided funding to Excel Medical Affairs for support in writing and editing this manuscript and participated in data collection and analysis.