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Fabry disease (FD, OMIM #301500) is caused by pathogenic GLA gene (OMIM #300644) variants, resulting in a deficiency of the α-galactosidase A enzyme with accumulation of its substrate globotriaosylceramide and its derivatives. The phenotype of FD is highly variable, with distinctive disease features and course in classical male patients but more diverse and often nonspecific features in non-classical and female patients. FD-specific therapies have been available for approximately two decades, yet establishing robust evidence for long-term effectiveness remains challenging. This review aims to identify the factors contributing to this lack of robust evidence for the treatment of FD with enzyme replacement therapy (ERT) (agalsidase-alfa and -beta and pegunigalsidase alfa) and chaperone therapy (migalastat). Major factors that have been identified are study population heterogeneity (concerning sex, age, phenotype, disease stage) and differences in study design (control groups, outcomes assessed), as well as the short duration of studies. To address these challenges, we advocate for patient matching to improve control group compatibility in future FD therapy studies. We recommend international collaboration and harmonization, facilitated by an independent FD registry. We propose a stepwise approach for evaluating the effectiveness of novel treatments, including recommendations for surrogate outcomes and required study duration.

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As an X-linked inherited lysosomal storage disease that is caused by α-galactosidase A gene variants resulting in progressive accumulation of pathogenic glycosphingolipid (Gb3) accumulation in multiple tissues and organs, Fabry disease (FD) can be classified into classic or late-onset phenotypes. In classic phenotype patients, α-galactosidase A activity is absent or severely reduced, resulting in a more progressive disease course with multi-systemic involvement. Conversely, late-onset phenotype, often with missense variants (e.g., IVS4+919G>A) in Taiwan, may present with a more chronic clinical course with predominant cardiac involvement (cardiac subtype), as they tend to have residual enzyme activity, remaining asymptomatic or clinically silent during childhood and adolescence. In either form, cardiac hypertrophy remains the most common feature of cardiac involvement, potentially leading to myocardial fibrosis, arrhythmias, and heart failure. Diagnosis is established through α-galactosidase enzyme activity assessment or biomarker analyisis (globotriaosylsphingosine, Lyso-Gb3), advanced imaging modalities (echocardiography and cardiac magnetic resonance imaging), and genotyping to differentiate FD from other cardiomyopathy. Successful therapeutic response relies on early recognition and by disease awareness from typical features in classic phenotype and cardiac red flags in cardiac variants for timely therapeutic interventions. Recent advances in pharmacological approach including enzyme replacement therapy (agalsidase alfa or beta), oral chaperone therapy (migalastat), and substrate reduction therapy (venglustat) aim to prevent from irreversible organ damage. Genotype- and gender-based monitoring of treatment effects through biomarker (Lyso-Gb3), renal assessment, and cardiac responses using advanced imaging modalities are key steps to optimizing patient care in FD.

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AIMS: Left ventricular hypertrophy (LVH) is frequently detected via echocardiography in individuals with Fabry disease (FD), sometimes leading to confusion with hypertrophic cardiomyopathy (HCM) of other aetiologies. Considering this diagnosis challenge, FD should be included in the list of differential diagnosis for patients presenting with LVH. To address this concern, we conducted a prospective screening study in China, using dried blood spot (DBS) testing, to evaluate patients with unexplained LVH. METHODS: Our study was designed as a nationwide, multicentre prospective investigation. A total of 1015 patients from 55 different centres who were diagnosed with LVH by echocardiography were screened in the study from September 2022 to December 2023. Demographic information, biochemistry data, echocardiography parameters and clinical observations were meticulously collected from all participants. The DBS method was used to assess α-galactosidase A (α-Gal A) activity in males and both α-Gal A and globotriaosylsphingosine (lyso-Gb3) levels in females. RESULTS: The final screening population included 906 patients (589 males, 65%) with LVH, characterized by a mean maximal myocardial thickness of 14.8 ± 4.6 mm and an average age of 56.9 ± 17.2 years. In total, 43 patients (38 males, 5 females) exhibited low α-Gal A activity measurement (<2.2 µmol/L), while 21 patients (10 males, 11 females) presented low α-Gal A activity or elevated lyso-Gb3 levels (>1.1 ng/mL). Among these patients, eight individuals (7 males and 1 female) were genetically confirmed to harbour pathogenic GLA mutations, resulting in a total prevalence of 0.88%. Compared with patients without FD, patients with FD tended to have proteinuria (75% vs. 21.2%, P = 0.001), family history of HCM (37.5% vs. 2.3%, P < 0.01) and neuropathic pain (37.5% vs. 4.4%, P < 0.01) but lower systolic blood pressure (118.5 ± 12.5 vs. 143.3 ± 29.3 mmHg, P = 0.017). Five mutations were previously recognized as associated with FD while the remaining two, p.Asp313Val (c.938A>T) and c.547+3A>G, were deemed potentially pathogenic. Subsequent familial validation post-diagnosis identified an additional 14 confirmed cases. CONCLUSIONS: This pioneering screening study for FD among Chinese patients with unexplained LVH using DBS measurement, revealed an FD detection rate of 0.88%. Our findings confirmed that the combined measurement of lyso-Gb3 and α-Gal A activity is beneficial for primary screening of FD in patients with LVH. Given the availability of efficacious therapies and the value of cascade screening in extended families, early detection of FD in LVH patients is clinically important.

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OBJECTIVES: Human recombinant enzyme replacement therapy, given to compensate for genetic enzyme deficiency in lysosomal storage diseases, delays the progression of the disease and improves the quality of life. However, enzyme replacement therapy may cause hypersensitivity reactions. Within the scope of this research, we aimed to elucidate the frequency and clinical features of hypersensitivity reactions against enzyme replacement therapy in children with lysosomal storage diseases and clarify the management of these reactions. METHODS: Medical records of pediatric patients with lysosomal storage disease and receiving enzyme replacement therapy were retrospectively reviewed, and patients who experienced allergic reactions were included in the study. The demographic characteristics of the patients, their diagnosis, the responsible enzyme, the time at which the reaction started and at what dose, the signs and symptoms associated with the reaction, diagnostic tests, the management of the reaction, and the protocol applied for the maintenance of enzyme replacement therapy after the reaction were recorded. RESULTS: Hypersensitivity reactions developed in 18 of 71 patients (25.3 %) who received enzyme replacement therapy. The most common cutaneous findings were observed. Anaphylaxis developed in 6 of 18 patients. Patients who experienced recurrent hypersensitivity reactions with premedication or a slower infusion rate, those with positive skin test results, and patients who developed anaphylaxis were given enzyme replacement therapy with desensitization. CONCLUSIONS: HSR may develop during enzyme replacement therapy, which are vital in lysosomal storage diseases, and discontinuation of enzyme replacement therapy is a significant loss for patients with metabolic disorders. These reactions can be treated with premedication and long-term infusions, but some patients may require desensitization protocols for continued treatment.

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Objectives: The aim of this study is to explore the expression of inflammatory cytokines (ICs) in Fabry disease (FD), the correlation between ICs and FD phenotypes, and the impact of enzyme replacement therapy (ERT) on IC expression. Methods: We recruited 67 FD patients and 44 healthy controls (HCs) and detected concentrations of the following ICs: interferon-γ, interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12P70, IL-17A, IL-17F, IL-22, tumor necrosis factor (TNF)-α, and TNF-ß. We also analyzed the impact of ERT on IC expression in FD patients and the relationship between IC expression and sex, genotype, phenotype, disease burden, and biomarkers. Results: Most ICs were significantly higher in FD patients than in HCs. A number of ICs were positively correlated with clinical aspects, including disease burden (Mainz Severity Score Index [MSSI]) and cardiac and renal markers. IL-8 was higher in the high MSSI (P-adj=0.026*) than in the low MSSI. Conclusions: ICs were upregulated in FD patients, indicating the role of the innate immune process in FD etiology. ERT ameliorated FD-related inflammatory activation, at least to some extent. IC expression was positively correlated with disease burden and clinical markers in FD. Our findings indicated that the inflammatory pathway may be a promising therapeutic target for FD.

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Fabry disease (FD) is an X-linked lysosomal storage disorder caused by α-galactosidase A gene mutations. Its global incidence ranges from 1:40,000 to 1:170,000. This expert review evaluates the available guidelines, the status of diagnosed but untreated patients with FD, and the challenges in diagnosing and managing FD in the Kingdom of Saudi Arabia (KSA). An advisory board meeting (ABM) was conducted in two phases, with a survey that aimed to receive insights on the current unmet needs in the management of patients with FD in November 2022, and a second, offline meeting in February 2023. The goal of this ABM was to discuss current unmet needs in the management of Fabry patients in the Kingdom of Saudi Arabia. In the first ABM, experts opined on the best practices in the diagnosis, screening, and management of FD for healthcare professionals. These opinions on the management of FD relied on data from research and expert clinical judgments. In the second ABM, the same panel discussed different aspects of FD diagnosis, treatment, and management in the member countries of the Gulf Cooperation Council. The experts discussed the stigma associated with FD, patient awareness and knowledge, genetic screening, biomarkers, and home infusion therapy. They reviewed international guidelines and clinical criteria for enzyme replacement therapy (ERT). Furthermore, they also discussed the diagnosis of FD in men and women, the current guidelines followed for monitoring patients with FD, monitoring untreated patients with FD, Fabry Stabilization IndeX (FASTEX) as an assessment tool for the diagnosis of FD, FD management in KSA, challenges encountered while prescribing ERT in patients with FD, and the clinical criteria for starting ERT. The discussions led to the conclusion that currently, ERT is the only available therapy to manage FD and research should be focused on the early diagnosis and management of FD.

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Mucopolysaccharidosis II (MPS II; Hunter syndrome; OMIM 309900) is a rare, X-linked, heterogeneous lysosomal storage disease. Approximately two-thirds of patients develop cognitive impairment, which is difficult to assess in clinical trials, partly owing to the variable nature of cognitive impairment. Analyzing data from siblings can help to minimize this heterogeneity. We report analyses of cognitive function from siblings with MPS II enrolled in clinical trials: a natural history study (NCT01822184), a randomized, open-label, phase 2/3 study of intravenous (IV) idursulfase with or without intrathecal idursulfase (idursulfase-IT; NCT02055118), and its extension (NCT2412787). Cognitive function was assessed using Differential Abilities Scales, Second Edition General Conceptual Ability (DAS-II GCA) scores; Bayley Scales of Infant and Toddler Development, Third Edition; and Vineland Adaptive Behavior Scales, Second Edition Adaptive Behavior Composite (VABS-II ABC). Seven sets of siblings (six pairs and one set of three) were included. All patients received IV idursulfase and 10 received subsequent idursulfase-IT. Younger siblings initiated IV idursulfase at an earlier age than their older sibling(s) in six of the sets; the younger sibling started treatment before 1 year of age in three sets. Monthly idursulfase-IT was generally associated with a stabilization of cognitive function: DAS-II GCA and VABS-II ABC scores were higher at age-matched assessments in the majority of those who either received idursulfase-IT earlier than their sibling or who received idursulfase-IT versus no idursulfase-IT. These data suggest that early initiation of intrathecal enzyme replacement therapy may stabilize or slow cognitive decline in some patients with neuronopathic MPS II.

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Enzyme replacement therapy (ERT) with recombinant human α-galactosidase A (α-Gal A) drugs (agalsidases) has been successfully used for treatment of Fabry disease, and three kinds of agalsidases are now available in Japan. To compare the biochemical characteristics of these drugs, especially focusing on their incorporation into cultured fibroblasts and organs/tissues of Fabry mice, we performed in vitro, cell, and animal experiments. The results revealed that there were no differences in the kinetic parameters and enzyme activity between these agalsidases. But their affinity for domain 9 of cation-independent mannose 6-phosphate receptor (CI-M6PR), which exists in various cells, was higher in the order: agalsidase beta biosimilar 1 (agalsidase beta BS) > agalsidase beta > agalsidase alfa, which almost coincided with the experimental results regarding the efficiency of their incorporation into cultured fibroblasts derived from a Fabry mouse. The results of animal experiments using Fabry mice revealed that the incorporation of the agalsidases into the kidneys and heart, where CI-M6PRs are widely distributed, was efficient in the order: agalsidase beta/agalsidase beta BS > agalsidase alfa, which reflected the degree of reduction of glycosphingolipids accumulated in the organs/tissues. On the other hand, no differences in the efficiency of their uptake or reduction of the accumulated substances were observed in the liver, probably due to asialoglycoprotein receptors expressed on the surface of hepatocytes. This information will be useful for making a suitable ERT plan for individual Fabry patients with various backgrounds and for developing new ERT drugs in the future.

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Hypophosphatasia (HPP) is characterized by low activity of tissue nonspecific alkaline phosphatase (TNSALP). The enzyme replacement therapy asfotase alfa has been approved for childhood-onset forms of HPP. MicroRNAs (miRNAs) have emerged as a novel disease biomarker, with potential application in therapy monitoring. Circulating miRNAs were analyzed at baseline, months 1, 2, 4, and 16 in a 49-yr-old woman with childhood-onset HPP, chronic musculoskeletal pain, and non-traumatic fractures prior to enzyme replacement therapy. Serum RNA was extracted and sequenced using miRNeasy Mini Kit (Qiagen, Germany), RealSeq Biosciences Kit (Santa Cruz, US) together with miND spike-in control kit (TAmiRNA, Austria) and Illumina NovaSeq 6000 SP1 flow cell (San Diego, US). Brief Pain Inventory Severity and Interference scores (BPI-S/BPI-I), fatigue severity scale (FSS), Patient Global Impression of Improvement (PGI-I), Western Ontario and McMaster university hip disability and osteoarthritis outcome score (WOMAC), fibromyalgia impact questionnaire (FIQ), 6-Minute Walking Test (6-MWT), chair-rise-test (CRT), and handgrip dynamometry (HD) were performed at baseline and different timepoints during the therapy. Out of >800 screened, 84 miRNAs were selected based on differences in expression profiles between 24 HPP patients and 24 healthy controls. Six miRNAs showed a clear graphic trend and were up- or downregulated by ≥50% reads per million (rpm). These included hsa-let-7i-5p (+50%), hsa-miR-1-3p (-66.66%), hsa-miR-1294 (+63.63%), hsa-miR-206 (-85.57%), hsa-miR-375-3p (-71.43%), and hsa-miR-624-5p (+69.44%). hsa-miR-1-3p and hsa-miR-206 were identified as muscle-specific miRNAs. hsa-mir-375-3p, which negatively regulates osteogenesis, was significantly downregulated. In terms of patient-reported outcomes, BPI-S, BPI-I, FSS, PGI-I, WOMAC, and FIQ showed a reduction by -58.62%, -68.29%, -33.33%, -75.00%, -63.29%, and -43.02%, respectively. 6-MWT improved by +33.89% and CRT by -44.46%. Mean hand grip strength of the right/left hand measured by HD improved by +12.50% and + 23.53%, respectively. miRNA profile changes during the therapy with asfotase alfa, accompanying improvements in functionality tests and quality of life scores.

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BACKGROUND: There have been few descriptions in the literature on long-term enzyme replacement therapy (ERT) in patients with advanced late-onset Pompe disease (LOPD). OBJECTIVES: This study aimed to assess the efficacy and limitations of ERT in advanced LOPD patients. METHODS: We retrospectively reviewed the clinical courses of patients with advanced LOPD (two juvenile-onset and five adult-onset patients) who were treated with recombinant human alglucosidase alfa to examine improvements achieved with and limitations of ERT until their death or when switching to avalglucosidase alfa occurred. RESULTS: All patients were non-ambulant and ventilator dependent. The duration of follow-up ranged from 3.7 to 15.0 years (median 9.0 years). All patients reported improvements in their lives during the first two or three years of ERT. Vital capacity was clearly improved in patients with relatively spared respiratory function, although it deteriorated after respiratory complications such as pneumothorax. Pinch and grip power tended to be preserved during the treatment period. Muscle CT revealed progression of atrophy and fatty replacement predominantly in the proximal limb muscles without improvement after ERT. Four patients died due to aspergillosis, respiratory failure, ileus, and sudden death of unknown cause. CONCLUSIONS: Our findings demonstrate that patients undergoing ERT show certain improvements, even in the advanced stage of Pompe disease. Respiratory complications are lethal even during ERT, and early diagnosis and induction of therapy are critical. Muscle wasting progressed more severely in the proximal limbs, even after ERT.

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Acid sphingomyelinase deficiency (ASMD) is an ultra-rare lysosomal storage disease with a broad spectrum of manifestations ranging from severe neuropathic forms to attenuated, chronic visceral forms. Manifestations of the chronic visceral subtype are variable and encompass different degrees of hepatosplenomegaly, pulmonary disease and dyslipidemia. The aim of this study was to provide insights into the natural course of adult patients with the chronic visceral subtype. Based on these insights, we proposed tentative criteria for initiation and follow-up of enzyme replacement therapy (ERT). The data of 23 adult patients were collected in a prospective study. Clinical, genetic and demographic data, plasma measurements, abdominal imaging, pulmonary imaging, pulmonary function tests and quality of life questionnaires were collected. Stability of disease based on several clinical, biochemical and radiological markers (i.e., spleen volume, platelet levels, liver volume, alanine aminotransferase [ALT] levels, diffusion capacity of the lungs for carbon monoxide [DLCO] chitotriosidase activity and lysosphingomyelin [LSM]) was assessed. Cardiovascular risk was estimated based on sex, age, smoking, systolic blood pressure and lipid profile. Quality of life was evaluated with the 36-Item Short Form Health Survey and the Health Assessment Questionnaire. Median follow-up was 6.1 years (range 1.3-19.5 years). The most common manifestations were splenomegaly (100%), decreased high-density lipoprotein cholesterol (HDL-C) plasma levels (83%), (signs of) steatosis measured with transient elastography (82%), thrombocytopenia (64%), hepatomegaly (52%) and decreased diffusion capacity (45%). The majority of markers remained stable during follow-up. Twelve patients showed progression of disease: four for spleen volume, two for liver volume, three for DLCO, seven for chitotriosidase activity and three for LSM. One patient showed progression of disease based on four markers, although this patient did not report any problems at the last visit. Cardiovascular risk was estimated and was increased in half of the patients older than 40 years. Patient-reported quality of life did not differ from the general population, but differences in median 36-Item Short Form Health Survey (SF-36) scores of patients with severe pulmonary involvement and those of patients without pulmonary involvement were observed. Tentative criteria for initiation and effect of therapy were proposed. In conclusion, the chronic visceral subtype of ASMD showed a predominantly stable disease course in this cohort. We propose that ERT should be initiated on an individual basis and only in case of progression or symptomatic disease. Collection and analysis of real world data are necessary to refine start, stop and follow-up criteria in the future.

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Background: Pompe disease (PD) is a rare autosomal recessive genetic disorder (1 in 14,000) which affects the synthesis of acid alpha-glucosidase (AGA), leading to intralysosomal glycogen accumulation in muscle tissue. The clinical presentation is heterogeneous, with variable degrees of involvement and progression, classifiable based on the age of onset into infantile (classic or non-classic) and late-onset forms (juvenile or adult). The diagnostic test of choice is the enzymatic analysis of AGA, and the only pharmacological treatment is enzyme replacement therapy (ERT). This document aims to report a clinical case of late-onset PD. Clinical case: 14-year-old male who started at the age of 5 with postural alterations, gait changes, and decreased physical performance compared to his peers. A diagnostic evaluation was initiated in 2022 due to worsening neuromuscular symptoms, accompanied by dyspnea, tachycardia, and chest pain. A suspicion of a lysosomal storage myopathy was established, and through enzymatic determination of AGA the diagnosis of PD was confirmed. The study of the GAA gene revealed the association of 2 previously unreported genomic variants. ERT was initiated, resulting in clinical improvement. Conclusions: The age of symptom onset, severity of clinical presentation, and prognosis of the disease depend on the specific mutations involved. In this case, the identified genetic alterations are associated with different phenotypes. However, based on the clinical presentation, it is categorized as juvenile PD with an indeterminate prognosis.

Introducción: la enfermedad de Pompe (EP) es un padecimiento genético autosómico recesivo poco frecuente (1:14,000) que afecta la síntesis de alfa-glucosidasa ácida (AGA) y condiciona un depósito de glucógeno intralisosomal en tejido muscular. La presentación clínica es heterogénea, con grados variables de afectación y progresión, clasificable según la edad de aparición en infantil (clásica y no clásica) y de inicio tardío (juvenil o de adultez). La prueba diagnóstica de elección es el análisis enzimático de AGA y el único tratamiento farmacológico es la terapia de reemplazo enzimático (TRE). Este documento tiene como objetivo reportar un caso clínico de EP de inicio tardío. Caso clínico: paciente de sexo masculino de 14 años que comenzó a los 5 años con alteraciones de la postura, marcha y desempeño físico. Se inició protocolo de estudio ante agravamiento de los síntomas neuromusculares, a los que se agregaron disnea, taquicardia y dolor torácico. Se sospechó de una miopatía metabólica de depósito lisosomal y mediante determinación enzimática de AGA se confirmó el diagnóstico de EP. El estudio molecular del gen GAA reportó una asociación de 2 variantes genómicas no descritas previamente. Se empleó la TRE con mejoría clínica. Conclusiones: la edad de inicio del cuadro clínico, severidad y pronóstico dependen de las mutaciones presentadas. En este caso, las alteraciones genéticas encontradas están relacionadas con diferentes fenotipos; no obstante, por clínica es categorizado como una EP juvenil con pronóstico indeterminado.

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Fabry's disease is a rare X chromosome-linked inherited lysosomal storage disease characterized by insufficient metabolism of the substrate globotriaosylceramide (Gb3) due to reduced alpha-galactosidase A (AGAL) activity. Lysosomal Gb3 accumulation causes a multisystemic disease which, if untreated, reduces the life expectancy in females and males by around 10 and 20 years, respectively, due to progressive renal dysfunction, hypertrophic cardiomyopathy, cardiac arrhythmia and early occurrence of cerebral infarction. The diagnosis is confirmed by determining the reduced AGAL activity in leukocytes in males and molecular genetic detection of a -mutation causing the disease in females. The treatment comprises enzyme replacement therapy (ERT), agalsidase alfa, 0.2 mg/kg body weight (BW), agalsidase beta 1.0 mg/kg BW or pegunigalsidase alfa 1.0 mg/kg BW every 2 weeks i.v. or oral chaperone therapy (one capsule of migalastat 123 mg every other day) in the presence of amenable mutations. This article summarizes the data on the treatment of Fabry's disease and on complications in practice. The current guideline recommendations are addressed and new study results that could expand the therapeutic repertoire in the future are discussed.

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BACKGROUND: This study aimed to identify postoperative recurrence and prognostic factors, including osteosarcopenia for borderline resectable (BR) and unresectable locally advanced (UR-LA) pancreatic cancer and to examine the impact of postoperative pancreatic enzyme replacement therapy (PERT). METHODS: We retrospectively examined 32 resected patients with BR and UR-LA pancreatic cancer. We investigated independent factors in the disease-free survival and overall survival. The relation of osteosarcopenia with the clinicopathological factors was investigated. Additionally, the association of the administration of a standard dose of pancrelipase, the amount of lipase required for patients with pancreatic exocrine insufficiency, for ≥6 months postoperatively with improvement of sarcopenia, osteopenia, and osteosarcopenia and completion rate of adjuvant chemotherapy was investigated. RESULTS: Multivariate analyses identified osteosarcopenia (P = 0.049) and lymph node metastasis (P = 0.01) as independent recurrence predictors, and osteosarcopenia (P = 0.002), maximum tumor diameter ≥40 mm (P = 0.006), and no adjuvant therapy (P = 0.01) as independent prognostic predictors. In the osteosarcopenia group, serum CA19-9 levels were higher (P = 0.03). The administration of a standard dose of pancrelipase for ≥6 months postoperatively was none in the osteosarcopenia group (0% vs 42.9%, P = 0.01), while significantly improved postoperative sarcopenia (33% vs 0%, P = 0.004), increased number of cycles of adjuvant chemotherapy (n = 6 vs n = 3, P = 0.03), and the completion rate of adjuvant chemotherapy in excluding cases interrupted because of recurrence (86% vs 25%, P = 0.007). CONCLUSIONS: Osteosarcopenia was an independent recurrent and prognostic factor in patients after pancreatectomy for locally advanced pancreatic cancer. Appropriate postoperative PERT may contribute to a better prognosis by improving sarcopenia and increasing the completion rate of adjuvant chemotherapy.

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Mucopolysaccharidosis type I (MPS I) is a rare genetic disorder caused by mutations in the IDUA gene, leading to alpha-L-iduronidase enzyme deficiency and resulting in the accumulation of glycosaminoglycans (GAG; heparan and dermatan sulfate) in lysosomes. The consequent GAG accumulation within cells leads to organ dysfunction and a range of debilitating symptoms. Enzyme replacement therapy (ERT) is the prevailing treatment, but its limitations (including high cost, time requirements, inefficiency in treatment of central nervous system (CNS), and immunogenicity) necessitate exploration of alternative therapeutic strategies. This research propose a novel approach leveraging the synergistic effects of ERT and resveratrol-induced autophagy. Resveratrol, with its immunomodulatory and GAG degradation-stimulating properties, holds a promise in mitigating immune responses triggered by ERT. Moreover, its ability to penetrate the blood-brain barrier presents a potential solution for addressing CNS manifestations. This study employed cells from MPS I patients to investigate the combined effects of resveratrol and the enzyme. Evaluation of the therapeutic impact involved assessing GAG accumulation, enzyme testing, and examining lysosome functionality and the autophagy process through fluorescence microscopy and Western blotting. The combined therapy stimulated the lysosomal mannose-6-phosphate receptor (M6PR) and lysosome biogenesis through the transcription factor EB (TFEB). Additionally, initial block of autophagy in autophagosome formation was relieved after the combined therapy and resveratrol alone. Together with increased enzyme activity through stimulation of the receptor, this synergistic therapy can be considered a new potential treatment for MPS I patients, improving their overall quality of life.

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Tay-Sachs (TS) disease is a neurodegenerative disease resulting from mutations in the gene encoding the α-subunit (HEXA) of lysosomal ß-hexosaminidase A (HexA). We report that (1) recombinant HEXA alone increased HexA activity and decreased GM2 content in human TS glial cells and peripheral mononuclear blood cells; 2) a recombinant chimeric protein composed of HEXA linked to two blood-brain barrier (BBB) entry elements, a transferrin receptor binding sequence and granulocyte-colony stimulating factor, associates with HEXB in vitro; reaches human cultured TS cells lysosomes and mouse brain cells, especially neurons, in vivo; lowers GM2 in cultured human TS cells; lowers whole brain GM2 concentration by approximately 40% within 6 weeks, when injected intravenously (IV) to adult TS-mutant mice mimicking the slow course of late-onset TS; and increases forelimbs grip strength. Hence, a chimeric protein equipped with dual BBB entry elements can transport a large protein such as HEXA to the brain, decrease the accumulation of GM2, and improve muscle strength, thereby providing potential treatment for late-onset TS.

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We report on a 4-year-old boy affected by Gaucher disease (GD) type 3, who presented with splenomegaly and a history of oculomotor apraxia. GD is a rare lysosomal storage disorder caused by glucocerebrosidase deficiency with multi-organ involvement. Besides common clinical features such as hepatosplenomegaly and skeletal involvement, less frequent neurological symptoms, such as oculomotor apraxia, are indicative of neuronopathic forms of the disease, namely GD type 3, to be confirmed both by enzyme activity and genetic testing. Overall, GD management requires a multidisciplinary approach involving metabolic pediatricians, neurologists, psychologists, and geneticists, and currently relies on early enzyme replacement therapy. Although enzyme replacement therapy has proved to be effective in improving systemic signs and symptoms, it is unable to alleviate neurological complications once these have occurred, as it does not pass across the blood-brain barrier. Neurological improvements may occur through indirect mechanisms. Thus, our case report aims to highlight the importance of considering GD in the differential diagnosis of pediatric patients presenting with splenomegaly associated with neurological manifestations, as early intervention may significantly modify the disease progression and prevent further irreversible complications.

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BACKGROUND: Late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) is a rare neurodegenerative disease that generally appears in children between 2 and 4 years old, leading to seizures and a progressive loss of language and motor functions. As the disease progresses, affected individuals typically experience blindness and ultimately pass away in late childhood. Treatment with intracerebroventricular cerliponase alfa has been shown to slow the deterioration of motor and language functions compared to the natural progression of the disease. We aim to highlight the early symptoms of CLN2 which help with early diagnosis and timely treatment initiation in children with specific medical indications, as well as identify medical contraindications for enzyme replacement therapy. METHODS: We describe five Croatian patients and one Bosnia and Herzegovinian patient with CLN2 disease, analyzing the clinical characteristics, neuroimaging findings, electroencephalogram results, genetic analysis, treatment indications and contraindications, and disease progression. RESULTS: All six patients presented with seizures: focal seizures (n = 1), myoclonic-atonic seizures (n = 1), febrile seizures (n = 2), and tonic-clonic seizures (n = 2), along with language delay (n = 6). Despite this, one patient refused treatment, two were initially included in the clinical trial and then continued treatment, one did not indicate starting treatment, and three continued treatment. One patient, after 4.5 years of treatment, no longer had medical indications for the therapy, which was discontinued. The other two patients who received treatment had a significant slowing of disease progression. CONCLUSIONS: The early onset of seizures between ages 2 and 4, alongside delayed language development, is a defining characteristic of CLN2 disease. Enzyme replacement therapy using cerliponase alfa represents the initial treatment for neuronal ceroid lipofuscinosis type 2, targeting the underlying cause of the disease. It effectively delays the progression of language and motor decline in patients diagnosed with this condition.

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Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is a rare, X-linked disorder caused by deficient activity of the enzyme iduronate-2-sulfatase. Signs and symptoms typically emerge at 1.5-4 years of age and may include cognitive impairment, depending on whether patients have the neuronopathic or non-neuronopathic form of the disease. Treatment is available in the form of enzyme replacement therapy (ERT) with recombinant iduronate-2-sulfatase (idursulfase). A systematic literature review was conducted to assess the evidence regarding efficacy, effectiveness, and safety of ERT with intravenous idursulfase for MPS II. Electronic databases were searched in January 2023, and 33 eligible articles were found. These were analyzed to evaluate the effects of intravenous idursulfase and the overall benefits and disadvantages in patient subgroups. Studies showed that intravenous idursulfase treatment resulted in improved short- and long-term clinical and patient-centered outcomes, accompanied by a favorable safety profile. Patients with non-neuronopathic MPS II had more pronounced improvements in clinical outcomes than those with neuronopathic MPS II. In addition, the review identified that improvements in clinical outcomes are particularly apparent if intravenous idursulfase is started early in life, strengthening previous recommendations for early ERT initiation to maximally benefit patients. This review provides a comprehensive summary of our current knowledge on the efficacy of ERT in different populations of patients with MPS II and will help to inform the overall management of the disease in an evolving treatment landscape.

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