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[Management of Fabry disease].

Fabry disease is a rare, X-linked lysosomal storage disorder that leads to accumulation of globotriaosylceramide in different tissues of the body. The disease is progressive and the first symptoms usually present in childhood. Consequences of the disease are disability and premature death. The disease in females could be as severe as in males although women may be asymptomatic. The possibility of enzyme replacement therapy has made it necessary to elaborate a comprehensive guideline for the diagnosis and treatment follow-up. The guideline has been summarized by a Hungarian multi-disciplinary w…

Hypophosphatasia in children: From low alkaline phosphatase activity to diagnosis, genetic testing, and treatment options. A narrative review.

Hypophosphatasia (HPP) is an inherited metabolic disorder caused by loss-of-function mutations in the ALPL gene encoding a tissue-nonspecifi … iants in the world are c.1250A>G, c.571G>A and c.1133A>T. Asfotase alfa, a recombinant human TNSALP enzyme replacement therapy, is now available for the treatment of HPP. The article provides an up-to-date overview of clinical, biochemical and molecular features of HPP. Treatment strategy in HPP was also described.

Long-term efficacy and safety of pegunigalsidase alfa administered every 4 weeks in adults with Fabry disease: results from up to 5 years of the BRIGHT F51 phase III, open-label extension study.

BACKGROUND: Enzyme replacement therapies (ERTs) approved for Fabry disease require infusions every 2 weeks (E2W). Pegunigalsidase alfa, a PEGylated ERT with a prolonged half-life vs. other ERTs, may allow extension of the dosing interval to every 4 weeks (E4W). BRIGHT F51 (NCT03614234) is an ongoing phase III, open-label extension study evaluating long-term efficacy and safety of pegunigalsidase alfa 2 mg/kg E4W in adults with Fabry disease previously treated with agalsidase alfa or beta E2W for ≥ 3 years who completed one year of pegunigalsidase alfa treatment in the BRIGHT study. This interi

Recognizing Exocrine Pancreatic Insufficiency in Patients with Diabetes: A Case Study.

BACKGROUND Exocrine pancreatic insufficiency (EPI) is characterized by inadequate delivery of pancreatic digestive enzymes to the small inte … without any sign of pancreatic tumor. He was diagnosed with EPI, and with initiation of pancreatic enzyme replacement therapy (PERT), his diarrhea improved, allowing him to regain weight to his prior baseline and to reduce caloric intake. CONCLUSIONS Although exocrine pancreatic insufficiency affects close to one-third of patients with type 2 diabetes mellitus, it remains …

Efficacy of asfotase alfa in a patient with adult-onset hypophosphatasia without obvious bone lesions: a case report with review of literature.

The use of asfotase alfa, a bone-targeted recombinant alkaline phosphatase (ALP) enzyme, for the treatment of adult-onset hypophosphatasia (HPP) remains controversial, particularly in patients without evident bone abnormalities. We report the case of a 41-year-old woman with a history of Graves' disease, who presented with progressive joint pain and severe fatigue. Despite the absence of bone lesions, the patient was diagnosed with HPP based on persistently low alkaline phosphatase levels, family history, and a novel heterozygous ALPL variant (p.Ala205Thr). Functional analysis revealed a domin

Single-cell RNA sequencing reveals important role of monocytes and macrophages during mucopolysaccharidosis treatment.

Mucopolysaccharidosis (MPS) encompasses a heterogeneous group of lysosomal storage diseases resulting from mutations in genes encoding lysosomal enzymes responsible for the degradation of mucopolysaccharides, also known as glycosaminoglycans (GAGs). Current therapeutic strategies for MPS include hematopoietic stem cell transplantation (HSCT), enzyme replacement therapy (ERT), and symptomatic therapy. This study investigated dynamic changes in MPS type II (MPS-II) through genomic and single-cell sequencing in a patient undergoing ERT. Analysis of peripheral blood mononuclear cells (PBMCs) from …

Long-Term Experience with Anaphylaxis and Desensitization to Alglucosidase Alfa in Pompe Disease.

BACKGROUND AND OBJECTIVE: Pompe disease (PD) is an inherited lysosomal storage disease that progresses with glycogen accumulation in many tissues, due to the deficiency of the acid-alpha glucosidase enzyme. Recombinant alglucosidase alfa (rhGAA) is the only disease-specific treatment option, in the form of enzyme replacement therapy (ERT). Anaphylaxis can develop with rhGAA. There is no study evaluating anaphylaxis and its management in PD in the long term. We aimed to evaluate the development of anaphylaxis and rapid drug desensitization (RDD) with rhGAA in children with PD. MATERIALS AND ME…

Case report and literature review: Fabry disease misdiagnosing as polymyalgia rheumatica.

RATIONALE: The clinical manifestations of Fabry disease affect the nerves, kidneys, heart, skin, gastrointestinal tract and eyes. Our aim is … agnosed with Fabry disease through proteomics and genetic testing. INTERVENTIONS: The treatment is enzyme replacement therapy (ERT). But this patient could not afford ERT and was given only general symptomatic treatment, pregabalin, and a gradual reduction in glucocorticoid. OUTCOMES: The patient's symptoms of joint pain and muscle weakness reduced significantly, and ESR …

L-alanine supplementation in Pompe disease (IOPD): a potential therapeutic implementation for patients on ERT? A case report.

BACKGROUND: Pompe disease (PD) is a disorder of glycogen metabolism conditioning a progressive and life conditioning myopathy. Enzyme replacement therapy (ERT) is currently the best treatment option for PD, but is not resolutive. While other potential therapeutic approaches have been reported before, these have never been tried as co- treatments. L-alanine oral supplementation (LAOS) has been proven to reduce muscle breakdown: we hereby report the first case of supplementation on a PD patient on ERT. CASE PRESENTATION: F. is a 9 y.o. infantile onset Pompe Disease (IOPD) girl ERT-treated since…

Classic infantile-onset Pompe disease with histopathological neurologic findings linked to a novel GAA gene 4 bp deletion: A case study.

Pompe disease (PD) is an autosomal recessive disorder by a deficiency of acid α-glucosidase (GAA) with intralysosomal glycogen accumulation … the GAA gene (c.2066_2069delAGCC/p.Glu689Glyfs*6). IOPD was diagnosed. At 5 months old, we started enzyme replacement therapy with an alpha-alglucosidase of 20 mg/kg weekly and immunomodulation with intravenous immunoglobulin. He developed two cardiorespiratory arrests with subsequent neurologic deterioration, convulsive crisis, and respiratory failure and died at 9 months …

MRI changes in diaphragmatic motion and curvature in Pompe disease over time.

OBJECTIVES: To evaluate changes in diaphragmatic function in Pompe disease using MRI over time, both during natural disease course and during treatment with enzyme replacement therapy (ERT). METHODS: In this prospective study, 30 adult Pompe patients and 10 healthy controls underwent pulmonary function tests and spirometry-controlled MRI twice, with an interval of 1 year. In the sagittal view of 3D gradient echo breath-hold acquisitions, diaphragmatic motion (cranial-caudal ratio between end-inspiration and end-expiration) and curvature (diaphragm height and area ratio) were calculated using …

Safety and efficacy of avalglucosidase alfa in individuals with infantile-onset Pompe disease enrolled in the phase 2, open-label Mini-COMET study: The 6-month primary analysis report.

PURPOSE: Mini-COMET (NCT03019406; Sanofi) is a phase 2, open-label, ascending-dose, 3-cohort study, evaluating avalglucosidase alfa safety, pharmacokinetics, and efficacy in individuals with infantile-onset Pompe disease aged <18 years who previously received alglucosidase alfa and showed clinical decline (cohorts 1 and 2) or suboptimal response (cohort 3). METHODS: During a 25-week primary analysis period, cohorts 1 and 2 received avalglucosidase alfa 20 and 40 mg/kg every other week, respectively, for 6 months, whereas cohort 3 individuals were randomized (1:1) to receive avalglucosidase al

Intrathecal idursulfase-IT in patients with neuronopathic mucopolysaccharidosis II: Results from a phase 2/3 randomized study.

Two-thirds of patients with mucopolysaccharidosis II (MPS II; Hunter syndrome) have cognitive impairment. This phase 2/3, randomized, controlled, open-label, multicenter study (NCT02055118) investigated the effects of intrathecally administered idursulfase-IT on cognitive function in patients with MPS II. Children older than 3 years with MPS II and mild-to-moderate cognitive impairment (assessed by Differential Ability Scales-II [DAS-II], General Conceptual Ability [GCA] score) who had tolerated intravenous idursulfase for at least 4 months were randomly assigned (2:1) to monthly idursulfase-I

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… replacement therapy in paediatric onset mucopolysaccharidosis II in England , Mol. … Rare Dis 6 ( 2011 ) 72 . 22059643 10.1186/1750-1172-6-72 PMC3223498 [31] Muenzer J , Early initiation of enzyme replacement therapy for the mucopolysaccharidoses , Mol. Genet. …

Clinical outcomes among young patients with Fabry disease who initiated agalsidase beta treatment before 30 years of age: An analysis from the Fabry Registry.

BACKGROUND: Clinical manifestations of classic Fabry disease (α-galactosidase A deficiency) usually occur in childhood, while complications involving major organs typically develop in adulthood. Outcomes of Fabry-specific treatment among young patients have not been extensively reported. Our aim was to analyze clinical outcomes among patients aged 5-30 years at initiation of treatment with agalsidase beta using data from the Fabry Registry (NCT00196742, sponsor: Sanofi). METHODS: Reported GLA variants were predicted to be associated with the classic phenotype or not classified in fabry-databa

Thirty-year clinical outcomes after haematopoietic stem cell transplantation in neuronopathic Gaucher disease.

BACKGROUND: Neuronopathic Gaucher Disease (nGD) describes the condition of a subgroup of patients with the Lysosomal Storage Disorder (LSD), Gaucher disease with involvement of the central nervous system (CNS) which results from inherited deficiency of β-glucosylceramidase. Although systemic manifestations of disease are now corrected by augmentation with macrophage-targeted therapeutic enzyme (enzyme replacement therapy, ERT), neurological disease progresses unpredictably as a result of failure of therapeutic enzyme to cross the blood-brain barrier (BBB). Without therapy, the systemic and neu…

Rare presentation of Fabry disease as 'burnt-out' hypertrophic cardiomyopathy.

We herein report the case of a 53-year-old man who was historically diagnosed with hypertrophic cardiomyopathy (HCM) and was lost to follow- … frequently comprises left ventricular hypertrophy. Early treatment of the underlying condition with enzyme replacement therapy may prevent the progression to end-stage heart failure. Fabry disease should be considered in all patients presenting with a clinical phenotype of HCM and a historical diagnosis should be re-evaluated in light of new diagnostic tools. Untreated Fabr …

Current status of newborn screening for Pompe disease in Japan.

BACKGROUND: Pompe disease is an autosomal recessive inherited metabolic disorder caused by a deficiency of the acid α-glucosidase (GAA). Pom … e United States, but significantly lower than that in Taiwan. One patient with IOPD underwent early enzyme replacement therapy within a month after birth before presenting exacerbated manifestations, whereas those with potential LOPD showed no manifestations during the follow-up period of six years. CONCLUSIONS: The frequency of IOPD in Japan was similar to that in the Uni …

Higher dosing of alglucosidase alfa improves outcomes in children with Pompe disease: a clinical study and review of the literature.

PURPOSE: Enzyme replacement therapy (ERT) with recombinant human acid-α glucosidase (rhGAA) at standard dose of 20 mg/kg every other week is insufficient to halt the long-term progression of myopathy in Pompe disease. METHODS: We conducted a retrospective study on infantile-onset Pompe disease (IPD) and late-onset Pompe disease (LOPD) patients with onset before age 5 years, ≥12 months of treatment with standard dose ERT, and rhGAA immunogenic tolerance prior to dose escalation. Long-term follow-up of up to 18 years was obtained. We obtained physical therapy, lingual strength, biochemical, and…

Exocrine Pancreas Dysfunction in Type 1 Diabetes.

OBJECTIVE: Type 1 diabetes (T1D) is characterized by autoimmune β-cell destruction, but exocrine pancreas abnormalities may also play a role … dence of PEI are asymptomatic. However, in PEI-symptomatic patients reported benefits of pancreatic enzyme replacement therapy (PERT) include relief of gastrointestinal symptoms, improved quality of life, better glycemic control, and optimal nutrition. CONCLUSION: Exocrine pancreas abnormalities often occur in T1D. Whether exocrine dysfunction occurs simultaneously with β- …

Glucosylsphingosine (lyso-Gb1) as a Biomarker for Monitoring Treated and Untreated Children with Gaucher Disease.

The role of glucosylsphingosine (lyso-Gb1), a downstream metabolic product of glucosylceramide, for monitoring treated and untreated children with Gaucher disease (GD) has not yet been studied. We reviewed the clinical charts of 81 children (<18 years), 35 with mild type 1 GD (GD1), 34 with severe GD1 and 12 with type 3 GD (GD3), followed at Shaare Zedek Medical Center between 2014-2018. Disease severity for GD1 was based on genotypes. Forty children (87%) with severe GD1 and GD3 received enzyme replacement therapy (ERT) compared to two children (6%) with mild GD1. Lyso-Gb1 measurements were c…