Outcome of early-treated type III Gaucher disease patients

Lee, Ni‐Chung; Chien, Yin‐Hsiu; Wong, Siew Lee; Sheen, Jiunn‐Ming; Tsai, Fuu Jen; Peng, Steven Shinn-Forng; Leung, Joseph Hang; Chao, Mei; Shun, Chia‐Tung; Hwu, Wuh‐Liang

doi:10.1016/j.bcmd.2014.05.007

Cited by 22 publications

(8 citation statements)

References 28 publications

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“…Unfortunately, recombinant enzymes do not cross the blood-brain barrier (BBB) and therefore do not impact on the CNS. The situation with the SRT available today is that both miglustat (despite crossing the BBB) and eliglustat (which is pumped out across the BBB) do not affect the CNS features of nGD, nevertheless—this modality, using different formulations, can lead to changes in nGD, but at present there is only one drug in early phases of clinical trials (venglustat) 4–6…”

Section: Introductionmentioning

confidence: 99%

Pharmacologic properties of high-dose ambroxol in four patients with Gaucher disease and myoclonic epilepsy

et al. 2019

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BackgroundAmbroxol (ABX) has been suggested as an augmentative pharmacological agent for neuronopathic Gaucher disease (nGD). This study assessed the long-term safety and efficacy of combined therapy with high-dose ABX and enzyme replacement therapy (ERT) in nGD.MethodsABX+ERT therapy was administered for 4.5 years in four patients with nGD. ABX was initiated at a dose of 1.5 mg/kg/day, and the dose was escalated up to 27 mg/kg/day. The target plasma level was 10 µmol/L or less. The changes in glucocerebrosidase activity, biochemical, safety and neurocognitive findings were assessed.ResultsEnhanced residual GCcase activity was observed in all patients, as evidenced in both in vitro and in vivo studies. During the first 2 years of study with ABX (up to 21 mg/kg/day), mean seizure frequencies and neurocognitive function worsened. After ABX dosage was increased up to 27 mg/kg/day of ABX, its trough plasma concentration was 3.2–8.8 µmol/L. Drug-to-drug interaction, especially with antiepileptic drug significantly affected the pharmacokinetic parameters of ABX. Importantly, at 27 mg/kg/day of ABX, the seizure frequencies markedly decreased from the baseline, and the neurocognitive function was improved. In addition, Lyso-Gb1, a biomarker for the severity and progression of GD, was normalised in all patients. High-dose ABX was well-tolerated with no severe adverse events.ConclusionsLong-term treatment with high-dose ABX+ERT was safe and might help to arrest the progression of the neurological manifestations in GD.

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Section: Introductionmentioning

confidence: 99%

Pharmacologic properties of high-dose ambroxol in four patients with Gaucher disease and myoclonic epilepsy

et al. 2019

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“…As with type 1 Gaucher disease, equally striking responses of visceral, hematological and skeletal responses have been described in patients with type 3 Gaucher disease [109]. In fact, early childhood lethality due to massive visceral and hematological disease have been averted, although eventually, these patients may succumb to progressive neurological and pulmonary disease.…”

Section: Current Therapies For Gaucher Diseasementioning

confidence: 99%

Gaucher disease: Progress and ongoing challenges

Mistry

Lopez

Schiffmann³

et al. 2017

Molecular Genetics and Metabolism

123

113

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Over the past decades, tremendous progress has been made in the field of Gaucher disease, the inherited deficiency of the lysosomal enzyme glucocerebrosidase. Many of the colossal achievements took place during the course of the sixty-year tenure of Dr. Roscoe Brady at the National Institutes of Health. These include the recognition of the enzymatic defect involved, the isolation and characterization of the protein, the localization and characterization of the gene and its nearby pseudogene, as well as the identification of the first mutant alleles in patients. The first treatment for Gaucher disease, enzyme replacement therapy, was conceived of, developed and tested at the Clinical Center of the National Institutes of Health. Advances including recombinant production of the enzyme, the development of mouse models, pioneering gene therapy experiments, high throughput screens of small molecules and the generation of induced pluripotent stem cell models have all helped to catapult research in Gaucher disease into the twenty-first century. The appreciation that mutations in the glucocerebrosidase gene are an important risk factor for parkinsonism further expands the impact of this work. However, major challenges still remain, some of which are described here, that will provide opportunities, excitement and discovery for the next generations of Gaucher investigators.

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“…In one study, age at GD1 diagnosis was reported by genotype: mean age at diagnosis was older than 10 years for patients with genotypes N370S/?, N370S/N370S, N370S/L444P, and N370S/rare allele; age at diagnosis of younger than 10 years was reported in patients with N370S/ 84GG, L444P/L444P, L444P/?, and N370S/IVS2+1 genotypes all of which are often associated with severe GD symptomatology [3]. Three additional studies reported a mean age at diagnosis ranging from 6 years in the Moroccan study of 11 patients to 50 years in 93 patients from South Florida included in the ICGG Gaucher Registry [43,44]; the Moroccan study also identified two cases of GD2 diagnosed at 3 months and 18 months, respectively; age at diagnosis of seven GD3 cases ranged from 10 months to 2 years and 7 months in a study of Taiwanese patients [58]. In a multinational observational study (24-month study duration) enrolling all non-Ashkenazi patients (who had been seen for a hematological evaluation), the mean age at diagnosis was 32.6 years [60].…”

Section: Age and Timeliness Of Diagnosis Of Gdmentioning

confidence: 99%