Gaucher disease type 2

Ambroxol hydrochloride (ABX), an oral mucolytic drug available over the counter for many years, acts as a pharmacological chaperone for mutant glucocerebrosidase, albeit at higher doses. Proof-of-concept reports have been published over the past decade on all three types of Gaucher disease (GD). Here, we assess the safety and efficacy of 12 months of 600 mg ambroxol per day in three groups of Type 1 GD patients with a suboptimal response to enzyme replacement therapy (ERT) or substrate reduction therapy (SRT), defined as platelet count < 100 × 103 /L, lumbar spine bone density T-score < -2...

BACKGROUND: Continuation of standard management of Gaucher disease (GD) has been challenging during the COVID-19 pandemic, resulting in infrequent/missed infusions and follow-up appointments. Little data are available on the consequences of these changes and on the SARS-CoV-2 vaccinations in German GD patients. METHODS: A survey with 22 questions about GD management during the pandemic was sent to 19 German Gaucher centres. It was answered by 11/19 centres caring for 257 GD patients (almost ¾ of the German GD population); 245 patients had type 1 and 12 had type 3 GD; 240 were ≥ 18 years old...

Gaucher disease is the most common of the lysosomal storage diseases. It presents a wide phenotypic continuum, in which one may identify the classically described phenotypes, including type 1 form with visceral involvement, type 2 acute neuropathic early-infantile form, and type 3 subacute neuronopathic form. At the most severe end there is the perinatal form with onset in utero or during the neonatal period. The very few reported cases of neonatal onset Gaucher disease presented high and early mortality, due to neurological or visceral involvement, including liver failure...

BACKGROUND AND AIMS: Gaucher disease (GD) is one of the most common lysosomal storage diseases. It is characterized by the accumulation of glucocerebroside lipids in the macrophages, with liver, spleen and bone marrow frequently affected. The affected organs can develop tumor-like lesions (Gaucheromas), which are difficult to diagnose. We present the Gaucheromas and their ultrasonographic characteristics. METHODS: We selected Gaucheromas and their ultrasonographic characteristics found in the last 5 years during the periodical evaluation of 74 adult GD patients in Romania...

Chitotriosidase is an enzyme produced and secreted in large amounts by activated macrophages, especially macrophages loaded with phagocytozed glycosphingolipid in Gaucher disease. Macrophages phagocytose decayed blood cells that contain a lot of sphingolipid-rich cell membranes. In Gaucher disease, due to a deficit in beta-glucocerebrosidase activity, the phagocytozed substrate glucocerebroside cannot undergo further catabolism. In such a situation, macrophages secrete chitotriosidase in proportion to the degree of overload...

Gaucher disease (GD), one of the most common lysosomal storage diseases, is caused by GBA1 mutations resulting in defective glucocerebrosidase (GCase) and consequent accumulation of its substrates β-glucosylceramide (β-GlcCer). We reported progranulin (PGRN), a secretary growth factor-like molecule and an intracellular lysosomal protein was a crucial co-factor of GCase. PGRN binds to GCase and recruits Heat Shock Protein 70 (Hsp70) to GCase through its C-terminal Granulin (Grn) E domain, termed as ND7...

Acid-β-glucosidase (GCase, EC 3.2.1.45), the lysosomal enzyme which hydrolyzes the simple glycosphingolipid, glucosylceramide (GlcCer), is encoded by the GBA1 gene. Biallelic mutations in GBA1 cause the human inherited metabolic disorder, Gaucher disease (GD), in which GlcCer accumulates, while heterozygous GBA1 mutations are the highest genetic risk factor for Parkinson's disease (PD). Recombinant GCase (e.g., Cerezyme®) is produced for use in enzyme replacement therapy for GD and is largely successful in relieving disease symptoms, except for the neurological symptoms observed in a subset of patients...

Gaucher disease (GD) is a lysosomal storage disorder caused by a deficiency of the enzyme beta-glucocerebrosidase. This leads to the accumulation of glycolipids in macrophages and ultimately results in tissue damage. Recent metabolomic studies highlighted several potential biomarkers in plasma specimens. In hopes of better understanding the distribution, importance, and clinical significance of these potential markers, a UPLC-MS/MS method was developed and validated to quantify lyso-Gb1 and six related analogs (with the following modifications on the sphingosine moiety: -C2 H4 (-28 Da), -C2 H4 +O (-12 Da), -H2 (-2 Da), -H2 +O (+14 Da), +O (+16 Da), and +H2 O (+18 Da)), sphingosylphosphorylcholine, and N-palmitoyl-O-phosphocholineserine in plasma specimens of treated and untreated patients...

In Gaucher disease type 1 (GD1), accumulation of the lipid substrates glucosylceramide and glucosylsphingosine (lyso-GL-1 or lyso-Gb1), primarily in the spleen, liver, and bone marrow, leads to progressive hepatosplenomegaly, anemia, thrombocytopenia, and skeletal disease. Plasma glucosylceramide elevations are modest, variable, and normalize within weeks of starting treatment before clinical changes are evident, and therefore, have limited value for monitoring treatment responses. Serum chitotriosidase activity, a widely used GD biomarker, is also elevated in many other conditions but is not measurable in 5-10% of individuals due to a common CHIT1 null variant...

BACKGROUND: Gaucher disease (GD) is caused by a GBA1 gene mutation that leads to decreased acid β-glucosidase activity [glucocerebrosidase (GCase)]. This study aimed to identify and characterise compound heterozygous mutations in GBA1 in a patient with type 1 GD. CASE SUMMARY: Here, we report a rare adult-onset type 1 GD in a 46-year-old female patient with clinical manifestations of giant spleen, thrombocytopenia, and bone pain, diagnosed by enzymatic and genetic testing...

BACKGROUND: Gaucher disease is a rare, autosomal recessive genetic disorder. It is caused by a lack of sufficient activity of the lysosomal enzyme known as glucocerebrosidase, which leads to an accumulation of glucocerebroside, a fatty substance, in the spleen, liver, bone marrow, and rarely, the lungs or central nervous system. While there are several treatments available for people with Type 1 Gaucher disease and the visceral aspects of Type 3 Gaucher disease, no cure is present for any type of Gaucher disease...

BACKGROUND: Gaucher disease (GD) is a lysosomal storage disorder, characterized by hepatosplenomegaly, pancytopenia, bone diseases, with or without neurological symptoms. Plasma glucosylsphingosine (lyso-Gb1), a highly sensitive and specific biomarker for GD, has been used for diagnosis and monitoring the response to treatment. Enzyme replacement therapy (ERT) is an effective treatment for the non-neurologic symptoms of GD. Neuronopathic GD (type 2 and 3) accounts for 60%-70% of the Asian affected population...

PURPOSE: Most patients with Gaucher disease have progressive and often disabling skeletal manifestations. We examined the long-term effect of eliglustat treatment on bone outcomes in clinical trials in adults with Gaucher disease type 1. METHODS: Data from 4 completed phase 2 and 3 trials were evaluated in treatment-naïve patients or patients switching to eliglustat from enzyme replacement therapy (ERT). RESULTS: Overall, 319 of 393 (81%) eliglustat-treated patients remained in their trials until completion or commercial eliglustat became available...

BACKGROUND: Gaucher disease (GD) is an autosomal recessive disease caused by GBA1 mutations resulting in glucosylceramide accumulation in macrophages. GD is characterized by hepatosplenomegaly, anemia, thrombocytopenia, bone complications, and neurological complications. Glucosylsphingosine (lyso-Gb1), a deacylated form of glucosylceramide, has been identified as a promising biomarker for the diagnosis and treatment response in GD. The aim of this study was to examine the relationship between plasma lyso-Gb1 and therapeutic goals for GD (improvements in hepatomegaly, splenomegaly, anemia, thrombocytopenia, bone pain, and bone crisis), as well as disease type and GBA1 mutation type, in Japanese patients with GD receiving velaglucerase alfa, an enzyme replacement therapy (ERT)...

BACKGROUND: Gaucher disease (GD) is a lysosomal storage disorder. We evaluated the "real-world" effectiveness of first-line imiglucerase on long-term bone outcomes in Italian patients in the International Collaborative Gaucher Group (ICGG) Gaucher Registry. METHODS: Patients treated with imiglucerase for ≥2 years and with bone assessments at baseline and during follow-up were selected. Data on bone pain, bone crises, marrow infiltration, avascular necrosis, infarction, lytic lesions, Erlenmeyer flask deformity, bone fractures, mineral density, and imiglucerase dosage were evaluated...

Gaucher disease type 3 (GD3) is a chronic neuronopathic disorder with wide-ranging effects, including hepatosplenomegaly, anaemia, thrombocytopenia, skeletal disease, and diverse neurological manifestations. Biallelic mutations in GBA1 reduce lysosomal acid β-glucosidase activity, and its substrates, glucosylceramide and glucosylsphingosine, accumulate. Enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) ameliorate systemic features of Gaucher disease, but no therapies are approved for neurological manifestations...

Perinatal lethal Gaucher disease is a very rare variant of type 2 Gaucher disease that occurs in the neonatal period and leads to death in early infancy. The disease is characterized by hydrops fetalis or a collodion baby phenotype accompanied with progressive neurological manifestations, hepatosplenomegaly, thrombocytopenia, anemia, and failure to thrive. We report a case of perinatal lethal Gaucher disease treated with enzyme replacement therapy (ERT) who survived for 9 months and present a literature review of perinatal lethal Gaucher disease cases...

Neuronopathic Gaucher disease (nGD) is an inherited neurodegenerative disease caused by mutations in GBA1 gene and is associated with premature death. Neuroinflammation plays a critical role in disease pathogenesis which is characterized by microgliosis, reactive astrocytosis, and neuron loss, although molecular mechanisms leading to neuroinflammation are not well-understood. In this report, we developed a convenient tool to quantify microglia proliferation and activation independently and uncovered abnormal proliferation of microglia (∼2-fold) in an adult genetic nGD model...

BACKGROUND: A term neonate presented with persistent severe thrombocytopenia, elevated liver enzymes, conjugated hyperbilirubinemia, hepatosplenomegaly, and mild hypotonia. OBSERVATIONS: A thorough workup for infections, congenital thrombocytopenias, and neonatal malignancies was negative. Because of increased anti-SARS-CoV-2 IgG antibodies after maternal Covid-19, multisystem inflammatory syndrome of neonates was considered and intravenous immunoglobulin was administered...

Eliglustat is a glucosylceramide synthase inhibitor indicated as a long-term substrate reduction therapy for adults with type 1 Gaucher disease, a lysosomal rare disease. It is primarily metabolized by cytochrome P450 2D6 (CYP2D6), and variants in the gene encoding this enzyme are important determinants of eliglustat pharmacokinetics (PK) and drug-drug interactions (DDIs). The existing drug label addresses the DDIs to some extent but has omitted scenarios where both metabolizing CYPs (2D6 and 3A4) are mildly or moderately inhibited...