scholarly journals Busulfan disposition below the age of three: alteration in children with lysosomal storage disease

Blood ◽  
1993 ◽  
Vol 82 (3) ◽  
pp. 1030-1034 ◽  
Author(s):  
G Vassal ◽  
A Fischer ◽  
D Challine ◽  
I Boland ◽  
F Ledheist ◽  
...  
Keyword(s):  
Young Children ◽  
Lysosomal Storage Disease ◽  
Storage Disease ◽  
Dose Range ◽  
Lysosomal Storage Diseases ◽  
Volume Of Distribution ◽  
Optimal Dosage ◽  
Lysosomal Storage ◽  
Acute Leukemias ◽  
Storage Diseases

Busulfan disposition is age-dependent with a higher clearance and a larger volume of distribution in children than in adults. The optimal dosage of busulfan needed to achieve bone marrow (BM) displacement in young children with malignant or nonmalignant disease remains to be defined. Using a gas chromatography-mass spectrometry assay, we evaluated plasma pharmacokinetics of busulfan in 33 children (median age, 9 months; range, 2 months to 2.75 years) with immune deficiencies, lysosomal storage diseases, acute leukemias, and malignant lymphohistiocytosis after an oral dose ranging from 0.9 to 2.6 mg/kg. The busulfan clearance (assuming a bioavailability of 1) ranged from 2.1 to 13.4 mL/min/kg with a mean of 6.8 mL/min/kg, which is higher than that reported in older children (4.5 mL/min/kg) and adults (2.9 mL/min/kg). Six children with lysosomal storage disease (5 with Hurler's disease, 1 with San Filippo's disease) had a prolonged elimination half-life (4.9 v 2.4 hours), a larger volume of distribution (3.4 v 1.2 L/kg) and a faster clearance (8.7 v 6.3 mL/min/kg) than the other 27 children. This suggests that a higher dose of busulfan will be required to achieve BM displacement in children with lysosomal storage disease. Over the dose range of 0.9 to 2.6 mg/kg, busulfan pharmacokinetics were linear. However, only 46% of the interpatient variation in systemic exposure could be ascribed to the dose. Given the wide interpatient variability in busulfan disposition, dose adjustment and drug monitoring will be needed to achieve the optimal dosage of busulfan in young children. The plasma busulfan levels required to achieve BM displacement need to be defined, especially in lysosomal storage diseases.

scholarly journals Busulfan disposition below the age of three: alteration in children with lysosomal storage disease

Blood ◽  
1993 ◽  
Vol 82 (3) ◽  
pp. 1030-1034 ◽  
Author(s):  
G Vassal ◽  
A Fischer ◽  
D Challine ◽  
I Boland ◽  
F Ledheist ◽  
...  
Keyword(s):  
Young Children ◽  
Lysosomal Storage Disease ◽  
Storage Disease ◽  
Dose Range ◽  
Lysosomal Storage Diseases ◽  
Volume Of Distribution ◽  
Optimal Dosage ◽  
Lysosomal Storage ◽  
Acute Leukemias ◽  
Storage Diseases

Abstract Busulfan disposition is age-dependent with a higher clearance and a larger volume of distribution in children than in adults. The optimal dosage of busulfan needed to achieve bone marrow (BM) displacement in young children with malignant or nonmalignant disease remains to be defined. Using a gas chromatography-mass spectrometry assay, we evaluated plasma pharmacokinetics of busulfan in 33 children (median age, 9 months; range, 2 months to 2.75 years) with immune deficiencies, lysosomal storage diseases, acute leukemias, and malignant lymphohistiocytosis after an oral dose ranging from 0.9 to 2.6 mg/kg. The busulfan clearance (assuming a bioavailability of 1) ranged from 2.1 to 13.4 mL/min/kg with a mean of 6.8 mL/min/kg, which is higher than that reported in older children (4.5 mL/min/kg) and adults (2.9 mL/min/kg). Six children with lysosomal storage disease (5 with Hurler's disease, 1 with San Filippo's disease) had a prolonged elimination half-life (4.9 v 2.4 hours), a larger volume of distribution (3.4 v 1.2 L/kg) and a faster clearance (8.7 v 6.3 mL/min/kg) than the other 27 children. This suggests that a higher dose of busulfan will be required to achieve BM displacement in children with lysosomal storage disease. Over the dose range of 0.9 to 2.6 mg/kg, busulfan pharmacokinetics were linear. However, only 46% of the interpatient variation in systemic exposure could be ascribed to the dose. Given the wide interpatient variability in busulfan disposition, dose adjustment and drug monitoring will be needed to achieve the optimal dosage of busulfan in young children. The plasma busulfan levels required to achieve BM displacement need to be defined, especially in lysosomal storage diseases.

scholarly journals A Fourteen Years Old Boy with Cholesterol Ester Storage Disease

1970 ◽  
Vol 10 (2) ◽  
pp. 146-148
Author(s):  
Faizul Islum Chowdhury ◽  
Ahmedul Kabir ◽  
Jayanta Banik ◽  
Pinaki Paul ◽  
Mostofa Kamal ◽  
...  
Keyword(s):  
Liver Biopsy ◽  
Cholesterol Ester ◽  
Autosomal Recessive ◽  
Storage Disease ◽  
Specific Treatment ◽  
Autosomal Recessive Disorder ◽  
Lysosomal Storage Diseases ◽  
Lysosomal Storage ◽  
Acid Lipase ◽  
Storage Diseases

Cholesterol ester storage disease (CESD) is a rare autosomal recessive disorder resulting from lysosomal acid lipase deficiency and is usually characterized by hepatomegaly and hyperlipidemia. It is diagnosed by liver biopsy which characteristically shows microvesicular steatosis and periportal fibrosis. Here we report a fourteen years old boy who had presented with unexplained hepatomegaly, and hyperlipidemia determined incidentally. He was finally diagnosed as a case of cholesterol ester storage disease by liver biopsy. Though there is yet no specific treatment for CESD; however, the early detection of cases would make the timely control of complications possible. Keyword: Cholesterol Ester Storage Disease, Lysosomal Storage Diseases, Lipidoses    doi: 10.3329/jom.v10i2.2835   J MEDICINE 2009; 10 : 146-148

scholarly journals Neurodegeneration Upon Dysfunction of Endosomal/Lysosomal CLC Chloride Transporters

2021 ◽  
Vol 9 ◽  
Author(s):  
Shroddha Bose ◽  
Hailan He ◽  
Tobias Stauber
Keyword(s):  
Lysosomal Storage Disease ◽  
Storage Disease ◽  
Ion Homeostasis ◽  
Lysosomal Storage Diseases ◽  
Epileptic Encephalopathy ◽  
Lysosomal Storage ◽  
Specific Expression ◽  
Intracellular Organelles ◽  
And Function ◽  
Encoding Genes

The regulation of luminal ion concentrations is critical for the function of, and transport between intracellular organelles. The importance of the acidic pH in the compartments of the endosomal-lysosomal pathway has been well-known for decades. Besides the V-ATPase, which pumps protons into their lumen, a variety of ion transporters and channels is involved in the regulation of the organelles' complex ion homeostasis. Amongst these are the intracellular members of the CLC family, ClC-3 through ClC-7. They localize to distinct but overlapping compartments of the endosomal-lysosomal pathway, partially with tissue-specific expression. Functioning as 2Cl−/H+ exchangers, they can support the vesicular acidification and accumulate luminal Cl−. Mutations in the encoding genes in patients and mouse models underlie severe phenotypes including kidney stones with CLCN5 and osteopetrosis or hypopigmentation with CLCN7. Dysfunction of those intracellular CLCs that are expressed in neurons lead to neuronal defects. Loss of endosomal ClC-3, which heteromerizes with ClC-4, results in neurodegeneration. Mutations in ClC-4 are associated with epileptic encephalopathy and intellectual disability. Mice lacking the late endosomal ClC-6 develop a lysosomal storage disease with reduced pain sensitivity. Human gene variants have been associated with epilepsy, and a gain-of-function mutation causes early-onset neurodegeneration. Dysfunction of the lysosomal ClC-7 leads to a lysosomal storage disease and neurodegeneration in mice and humans. Reduced luminal chloride, as well as altered calcium regulation, has been associated with lysosomal storage diseases in general. This review discusses the properties of endosomal and lysosomal Cl−/H+ exchange by CLCs and how various alterations of ion transport by CLCs impact organellar ion homeostasis and function in neurodegenerative disorders.

scholarly journals Lysosomal Storage Diseases of Animals: An Essay in Comparative Pathology

1997 ◽  
Vol 34 (6) ◽  
pp. 527-548 ◽  
Author(s):  
R. D. Jolly ◽  
S. U. Walkley
Keyword(s):  
Cell Biology ◽  
Storage Disease ◽  
Gene Dosage ◽  
Molecular Genetic ◽  
Lysosomal Storage Diseases ◽  
Lysosomal Storage ◽  
Lysosomal Hydrolase ◽  
Storage Diseases ◽  
Veterinary Importance ◽  
Genetic Techniques

A wide variety of inherited lysosomal hydrolase deficiencies have been reported in animals and are characterized by accumulation of sphingolipids, glycolipids, oligosaccharides, or mucopolysaccharides within lysosomes. Inhibitors of a lysosomal hydrolase, e.g., swainsonine, may also induce storage disease. Another group of lysosomal storage diseases, the ceroid-lipofuscinoses, involve the accumulation of hydrophobic proteins, but their pathogenesis is unclear. Some of these diseases are of veterinary importance, and those caused by a hydrolase deficiency can be controlled by detection of heterozygotes through the gene dosage phenomenon or by molecular genetic techniques. Other of these diseases are important to biomedical research either as models of the analogous human disease and/or through their ability to help elucidate specific aspects of cell biology. Some of these models have been used to explore possible therapeutic strategies and to define their limitations and expectations.

Detection of aspartylglycosaminuria by gas--liquid chromatography.

1981 ◽  
Vol 27 (12) ◽  
pp. 2058-2060 ◽  
Author(s):  
C P Maury
Keyword(s):  
Liquid Chromatography ◽  
Lysosomal Storage Disease ◽  
Chromatographic Method ◽  
Storage Disease ◽  
Gas Liquid Chromatography ◽  
Lysosomal Storage ◽  
Specific Detection ◽  
Storage Diseases ◽  
Control Subjects ◽  
Gas Chromatographic Method

Abstract I describe a rapid gas-chromatographic method for specific detection of the lysosomal storage disease aspartylglycosaminuria, based on the identification of the major storage compound, 2-acetamido-1-N-(4'-L-aspartyl)-2-deoxy-beta-D-glucopyranosylamine (GlcNAc-Asn) in the urine of affected individuals. A 50-microL sample of urine is methylated without prior purification; the methylation products are then analyzed by gas--liquid chromatography. Under these conditions a diagnostic GlcNAc-Asn peak can be seen in the urine of patients with aspartylglycosaminuria, but not in the urine of control subjects or patients with related storage diseases.

Electron Microscopy in the diagnosis of lysosomal storage diseases

1989 ◽  
Vol 47 ◽  
pp. 866-867
Author(s):  
Carole Vogler ◽  
Harvey S. Rosenberg
Keyword(s):  
Electron Microscopy ◽  
Lysosomal Enzyme ◽  
Rectal Mucosa ◽  
Lysosomal Storage Diseases ◽  
Cell Types ◽  
Lysosomal Storage ◽  
Storage Material ◽  
Ultrastructural Examination ◽  
Blood Leukocytes ◽  
Storage Diseases

Diagnostic procedures for evaluation of patients with lysosomal storage diseases (LSD) seek to identify a deficiency of a responsible lysosomal enzyme or accumulation of a substance that requires the missing enzyme for degradation. Most patients with LSD have progressive neurological degeneration and may have a variety of musculoskeletal and visceral abnormalities. In the LSD, the abnormally diminished lysosomal enzyme results in accumulation of unmetabolized catabolites in distended lysosomes. Because of the subcellular morphology and size of lysosomes, electron microscopy is an ideal tool to study tissue from patients with suspected LSD. In patients with LSD all cells lack the specific lysosomal enzyme but the distribution of storage material is dependent on the extent of catabolism of the substrate in each cell type under normal circumstances. Lysosmal storages diseases affect many cell types and tissues. Storage material though does not accumulate in all tissues and cell types and may be different biochemically and morphologically in different tissues.Conjunctiva, skin, rectal mucosa and peripheral blood leukocytes may show ultrastructural evidence of lysosomal storage even in the absence of clinical findings and thus any of these tissues can be used for ultrastructural examination in the diagnostic evaluation of patients with suspected LSD. Biopsy of skin and conjunctiva are easily obtained and provide multiple cell types including endothelium, epithelium, fibroblasts and nerves for ultrastructural study. Fibroblasts from skin and conjunctiva can also be utilized for the initiation of tissue cultures for chemical assays. Brain biopsy has been largely replaced by biopsy of more readily obtained tissue and by biochemical assays. Such assays though may give equivical or nondiagnostic results and in some lysosomal storage diseases an enzyme defect has not yet been identified and diagnoses can be made only by ultrastructural examination.

Is there a role for scintigraphic imaging of bone manifestations in Gaucher disease?

2008 ◽  
Vol 47 (06) ◽  
pp. 239-247 ◽  
Author(s):  
S. Kohlfürst ◽  
H. J. Gallowitsch ◽  
E. Kresnik ◽  
P. Lind ◽  
A. B. Mehta ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Lysosomal Storage Disease ◽  
Gaucher Disease ◽  
Storage Disease ◽  
Lysosomal Storage ◽  
Scintigraphic Imaging ◽  
Imaging Methods ◽  
X Ray ◽  
Deficient Activity

SummaryGaucher disease is the most prevalent inherited, lysosomal storage disease and is caused by deficient activity of the enzyme β-glucocerebrosidase. Bone and bone marrow alterations are frequent in the most prevalent non-neuronopathic form of Gaucher disease. Imaging of bone manifestations in Gaucher disease is performed by a variety of imaging methods, conventional X-ray and MRI as the most frequently and most important ones. However, different modalities of scintigraphic imaging have also been used. This article gives an overview on scintigraphic imaging with respect to bone manifestations in Gaucher disease discussing the advantages and limitations of scintigraphic imaging in comparison to other imaging methods.

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