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1.
Mol Genet Metab ; 116(1-2): 80-7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25971245

RESUMO

Sandhoff disease (SD) is a fatal neurodegenerative disease caused by a mutation in the enzyme ß-N-acetylhexosaminidase. Children with infantile onset SD develop seizures, loss of motor tone and swallowing problems, eventually reaching a vegetative state with death typically by 4years of age. Other symptoms include vertebral gibbus and cardiac abnormalities strikingly similar to those of the mucopolysaccharidoses. Isolated fibroblasts from SD patients have impaired catabolism of glycosaminoglycans (GAGs). To evaluate mucopolysaccharidosis-like features of the feline SD model, we utilized radiography, MRI, echocardiography, histopathology and GAG quantification of both central nervous system and peripheral tissues/fluids. The feline SD model exhibits cardiac valvular and structural abnormalities, skeletal changes and spinal cord compression that are consistent with accumulation of GAGs, but are much less prominent than the severe neurologic disease that defines the humane endpoint (4.5±0.5months). Sixteen weeks after intracranial AAV gene therapy, GAG storage was cleared in the SD cat cerebral cortex and liver, but not in the heart, lung, skeletal muscle, kidney, spleen, pancreas, small intestine, skin, or urine. GAG storage worsens with time and therefore may become a significant source of pathology in humans whose lives are substantially lengthened by gene therapy or other novel treatments for the primary, neurologic disease.


Assuntos
Terapia Genética , Doença de Sandhoff/genética , Doença de Sandhoff/terapia , beta-N-Acetil-Hexosaminidases/genética , beta-N-Acetil-Hexosaminidases/uso terapêutico , Adenoviridae/genética , Estruturas Animais/patologia , Animais , Gatos , Modelos Animais de Doenças , Vetores Genéticos , Humanos , Mucopolissacaridoses/genética , Mucopolissacaridoses/patologia , Mucopolissacaridoses/terapia , Fenótipo , Doença de Sandhoff/fisiopatologia , Doença de Sandhoff/urina
2.
Anal Bioanal Chem ; 406(18): 4337-43, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24788891

RESUMO

The most widely used method for the biochemical screening of oligosaccharidoses is the analysis of the urinary oligosaccharide pattern by thin-layer chromatography on silica gel plates. However, this method is not always sensitive enough, and it is extremely time-consuming and laborious. In this work, the analysis of the urine oligosaccharide pattern was standardized for the first time by using capillary electrophoresis with laser-induced fluorescence (CE-LIF) detection (Beckman P/ACE MDQ) with a 488-nm argon ion laser module. All of the analyses were conducted using the Carbohydrate Labeling and Analysis Kit (Beckman-Coulter), which derivatizes samples with 8-aminopyrene-1,3,6-trisulfonate. Urine samples from 40 control subjects (age range, 1 week to 16 years) and from ten patients diagnosed with eight different lysosomal diseases (six of them included in the Educational Oligosaccharide Kit from ERNDIM EQA schemes) were analyzed. Two oligosaccharide excretion patterns were established in our control population according to age (younger or older than 1 year of age). Abnormal peaks with slower migration times than the tetrasaccharide position were observed for fucosidosis, α-mannosidosis, GM1 gangliosidosis, GM2 gangliosidosis variant 0, Pompe disease, and glycogen storage disease type 3. In conclusion, the first CE-LIF method to screen for oligosaccharidoses and related diseases, which also present oligosacchariduria, has been standardized. In all of the cases, the urine oligosaccharide analysis was strongly informative and showed abnormal patterns that were not present in any of the urine samples from the control subjects. Only urine from patients with aspartylglucosaminuria and Schindler disease displayed normal results.


Assuntos
Eletroforese Capilar/métodos , Doenças por Armazenamento dos Lisossomos/urina , Oligossacarídeos/urina , Adolescente , Aspartilglucosaminúria/urina , Estudos de Casos e Controles , Criança , Pré-Escolar , Eletroforese Capilar/instrumentação , Eletroforese Capilar/normas , Fucosidose/urina , Doença de Depósito de Glicogênio Tipo II/urina , Humanos , Lactente , Recém-Nascido , Lasers , Doenças por Armazenamento dos Lisossomos/diagnóstico , Distrofias Neuroaxonais/urina , Doença de Sandhoff/urina , alfa-N-Acetilgalactosaminidase/deficiência , alfa-N-Acetilgalactosaminidase/urina
3.
Clin Chim Acta ; 154(3): 151-64, 1986 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-3955841

RESUMO

The N-acetyl-glucosaminyl oligosaccharides excreted in urine and accumulating in tissues of Sandhoff disease patients have been analyzed and characterized using a combination of high performance liquid chromatography and 500 MHz proton magnetic resonance spectroscopy. Delineation between infantile and juvenile onset forms of the disease was possible, as the latter forms had 6- to 13-fold lower levels of urinary oligosaccharides. Patients from a geographically isolated population deme in the La Rioja region of Argentina had urinary oligosaccharides similar to unrelated non-Argentinean patients with identical clinical phenotype. Together, these results indicate that the urinary oligosaccharides serve as useful indicators of the mutation differences or clinical heterogeneity within this disease only in cases of markedly differing clinical presentation. Analysis of the accumulating metabolites in liver, kidney, pancreas, lung and spleen, showed a similar oligosaccharide pattern which differed dramatically from brain. These results suggest the possibility of tissue specific regulation of oligosaccharide biosynthesis since there are notable differences between neural and visceral tissues.


Assuntos
Oligossacarídeos/metabolismo , Doença de Sandhoff/diagnóstico , Acetilglucosamina/metabolismo , Química Encefálica , Cromatografia Líquida de Alta Pressão , Cromatografia em Camada Fina , Glicoproteínas/metabolismo , Humanos , Lactente , Fígado/metabolismo , Espectroscopia de Ressonância Magnética , Oligossacarídeos/urina , Doença de Sandhoff/metabolismo , Doença de Sandhoff/urina , Álcoois Açúcares/metabolismo
4.
Clin Chem ; 40(6): 914-21, 1994 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-8087986

RESUMO

Analysis of urinary oligosaccharides by thin-layer chromatography (TLC) is used as screening procedure for 10 different lysosomal diseases. We tested the usefulness of HPLC in screening, using a CarboPac PA1 column (Dionex), pulsed amperometric detection (PAD), and post-column derivatization (PCD). Patterns from six types of oligosaccharidoses were compared with normal urinary patterns and with the TLC patterns. PAD appeared to be nonspecific and therefore is applicable only to desalted urine samples. PCD was more specific and applicable to nondesalted urine samples, albeit with a lower resolving power. Peaks in urines from oligosaccharidoses patients were identified on the basis of retention times of commercially available oligosaccharides or TLC bands after isolation and HPLC of the corresponding oligosaccharides. Abnormal oligosaccharide peaks were seen in urines from patients with alpha-mannosidosis, GM1-gangliosidosis (juvenile), GM2-gangliosidosis (Sandhoff disease), Pompe disease, and beta-mannosidosis. HPLC detected no abnormal oligosaccharides in urine from patients with fucosidosis. Although TLC is a simple and reliable screening procedure for detecting classical lysosomal diseases with oligosaccharide excretion, HPLC, by its higher resolution and possibility of quantification, can more generally be used for recognition of abnormal oligosaccharides or detection of increased excretion or content for known oligosaccharides in urine, other body fluids, and cells.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Doenças por Armazenamento dos Lisossomos/urina , Oligossacarídeos/urina , Adolescente , Adulto , Criança , Pré-Escolar , Cromatografia em Camada Fina , Feminino , Fucosidose/urina , Gangliosidose GM1/urina , Doença de Depósito de Glicogênio Tipo II/urina , Humanos , Lactente , Recém-Nascido , Masculino , Doença de Sandhoff/urina , alfa-Manosidose/urina
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