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1.
Anal Chem ; 96(22): 8956-8964, 2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38776126

RESUMEN

Glycoproteins play important roles in numerous physiological processes and are often implicated in disease. Analysis of site-specific protein glycobiology through glycoproteomics has evolved rapidly in recent years thanks to hardware and software innovations. Particularly, the introduction of parallel accumulation serial fragmentation (PASEF) on hybrid trapped ion mobility time-of-flight mass spectrometry instruments combined deep proteome sequencing with separation of (near-)isobaric precursor ions or converging isotope envelopes through ion mobility separation. However, the reported use of PASEF in integrated glycoproteomics workflows to comprehensively capture the glycoproteome is still limited. To this end, we developed an integrated methodology using timsTOF Pro 2 to enhance N-glycopeptide identifications in complex mixtures. We systematically optimized the ion optics tuning, collision energies, mobility isolation width, and the use of dopant-enriched nitrogen gas (DEN). Thus, we obtained a marked increase in unique glycopeptide identification rates compared to standard proteomics settings, showcasing our results on a large set of glycopeptides. With short liquid chromatography gradients of 30 min, we increased the number of unique N-glycopeptide identifications in human plasma samples from around 100 identifications under standard proteomics conditions to up to 1500 with our optimized glycoproteomics approach, highlighting the need for tailored optimizations to obtain comprehensive data.


Asunto(s)
Glicopéptidos , Proteómica , Proteómica/métodos , Humanos , Glicopéptidos/análisis , Glicopéptidos/química , Glicopéptidos/sangre , Flujo de Trabajo , Glicoproteínas/análisis , Glicoproteínas/química , Glicoproteínas/sangre , Cromatografía Liquida , Espectrometría de Masas en Tándem
2.
J Inherit Metab Dis ; 46(2): 313-325, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36651519

RESUMEN

Congenital disorders of glycosylation (CDG) are a clinically and biochemically heterogeneous subgroup of inherited metabolic disorders. Most CDG with abnormal N-glycosylation can be detected by transferrin screening, however, MOGS-CDG escapes this routine screening. Combined with the clinical heterogeneity of reported cases, diagnosing MOGS-CDG can be challenging. Here, we clinically characterize ten MOGS-CDG cases including six previously unreported individuals, showing a phenotype characterized by dysmorphic features, global developmental delay, muscular hypotonia, and seizures in all patients and in a minority vision problems and hypogammaglobulinemia. Glycomics confirmed accumulation of a Glc3 Man7 GlcNAc2 glycan in plasma. For quantification of the diagnostic Glcα1-3Glcα1-3Glcα1-2Man tetrasaccharide in urine, we developed and validated a liquid chromatography-mass spectrometry method of 2-aminobenzoic acid (2AA) labeled urinary glycans. As an internal standard, isotopically labeled 13 C6 -2AA Glc3 Man was used, while labeling efficiency was controlled by use of 12 C6 -2AA and 13 C6 -2AA labeled laminaritetraose. Recovery, linearity, intra- and interassay coefficients of variability of these labeled compounds were determined. Furthermore, Glc3 Man was specifically identified by retention time matching against authentic MOGS-CDG urine and compared with Pompe urine. Glc3 Man was increased in all six analyzed cases, ranging from 34.1 to 618.0 µmol/mmol creatinine (reference <5 µmol). In short, MOGS-CDG has a broad manifestation of symptoms but can be diagnosed with the use of a quantitative method for analysis of urinary Glc3 Man excretion.


Asunto(s)
Trastornos Congénitos de Glicosilación , Humanos , Trastornos Congénitos de Glicosilación/genética , Espectrometría de Masas/métodos , Oligosacáridos/metabolismo , Polisacáridos , Convulsiones
3.
Int J Mol Sci ; 24(3)2023 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-36768261

RESUMEN

The glycosylation of proteins plays an important role in neurological development and disease. Glycoproteomic studies on cerebrospinal fluid (CSF) are a valuable tool to gain insight into brain glycosylation and its changes in disease. However, it is important to consider that most proteins in CSFs originate from the blood and enter the CSF across the blood-CSF barrier, thus not reflecting the glycosylation status of the brain. Here, we apply a glycoproteomics method to human CSF, focusing on differences between brain- and blood-derived proteins. To facilitate the analysis of the glycan site occupancy, we refrain from glycopeptide enrichment. In healthy individuals, we describe the presence of heterogeneous brain-type N-glycans on prostaglandin H2-D isomerase alongside the dominant plasma-type N-glycans for proteins such as transferrin or haptoglobin, showing the tissue specificity of protein glycosylation. We apply our methodology to patients diagnosed with various genetic glycosylation disorders who have neurological impairments. In patients with severe glycosylation alterations, we observe that heavily truncated glycans and a complete loss of glycans are more pronounced in brain-derived proteins. We speculate that a similar effect can be observed in other neurological diseases where a focus on brain-derived proteins in the CSF could be similarly beneficial to gain insight into disease-related changes.


Asunto(s)
Encéfalo , Transferrina , Humanos , Glicosilación , Transferrina/metabolismo , Encéfalo/metabolismo , Polisacáridos/metabolismo
4.
Int J Mol Sci ; 24(9)2023 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-37175577

RESUMEN

Real-time database searching allows for simpler and automated proteomics workflows as it eliminates technical bottlenecks in high-throughput experiments. Most importantly, it enables results-dependent acquisition (RDA), where search results can be used to guide data acquisition during acquisition. This is especially beneficial for glycoproteomics since the wide range of physicochemical properties of glycopeptides lead to a wide range of optimal acquisition parameters. We established here the GlycoPaSER prototype by extending the Parallel Search Engine in Real-time (PaSER) functionality for real-time glycopeptide identification from fragmentation spectra. Glycopeptide fragmentation spectra were decomposed into peptide and glycan moiety spectra using common N-glycan fragments. Each moiety was subsequently identified by a specialized algorithm running in real-time. GlycoPaSER can keep up with the rate of data acquisition for real-time analysis with similar performance to other glycoproteomics software and produces results that are in line with the literature reference data. The GlycoPaSER prototype presented here provides the first proof-of-concept for real-time glycopeptide identification that unlocks the future development of RDA technology to transcend data acquisition.


Asunto(s)
Glicopéptidos , Motor de Búsqueda , Secuencia de Aminoácidos , Glicopéptidos/química , Glicosilación , Programas Informáticos , Polisacáridos/química
5.
J Hum Genet ; 65(9): 743-750, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32313197

RESUMEN

Variants in SLC35C1 underlie leucocyte adhesion deficiency (LADII) or congenital disorder of glycosylation type 2c (CDGIIc), an autosomal recessive disorder of fucosylation. This immunodeficiency syndrome is generally characterized by severe recurrent infections, Bombay blood group, reduced growth and intellectual disability (ID). Features are all caused by an inability to generate key fucosylated molecules due to a defective transport of GDP-fucose into the Golgi. Here we report the use of exome sequencing to identify biallelic variants in SLC35C1 (c.501_503delCTT, p.(Phe168del) and c.891T > G, p.(Asn297Lys)) in an individual with short stature and ID. Retrospective clinical examination based on the genetic findings revealed increased otitis media as the only immunological feature present in this child. Biochemical analysis of patient serum identified a clear but mild decrease in protein fucosylation. Modelling all described missense mutations on a SLC35C1 protein model showed pathogenic substitutions localise to close to the dimer interface, providing insight into the possible pathophysiology of non-synonymous causative variants identified in patients. Our evidence confirms this is the second family presenting with only a subset of features and broadens the clinical presentation of this syndrome. Of note, both families segregated a common allele (p.Phe168del), suggesting there could be an associated genotype-phenotype relationship for specific variants. Based on two out of 14 reported families not presenting with the characteristic features of SLC35C1-CDG, we suggest there is clinical utility in considering this gene in patients with short stature and ID.


Asunto(s)
Trastornos Congénitos de Glicosilación/genética , Enanismo/genética , Discapacidad Intelectual/genética , Proteínas de Transporte de Monosacáridos/genética , Alelos , Preescolar , Cromatografía Liquida , Trastornos Congénitos de Glicosilación/sangre , Trastornos Congénitos de Glicosilación/complicaciones , Enanismo/sangre , Enanismo/complicaciones , Enanismo/fisiopatología , Femenino , Estudios de Asociación Genética , Glicómica , Humanos , Discapacidad Intelectual/sangre , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/fisiopatología , Proteínas de Transporte de Monosacáridos/química , Mutación Missense , Plasma/química , Plasma/inmunología , Plasma/metabolismo , Estudios Retrospectivos , Alineación de Secuencia , Espectrometría de Masas en Tándem , Secuenciación del Exoma
6.
J Inherit Metab Dis ; 43(6): 1310-1320, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32557671

RESUMEN

Congenital disorders of glycosylation (CDG) are a rapidly expanding group of rare genetic defects in glycosylation. In a novel CDG subgroup of vacuolar-ATPase (V-ATPase) assembly defects, various degrees of hepatic injury have been described, including end-stage liver disease. However, the CDG diagnostic workflow can be complex as liver disease per se may be associated with abnormal glycosylation. Therefore, we collected serum samples of patients with a wide range of liver pathology to study the performance and yield of two CDG screening methods. Our aim was to identify glycosylation patterns that could help to differentiate between primary and secondary glycosylation defects in liver disease. To this end, we analyzed serum samples of 1042 adult liver disease patients. This cohort consisted of 567 liver transplant candidates and 475 chronic liver disease patients. Our workflow consisted of screening for abnormal glycosylation by transferrin isoelectric focusing (tIEF), followed by in-depth analysis of the abnormal samples with quadruple time-of-flight mass spectrometry (QTOF-MS). Screening with tIEF resulted in identification of 247 (26%) abnormal samples. QTOF-MS analysis of 110 of those did not reveal glycosylation abnormalities comparable with those seen in V-ATPase assembly factor defects. However, two patients presented with isolated sialylation deficiency. Fucosylation was significantly increased in liver transplant candidates compared to healthy controls and patients with chronic liver disease. In conclusion, a significant percentage of patients with liver disease presented with abnormal CDG screening results. However, the glycosylation pattern was not indicative for a V-ATPase assembly factor defect. Advanced glycoanalytical techniques assist in the dissection of secondary and primary glycosylation defects.


Asunto(s)
Trastornos Congénitos de Glicosilación/metabolismo , Enfermedad Hepática en Estado Terminal/metabolismo , Espectrometría de Masas/métodos , Transferrina/análisis , Adulto , Anciano , Estudios de Casos y Controles , Estudios de Cohortes , Trastornos Congénitos de Glicosilación/diagnóstico , Femenino , Glicosilación , Humanos , Hígado/metabolismo , Masculino , Persona de Mediana Edad , Transferrina/metabolismo
7.
J Inherit Metab Dis ; 43(5): 994-1001, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32441338

RESUMEN

Nucleotide sugars (NS) are fundamental molecules in life and play a key role in glycosylation reactions and signal conduction. Several pathways are involved in the synthesis of NS. The Leloir pathway, the main pathway for galactose metabolism, is crucial for production of uridine diphosphate (UDP)-glucose and UDP-galactose. The most common metabolic disease affecting this pathway is galactose-1-phosphate uridylyltransferase (GALT) deficiency, that despite a lifelong galactose-restricted diet, often results in chronically debilitating complications. Alterations in the levels of UDP-sugars leading to galactosylation abnormalities have been hypothesized as a key pathogenic factor. However, UDP-sugar levels measured in patient cell lines have shown contradictory results. Other NS that might be affected, differences throughout development, as well as tissue specific profiles have not been investigated. Using recently established UHPLC-MS/MS technology, we studied the complete NS profiles in wildtype and galt knockout zebrafish (Danio rerio). Analyses of UDP-hexoses, UDP-hexosamines, CMP-sialic acids, GDP-fucose, UDP-glucuronic acid, UDP-xylose, CDP-ribitol, and ADP-ribose profiles at four developmental stages and in tissues (brain and gonads) in wildtype zebrafish revealed variation in NS levels throughout development and differences between examined tissues. More specifically, we found higher levels of CMP-N-acetylneuraminic acid, GDP-fucose, UDP-glucuronic acid, and UDP-xylose in brain and of CMP-N-glycolylneuraminic acid in gonads. Analysis of the same NS profiles in galt knockout zebrafish revealed no significant differences from wildtype. Our findings in galt knockout zebrafish, even when challenged with galactose, do not support a role for abnormalities in UDP-glucose or UDP-galactose as a key pathogenic factor in GALT deficiency, under the tested conditions.


Asunto(s)
Galactosa/metabolismo , Galactosemias/enzimología , UDP-Glucosa-Hexosa-1-Fosfato Uridiltransferasa/deficiencia , UTP-Hexosa-1-Fosfato Uridililtransferasa/metabolismo , Animales , Femenino , Galactosemias/genética , Cinética , Masculino , Espectrometría de Masas en Tándem , Pez Cebra
8.
J Adv Res ; 2023 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-37683725

RESUMEN

INTRODUCTION: The human plasma glycoproteome holds enormous potential to identify personalized biomarkers for diagnostics. Glycoproteomics has matured into a technology for plasma N-glycoproteome analysis but further evolution towards clinical applications depends on the clinical validity and understanding of protein- and site-specific glycosylation changes in disease. OBJECTIVES: Here, we exploited the uniqueness of a patient cohort of genetic defects in well-defined glycosylation pathways to assess the clinical applicability of plasma N-glycoproteomics. METHODS: Comparative glycoproteomics was performed of blood plasma from 40 controls and 74 patients with 13 different genetic diseases that impact the protein N-glycosylation pathway. Baseline glycosylation in healthy individuals was compared to reference glycome and intact transferrin protein mass spectrometry data. Use of glycoproteomics data for biomarker discovery and sample stratification was evaluated by multivariate chemometrics and supervised machine learning. Clinical relevance of site-specific glycosylation changes were evaluated in the context of genetic defects that lead to distinct accumulation or loss of specific glycans. Integrated analysis of site-specific glycoproteome changes in disease was performed using chord diagrams and correlated with intact transferrin protein mass spectrometry data. RESULTS: Glycoproteomics identified 191 unique glycoforms from 58 unique peptide sequences of 34 plasma glycoproteins that span over 3 magnitudes of abundance in plasma. Chemometrics identified high-specificity biomarker signatures for each of the individual genetic defects with better stratification performance than the current diagnostic standard method. Bioinformatic analyses revealed site-specific glycosylation differences that could be explained by underlying glycobiology and protein-intrinsic factors. CONCLUSION: Our work illustrates the strong potential of plasma glycoproteomics to significantly increase specificity of glycoprotein biomarkers with direct insights in site-specific glycosylation changes to better understand the glycobiological mechanisms underlying human disease.

9.
Biochim Biophys Acta ; 1802(11): 1028-35, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20600873

RESUMEN

BACKGROUND: Sedoheptulose, arabitol, ribitol, and erythritol have been identified as key diagnostic metabolites in TALDO deficiency. METHOD: Urine from 6 TALDO-deficient patients and TALDO-deficient knock-out mice were analyzed using ¹H-NMR spectroscopy and GC-mass spectrometry. RESULTS: Our data confirm the known metabolic characteristics in TALDO-deficient patients. The ß-furanose form was the major sedoheptulose anomer in TALDO-deficient patients. Erythronic acid was identified as a major abnormal metabolite in all patients and in knock-out TALDO mice implicating an as yet unknown biochemical pathway in this disease. A putative sequence of enzymatic reactions leading to the formation of erythronic acid is presented. The urinary concentration of the citric acid cycle intermediates 2-oxoglutaric acid and fumaric acid was increased in the majority of TALDO-deficient patients but not in the knock-out mice. CONCLUSION: Erythronic acid is a novel and major hallmark in TALDO deficiency. The pathway leading to its production may play a role in healthy humans as well. In TALDO-deficient patients, there is an increased flux through this pathway. The finding of increased citric acid cycle intermediates hints toward a disturbed mitochondrial metabolism in TALDO deficiency.


Asunto(s)
Biomarcadores/orina , Butiratos/orina , Mitocondrias/metabolismo , Transaldolasa/deficiencia , Adolescente , Animales , Butiratos/química , Preescolar , Fumaratos/química , Fumaratos/orina , Cromatografía de Gases y Espectrometría de Masas , Heptosas/química , Heptosas/orina , Humanos , Lactante , Recién Nacido , Ácidos Cetoglutáricos/química , Ácidos Cetoglutáricos/orina , Espectroscopía de Resonancia Magnética , Ratones , Ratones Noqueados , Estructura Molecular , Vía de Pentosa Fosfato , Ribitol/química , Ribitol/orina , Alcoholes del Azúcar/química , Alcoholes del Azúcar/orina , Transaldolasa/genética
10.
Nat Commun ; 12(1): 6227, 2021 10 28.
Artículo en Inglés | MEDLINE | ID: mdl-34711829

RESUMEN

The SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) protein syntaxin-5 (Stx5) is essential for Golgi transport. In humans, the STX5 mRNA encodes two protein isoforms, Stx5 Long (Stx5L) from the first starting methionine and Stx5 Short (Stx5S) from an alternative starting methionine at position 55. In this study, we identify a human disorder caused by a single missense substitution in the second starting methionine (p.M55V), resulting in complete loss of the short isoform. Patients suffer from an early fatal multisystem disease, including severe liver disease, skeletal abnormalities and abnormal glycosylation. Primary human dermal fibroblasts isolated from these patients show defective glycosylation, altered Golgi morphology as measured by electron microscopy, mislocalization of glycosyltransferases, and compromised ER-Golgi trafficking. Measurements of cognate binding SNAREs, based on biotin-synchronizable forms of Stx5 (the RUSH system) and Förster resonance energy transfer (FRET), revealed that the short isoform of Stx5 is essential for intra-Golgi transport. Alternative starting codons of Stx5 are thus linked to human disease, demonstrating that the site of translation initiation is an important new layer of regulating protein trafficking.


Asunto(s)
Anomalías Congénitas/metabolismo , Proteínas Qa-SNARE/metabolismo , Secuencias de Aminoácidos , Anomalías Congénitas/genética , Fibroblastos/metabolismo , Glicosilación , Aparato de Golgi/metabolismo , Humanos , Mutación , Biosíntesis de Proteínas , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Transporte de Proteínas , Proteínas Qa-SNARE/química , Proteínas Qa-SNARE/genética
11.
Hum Mutat ; 29(4): 532-6, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18186520

RESUMEN

The most common mutation in the nephropathic cystinosis (CTNS) gene is a homozygous 57-kb deletion that also includes an adjacent gene carbohydrate kinase-like (CARKL). The latter gene encodes a protein that is predicted to function as a carbohydrate kinase. Cystinosis patients with the common 57-kb deletion had strongly elevated urinary concentrations of sedoheptulose (28-451 mmol/mol creatinine; controls and other cystinosis patients <9) and erythritol (234-1110 mmol/mol creatinine; controls and other cystinosis patients <148). Enzyme studies performed on fibroblast homogenates derived from patients carrying the 57-kb deletion revealed 80% reduction in their sedoheptulose phosphorylating activity compared to cystinosis patients with other mutations and controls. This indicates that the CARKL-encoded protein, sedoheptulokinase (SHK), is responsible for the reaction: sedoheptulose + ATP --> sedoheptulose-7-phosphate + ADP and that deletion of CARKL causes urinary accumulation of sedoheptulose and erythritol.


Asunto(s)
Cistinosis/enzimología , Cistinosis/genética , Heptosas/orina , Fosfotransferasas/deficiencia , Fosfotransferasas/genética , Factores de Transcripción/deficiencia , Factores de Transcripción/genética , Adolescente , Adulto , Sistemas de Transporte de Aminoácidos Neutros/deficiencia , Sistemas de Transporte de Aminoácidos Neutros/genética , Estudios de Casos y Controles , Niño , Mapeo Cromosómico , Cistinosis/orina , Eritritol/orina , Fibroblastos/enzimología , Genes Recesivos , Humanos , Lactante , Modelos Biológicos , Vía de Pentosa Fosfato , Fosfotransferasas (Aceptor de Grupo Alcohol) , Eliminación de Secuencia
12.
JCI Insight ; 3(24)2018 12 20.
Artículo en Inglés | MEDLINE | ID: mdl-30568043

RESUMEN

Sialic acids are important components of glycoproteins and glycolipids essential for cellular communication, infection, and metastasis. The importance of sialic acid biosynthesis in human physiology is well illustrated by the severe metabolic disorders in this pathway. However, the biological role of sialic acid catabolism in humans remains unclear. Here, we present evidence that sialic acid catabolism is important for heart and skeletal muscle function and development in humans and zebrafish. In two siblings, presenting with sialuria, exercise intolerance/muscle wasting, and cardiac symptoms in the brother, compound heterozygous mutations [chr1:182775324C>T (c.187C>T; p.Arg63Cys) and chr1:182772897A>G (c.133A>G; p.Asn45Asp)] were found in the N-acetylneuraminate pyruvate lyase gene (NPL). In vitro, NPL activity and sialic acid catabolism were affected, with a cell-type-specific reduction of N-acetyl mannosamine (ManNAc). A knockdown of NPL in zebrafish resulted in severe skeletal myopathy and cardiac edema, mimicking the human phenotype. The phenotype was rescued by expression of wild-type human NPL but not by the p.Arg63Cys or p.Asn45Asp mutants. Importantly, the myopathy phenotype in zebrafish embryos was rescued by treatment with the catabolic products of NPL: N-acetyl glucosamine (GlcNAc) and ManNAc; the latter also rescuing the cardiac phenotype. In conclusion, we provide the first report to our knowledge of a human defect in sialic acid catabolism, which implicates an important role of the sialic acid catabolic pathway in mammalian muscle physiology, and suggests opportunities for monosaccharide replacement therapy in human patients.


Asunto(s)
Músculo Esquelético/metabolismo , Enfermedades Musculares/genética , Enfermedades Musculares/metabolismo , Ácido N-Acetilneuramínico/metabolismo , Oxo-Ácido-Liasas/genética , Oxo-Ácido-Liasas/metabolismo , Adulto , Animales , Modelos Animales de Enfermedad , Edema Cardíaco/metabolismo , Regulación del Desarrollo de la Expresión Génica , Técnicas de Silenciamiento del Gen , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/metabolismo , Células HEK293 , Hexosaminas/metabolismo , Humanos , Masculino , Músculo Esquelético/crecimiento & desarrollo , Enfermedades Musculares/fisiopatología , Mutación , Oxo-Ácido-Liasas/uso terapéutico , Enfermedad por Almacenamiento de Ácido Siálico/metabolismo , Adulto Joven , Pez Cebra/embriología
13.
Nat Genet ; 48(7): 777-84, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27213289

RESUMEN

We identified biallelic mutations in NANS, the gene encoding the synthase for N-acetylneuraminic acid (NeuNAc; sialic acid), in nine individuals with infantile-onset severe developmental delay and skeletal dysplasia. Patient body fluids showed an elevation in N-acetyl-D-mannosamine levels, and patient-derived fibroblasts had reduced NANS activity and were unable to incorporate sialic acid precursors into sialylated glycoproteins. Knockdown of nansa in zebrafish embryos resulted in abnormal skeletal development, and exogenously added sialic acid partially rescued the skeletal phenotype. Thus, NANS-mediated synthesis of sialic acid is required for early brain development and skeletal growth. Normal sialylation of plasma proteins was observed in spite of NANS deficiency. Exploration of endogenous synthesis, nutritional absorption, and rescue pathways for sialic acid in different tissues and developmental phases is warranted to design therapeutic strategies to counteract NANS deficiency and to shed light on sialic acid metabolism and its implications for human nutrition.


Asunto(s)
Enfermedades del Desarrollo Óseo/patología , Encéfalo/embriología , Discapacidades del Desarrollo/patología , Mutación/genética , Oxo-Ácido-Liasas/genética , Ácidos Siálicos/metabolismo , Pez Cebra/embriología , Adulto , Edad de Inicio , Animales , Enfermedades del Desarrollo Óseo/genética , Enfermedades del Desarrollo Óseo/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Preescolar , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/metabolismo , Embrión no Mamífero/metabolismo , Embrión no Mamífero/patología , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Lactante , Recién Nacido , Masculino , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/metabolismo , Errores Innatos del Metabolismo/patología , Pez Cebra/genética , Pez Cebra/metabolismo
15.
Am J Med Genet A ; 139A(2): 114-7, 2005 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-16278884

RESUMEN

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disease caused by a deficiency of the mitochondrial enzyme 27-sterol hydroxylase (CYP27). We report a 53-year-old man, with an unusual phenotype of CTX. He had xanthomas since adolescence. He had no mental retardation and developed at 44 years a progressive neuropsychiatric phenotype, suggestive of fronto-temporal dementia according to clinical Neary criteria. Cataract and ataxia were absent. Cerebral MRI revealed diffuse hyperintense T2 abnormalities in the supratentorial white matter without cerebellar atrophy or lesions, while Technetium-99m-ECD brain SPECT revealed a severe cerebellar hypoperfusion. Serum cholestanol level was elevated with excessive urinary bile alcohols excretion. Mutation analysis revealed that he was compound heterozygous for two mutations in the CYP27A1 gene: 1016 C > T (exon 5) on one allele and a novel mutation, 1435C > G (exon 8) on the other allele. A follow-up study was conducted to evaluate the effects of chenodeoxycholic acid (CDCA) and simvastatin treatment during 3 years. In spite of this treatment, cognitive functions declined but no other signs of neurological deterioration appeared.


Asunto(s)
Demencia/fisiopatología , Xantomatosis Cerebrotendinosa/fisiopatología , Demencia/diagnóstico por imagen , Demencia/psicología , Humanos , Masculino , Trastornos Mentales/diagnóstico por imagen , Trastornos Mentales/fisiopatología , Trastornos Mentales/psicología , Persona de Mediana Edad , Pruebas Neuropsicológicas , Fenotipo , Tomografía Computarizada de Emisión de Fotón Único , Xantomatosis Cerebrotendinosa/diagnóstico por imagen , Xantomatosis Cerebrotendinosa/psicología
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