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1.
J Int Med Res ; 49(4): 3000605211005975, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33906529

RESUMO

Fucosidosis is a rare lysosomal storage disorder characterized by deficiency of α-L-fucosidase with an autosomal recessive mode of inheritance. Here, we describe a 4-year-old Chinese boy with signs and symptoms of fucosidosis but his parents were phenotypically normal. Whole exome sequencing (WES) identified a novel homozygous single nucleotide deletion (c.82delG) in the exon 1 of the FUCA1 gene. This mutation will lead to a frameshift which will result in the formation of a truncated FUCA1 protein (p.Val28Cysfs*105) of 132 amino acids approximately one-third the size of the wild type FUCA1 protein (466 amino acids). Both parents were carrying the mutation in a heterozygous state. This study expands the mutational spectrum of the FUCA1 gene associated with fucosidosis and emphasises the benefits of WES for accurate and timely clinical diagnosis of this rare disease.


Assuntos
Fucosidose , Pré-Escolar , Éxons , Fucosidose/diagnóstico , Fucosidose/genética , Homozigoto , Humanos , Masculino , Mutação , alfa-L-Fucosidase/genética
2.
Genes (Basel) ; 12(1)2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33435586

RESUMO

Fucosidosis is a rare neurodegenerative autosomal recessive disorder, which manifests as progressive neurological and psychomotor deterioration, growth retardation, skin and skeletal abnormalities, intellectual disability and coarsening of facial features. It is caused by biallelic mutations in FUCA1 encoding the α-L-fucosidase enzyme, which in turn is responsible for degradation of fucose-containing glycoproteins and glycolipids. FUCA1 mutations lead to severe reduction or even loss of α-L-fucosidase enzyme activity. This results in incomplete breakdown of fucose-containing compounds leading to their deposition in different tissues and, consequently, disease progression. To date, 36 pathogenic variants in FUCA1 associated with fucosidosis have been documented. Among these are three splice site variants. Here, we report a novel fucosidosis-related 9-base-pair deletion (NG_013346.1:g.10233_10241delACAGGTAAG) affecting the exon 3/intron 3 junction within a FUCA1 sequence. This novel pathogenic variant was identified in a five-year-old Polish girl with a well-defined pattern of fucosidosis symptoms. Since it is postulated that other genetic, nongenetic or environmental factors can also contribute to fucosidosis pathogenesis, we performed further analysis and found two rare de novo chromosomal aberrations in the girl's genome involving a 15q11.1-11.2 microdeletion and an Xq22.2 gain. These abnormalities were associated with genome-wide changes in DNA methylation status in the epigenome of blood cells.


Assuntos
Aberrações Cromossômicas , Fucosidose/genética , alfa-L-Fucosidase/genética , Pré-Escolar , Cromossomos Humanos Par 15/genética , Cromossomos Humanos X/genética , Metilação de DNA , Análise Mutacional de DNA , Feminino , Fucosidose/diagnóstico , Humanos , Polônia , Deleção de Sequência
3.
Orphanet J Rare Dis ; 16(1): 24, 2021 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-33422100

RESUMO

BACKGROUND: Oligosaccharidoses are storage disorders due to enzymatic defects involved in the breakdown of the oligosaccharidic component of glycosylated proteins. The defect cause the accumulation of oligosaccharides (OS) and, depending on the lacking enzyme, results in characteristic profiles which are helpful for the diagnosis. We developed a new tandem mass spectrometry method for the screening of urinary OS which was applied to identify a large panel of storage disorders. METHODS: The method was set-up in urine and dried urine spots (DUS). Samples were analysed, without derivatization and using maltoheptaose as internal standard, by UHPLC-MS/MS with MRM acquisition of target OS transitions, including Glc4, the biomarker of Pompe disease. The chromatographic run was < 30 min. Samples from patients with known storage disorders were used for clinical validation. RESULTS: The method allowed to confirm the diagnosis of oligosaccharidoses (sialidosis, α-/ß-mannosidosis, fucosidosis, aspartylglucosaminuria) and of GM1 and GM2 (Sandhoff type) gangliosidosis, by detecting specific OS profiles. In other storage disorders (mucolipidosis II and III, mucopolysaccharidosis type IVB) the analyisis revealed abnormal OS excretion with non-specific profiles. Besides Pompe disease, the tetrasaccharide Glc4 was increased also in disorders of autophagy (Vici syndrome, Yunis-Varon syndrome, and Danon disease) presenting cardiomuscular involvement with glycogen storage. Overall, results showed a clear separation between patients and controls, both in urine and in DUS. CONCLUSION: This new UHPLC/MS-MS method, which is suitable for rapid and easy screening of OS in urine and DUS, expands the detection of storage disorders from oligosaccharidoses to other diseases, including the novel category of inherited disorders of autophagy.


Assuntos
Fucosidose , Doença de Depósito de Glicogênio Tipo II , Doenças por Armazenamento dos Lisossomos , Cromatografia Líquida de Alta Pressão , Humanos , Doenças por Armazenamento dos Lisossomos/diagnóstico , Oligossacarídeos , Espectrometria de Massas em Tandem
4.
Genes (Basel) ; 11(11)2020 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-33266441

RESUMO

Fucosidosis is a neurodegenerative disorder which progresses inexorably. Clinical features include coarse facial features, growth retardation, recurrent upper respiratory infections, dysostosis multiplex, and angiokeratoma corporis diffusum. Fucosidosis is caused by mutations in the FUCA1 gene resulting in α-L-fucosidase deficiency. Only 36 pathogenic variants in the FUCA1 gene are related to fucosidosis. Most of them are missense/nonsense substitutions; six missense and 11 nonsense mutations. Among deletions there were eight small and five gross changes. So far, only three splice site variants have been described-one small deletion, one complete deletion and one stop-loss mutation. The disease has a significant clinical variability, the cause of which is not well understood. The genotype-phenotype correlation has not been well defined. This review describes the genetic profile and clinical manifestations of fucosidosis in pediatric and adult cases.


Assuntos
Fucosidose/diagnóstico , Fucosidose/etiologia , alfa-L-Fucosidase/genética , Animais , Modelos Animais de Doenças , Terapia de Reposição de Enzimas , Fucosidose/genética , Fucosidose/terapia , Estudos de Associação Genética , Transplante de Células-Tronco Hematopoéticas , Humanos , Técnicas de Diagnóstico Molecular/métodos , Diagnóstico Pré-Natal
7.
Mol Genet Metab ; 127(3): 207-211, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31235216

RESUMO

Multiplex tandem mass spectrometry (MS/MS)-based enzyme activity assays for newborn screening (NBS) and diagnosis of lysosomal storage diseases (LSDs) in newborns, using dried blood spots (DBS) on newborn screening cards, have garnered much attention due to its sensitivity, high precision, and the capability to screen for an unprecedented number of diseases in a single assay. Herein we report the development of MS/MS-based enzyme assays for the diagnosis of α-mannosidosis and fucosidosis. These new protocols are able to distinguish untreated patients from random newborns, carriers and a post-bone marrow transplant patient. We have successfully multiplexed the α-mannosidosis assay with a multiplex MS/MS assay for the screening and diagnosis of other LSDs, namely Fabry, Pompe, MPS I, Gaucher, Niemann-Pick-A/B, and Krabbe diseases. Additionally, we also multiplexed the fucosidosis NBS assay with a 5-plex assay that tests for MPS-II, MPS-IIIB, MPS-IVA, MPS-VI and MPS-VII.


Assuntos
Fucosidose/diagnóstico , Doenças por Armazenamento dos Lisossomos/diagnóstico , Triagem Neonatal/métodos , Espectrometria de Massas em Tandem/métodos , alfa-Manosidose/diagnóstico , Ensaios Enzimáticos , Humanos , Recém-Nascido
8.
Neuropediatrics ; 50(4): 248-252, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31064022

RESUMO

BACKGROUND: Fucosidosis is a rare lysosomal disorder caused by mutations in the FUCA1 gene. We describe here a novel homozygous mutation in FUCA1 in an Indian fucosidosis case. Furthermore, we summarize the clinical and genetic findings in the most recently reported individuals with fucosidosis. CASE: The proband is an 8-year-old boy born to consanguineous parents. He had generalized dystonia and bilateral spasticity as well as coarse facies, dysostosis multiplex, recurrent infections, angiokeratoma corporis diffusum, and visceromegaly. Whole exome sequencing analysis detected a homozygous canonical splice variant in the FUCA1 gene [Chr1(GRCh37):g.24172346C > T; NM_000147.4:c.1261-1G > A], not previously reported as causative of a human phenotype. Low levels of α-fucosidase in patient leukocytes and a positive qualitative urine based thin layer chromatography test for fucosidosis confirmed the diagnosis. Our literature review identified 89 cases of fucosidosis since the last major review. We show that dystonia is a rare manifestation (12%) and that only a small minority of cases receive treatment with transplantation (3.37%). CONCLUSION: We report a novel homozygous mutation in FUCA1 as the cause of severe neurological phenotype including generalized dystonia. Early recognition of fucosidosis may be important for consideration of promising treatment options, such as bone marrow transplantation.


Assuntos
Distonia/etiologia , Fucosidose/complicações , Mutação , alfa-L-Fucosidase/genética , Criança , Distonia/genética , Fucosidose/genética , Humanos , Masculino , Fenótipo
9.
Exp Dermatol ; 27(6): 663-667, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29518279

RESUMO

Fucosidosis is a rare lysosomal storage disease which has been classified into two subtypes, depending on the severity of clinical signs and symptoms. Fucosidosis patients' skin abnormalities include angiokeratoma corporis diffusum, widespread telangiectasia, thick skin, hyperhidrosis and hypohidrosis, acrocyanosis and distal transverse nail bands. It has been described that >50% of fucosidosis patients have angiokeratoma. At molecular level, fucosidosis is caused by lysosomal alpha-L-fucosidase (FUCA1) gene mutations. Obtaining samples for functional studies has been challenging due to the inherent difficulty in finding affected individuals. The effect of FUCA1 dysfunction on gene expression is unknown. The aim of this study was to analyse, in keratinocytes, the transcriptomic effect of FUCA1 knock-down for a better understanding of skin lesions' pathogenesis affecting fucosidosis patients. FUCA1 knock-down (siRNA) was performed in human HaCaT immortalised keratinocytes. Affymetrix arrays and qPCR were used for analysing gene expression. Bioinformatics was used for functional clustering of modified genes. In total, 387 genes showed differential expression between FUCA1 silenced and non-silenced cells (222 up-regulated and 165 down-regulated). Up-regulated genes belonged to two major groups: keratinocyte differentiation/epidermal development (n = 17) and immune response (n = 61). Several transcription factors were up-regulated in FUCA1-siRNA transfected cells. This effect might partly have been produced by abnormal transcription factor expression, that is FOXN1. We thus propose that fucosidosis-related skin lesions (eg angiokeratoma) and those of other diseases (eg psoriasis) might be caused by dysfunctions in common aetiological overlapping molecular cascades.


Assuntos
Fucosidose/genética , Dermatopatias/genética , Transcriptoma/genética , alfa-L-Fucosidase/genética , Angioceratoma/genética , Diferenciação Celular/genética , Linhagem Celular , Biologia Computacional , Regulação para Baixo/genética , Epiderme/crescimento & desenvolvimento , Epiderme/imunologia , Fucosidose/complicações , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Queratinócitos , Análise de Sequência com Séries de Oligonucleotídeos , Dermatopatias/etiologia , Regulação para Cima/genética
10.
J Clin Pathol ; 71(9): 821-824, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29588375

RESUMO

AIMS: Fucosidosis is a rare autosomal recessive lysosomal storage disorder caused by α-L-fucosidase deficiency as a result of FUCA1 gene mutations. Here, we studied clinical features and the molecular basis of fucosidosis in a family from Iran, including two probands and nine family members. METHODS: DNA sample of two probands were screened for gene defects using a next generation sequencing technique. The sequencing processes were performed on an Illumina Hiseq 4000 platform. Sequence reads were analysed using BWA-GATK. RESULTS: Next generation sequencing revealed a frameshift mutation caused by 2 bp deletion (c.837_838 delTG; p.Cys279) in the FUCA1 gene. The identified mutation was tested in all participants. Homozygous patients had almost all the complications associated with fucosidosis, while heterozygous carriers were unaffected. CONCLUSIONS: The variant c.837_838 delTG; p.Cys279 has not been reported previously and is predicted to be pathogenic due to a premature stop codon.


Assuntos
Mutação da Fase de Leitura , Fucosidose/genética , Homozigoto , alfa-L-Fucosidase/genética , Pré-Escolar , Códon sem Sentido , Análise Mutacional de DNA , Feminino , Fucosidose/diagnóstico , Fucosidose/enzimologia , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Irã (Geográfico) , Masculino , Linhagem , Fenótipo , Índice de Gravidade de Doença , Adulto Jovem
11.
Int J Pediatr Otorhinolaryngol ; 103: 5-9, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29224764

RESUMO

Fucosidosis is an autosomal recessive lysosomal storage disorder caused by the deficiency of alpha-L-fucosidase. We present the case of an affected female in the second decade of life with chronic rhinosinusitis (CRS) including recalcitrant polypoid inflammation, which has not been previously reported in the literature. With the advancement of life-prolonging measures, children with lysosomal storage disorders may suffer increasingly from CRS due to the lymphohistiocytic and macrophage infiltrate of the paranasal sinus mucosa that resembles severe polypoid inflammation.


Assuntos
Fucosidose/complicações , Rinite/etiologia , Sinusite/etiologia , Adolescente , Criança , Doença Crônica , Feminino , Humanos , Inflamação , Tomografia Computadorizada por Raios X , alfa-L-Fucosidase/deficiência
12.
Immunol Res ; 65(5): 1025-1030, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28808940

RESUMO

Human α-fucosidase (EC 3.2.1.51) is an enzyme (hydrolase) of particular biological and medical interest, as the inherited deficiency in its activity leads to fucosidosis, a pathology belonging to severe glycoprotein lysosomal storage disorders. Although its importance has increased in latest years, data about its plasma level in children with inflammatory disorders are still lacking. In the present study, plasma activity of α-L-fucosidase-1 (FUCA-1) and its potential association with chronic inflammatory pathologies was evaluated in hospitalized individuals, both pediatric and adult ones. A number of 201 Hungarian hospitalized patients, 144 children (1-13 years) and 57 adults (31-88 years), were enrolled in the study and underwent plasma assay of FUCA-1 activity, following the normal routine analytical run in the hospital service. Regression and Pearson tests were evaluated to investigate the relationship between FUCA-1 plasma levels and inflammatory disorders diagnosed with subjects recruited in the study. No correlation of FUCA-1 activity was observed in the pediatric patients with immune (p = 0.9677) or metabolic (p = 0.6974) disorders, but a correlation was reported when comparing clusters of chronic inflammatory and autoimmune disease vs. controls (p < 0.05). Furthermore, a relationship was found between FUCA-1 activity in plasma and inflammatory disorders and autoimmunity both in adults and in the pediatric cohort of patients (Pearson test, p = 0.000148). Alterations in plasma levels of FUCA-1 were significantly associated with chronic inflammatory and autoimmune disorders, both in children and adults. The result of the present study should encourage further research on FUCA-1 as a marker of chronic inflammation and autoimmunity.


Assuntos
Doenças Autoimunes/metabolismo , Inflamação/metabolismo , alfa-L-Fucosidase/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Fucosidose/genética , Hospitalização , Humanos , Hungria , Lactente , Masculino , Pessoa de Meia-Idade , alfa-L-Fucosidase/genética
13.
Metab Brain Dis ; 32(2): 317-320, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28238202

RESUMO

Fucosidosis is a rare lysosomal storage disease caused by α-fucosidase deficiency, which leads to progressive neurological deterioration and death. Hematopoietic stem cell transplantation is the best curative therapy if performed during the early stages of disease. We report two fucosidosis patients with brain abnormalities and the challenge faced in their management. The first patient received supportive therapy and the second one firstly underwent unrelated donor umbilical cord blood transplantation. After a period of follow-up, we found neurological symptoms were worsening day by day on patient1. By contrast, patient2 who received cord blood transplantation acquired clinical neurologic improvement in response to normalization of deficient enzymatic activity. This report indicates that hematopoietic transplant could reduce the severity and retard the progression of clinical neurological deterioration. Umbilical cord blood transplantation is a novel approach for treating fucosidosis patients who lack suitable bone morrow donors.


Assuntos
Encéfalo/patologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Fucosidose/patologia , Fucosidose/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Atrofia , Encéfalo/diagnóstico por imagem , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/etiologia , Progressão da Doença , Feminino , Fucosidose/diagnóstico por imagem , Humanos , Lactente , Masculino , Resultado do Tratamento
14.
Genet Mol Res ; 15(3)2016 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-27706744

RESUMO

Fucosidosis is a rare lysosomal storage disorder inherited in an autosomal recessive manner. Its estimated frequency is below 1 in 200,000 live births. Its clinical phenotypes include progressive neurological and mental deterioration, coarse facial features, growth retardation, visceromegaly, angiokeratomas, and seizures. The disease is caused by mutations in the FUCA1 gene that lead to deficiency of a-L-fucosidase. Here, we describe the clinical and molecular features of a Thai boy with fucosidosis. Whole exome sequencing and array-based comparative genomic hybridization analysis revealed that the patient was compound heterozygous for a single base-pair deletion (c.670delC; p.P224LfsX2) inherited from his father, and a 3281-base-pair deletion covering exon 3 inherited from his mother. Neither mutation has been reported before so the FUCA1 mutational spectrum is herein expanded.


Assuntos
Fucosidose/genética , Doenças por Armazenamento dos Lisossomos/genética , alfa-L-Fucosidase/genética , Adulto , Criança , Hibridização Genômica Comparativa , Éxons/genética , Feminino , Fucosidose/fisiopatologia , Genes Recessivos , Humanos , Doenças por Armazenamento dos Lisossomos/patologia , Masculino , Mutação , Linhagem , Fenótipo
15.
Dis Model Mech ; 9(9): 1015-28, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27491075

RESUMO

Fucosidosis is a rare lysosomal storage disorder caused by the inherited deficiency of the lysosomal hydrolase α-L-fucosidase, which leads to an impaired degradation of fucosylated glycoconjugates. Here, we report the generation of a fucosidosis mouse model, in which the gene for lysosomal α-L-fucosidase (Fuca1) was disrupted by gene targeting. Homozygous knockout mice completely lack α-L-fucosidase activity in all tested organs leading to highly elevated amounts of the core-fucosylated glycoasparagine Fuc(α1,6)-GlcNAc(ß1-N)-Asn and, to a lesser extent, other fucosylated glycoasparagines, which all were also partially excreted in urine. Lysosomal storage pathology was observed in many visceral organs, such as in the liver, kidney, spleen and bladder, as well as in the central nervous system (CNS). On the cellular level, storage was characterized by membrane-limited cytoplasmic vacuoles primarily containing water-soluble storage material. In the CNS, cellular alterations included enlargement of the lysosomal compartment in various cell types, accumulation of secondary storage material and neuroinflammation, as well as a progressive loss of Purkinje cells combined with astrogliosis leading to psychomotor and memory deficits. Our results demonstrate that this new fucosidosis mouse model resembles the human disease and thus will help to unravel underlying pathological processes. Moreover, this model could be utilized to establish diagnostic and therapeutic strategies for fucosidosis.


Assuntos
Encéfalo/patologia , Fucosidose/metabolismo , Fucosidose/patologia , Animais , Comportamento Animal , Encéfalo/ultraestrutura , Modelos Animais de Doenças , Ativação Enzimática , Fucose/metabolismo , Fucosidose/urina , Gangliosídeo G(M2)/metabolismo , Glicoconjugados/urina , Glicoproteínas/metabolismo , Humanos , Inflamação/patologia , Lisossomos/enzimologia , Lisossomos/ultraestrutura , Camundongos Endogâmicos C57BL , Especificidade de Órgãos , Proteólise , Células de Purkinje/metabolismo , Células de Purkinje/patologia , Vísceras/metabolismo , Vísceras/patologia , alfa-L-Fucosidase/deficiência , alfa-L-Fucosidase/metabolismo
16.
Pediatr Endocrinol Rev ; 13 Suppl 1: 697-706, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27491218

RESUMO

Abstract Fucosidosis (OMIM 23000) is an inherited neurodegenerative lysosomal storage disease caused by a deficiency of the lysosomal hydrolase a-L-fucosidase due to mutations in the FUCA1 gene. Without enzyme-targeted therapy patients rarely survive beyond the first decade of life, and therapy options other than supportive care are limited. Hematopoietic transplants, first developed in the fucosidosis dog model, are the only treatment option available capable of delaying the disease course. However, due to the risks and exclusion criteria of this treatment additional therapies are required. The development of additional therapies including intravenous and intra-cerebrospinal fluid enzyme replacement therapy and gene therapy, which have been trialed in the canine model, will be discussed.


Assuntos
Terapia de Reposição de Enzimas , Fucosidose/terapia , Terapia Genética , Transplante de Células-Tronco Hematopoéticas , alfa-L-Fucosidase/uso terapêutico , Animais , Terapia Combinada , Modelos Animais de Doenças , Cães , Humanos , alfa-L-Fucosidase/genética
17.
Brain Dev ; 38(4): 435-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26515723

RESUMO

Fucosidosis is a rare lysosomal storage disorder caused by deficient activity of the enzyme l-fucosidase in all tissues. We presented magnetic resonance imaging [MRI] and MR spectroscopy [MRS] findings of a 4-year-old boy with genetically proven fucosidosis. He had a history and clinical findings of recurrent sinopulmonary infections, hypertonicity on lower extremities, gingival hypertrophy, bilateral ptosis, angiokeratoma corporis diffusum, and dysostosis multiplex. He had no organomegaly and urine glycosaminoglycan analysis were normal. MRI revealed abnormalities within the globus pallidus and periventricular and subcortical white matter. MRS showed a peak at the 3.8-3.9 ppm as a result of accumulating carbohydrate containing macromolecules and another peak at 1.2 which was doublet and inverted on TE 135, suggesting fructose peak. A final diagnosis of fucosidosis was proved by mutational analysis of FUCA1 gene which is responsible for the Fucosidosis phenotype. Two recent reports of MRS of two patients demonstrated that MRS is specific for fucosidosis. In this case, we aim to discuss fucosidosis with MRI and MRS findings accompanied by the literature.


Assuntos
Encéfalo/patologia , Fucosidose/diagnóstico por imagem , Fucosidose/patologia , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Pré-Escolar , Fucosidose/genética , Humanos , Masculino , alfa-L-Fucosidase/genética
18.
Genes Brain Behav ; 15(4): 420-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26711085

RESUMO

Canine fucosidosis in English Springer spaniels is the only animal model of the neurovisceral lysosomal storage disease fucosidosis available for preclinical therapeutic trials. For this reason, it is crucial to identify critical time points in disease progression, and if there are particular lesions associated with specific aspects of neurologic dysfunction. Historical records of 53 canine fucosidosis cases from 1979 to 2009 containing a neurologic dysfunction score assessing motor, behavioral and sensory dysfunction were interrogated by statistical analysis. Motor and behavioral dysfunction scores assessing gait deficits and apprehensive behavior first significantly increased at 12-17 months, and increased at each 6-month interval thereafter. Sensory dysfunction scores, assessing hearing loss, balance and vision deterioration, did not significantly increase until 18-23 months, and coincided with a rapid decline in neurologic function. Regression analysis incorporating published neuropathology data, measured by image analysis, identified neuroinflammation and apoptotic cell death as significant informative predictors of increasing neurologic dysfunction. These findings indicate that the level of neuropathology required to induce consistent and conspicuous clinical signs in canine fucosidosis is reached by approximately 12 months of age in the absence of other disease processes. Significant association between neuroinflammation and apoptotic cell death also suggests that specifically targeting these lesions combined with enzyme replacement in future studies may reduce disease burden in fucosidosis. Overall, examining this historical clinical data to identify associations between the extent of neuropathology and degree of clinical dysfunction provides a useful reference tool for monitoring disease and evaluating therapeutic trials conducted in canine fucosidosis.


Assuntos
Doenças do Cão/fisiopatologia , Fucosidose/veterinária , Animais , Apoptose/fisiologia , Encéfalo/patologia , Modelos Animais de Doenças , Doenças do Cão/metabolismo , Cães , Fucosidose/metabolismo , Fucosidose/fisiopatologia , Doenças do Sistema Nervoso
19.
J Radiol Case Rep ; 9(5): 30-8, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-26622931

RESUMO

Fucosidosis is a rare genetic lysosomal storage disorder caused by a deficiency in alpha- L-fucosidase. We present a case of a 4-year, 11-month-old girl with developmental delay, as well as skeletal and brain abnormalities as shown on X-ray and MRI. Her spinal X- rays demonstrated lumbar kyphosis and anterior beaking of lumbar vertebral bodies. Lower iliac segment constriction, increased angulation of the acetabular roof, and widening of the ribs were apparent on abdominal X-ray. Her brain MRI illustrated symmetric T1 hyperintensity and T2 hypointensity of the bilateral globi pallidi. The case report highlights clinical and imaging findings of this rare disease.


Assuntos
Encéfalo/patologia , Fucosidose/diagnóstico por imagem , Fucosidose/patologia , Vértebras Lombares/diagnóstico por imagem , Acetábulo/diagnóstico por imagem , Pré-Escolar , Deficiências do Desenvolvimento/etiologia , Diagnóstico Diferencial , Feminino , Fucosidose/complicações , Humanos , Ílio/diagnóstico por imagem , Imageamento por Ressonância Magnética , Prognóstico , Costelas/diagnóstico por imagem , Tomografia Computadorizada por Raios X
20.
Orphanet J Rare Dis ; 10: 143, 2015 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-26537923

RESUMO

BACKGROUND: Fucosidosis results from lack of α-L-fucosidase activity, with accumulation of fucose-linked substrates in the nervous system and viscera leading to progressive motor and mental deterioration, and death. The naturally occurring dog model of fucosidosis was used to evaluate the neuropathological responses to partial enzyme replacement, and substrate reduction in early disease following treatment with recombinant canine α-L-fucosidase delivered through cerebrospinal fluid. METHODS: Neuropathology in both treated (n = 3) and untreated fucosidosis-affected (n = 3) animals was evaluated with immunohistochemistry, image analysis, manual quantification and gene expression analysis and compared with unaffected age-matched controls (n = 3) in an extension of our previous biochemical report on the same cohort. Data were analyzed by ANOVA. RESULTS: Quantification demonstrated a consistent trend to reduction in vacuolation, pyramidal neuron loss, astrocytosis, microgliosis, perivascular storage, apoptosis, oligodendrocyte loss, and hypomyelination throughout the central nervous system of enzyme treated animals compared to placebo-treated, age-matched affected controls. Key lesions including lysosomal expansion in neurons of deep cortex, astrocytosis in cerebral cortex and medulla, and increased lysosomal membrane associated protein-1 (LAMP-1) gene expression were ameliorated in treated animals. There was no change in spheroid formation and loss of Purkinje cells, but Purkinje cell vulnerability to apoptosis was reduced with treatment. CONCLUSIONS: Despite reduced severity of fucosidosis neuropathology with partial enzyme replacement, more complete and sustained biochemical correction is required to halt neuropathological processes in this large animal model of lysosomal storage disease.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Modelos Animais de Doenças , Fucosidose/tratamento farmacológico , Fucosidose/patologia , alfa-L-Fucosidase/administração & dosagem , Animais , Cisterna Magna , Cães , Infusão Espinal , Resultado do Tratamento
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