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1.
Orphanet J Rare Dis ; 14(1): 143, 2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31200731

RESUMO

BACKGROUND: Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive lysosomal storage disease due to N-acetylgalactosamine-6-sulfatase (GALNS) deficiency. It results in accumulation of the glycosaminoglycans, keratan sulfate and chondroitin-6-sulfate, leading to skeletal and other systemic impairments. Data on MPS IVA in Asian populations are scarce. METHODS: This is a multicentre descriptive case series of 21 patients comprising all MPS IVA patients in Malaysia. Mutational analysis was performed by PCR and Sanger sequencing of the GALNS gene in 17 patients. RESULTS: The patients (15 females and 6 males) had a mean age (± SD) of 15.5 (± 8.1) years. Mean age at symptom onset was 2.6 (± 2.1) years and at confirmed diagnosis was 6.9 (± 4.5) years. The study cohort included patients from all the main ethnic groups in Malaysia - 57% Malay, 29% Chinese and 14% Indian. Common presenting symptoms included pectus carinatum (57%) and genu valgum (43%). Eight patients (38%) had undergone surgery, most commonly knee surgeries (29%) and cervical spine decompression (24%). Patients had limited endurance with lower mean walking distances with increasing age. GALNS gene analysis identified 18 distinct mutations comprising 13 missense, three nonsense, one small deletion and one splice site mutation. Of these, eight were novel mutations (Tyr133Ser, Glu158Valfs*12, Gly168*, Gly168Val, Trp184*, Leu271Pro, Glu320Lys, Leu508Pro). Mutations in exons 1, 5 and 9 accounted for 51% of the mutant alleles identified. CONCLUSIONS: All the MPS IVA patients in this study had clinical impairments. A better understanding of the natural history and the clinical and genetic spectrum of MPS IVA in this population may assist early diagnosis, improve management and permit timely genetic counselling and prenatal diagnosis.


Assuntos
Mucopolissacaridose IV/genética , Mucopolissacaridose IV/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Condroitina Sulfatases/genética , Condroitina Sulfatases/metabolismo , Estudos de Coortes , Feminino , Humanos , Malásia , Masculino , Mucopolissacaridose IV/metabolismo , Adulto Jovem
2.
Mol Genet Metab ; 126(2): 139-150, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30528226

RESUMO

Deficiencies in the lysosomal hydrolase ß-galactosidase (ß-gal) lead to two distinct diseases: the skeletal disease Morquio syndrome type B, and the neurodegenerative disease GM1-gangliosidosis. Utilizing CRISPR-Cas9 genome editing, the mouse ß-gal encoding gene, Glb1, was targeted to generate both models of ß-gal deficiency in a single experiment. For Morquio syndrome type B, the common human missense mutation W273L (position 274 in mice) was introduced into the Glb1 gene (Glb1W274L), while for GM1-gangliosidosis, a 20 bp mutation was generated to remove the catalytic nucleophile of ß-gal (ß-gal-/-). Glb1W274L mice showed a significant reduction in ß-gal enzyme activity (8.4-13.3% of wildtype), but displayed no marked phenotype after one year. In contrast, ß-gal-/- mice were devoid of ß-gal enzyme activity (≤1% of wildtype), resulting in ganglioside accumulation and severe cellular vacuolation throughout the central nervous system (CNS). ß-gal-/- mice also displayed severe neuromotor and neurocognitive dysfunction, and as the disease progressed, the mice became emaciated and succumbed to the disease by 10 months of age. Overall, in addition to generating a novel murine model that phenotypically resembles GM1-gangliosidosis, the first model of ß-galactosidase deficiency with residual enzyme activity has been developed.


Assuntos
Modelos Animais de Doenças , Gangliosidose GM1/patologia , Mucopolissacaridose IV/patologia , beta-Galactosidase/metabolismo , Animais , Sistemas CRISPR-Cas , Feminino , Fluorometria , Gangliosidose GM1/genética , Edição de Genes , Testes de Estado Mental e Demência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucopolissacaridose IV/genética , Mutação , Mutação de Sentido Incorreto , Fenótipo , beta-Galactosidase/genética
3.
Bioanalysis ; 10(15): 1181-1192, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30059256

RESUMO

AIM: Since 2014, enzyme replacement therapy (ERT) has been available for treatment of Morquio A syndrome. During clinical trials, urinary keratan sulfate (KS) has been a useful biomarker and showed a marked decrease in patients on ERT, demonstrating therapy efficacy. Unfortunately, quantitative urinary KS testing is not widely available in biochemical genetics laboratories for efficient monitoring and follow-up of treated patients. MATERIALS & METHODS: A tandem mass spectrometry methodology was devised to analyze KS disaccharides and creatinine in urine specimens collected on filter paper. RESULTS: All Morquio A patients presented abnormal results pretreatment compared with reference values. CONCLUSION: This collection procedure can be performed by patients at home and filter papers sent by regular mail to a specialized laboratory, facilitating follow-up of patients.


Assuntos
Cromatografia Líquida de Alta Pressão , Sulfato de Ceratano/urina , Mucopolissacaridose IV/patologia , Espectrometria de Massas em Tandem , Coleta de Urina/métodos , Adolescente , Adulto , Biomarcadores/urina , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão/normas , Creatinina/urina , Terapia de Reposição de Enzimas , Seguimentos , Humanos , Sulfato de Ceratano/normas , Limite de Detecção , Masculino , Mucopolissacaridose IV/terapia , Papel , Valores de Referência , Espectrometria de Massas em Tandem/normas , Adulto Jovem
4.
Mol Genet Metab ; 125(1-2): 44-52, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29779903

RESUMO

To explore the correlation between glycosaminoglycan (GAG) levels and mucopolysaccharidosis (MPS) type, we have evaluated the GAG levels in blood of MPS II, III, IVA, and IVB and urine of MPS IVA, IVB, and VI by tandem mass spectrometry. Dermatan sulfate (DS), heparan sulfate (HS), keratan sulfate (KS; mono-sulfated KS, di-sulfated KS), and the ratio of di-sulfated KS in total KS were measured. Patients with untreated MPS II had higher levels of DS and HS in blood while untreated MPS III had higher levels of HS in blood than age-matched controls. Untreated MPS IVA had higher levels of KS in blood and urine than age-matched controls. The ratio of blood di-sulfated KS/total KS in untreated MPS IVA was constant and higher than that in controls for children up to 10 years of age. The ratio of urine di-sulfated KS/total KS in untreated MPS IVA was also higher than that in age-matched controls, but the ratio in untreated MPS IVB was lower than controls. ERT reduced blood DS and HS in MPS II, and urine KS in MPS IVA patients, although GAGs levels remained higher than the observed in age-matched controls. ERT did not change blood KS levels in MPS IVA. MPS VI under ERT still had an elevation of urine DS level compared to age-matched controls. There was a positive correlation between blood and urine KS in untreated MPS IVA patients but not in MPS IVA patients treated with ERT. Blood and urine KS levels were secondarily elevated in MPS II and VI, respectively. Overall, measurement of GAG levels in blood and urine is useful for diagnosis of MPS, while urine KS is not a useful biomarker for monitoring therapeutic efficacy in MPS IVA.


Assuntos
Glicosaminoglicanos/sangue , Glicosaminoglicanos/urina , Mucopolissacaridoses/sangue , Mucopolissacaridoses/urina , Adolescente , Adulto , Biomarcadores/sangue , Biomarcadores/urina , Criança , Pré-Escolar , Dermatan Sulfato/sangue , Dermatan Sulfato/urina , Feminino , Glicosaminoglicanos/isolamento & purificação , Heparitina Sulfato/sangue , Heparitina Sulfato/urina , Humanos , Sulfato de Ceratano/sangue , Sulfato de Ceratano/urina , Masculino , Mucopolissacaridoses/classificação , Mucopolissacaridoses/patologia , Mucopolissacaridose II/sangue , Mucopolissacaridose II/patologia , Mucopolissacaridose II/urina , Mucopolissacaridose III/sangue , Mucopolissacaridose III/patologia , Mucopolissacaridose III/urina , Mucopolissacaridose IV/sangue , Mucopolissacaridose IV/patologia , Mucopolissacaridose IV/urina , Mucopolissacaridose VI/sangue , Mucopolissacaridose VI/patologia , Mucopolissacaridose VI/urina , Espectrometria de Massas em Tandem , Adulto Jovem
5.
Cogn Neuropsychol ; 35(3-4): 120-147, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29741470

RESUMO

We characterized cognitive function in two metabolic diseases. MPS-IVa (mucopolysaccharidosis IVa, Morquio) and tyrosinemia type III individuals were assessed using tasks of attention, language and oculomotor function. MPS-IVa individuals were slower in visual search, but the display size effects were normal, and slowing was not due to long reaction times (ruling out slow item processing or distraction). Maintaining gaze in an oculomotor task was difficult. Results implicated sustained attention and task initiation or response processing. Shifting attention, accumulating evidence and selecting targets were unaffected. Visual search was also slowed in tyrosinemia type III, and patterns in visual search and fixation tasks pointed to sustained attention impairments, although there were differences from MPS-IVa. Language was impaired in tyrosinemia type III but not MPS-IVa. Metabolic diseases produced selective cognitive effects. Our results, incorporating new methods for developmental data and model selection, illustrate how cognitive data can contribute to understanding function in biochemical brain systems.


Assuntos
Cognição/fisiologia , Doenças Metabólicas/diagnóstico , Mucopolissacaridose IV/diagnóstico , Tirosinemias/diagnóstico , Humanos , Doenças Metabólicas/patologia , Mucopolissacaridose IV/patologia , Tirosinemias/patologia
6.
Mol Genet Metab ; 123(4): 479-487, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29526614

RESUMO

Elosulfase alfa is an enzyme replacement therapy for Morquio A syndrome (mucopolysaccharidosis IVA), a multisystemic progressive lysosomal storage disorder. This report includes the primary treatment outcomes and immunogenicity profile of elosulfase alfa in patients with Morquio A syndrome from 2 sequential studies, MOR-002 (ClinicalTrials.govNCT00884949) and MOR-100 (NCT01242111), representing >5 years of clinical study data. MOR-002 was an open-label, single-arm phase 1/2 study that evaluated the pharmacokinetics, safety, immunogenicity, and preliminary efficacy of 3 sequential doses of elosulfase alfa (0.1, 1.0, and 2.0 mg/kg/week) in patients with Morquio A syndrome (n = 20) over 36 weeks, followed by an optional 36- to 48-week treatment period using elosulfase alfa 1.0 mg/kg once weekly (qw). During the 0.1 mg/kg dosing phase, 1 patient discontinued due to a type I hypersensitivity adverse event (AE), and that patient's sibling voluntarily discontinued in the absence of AEs. An additional patient discontinued due to recurrent infusion reactions during the 1.0 mg/kg continuation phase. The remaining 17 patients completed MOR-002 and enrolled in MOR-100, an open-label, long-term extension study that further evaluated safety and clinical outcomes with elosulfase alfa administered at 2.0 mg/kg qw. During the course of MOR-100, patients were given the option of receiving elosulfase alfa infusions at home with nursing assistance. Over the course of both studies, all patients experienced ≥1 AE and most patients experienced a drug-related AE, generally of mild or moderate severity. Hypersensitivity reactions reported as related to study drug occurred in 25% of patients. Thirteen patients who chose to receive infusions at home had the same tolerability and safety profile, as well as comparable compliance rates, as patients who chose to receive on-site infusions. All patients developed antibodies to elosulfase alfa. Positivity for neutralizing antibodies was associated with increased drug half-life and decreased drug clearance. Despite formation of antidrug-binding (total antidrug antibodies, TAb) and in vitro neutralizing antibodies (NAb) in all patients, these types of immunogenicity to elosulfase alfa were not correlated with safety or clinical outcomes. In contrast with the reported natural history of Morquio A, no trends toward decreasing endurance, respiratory function, or ability to perform activities of daily living were observed in this cohort over the 5-year period.


Assuntos
Anticorpos Neutralizantes/imunologia , Condroitina Sulfatases/administração & dosagem , Terapia de Reposição de Enzimas , Mucopolissacaridose IV/terapia , Adolescente , Criança , Pré-Escolar , Condroitina Sulfatases/deficiência , Feminino , Seguimentos , Humanos , Masculino , Mucopolissacaridose IV/enzimologia , Mucopolissacaridose IV/imunologia , Mucopolissacaridose IV/patologia , Segurança do Paciente , Prognóstico
7.
Clin Genet ; 93(5): 1008-1014, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29396849

RESUMO

Lysosomal storage diseases (LSDs) are a group of genetic disorders, resulting from deficiencies of lysosomal enzyme. Genotype-phenotype correlation is essential for timely and proper treatment allocation. Recently, by integrating prediction outcomes of 7 bioinformatics tools, we developed a SAAMP algorithm to predict the impact of individual amino-acid substitution. To optimize this approach, we evaluated the performance of these bioinformatics tools in a broad array of genes. PolyPhen and PROVEAN had the best performances, while SNP&GOs, PANTHER and I-Mutant had the worst performances. Therefore, SAAMP 2.0 was developed by excluding 3 tools with worst performance, yielding a sensitivity of 94% and a specificity of 90%. To generalize the guideline to proteins without known structures, we built the three-dimensional model of iduronate-2-sulfatase by homology modeling. Further, we investigated the phenotype severity of known disease-causing mutations of the GLB1 gene, which lead to 2 LSDs (GM1 gangliosidosis and Morquio disease type B). Based on the previous literature and structural analysis, we associated these mutations with disease subtypes and proposed a theory to explain the complicated genotype-phenotype correlation. Collectively, an updated guideline for phenotype prediction with SAAMP 2.0 was proposed, which will provide essential information for early diagnosis and proper treatment allocation, and they may be generalized to many monogenic diseases.


Assuntos
Estudos de Associação Genética , Iduronato Sulfatase/química , Doenças por Armazenamento dos Lisossomos/genética , beta-Galactosidase/química , Algoritmos , Substituição de Aminoácidos/genética , Biologia Computacional , Gangliosidose GM1/genética , Gangliosidose GM1/patologia , Predisposição Genética para Doença , Genótipo , Humanos , Iduronato Sulfatase/genética , Doenças por Armazenamento dos Lisossomos/patologia , Mucopolissacaridose IV/genética , Mucopolissacaridose IV/patologia , Proteínas Mutantes/química , Proteínas Mutantes/genética , Mutação , Conformação Proteica , beta-Galactosidase/genética
8.
Autops. Case Rep ; 7(2): 9-14, Apr.-June 2017. ilus, tab
Artigo em Inglês | LILACS | ID: biblio-905193

RESUMO

Morquio syndrome is a rare lysosomal storage disease that affects multiple organ systems. However, it is rarely associated with malignancy. We present the case of a 30-year old man with Morquio syndrome associated with gastric adenocarcinoma. This case also demonstrates two other findings that have not been previously described in patients with Morquio syndrome - malrotation of brainstem and cerebellum, without clinical neurologic deficit, and persistence of fetal lobulation in the kidneys.


Assuntos
Humanos , Masculino , Adulto , Doenças por Armazenamento dos Lisossomos/patologia , Mucopolissacaridose IV/patologia , Autopsia , Tronco Encefálico/anormalidades , Cerebelo/anormalidades , Evolução Fatal , Rim Fundido/patologia , Segunda Neoplasia Primária/complicações , Neoplasias Gástricas/patologia
9.
Gene ; 600: 48-54, 2017 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-27825773

RESUMO

Morquio A disease (Mucopolysaccharidosis IVA, MPS IVA) is an autosomal recessive lysosomal storage disorder caused by deficient activity of the enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS) encoded by the GALNS gene. This deficiency leads to a decreased ability to degrade the glycosaminoglycans (GAGs) keratan sulfate and chondroitin 6-sulfate, thereby causing their accumulation within the lysosomes and consequently prominent skeletal and visceral abnormalities. Clinical evaluation and biochemical GALNS enzyme activity determination were carried out for the patients from four unrelated Egyptian families. Mutational analysis was performed to PCR products by sequencing of the 14 exons and exon-intron boundaries of GALNS gene for the 4 patients. Sequence analysis revealed four novel mutations; three nonsense mutations (p.Q12X, p.Q220X, p.Y254X) and one missense mutation, p.D40G. All four patients were offspring of consanguineous marriages and were homozygous for the corresponding mutation. The activity of the GALNS enzyme was below normal reference range in all of them. The p.Q12X and p.Y254X were associated with severe MPS IVA phenotype. Molecular analysis of GALNS gene revealed four novel mutations in four different Morquio A Egyptian patients.


Assuntos
Condroitina Sulfatases/genética , Mucopolissacaridose IV/enzimologia , Mucopolissacaridose IV/genética , Mutação , Estudos de Casos e Controles , Criança , Pré-Escolar , Códon sem Sentido , Consanguinidade , Análise Mutacional de DNA , Egito , Feminino , Homozigoto , Humanos , Masculino , Mucopolissacaridose IV/patologia , Mutação de Sentido Incorreto
10.
Eur J Med Chem ; 126: 160-170, 2017 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-27750150

RESUMO

This report is about the identification, synthesis and initial biological characterization of derivatives of 4-epi-isofagomine as pharmacological chaperones (PC) for human lysosomal ß-galactosidase. The two epimers of 4-epi-isofagomine carrying a pentyl group at C-5a, namely (5aR)- and (5aS)-5a-C-pentyl-4-epi-isofagomine, were prepared by an innovative procedure involving in the key step the addition of nitrohexane to a keto-pentopyranoside. Both epimers were evaluated as inhibitors of the human ß-galactosidase: the (5aR)-stereoisomer (compound 1) was found to be a very potent inhibitor of the enzyme (IC50 = 8 nM, 30× more potent than 4-epi-isofagomine at pH 7.3) with a high selectivity for this glycosidase whereas the (5aS) epimer was a much weaker inhibitor. In addition, compound 1 showed a remarkable activity as a PC. It significantly enhanced the residual activity of mutant ß-galactosidase in 15 patient cell lines out of 23, with enhancement factors greater than 3.5 in 10 cell lines and activity restoration up to 91% of normal. Altogether, these results indicated that (5aR)-5a-C-pentyl-4-epi-isofagomine constitutes a promising PC-based drug candidate for the treatment of GM1-gangliosidosis and Morquio disease type B.


Assuntos
Inibidores Enzimáticos/farmacologia , Gangliosidose GM1/genética , Imino Piranoses/farmacologia , Lisossomos/enzimologia , Mucopolissacaridose IV/genética , Mutação , beta-Galactosidase/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Fibroblastos/efeitos dos fármacos , Gangliosidose GM1/enzimologia , Gangliosidose GM1/patologia , Temperatura Alta , Humanos , Concentração de Íons de Hidrogênio , Imino Piranoses/síntese química , Imino Piranoses/química , Mucopolissacaridose IV/enzimologia , Mucopolissacaridose IV/patologia , Desnaturação Proteica , beta-Galactosidase/química , beta-Galactosidase/genética , beta-Galactosidase/metabolismo
11.
Int J Mol Sci ; 17(12)2016 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-27916847

RESUMO

The prevalence of aortic root dilatation (ARD) in mucopolysaccharidosis (MPS) is not well documented. We investigated aortic root measurements in 34 MPS patients at the Children's Hospital of Orange County (CHOC). The diagnosis, treatment status, age, gender, height, weight and aortic root parameters (aortic valve annulus (AVA), sinuses of Valsalva (SoV), and sinotubular junction (STJ)) were extracted by retrospective chart review and echocardiographic measurements. Descriptive statistics, ANOVA, and paired post-hoc t-tests were used to summarize the aortic dimensions. Exact binomial 95% confidence intervals (CIs) were constructed for ARD, defined as a z-score greater than 2 at the SoV. The patient age ranged from 3.4-25.9 years (mean 13.3 ± 6.1), the height from 0.87-1.62 meters (mean 1.24 ± 0.21), and the weight from 14.1-84.5 kg (mean 34.4 ± 18.0). The prevalence of dilation at the AVA was 41% (14/34; 95% CI: 25%-59%); at the SoV was 35% (12/34; 95% CI: 20%-54%); and at the STJ was 30% (9/30; 95% CI: 15%-49%). The highest prevalence of ARD was in MPS IVa (87.5%). There was no significant difference between mean z-scores of MPS patients who received treatment with hematopoietic stem cell transplantation (HSCT) or enzyme replacement therapy (ERT) vs. untreated MPS patients at the AVA (z = 1.9 ± 2.5 vs. z = 1.5 ± 2.4; p = 0.62), SoV (z = 1.2 ± 1.6 vs. z = 1.3 ± 2.2; p = 0.79), or STJ (z = 1.0 ± 1.8 vs. z = 1.2 ± 1.6; p = 0.83). The prevalence of ARD was 35% in our cohort of MPS I-VII patients. Thus, we recommend screening for ARD on a routine basis in this patient population.


Assuntos
Doenças da Aorta/diagnóstico , Dilatação Patológica/diagnóstico , Mucopolissacaridose III/patologia , Mucopolissacaridose II/patologia , Mucopolissacaridose IV/patologia , Mucopolissacaridose I/patologia , Mucopolissacaridose VII/patologia , Mucopolissacaridose VI/patologia , Adolescente , Adulto , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/tratamento farmacológico , Doenças da Aorta/terapia , Criança , Dilatação Patológica/tratamento farmacológico , Dilatação Patológica/terapia , Feminino , Humanos , Masculino , Mucopolissacaridose I/metabolismo , Mucopolissacaridose II/metabolismo , Mucopolissacaridose III/metabolismo , Mucopolissacaridose IV/metabolismo , Mucopolissacaridose VI/metabolismo , Mucopolissacaridose VII/metabolismo , Estudos Retrospectivos , Adulto Jovem
12.
Mol Genet Metab ; 117(2): 144-9, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26670863

RESUMO

Mucopolysaccharidosis IV A (MPS IV A), Morquio A, is caused by deficiency in lysosomal enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS), which is responsible for the catabolism of the glycosaminoglycans (GAGs) keratan sulfate (KS) and chondroitin 6-sulfate (C6S). Accumulation of GAGs results in disrupted cartilage formation and skeletal dysplasia. In this prospective cross-sectional study, bone mineral density (BMD) of the whole body (WB), lumbar spine (LS), and lateral distal femur (LDF) was acquired by dual-energy X-ray absorptiometry (DXA) on patients with MPS IV A. Functional abilities, medical history, Tanner score, and laboratory results were reviewed. Age and sex-matched norms were used to calculate Z-scores. Participants included 18 patients (13 females; 16 were unrelated) with a mean age of 21.4years (3.3 to 40.8years). While every patient was able to bear weight, 9 were full-time ambulators. Whole-body DXA could be obtained on only 6 patients (5 full-time ambulators) because of respiratory compromise caused by the position, presence of hardware, or positioning difficulties. Mean WB Z-score was -2.0 (range-0.3 to -4.1). Technical issues invalidating LS DXA in 8 patients included kyphosis at the thoracolumbar junction resulting in overlap of vertebrae in the posterior-anterior view. Mean LS BMD Z-score in full-time ambulators was -3.4 (range-1.6 to -5.0) and in the non-/partial ambulator was -4.0 (-3.7 to -4.2). Lateral distal femur BMD was acquired on every patient, and average Z-scores were -2 or less at all sites; full-time ambulators exhibited higher BMD. In conclusion, the LDF proved to be the most feasible site to measure in patients with MPS IV A. The higher LDF values in ambulators suggest this should be a consideration in promoting bone health for this group.


Assuntos
Densidade Óssea , Mucopolissacaridose IV/diagnóstico por imagem , Absorciometria de Fóton , Adolescente , Adulto , Criança , Pré-Escolar , Estudos Transversais , Feminino , Fêmur/diagnóstico por imagem , Fêmur/patologia , Humanos , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/patologia , Masculino , Mucopolissacaridose IV/patologia , Estudos Prospectivos , Imagem Corporal Total , Adulto Jovem
13.
Mol Genet Metab ; 117(2): 150-6, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26432669

RESUMO

Patients with severe tracheal obstruction in Morquio A syndrome are at risk of dying of sleep apnea and related complications. Tracheal obstruction also leads to life-threatening complications during anesthesia as a result of the difficulty in managing the upper airway due to factors inherent to the Morquio A syndrome, compounded by the difficulty in intubating the trachea. A detailed description of the obstructive pathology of the trachea is not available in the literature probably due to lack of a homogenous group of Morquio A patients to study at any one particular center. We present a series of cases with significant tracheal obstruction who were unrecognized due to the difficulty in interpreting tracheal narrowing airway symptoms. Our goal is to provide the guidelines in the management of these patients that allow earlier recognition and intervention of tracheal obstruction. Sagittal MRI images of the cervical spine of 28 Morquio A patients (12±8.14years) showed that19/28 (67.9%) patients had at least 25% tracheal narrowing and that narrowing worsened with age (all 8 patients over 15years had greater than 50% narrowing). Eight out of 28 patients were categorized as severe (>75%) tracheal narrowing when images were evaluated in neutral head and neck position. Of the 19 patients with tracheal narrowing, compression by the tortuous brachiocephalic artery was the most common cause (n=15). Evidence of such tracheal narrowing was evident as early as at 2years of age. The etiology of tracheal impingement by the brachiocephalic artery in Morquio A appears to be due to a combination of the narrow thoracic inlet crowding structures and the disproportionate growth of trachea and brachiocephalic artery in relationship to the chest cavity leading to tracheal tortuosity. In conclusion, tracheal narrowing, often due to impression from the crossing tortuous brachiocephalic artery, increases with age in Morquio A patients. Greater attention to the trachea is needed when evaluating cervical spine MRIs as well as other imaging and clinical investigations, with the goal of establishing a timely treatment protocol to reduce the mortality rate in this patient population.


Assuntos
Obstrução das Vias Respiratórias/diagnóstico , Mucopolissacaridose IV/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Estudos Retrospectivos , Traqueia/patologia , Adulto Jovem
14.
Am J Med Genet A ; 167A(10): 2272-81, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26069231

RESUMO

The primary treatment outcomes of a phase 2, randomized, double-blind, pilot study evaluating safety, physiological, and pharmacological effects of elosulfase alfa in patients with Morquio A syndrome are herewith presented. Patients aged ≥7 years and able to walk ≥200 m in the 6-min walk test (6MWT) were randomized to elosulfase alfa 2.0 or 4.0 mg/kg/week for 27 weeks. The primary objective was to evaluate the safety of both doses. Secondary objectives were to evaluate effects on endurance (6MWT and 3-min stair climb test [3MSCT]), exercise capacity (cardio-pulmonary exercise test [CPET]), respiratory function, muscle strength, cardiac function, pain, and urine keratan sulfate (uKS) levels, and to determine pharmacokinetic parameters. Twenty-five patients were enrolled (15 randomized to 2.0 mg/kg/week and 10 to 4.0 mg/kg/week). No new or unexpected safety signals were observed. After 24 weeks, there were no improvements versus baseline in the 6MWT, yet numerical improvements were seen in the 3MSCT with 4.0 mg/kg/week. uKS and pharmacokinetic data suggested no linear relationship over the 2.0-4.0 mg/kg dose range. Overall, an abnormal exercise capacity (evaluated in 10 and 5 patients in the 2.0 and 4.0 mg/kg/week groups, respectively), impaired muscle strength, and considerable pain were observed at baseline, and there were trends towards improvements in all domains after treatment. In conclusion, preliminary data of this small study in a Morquio A population with relatively good endurance confirmed the acceptable safety profile of elosulfase alfa and showed a trend of increased exercise capacity and muscle strength and decreased pain.


Assuntos
Condroitina Sulfatases/genética , Condroitina Sulfatases/uso terapêutico , Terapia de Reposição de Enzimas , Mucopolissacaridose IV/tratamento farmacológico , Adolescente , Adulto , Criança , Condroitina Sulfatases/metabolismo , Método Duplo-Cego , Esquema de Medicação , Teste de Esforço , Feminino , Testes de Função Cardíaca , Humanos , Sulfato de Ceratano/urina , Masculino , Mucopolissacaridose IV/enzimologia , Mucopolissacaridose IV/genética , Mucopolissacaridose IV/patologia , Força Muscular , Segurança do Paciente , Projetos Piloto , Proteínas Recombinantes/uso terapêutico , Testes de Função Respiratória , Resultado do Tratamento , Caminhada
15.
Mol Genet Metab ; 114(2): 195-202, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24953405

RESUMO

We treated mucopolysaccharidosis IVA (MPS IVA) mice to assess the effects of long-term enzyme replacement therapy (ERT) initiated at birth, since adult mice treated by ERT showed little improvement in bone pathology [1]. To conduct ERT in newborn mice, we used recombinant human N-acetylgalactosamine-6-sulfate sulfatase (GALNS) produced in a CHO cell line. First, to observe the tissue distribution pattern, a dose of 250units/g body weight was administered intravenously in MPS IVA mice at day 2 or 3. The infused enzyme was primarily recovered in the liver and spleen, with detectable activity in the bone and brain. Second, newborn ERT was conducted after a tissue distribution study. The first injection of newborn ERT was performed intravenously, the second to fourth weekly injections were intraperitoneal, and the remaining injections from 5th to 14th weeks were intravenous into the tail vein. MPS IVA mice treated with GALNS showed clearance of lysosomal storage in the liver and spleen, and sinus lining cells in bone marrow. The column structure of the growth plate was organized better than that in adult mice treated with ERT; however, hyaline and fibrous cartilage cells in the femur, spine, ligaments, discs, synovium, and periosteum still had storage materials to some extent. Heart valves were refractory to the treatment. Levels of serum keratan sulfate were kept normal in newborn ERT mice. In conclusion, the enzyme, which enters the cartilage before the cartilage cell layer becomes mature, prevents disorganization of column structure. Early treatment from birth leads to partial remission of bone pathology in MPS IVA mice.


Assuntos
Doenças Ósseas/tratamento farmacológico , Condroitina Sulfatases/uso terapêutico , Terapia de Reposição de Enzimas , Mucopolissacaridose IV/tratamento farmacológico , Administração Intravenosa , Animais , Animais Recém-Nascidos , Doenças Ósseas/patologia , Células CHO , Cartilagem/efeitos dos fármacos , Cartilagem/ultraestrutura , Condrócitos/efeitos dos fármacos , Condrócitos/ultraestrutura , Condroitina Sulfatases/administração & dosagem , Condroitina Sulfatases/genética , Condroitina Sulfatases/farmacocinética , Cricetulus , Modelos Animais de Doenças , Lâmina de Crescimento/efeitos dos fármacos , Lâmina de Crescimento/ultraestrutura , Sulfato de Ceratano/sangue , Fígado/efeitos dos fármacos , Camundongos , Camundongos Knockout , Mucopolissacaridose IV/patologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapêutico , Baço/efeitos dos fármacos , Distribuição Tecidual/efeitos dos fármacos
16.
Toxicol Mech Methods ; 24(8): 603-7, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25141890

RESUMO

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate genotoxicity and mutagenicity in peripheral blood and buccal mucosal cells in mucopolysaccharidosis (MPS) I, II or VI patients. METHODS: A total of 12 patients with MPS type I, II and VI attended at the Institute of Genetics and Inborn Errors of Metabolism treated with enzyme replacement therapy (ERT) and 10 healthy control volunteers were included in this study. Mechanically exfoliated cells from cheek mucosa (left and right side) were used to micronucleus test and single cell gel (comet) assay in peripheral blood cells. RESULTS: The results of this study detected the presence of genetic damage in peripheral blood for all individuals with MPS treated with ERT, regardless of type of MPS as depicted by tail moment results. In addition, an increased number of micronucleated cells were found in buccal cells of MPS type II patients. It was also observed an increase of other nuclear alterations closely related to cytotoxicity as depicted by the frequency of pyknosis, karyolysis and karyorrhexis in buccal mucosa cells of MPS VI patients (p < 0.05). CONCLUSION: Taken together, such results demonstrate that metabolic alterations induced by the enzymatic deficiency characteristic of MPS associated with ERT therapy can induce genotoxicity and mutagenicity in peripheral blood and buccal mucosa cells, respectively. This effect appears to be more pronounced to MPS II.


Assuntos
Núcleo Celular/patologia , Cromatina/patologia , Dano ao DNA , Fragmentação do DNA , Mucopolissacaridose II/patologia , Mucopolissacaridose IV/patologia , Mucopolissacaridose I/patologia , Adolescente , Adulto , Células Sanguíneas/patologia , Brasil , Forma do Núcleo Celular , Criança , Pré-Escolar , Análise Citogenética , Terapia de Reposição de Enzimas , Feminino , Humanos , Masculino , Mucosa Bucal/patologia , Mucopolissacaridose I/sangue , Mucopolissacaridose I/genética , Mucopolissacaridose I/terapia , Mucopolissacaridose II/sangue , Mucopolissacaridose II/genética , Mucopolissacaridose II/terapia , Mucopolissacaridose IV/sangue , Mucopolissacaridose IV/genética , Mucopolissacaridose IV/terapia , Adulto Jovem
17.
Cardiovasc Pathol ; 23(3): 145-51, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24508139

RESUMO

INTRODUCTION: The mucopolysaccharidosis syndromes are a group of lethal inherited disorders affecting multiple organ systems by the progressive deposition of glycosaminoglycan. Advances in treatment such as enzyme replacement and hematopoietic stem cell transplantation have significantly improved the outcome of these disorders. An in-depth understanding of the pathophysiology of heart disease in these disorders is essential since death from cardiac causes continues to be common. Epicardial coronary artery luminal narrowing from myointimal proliferation and glycosaminoglycan deposition is well described in severe mucopolysaccharidosis type I [Hurler syndrome, mucopolysaccharide IH] but poorly understood in other "non-Hurler" phenotypes of these disorders. Given the rarity of these conditions, autopsy specimens are uncommon. METHODS: Tissue from epicardial coronary arteries from autopsies of four patients with non-Hurler mucopolysaccharidosis (attenuated type I, type IIIA, type IIIC, and type VI) who had died after hematopoietic cell transplantation (within 1 month in three cases; after 5 years in the fourth) was examined by light microscopy. RESULTS: Unexpectedly, near-normal coronary arteries were observed in the patient with attenuated mucopolysaccharidosis type I, while the coronaries from patients with type IIIA, IIIC, and VI demonstrated classic histologic features of glycosaminoglycan deposition. The most severe findings were found in the MPS IIIC patient who had 5 years of full donor engraftment after transplantation. CONCLUSIONS: Our current understanding of the cardiac manifestations of the mucopolysaccharidoses fails to explain why near-normal coronary arteries may be observed when abnormalities would be most likely to be expected and, conversely, why significant histopathology is present when it would be least expected. Identification of downstream effects of glycosaminoglycan deposition may identify other metabolites or metabolic pathways that are important in the clinicopathologic manifestations of these diseases. SUMMARY: The mucopolysaccharidosis diseases are a group of inherited disorders affecting multiple organ systems by the progressive deposition of glycosaminoglycan. Severe coronary artery disease is well recognized in severe type I mucopolysaccharidosis (Hurler syndrome), but unexpected coronary artery disease occurs in other, "non-Hurler" mucopolysaccharidoses. Factors responsible for the development of coronary pathology in the mucopolysaccharidoses remain elusive.


Assuntos
Doença da Artéria Coronariana/patologia , Vasos Coronários/patologia , Mucopolissacaridose III/patologia , Mucopolissacaridose IV/patologia , Mucopolissacaridose I/patologia , Autopsia , Biópsia , Criança , Pré-Escolar , Doença da Artéria Coronariana/metabolismo , Vasos Coronários/química , Evolução Fatal , Feminino , Glicosaminoglicanos/análise , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Mucopolissacaridose I/metabolismo , Mucopolissacaridose I/cirurgia , Mucopolissacaridose III/metabolismo , Mucopolissacaridose III/cirurgia , Mucopolissacaridose IV/metabolismo , Mucopolissacaridose IV/cirurgia , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
18.
Mol Genet Metab ; 111(2): 205-8, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24359664

RESUMO

Mucopolysaccharidosis IVA is a lysosomal storage disorder leading to an increase in glycosaminoglycans storage. Genistein is an isoflavone capable to inhibit glycosaminoglycans production. The objective of this study was to analyze the in vitro effect of different concentrations of genistein on DNA injury in mucopolysaccharidosis IVA patients. The lower concentration tested (10 µM) showed a significant increase on DNA injury in vitro, although higher concentrations (30 µM and 50 µM) showed higher DNA damage.


Assuntos
Genisteína/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Mucopolissacaridose IV/patologia , Adolescente , Adulto , Células Cultivadas , Criança , Ensaio Cometa , Fragmentação do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Humanos , Leucócitos Mononucleares/patologia , Masculino
19.
Cuad. Hosp. Clín ; 55(2): 40-46, 2014. ilus
Artigo em Espanhol | LILACS | ID: biblio-972726

RESUMO

Se presenta el caso de un paciente de 16 años de edad, con el diagnostico de mucopolisacaridosis (MPS) tipo IV-A, con una breve revisión teórica del curso y progresión crónica de esta enfermedad multi-sistémica, que se manifiesta con amplia signo sintomatología, hallazgos de laboratorio y anomalías radiológicas. El objetivo es documentar el caso y difundir a la comunidad médica boliviana, la importancia de los errores innatos del metabolismo, consideradas enfermedades "raras", que a criterio nuestro, sufren un sub-diagnóstico debido a las pocas publicaciones científicas sobre el tema en el medio.


We report the case of a patient 16 years old with a diagnosis of mucopolysaccharidosis (MPS) type IV- A, with a brief theoretical review of chronic course and progression of this multisystem disease, which manifests with extensive signs symptoms, findings are presented, with laboratory and radiological reported abnormalities. The aim is to document the event and communicated to Bolivian medical community, the importance of inborn errors of metabolism, considered "rare" diseases, which in our opinion; suffer a sub- diagnosis because of the few Bolivian scientific publications on the topic.


Assuntos
Mucopolissacaridose IV/diagnóstico , Mucopolissacaridose IV/patologia
20.
Zhonghua Er Ke Za Zhi ; 51(6): 414-9, 2013 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-24120057

RESUMO

OBJECTIVE: Mucopolysaccharidosis (MPS) type IVA (MPS IVA) is an autosomal recessive lysosomal storage disease caused by deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS) needed to degrade glycosaminoglycanes (GAGs), accumulation of GAGs in the tissue resulting in disorder of function. So far, the small number of articles about clinical study of Chinese MPS IVA were published and only one paper about gene mutation analysis was published. This study aimed to investigate the mutation spectrum and characteristic of GALNS gene in Chinese patients with MPS IVA who were diagnosed in our hospital. METHOD: Thirty-eight patients from 36 families (male 17, female 21) were diagnosed as MPS IVA by GALNS activity determination [(0.85 ± 1.33) nmol/(17 h·mg)] and clinical symptoms during 2006-2012. The average age of diagnosis was (5.7 ± 3.6) years. Mutation analysis of GALNS gene performed performed by PCR-direct DNA sequencing for 38 patients. PCR-restriction fragment length polymorphism analysis was used for validating novel mutation, and also to assess amino acid conservation for novel missense variants in five different species. PolyPhen-2 tool was used to predict the possible impact of missense mutations on the structure and function of the human GALNS protein, etc. Analysis of GALNS activity and gene mutation in amniotic fluid were performed to provide the prenatal diagnosis for some families with MPS type IVA. RESULT: (1) Thirty-eight kinds of mutation in GALNS gene were identified in 38 patients of them, 71% were missense mutations. p. M318R was a hot-spot mutation (21%) tested. Five kinds of mutation i.e., p. P163H, p.G168L, p. A324E, p. L366P and p. F452L were only found in Chinese patients with MPS IVA. Eighteen kinds of novel mutation were detected including p. E315K, p.G304D, p.R251Q, p.Y240C, p.G161E, p.N32D, p.L390P, p. D60E, p. P420S, W403C/T404S, p.L454P, for p.W405X, p. M1I, c.409_ c.420del12, c.1176_1178del3, c.1046delG, c.1188delG and IVS9-2A>C. (2) The polymorphism of novel missense variants were ruled out by the PCR-restriction fragment length polymorphism analysis and no related mutations were found in 50 normal controls. A splice site mutation IVS9-2A>C had been validated by reverse transcription PCR direct sequencing. The amino acid of mutant position of 10 kinds of missense variants are highly conserved and only p. L454 is moderately conserved position. These missense variants were predicted to cause damage to the structure and function of human GALNS protein possibly according to the PolyPhen-2 tool, so these novel missense variants may be disease-causing mutations. (3) Prenatal diagnosis was provided for 7 families and three fetuses were diagnosed as MPS IVA. CONCLUSION: The GALNS gene mutation spectrum in Chinese patients with MPS IVA is really different from that in other countries, five kinds of mutation were only found in Chinese patients with MPS IVA. The reports of hot-spot mutation in Chinese patients were also different, and should be analyzed by more data of gene mutation analysis and epidemiological study.


Assuntos
Condroitina Sulfatases/genética , Mucopolissacaridose IV/enzimologia , Mucopolissacaridose IV/genética , Mutação , Sequência de Aminoácidos , Grupo com Ancestrais do Continente Asiático/genética , Sequência de Bases , Criança , Pré-Escolar , Condroitina Sulfatases/metabolismo , Análise Mutacional de DNA , Feminino , Genótipo , Haplótipos , Humanos , Lactente , Masculino , Mucopolissacaridose IV/patologia , Mutação de Sentido Incorreto , Reação em Cadeia da Polimerase , Conformação Proteica
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