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1.
Am J Hum Genet ; 104(5): 925-935, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-30982609

RESUMO

Colony stimulating factor 1 receptor (CSF1R) plays key roles in regulating development and function of the monocyte/macrophage lineage, including microglia and osteoclasts. Mono-allelic mutations of CSF1R are known to cause hereditary diffuse leukoencephalopathy with spheroids (HDLS), an adult-onset progressive neurodegenerative disorder. Here, we report seven affected individuals from three unrelated families who had bi-allelic CSF1R mutations. In addition to early-onset HDLS-like neurological disorders, they had brain malformations and skeletal dysplasia compatible to dysosteosclerosis (DOS) or Pyle disease. We identified five CSF1R mutations that were homozygous or compound heterozygous in these affected individuals. Two of them were deep intronic mutations resulting in abnormal inclusion of intron sequences in the mRNA. Compared with Csf1r-null mice, the skeletal and neural phenotypes of the affected individuals appeared milder and variable, suggesting that at least one of the mutations in each affected individual is hypomorphic. Our results characterized a unique human skeletal phenotype caused by CSF1R deficiency and implied that bi-allelic CSF1R mutations cause a spectrum of neurological and skeletal disorders, probably depending on the residual CSF1R function.

2.
Ann Neurol ; 64(5): 514-22, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19067373

RESUMO

OBJECTIVE: To evaluate the efficacy and safety of miglustat, concomitant with enzyme replacement therapy (ERT), in patients with Gaucher's disease type 3 (GD3). METHODS: This 24-month, phase II, open-label clinical trial of miglustat in GD3 was conducted in two phases. During the initial 12 months, patients were randomized 2:1 to receive miglustat or "no miglustat treatment." The randomized phase was followed by an optional 12-month extension phase in which all patients received miglustat. All patients received ERT during the 24-month period. The primary efficacy end points were change from baseline to months 12 and 24 in vertical saccadic eye movement velocity as determined by the peak amplitude versus amplitude regression line slope. Secondary end points included changes in neurological and neuropsychological assessments, pulmonary function tests, liver and spleen organ volumes, hematological and clinical laboratory assessments, and safety evaluations. RESULTS: Thirty patients were enrolled, of whom 21 were randomized to miglustat and 9 to "no miglustat treatment." Twenty-eight patients entered the 12-month extension phase. No significant between-group differences in vertical saccadic eye movement velocity or in the other neurological or neuropsychological evaluations were observed. Organ volumes and hematological parameters remained stable in both treatment groups, but improvement in pulmonary function and decrease of chitotriosidase levels were observed with miglustat compared with patients receiving ERT alone. INTERPRETATION: Miglustat does not appear to have significant benefits on the neurological manifestations of GD3. However, miglustat may have positive effects on systemic disease (pulmonary function and chitotriosidase activity) in addition to ERT in patients with GD3.


Assuntos
1-Desoxinojirimicina/análogos & derivados , Doença de Gaucher/tratamento farmacológico , 1-Desoxinojirimicina/administração & dosagem , Adolescente , Criança , Pré-Escolar , Determinação de Ponto Final , Inibidores Enzimáticos/administração & dosagem , Feminino , Doença de Gaucher/enzimologia , Doença de Gaucher/fisiopatologia , Glucosilceramidase/metabolismo , Hexosaminidases/metabolismo , Humanos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Pneumopatias/tratamento farmacológico , Pneumopatias/enzimologia , Masculino , Transtornos da Motilidade Ocular/tratamento farmacológico , Transtornos da Motilidade Ocular/enzimologia , Transtornos da Motilidade Ocular/fisiopatologia , Movimentos Sacádicos/efeitos dos fármacos , Movimentos Sacádicos/fisiologia , Baço/efeitos dos fármacos , Baço/enzimologia , Resultado do Tratamento , Adulto Jovem
3.
J Bone Miner Res ; 2008 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-19016590

RESUMO

Ahead of Print abstract has been withdrawn by the Publisher. This abstract has not been published by the Journal of Bone and Mineral Research and was placed online due to an error.

4.
J Am Soc Nephrol ; 18(5): 1576-83, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17409308

RESUMO

This study was performed to determine whether adult male patients with Fabry disease who demonstrate a continuing decline in renal function despite 2 to 4 yr of conventionally dosed agalsidase alfa therapy (0.2 mg/kg every other week [EOW]) show an improved slope of decline with weekly administration using the same dosage. Eleven (27%) of 41 adult male patients with Fabry disease who participated in long-term agalsidase alfa clinical trials and who had demonstrated a slope of decline in estimated GFR (eGFR) of > or =5 ml/min per 1.73 m(2)/yr while receiving long-term treatment with agalsidase alfa at the currently recommended dosage of 0.2 mg/kg, infused EOW, were enrolled in this open-label, prospective study. Patients were switched from EOW to weekly infusions and followed for an additional 24 mo. Before switching to weekly dosing, eGFR was 53.7 +/- 6.3 ml/min per 1.73 m(2) (mean +/- SEM), and mean rate of change in eGFR was -8.0 +/- 0.8 ml/min per 1.73 m(2)/yr. During the 24-mo follow-up period after switching to weekly dosing, the mean rate of change in eGFR was observed to slow to -3.3 +/- 1.4 ml/min/1.73 m(2)/yr (P = 0.01 versus EOW). After switching to weekly dosing, three patients demonstrated an improvement in eGFR and six patients demonstrated a slowing in the rate of eGFR decline; only two patients failed to improve their eGFR slope. A multiple regression model confirmed that the weekly infusion regimen was the strongest explanatory variable for the change in eGFR (P = 0.0008), with a weaker contribution from the concomitant use of angiotensin converting enzyme inhibitors/angiotensin receptor blockers (P = 0.02). These results suggest that weekly infusions of agalsidase alfa at a dosage of 0.2 mg/kg may be beneficial in the subgroup of patients who have Fabry disease and whose kidney function continues to decline after 2 to 4 yr or more of standard EOW dosing.


Assuntos
Doença de Fabry/tratamento farmacológico , Doença de Fabry/fisiopatologia , Rim/fisiopatologia , alfa-Galactosidase/administração & dosagem , Adulto , Anticorpos/análise , Relação Dose-Resposta a Droga , Esquema de Medicação , Doença de Fabry/metabolismo , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Isoenzimas/administração & dosagem , Isoenzimas/efeitos adversos , Isoenzimas/imunologia , Rim/metabolismo , Masculino , Pessoa de Meia-Idade , Proteinúria/tratamento farmacológico , Proteínas Recombinantes , Tempo , alfa-Galactosidase/efeitos adversos , alfa-Galactosidase/imunologia
5.
Pediatrics ; 118(3): 924-32, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16950982

RESUMO

CONTEXT: Fabry disease is an X-linked multisystem disorder. Enzyme-replacement therapy in adults has limited efficacy in treating major sequelae of advanced Fabry disease, such as kidney failure or stroke. This prompted a study of the safety and efficacy of enzyme replacement at an earlier stage of Fabry disease. OBJECTIVES: Our purpose with this work was to evaluate safety and to explore efficacy of enzyme treatment with agalsidase alfa in pediatric patients with Fabry disease. METHODS: We conducted a 6-month open-label study at 3 tertiary care centers with 24 children (19 boys and 5 girls) with a mean age of 11.8 (range: 6.5-18) years, to examine safety parameters, including infusion reactions and antiagalsidase alfa antibodies. RESULTS: Agalsidase alfa was well tolerated, and all of the patients completed the study. Six boys and 1 girl had mild-to-moderate infusion reactions. One boy developed transient immunoglobulin G antibodies against agalsidase alfa. The boys showed a significant reduction in plasma globotriaosylceramide on treatment. Mean estimated glomerular filtration rate, cardiac structure, and function were normal and did not change over 26 weeks. Heart rate variability, as determined by 2-hour ambulatory monitoring, was decreased in the boys compared with the girls at baseline. All indices of heart rate variability improved significantly in the boys. Three patients with anhidrosis, as determined by quantitative sudomotor axon reflex testing, developed sweating. Six of 11 patients could reduce or cease their use of antineuropathic analgesics. CONCLUSIONS: Enzyme replacement with agalsidase alfa was safe in this study. The exploratory efficacy analysis documented increased clearance of globotriaosylceramide and improvement of autonomic function. Prospective long-term studies are needed to assess whether enzyme replacement initiated early in patients with Fabry disease is able to prevent major organ failure in adulthood.


Assuntos
Doença de Fabry/tratamento farmacológico , alfa-Galactosidase/uso terapêutico , Adolescente , Formação de Anticorpos , Sistema Nervoso Autônomo/efeitos dos fármacos , Criança , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Isoenzimas/efeitos adversos , Isoenzimas/uso terapêutico , Masculino , Proteínas Recombinantes , Resultado do Tratamento , alfa-Galactosidase/efeitos adversos
6.
Nephrol Dial Transplant ; 21(2): 345-54, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16204287

RESUMO

BACKGROUND: Fabry disease is an X-linked disorder of glycosphingolipid catabolism that is the result of an intracellular deficiency in the lysosomal enzyme alpha-galactosidase A (alpha-Gal A). This enzymatic defect results in the accumulation of globotriaosylceramide (Gb(3)) within cells and causes progressive neurological, cardiovascular and renal dysfunction. Our objective is to describe the safety and renal effects of long-term enzyme replacement therapy. METHODS: This was a single centre, prospective open-label treatment trial in 25 adult male Fabry patients who had completed a 6-month randomized placebo-controlled study and subsequently enrolled in an open-label extension study. Patients were treated every other week with agalsidase alfa (0.2 mg/kg) infused intravenously over 40 min. The main outcome measures were safety, antibody response and renal glomerular filtration rate (GFR). RESULTS: During the 4-4.5 years of enzyme replacement therapy, all eligible subjects were able to transition to home therapy. Eight patients developed persistent IgG antibodies to agalsidase alfa, but IgE antibodies were not detected in any patient. The development of IgG antibodies appeared not to affect any clinical end points. Estimated GFR remained stable in subgroups of patients with Stage I (GFR >90 ml/min) or Stage II (GFR 60-89 ml/min) chronic kidney disease at baseline. In contrast, in the subgroup of patients with Stage III chronic kidney disease (GFR 30-59 ml/min), the slope of the decline in GFR was reduced compared with comparable historical controls, suggesting that enzyme replacement therapy was slowing the decline of renal function in this susceptible population. CONCLUSIONS: Long-term enzyme replacement therapy with agalsidase alfa is safe and may slow the progressive decline in renal function that was commonly observed in adult males with Fabry disease.


Assuntos
Doença de Fabry/tratamento farmacológico , Taxa de Filtração Glomerular/efeitos dos fármacos , alfa-Galactosidase/administração & dosagem , Adulto , Serviços de Assistência Domiciliar , Humanos , Infusões Intravenosas , Isoenzimas/administração & dosagem , Isoenzimas/farmacologia , Masculino , Estudos Prospectivos , Proteínas Recombinantes , Segurança , Fatores de Tempo , alfa-Galactosidase/farmacologia
7.
Clin Chem ; 51(11): 2031-42, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16155092

RESUMO

BACKGROUND: A biomarker for the diagnosis of childhood-onset ataxia and central nervous system hypomyelination (CACH)/vanishing white matter disease (VWM) would have clinical utility and pathophysiologic significance. METHODS: We used 2-dimensional gel electrophoresis/mass spectrometry to compare the cerebrospinal fluid proteome of patients with mutation-confirmed CACH/VWM with that of unaffected controls. We characterized selected spots by in-gel digestion, matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry, and nanospray Fourier transform mass spectrometry. RESULTS: A specific transferrin spot pattern was detected in the CSF samples of the CACH/VWM group (n = 7), distinguishing them from the control group (n = 23) and revealing that patients with CACH/VWM have a deficiency of the asialo form of transferrin usually present in healthy cerebrospinal fluid. The glycopeptide structure, determined from isolated transferrin spots by use of in-gel digestion and extraction, was found to be consistent with earlier reports. CONCLUSIONS: The transferrin isoform abnormality in the cerebrospinal fluid of patients with CACH/VWM appears unique and is a potential clinical diagnostic biomarker. The rapid, efficient diagnosis of this disorder would have a significant impact on clinical studies exploring new strategies for the management and treatment of this disease.


Assuntos
Assialoglicoproteínas/líquido cefalorraquidiano , Ataxia/líquido cefalorraquidiano , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/líquido cefalorraquidiano , Transferrina/análogos & derivados , Assialoglicoproteínas/química , Ataxia/complicações , Criança , Eletroforese em Gel Bidimensional , Glicopeptídeos/química , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/complicações , Humanos , Espectrometria de Massas , Isoformas de Proteínas/líquido cefalorraquidiano , Transferrina/líquido cefalorraquidiano , Transferrina/química
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