RESUMO
Cholesteryl ester storage disease (CESD) is a rare autosomal recessive disease caused by mutations in LIPA. Here we describe two different clinical presentations of this disease: one case with a clear phenotype of familial hypercholesterolaemia and one case with hepatosplenomegaly from childhood onwards. These two cases exemplify the diversity of clinical phenotypes of patients with CESD. Knowledge on the phenotypic variability of the disease is of clinical relevance in light of enzyme replacement therapy (sebelipase alpha) for patients with mutations in LIPA, which is currently under development.
Assuntos
Doença do Armazenamento de Colesterol Éster/genética , DNA/genética , Hepatomegalia/genética , Hipercolesterolemia/genética , Mutação , Esplenomegalia/genética , Esterol Esterase/genética , Adulto , Doença do Armazenamento de Colesterol Éster/metabolismo , Análise Mutacional de DNA , Feminino , Hepatomegalia/metabolismo , Humanos , Hipercolesterolemia/metabolismo , Masculino , Fenótipo , Esplenomegalia/metabolismo , Esterol Esterase/metabolismo , Adulto JovemRESUMO
Gaucher disease (GD) is caused by deficiency of the enzyme glucocerebrosidase catalysing the regular lysosomal degradation of glucosylceramide. In the common non-neuropathic variant of GD, glucosylceramide-laden macrophages (Gaucher cells) accumulate in various tissues. Gaucher cells secrete chitotriosidase, an active chitinase, resulting in increased plasma chitotriosidase levels, which can be sensitively monitored by an enzyme activity assay. Plasma chitotriosidase is a rough estimate of body burden of Gaucher cells. Non-neuronopathic GD is presently treated by enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). We addressed the question whether plasma chitotriosidase acts as (predictive) marker of clinical manifestations in non-neuronopathic GD patients receiving treatment. Reductions in plasma chitotriosidase during therapy correlated with corrections in liver and spleen volumes and showed positive trends with improvements in haemoglobin and platelet count and bone marrow composition. The occurrence of long-term complications and associated conditions such as multiple myeloma, bone complications, Parkinson's disease, hepatocellular carcinoma and pulmonary hypertension positively correlated with the plasma chitotriosidase level pre-therapy, the average plasma chitotriosidase during 3 years of ERT and the residual plasma chitotriosidase after 2 years of ERT. In summary, plasma chitotriosidase is a valuable marker in the assessment and follow-up of GD patients.
Assuntos
Terapia de Reposição de Enzimas/métodos , Doença de Gaucher/tratamento farmacológico , Glucosilceramidase/uso terapêutico , Hexosaminidases/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Criança , Progressão da Doença , Feminino , Seguimentos , Glucosilceramidas/metabolismo , Humanos , Fígado/metabolismo , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Baço/metabolismo , Resultado do Tratamento , Adulto JovemRESUMO
CONTEXT: Gaucher disease (GD) is a lysosomal storage disorder characterized by abundant presence of macrophages. Bone complications and low bone density are believed to arise from enhanced bone resorption mediated through macrophage-derived factors. OBJECTIVE: The objective of the study was to investigate the relationship between bone turnover and bone complications in GD. DESIGN: This was a retrospective cohort study and review of the literature. PATIENTS: Forty adult type I GD patients were included in the study. OUTCOME MEASURES: Levels of the bone-resorption marker, type 1 collagen C-terminal telopeptide, and two bone-formation markers, N-terminal propeptide of type 1 procollagen and osteocalcin, were investigated in relation to clinical bone disease, measures of overall disease severity, and imaging data representing bone marrow infiltration. RESULTS: Osteocalcin was decreased in 50% of our patients (median 0.35 nmol/liter, normal 0.4-4.0), indicating a decrease of bone formation. Type 1 collagen C-terminal telopeptide and N-terminal propeptide of type 1 procollagen were within the normal range for most patients. Osteocalcin concentration was negatively correlated to measures of overall disease severity and positively correlated with imaging data (correlation coefficient 0.423; P = 0.025), suggesting a relation with disease severity. A review of the literature revealed variable outcomes on bone resorption markers but more consistent abnormalities in bone formation markers. Two of three reports conclude that bone-formation parameters increase in response to enzyme therapy, but none describes an effect on bone-resorption markers. CONCLUSIONS: In contrast to earlier hypotheses, we propose that in GD patients, primarily a decrease in bone formation causes an imbalance in bone remodeling.
Assuntos
Reabsorção Óssea/sangue , Colágeno Tipo I/sangue , Doença de Gaucher/sangue , Osteocalcina/sangue , Osteogênese , Peptídeos/sangue , Pró-Colágeno/sangue , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
Fabry disease is an X-linked lysosomal storage disorder due to deficiency of alpha-Galactosidase A, causing accumulation of globotriaosylceramide and elevated plasma globotriaosylsphingosine (lysoGb3). The diagnostic value and clinical relevance of plasma lysoGb3 concentration was investigated. All male and adult female patients with classical Fabry disease could be discerned by an elevated plasma lysoGb3. In young pre-symptomatic Fabry heterozygotes, lysoGb3 levels can be normal. Individuals carrying the R112H and P60L mutations, without classical Fabry symptoms, showed no elevated plasma lysoGb3. Multiple regression analysis showed that there is no correlation of plasma lysoGb3 concentration with total disease severity score in Fabry males. However, plasma lysoGb3 concentration did correlate with white matter lesions (odds ratio: 6.1 per 100 nM lysoGb3 increase (95% CI: 1.4-25.9, p=0.015). In females, plasma lysoGb3 concentration correlated with overall disease severity. Furthermore, plasma lysoGb3 level was related to left ventricular mass (19.5+/-5.5 g increase per 10 nM lysoGb3 increase; p=0.001). In addition, it was assessed whether lifetime exposure to lysoGb3 correlates with disease manifestations. Male Fabry patients with a high lysoGb3 exposure (>10,000 U), were moderately or severely affected, only one mildly. Female patients with a low exposure (<1000 U) were asymptomatic or mildly affected. A large proportion of the females with an exposure >1000 U showed disease complications. Plasma lysoGb3 is useful for the diagnosis of Fabry disease. LysoGb3 is an independent risk factor for development of cerebrovascular white matter lesions in male patients and left ventricular hypertrophy in females. Disease severity correlates with exposure to plasma lysoGb3.
Assuntos
Doença de Fabry/sangue , Doença de Fabry/diagnóstico , Glicolipídeos/sangue , Esfingolipídeos/sangue , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Doença de Fabry/classificação , Doença de Fabry/genética , Feminino , Glicolipídeos/análise , Glicolipídeos/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/fisiologia , Valor Preditivo dos Testes , Prognóstico , Índice de Gravidade de Doença , Esfingolipídeos/análise , Esfingolipídeos/metabolismo , Adulto Jovem , alfa-Galactosidase/genética , alfa-Galactosidase/metabolismoRESUMO
OBJECTIVE: A low plasma high-density lipoprotein cholesterol (HDL-c) concentration is an important risk factor for the development of atherosclerotic cardiovascular disease. HDL-c levels are abnormally low in type I Gaucher disease (GD) patients. The aim of this study was to determine whether GD is associated with premature atherosclerosis. METHODS: Lipid profiles, apolipoproteins, and carotid artery intima-media thickness (cIMT) were analyzed in 40 type I GD patients, 34 carriers and 41 control subjects. cIMT is a non-invasive validated biomarker for the status of atherosclerosis and present and future cardiovascular disease risk. RESULTS: Compared to control subjects, patients showed decreased HDL-c (1.1+/-0.3 mmol/L) as well as mildly decreased low-density lipoprotein cholesterol (LDL-c) levels (2.8+/-0.7 mmol/L), with an increased ApoB/ApoA1 ratio. In carriers, HDL-c levels were normal, but LDL-c levels were decreased (2.7+/-0.8 mmol/L). Mean cIMT measurements were not different in the three study groups (patients: 0.63+/-0.1mm versus carriers: 0.64+/-0.1mm versus control subjects: 0.65+/-0.1 mm). CONCLUSION: In Gaucher disease low HDL-c levels do not lead to premature atherosclerosis as assessed by cIMT measurement. This indicates that the inverse relationship between levels of HDL-c and risk of cardiovascular disease in the general population may not be present in all conditions characterised by low HDL-c levels.
Assuntos
Doenças Cardiovasculares/etiologia , HDL-Colesterol/sangue , Doença de Gaucher/sangue , Adulto , Idoso , Apolipoproteína A-I/sangue , Apolipoproteínas B/sangue , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico por imagem , Artéria Carótida Primitiva/diagnóstico por imagem , Artéria Carótida Interna/diagnóstico por imagem , Estudos de Casos e Controles , LDL-Colesterol/sangue , Estudos Transversais , Regulação para Baixo , Feminino , Doença de Gaucher/complicações , Doença de Gaucher/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , UltrassonografiaRESUMO
The concentrations of plasma glucosylceramide (GlcCer) and ceramide (Cer) were determined in a cohort of type 1 Gaucher disease patients. In plasma of untreated patients, GlcCer concentrations were on average 3-fold increased (median Gaucher: 17.5 nmol/ml, range: 6.5-45.5 (n=27); median control: 5.9 nmol/ml, range 4.0-8.6 (n=15)). Although plasma Cer concentrations were not significantly different between the two groups (median Gaucher: 7.2 nmol/ml, range: 4.2-10.9 (n=27); median control: 7.8 nmol/ml, range 5.7-11.9 (n=15)) in individual patients plasma GlcCer/Cer ratio yields slightly better discrimination between Gaucher disease patients and normal individuals than the GlcCer levels. Positive correlations were detected between plasma GlcCer concentration and GlcCer/Cer ratio and severity of disease, plasma chitotriosidase and CCL18, surrogate markers of storage cells. Gaucher disease is treated by enzyme replacement and substrate reduction therapy. Both therapies were found to result in decreases in plasma GlcCer already within 6 months, without causing abnormal plasma GlcCer or Cer concentrations. The corrections in plasma GlcCer were most robust in patients with a pronounced clinical response. In conclusion, plasma GlcCer concentration and GlcCer/Cer ratio is of value to monitor Gaucher disease manifestation and response to therapeutic intervention.
Assuntos
Ceramidas/sangue , Doença de Gaucher/sangue , Doença de Gaucher/terapia , Glucose/metabolismo , Adolescente , Adulto , Biomarcadores , Feminino , Doença de Gaucher/patologia , Humanos , Metabolismo dos Lipídeos , Masculino , Pessoa de Meia-Idade , FenótipoAssuntos
Doença de Fabry/genética , Mutação , alfa-Galactosidase/genética , Saúde da Família , HumanosRESUMO
BACKGROUND: Fabry disease (OMIM 301500) is an X-linked lysosomal storage disorder with characteristic vascular, renal, cardiac and cerebral complications. Globotriaosylceramide (Gb(3)) accumulates in Fabry patients as a result of alpha-galactosidase A deficiency. The phenotypic variability is high, but the relationship between clinical symptoms in individual Fabry patients has not been uniformly documented. Also, the relation between the most prominent biochemical abnormalities, elevated Gb(3) levels in plasma and urine, and clinical symptoms is not firmly established. METHODS: Clinical and biochemical characteristics of 96 (25 deceased) Dutch Fabry patients were collected retrospectively and before the initiation of enzyme therapy. RESULTS: Clinical assessment revealed that median life expectancy was 57 years for male and 72 years for female patients. Cerebral complications, acroparaesthesias and gastrointestinal complications, but not cardiac and auditory complications, were all seen more frequently in male than female patients. Glomerular filtration rate (GFR) was highly variable in male patients, including 2 patients with GFR < 30 ml/min, but median GFR did not differ between males and females (103 and 101 ml/min, respectively). Hyperfiltration was more frequently observed in the female patient group. Microalbuminuria was present in 60% of males and 45% of females. No specific pattern of combined symptoms existed except for a relationship between left ventricular hypertrophy (LVH) and cerebral complications (males 36%, females 32%), or proteinuria (males 35%, females 31%). Gb(3) was found to be more elevated in plasma samples from male (n = 26; median 6.27 micromol/L (1.39-9.74)) than female Fabry patients (n = 37; median 2.16 (0.77-4.18)). This was also observed for urinary Gb(3): males (n = 22) median 1851 nmol/24 h (40-3724); females (n = 29) median 672 (86-2052). Plasma and urinary Gb(3) levels correlated with each other in both males (r = 0.4, p = 0.05) and females (r = 0.4, p = 0.03), but no correlation between elevated Gb(3) levels and clinical symptoms could be detected. CONCLUSION: Analysis of the characteristics of the Dutch Fabry cohort has revealed that a limited relationship between various disease manifestations exists and that individual symptoms do not correlate with elevated urinary or plasma Gb(3) levels, limiting their value as surrogate disease markers.
Assuntos
Doença de Fabry/diagnóstico , Doença de Fabry/genética , Triexosilceramidas/sangue , Triexosilceramidas/urina , Adolescente , Idoso , Estudos de Coortes , Feminino , Taxa de Filtração Glomerular , Humanos , Hipertrofia Ventricular Esquerda/diagnóstico , Masculino , Pessoa de Meia-Idade , Países Baixos , Fenótipo , Qualidade de Vida , Estudos Retrospectivos , Fatores Sexuais , Inquéritos e QuestionáriosRESUMO
Increased plasma chitotriosidase is a well established surrogate marker for the occurrence of lipid-laden macrophages in the glycosphingolipidosis Gaucher disease. The complete lack of surrogate markers for Fabry disease, X-linked globotriaosylceramidosis stemming from deficiency in the lysosomal alpha-galactosidase A (AGA), prompted us to study chitotriosidase in this disorder. In male Fabry patients plasma chitotriosidase is significantly elevated, consistent with the presence of lipid-laden macrophages in several tissues. Increased levels are detectable at very young age and precede clinical manifestations. No strict correlation exists with severity of disease manifestations. Upon therapy with either of the two available recombinant AGA preparations, plasma chitotriosidase levels are nicely normalized in male Fabry patients. However, in patients developing neutralizing antibodies towards AGA, reduction in plasma chitotriosidase is hampered. In sharp contrast to the situation in male patients, females heterozygous for AGA deficiency show no significantly elevated plasma chitotriosidase. This suggests that circulating endogenous AGA in heterozygotes is sufficient to supplement enzyme-deficient macrophages. In conclusion, for the first time a biological marker for lipid-laden cells in Fabry patients is demonstrated; elevated plasma chitotriosidase levels reflecting lipid-laden macrophages. Corrections in this marker illustrate the efficacy of enzyme replacement therapy in clearing the lipid accumulation in this particular cell type.
Assuntos
Doença de Fabry/enzimologia , Doença de Fabry/terapia , Hexosaminidases/sangue , Metabolismo dos Lipídeos , Macrófagos/metabolismo , Adolescente , Adulto , Distribuição por Idade , Anticorpos/imunologia , Biomarcadores , Criança , Doença de Fabry/sangue , Doença de Fabry/patologia , Feminino , Fibroblastos/imunologia , Heterozigoto , Humanos , Células de Kupffer/ultraestrutura , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Testes de Neutralização , alfa-Galactosidase/imunologiaRESUMO
UNLABELLED: The value of biomarkers in the clinical management of lysosomal storage diseases is best illustrated by the present use of plasma chitotriosidase levels in the diagnosis and monitoring of Gaucher disease. The enzyme chitotriosidase is specifically produced and secreted by the pathological storage macrophages (Gaucher cells). Plasma chitotriosidase levels are elevated on average 1000-fold in symptomatic patients with Gaucher disease and reflect the body burden on storage cells. Changes in plasma chitotriosidase reflect changes in clinical symptoms. Monitoring of plasma chitotriosidase levels is nowadays commonly used in decision making regarding initiation and optimization of costly therapeutic interventions (enzyme replacement therapy or substrate reduction therapy). A novel substrate has been developed that further facilitates the measurement of chitotriosidase in plasma samples. Moreover, an alternative Gaucher-cell marker, CCL18, has been very recently identified and can also be employed to monitor the disease, particularly in those patients lacking chitotriosidase due to a genetic mutation. There is a need for comparable surrogate markers for other lysosomal storage diseases and the search for such molecules is an area of intense investigation. CONCLUSION: The use of biomarkers can provide valuable insight into the molecular pathogenesis of LSDs, such as Gaucher disease and Fabry disease.
Assuntos
Quimiocinas CC/genética , Doença de Gaucher , Hexosaminidases/metabolismo , Biomarcadores , Doença de Gaucher/enzimologia , Doença de Gaucher/genética , Doença de Gaucher/fisiopatologia , Humanos , Doenças por Armazenamento dos Lisossomos/diagnóstico , Doenças por Armazenamento dos Lisossomos/fisiopatologiaAssuntos
Mucolipidoses/genética , Mutação , Transferases (Outros Grupos de Fosfato Substituídos)/genética , Adolescente , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA , Éxons , Genoma Humano , Humanos , Íntrons , Mucolipidoses/diagnóstico , Mucolipidoses/patologia , Subunidades Proteicas/genéticaRESUMO
The GLUT-1 deficiency is a metabolic disorder caused by a defect in glucose transport across the blood-brain barrier as a result of a defect in the glucose-transport protein. Patients present with epileptic seizures, delayed development, ataxia and hypotonia, and in many cases acquired microcephaly. In most patients, treatment with a ketogenic diet proved to be successful in controlling the epilepsy. We report a 9-year-old boy with retardation and ataxia, but without epilepsy, caused by GLUT-1 deficiency, proven biochemically and by DNA analysis. Treatment with a medium-chain triglyceride ketogenic diet had a beneficial effect.
Assuntos
Erros Inatos do Metabolismo dos Carboidratos/genética , Epilepsia/genética , Proteínas de Transporte de Monossacarídeos/deficiência , Proteínas de Transporte de Monossacarídeos/genética , Ataxia/genética , Glicemia/metabolismo , Erros Inatos do Metabolismo dos Carboidratos/dietoterapia , Erros Inatos do Metabolismo dos Carboidratos/psicologia , Criança , DNA/genética , Análise Mutacional de DNA , Eritrócitos/metabolismo , Glucose/metabolismo , Transportador de Glucose Tipo 1 , Humanos , Deficiência Intelectual/genética , Testes de Inteligência , Ácido Láctico/sangue , Ácido Láctico/líquido cefalorraquidiano , Masculino , Triglicerídeos/uso terapêuticoRESUMO
A female patient, the first child of healthy non-consanguineous parents, presented at the age of 16 months with delayed motor development and facial dysmorphism. In addition she displayed a palatoschizis and multiple skeletal abnormalities as hypoplastic scapulae, hypoplastic os ilea, and an extreme cervical kyphosis. Biochemical investigation of urine revealed no abnormalities except for the presence of large amounts of reducing sugars. The sugar was identified as L-arabinose, which mainly originated from fruit formula in her diet. In addition highly elevated levels of L-arabitol were found in urine, plasma, and cerebrospinal fluid. Although little is known about human arabinose metabolism, we presume that L-arabitol dehydrogenase is deficient in our patient. As polyols are potentially toxic to the central nervous system there could be deleterious long-term effects of this disorder. Withdrawal of dietary fruit led to normalization of polyol levels. The above-mentioned clinical abnormalities are probably not related to this new inborn error of metabolism and should be considered as a separate entity.