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Biomedical subjects

Roberto Giugliani

Publications and source records attributed to Roberto Giugliani.

At least 37 records · Page 2Linked to original sources
PubMed2005

Threshold effect of urinary glycosaminoglycans and the walk test as indicators of disease progression in a survey of subjects with Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome).

A cross-sectional survey in individuals affected with the lysosomal storage disease Mucopolysaccharidosis VI (MPS VI) was conducted to establish demographics, urinary glycosaminoglycan (GAG) levels, and clinical progression of the disease. The survey evaluated 121 bona fide MPS VI-affected individuals over the age of 4 years from 15 countries across the Americas, Europe, and Australasia representing greater than 10% of the estimated world prevalence of the disease. A medical history, complete physical exam, urinary GAG determination, and assessment of several clinical measures related to physical endurance, pulmonary function, joint range of motion, strength, and quality of life were completed for each participant. Although a wide variation in clinical presentation was observed, several general findings were obtained reflecting progression of the disease. Impaired physical endurance, as measured by the distance achieved in a 6-min walk, could be demonstrated across all age groups of MPS VI-affected individuals. High urinary GAG values (>200 mug/mg creatinine) were associated with an accelerated clinical course comprised of age-adjusted short stature and low body weight, impaired endurance, compromised pulmonary function, and reduced joint range of motion. An unexpected result was the predominance of urinary GAG values <100 mug/mg creatinine for those participants over the age of 20 years. Pending the collection of longitudinal data, these results suggest that urinary GAG levels predict clinical morbidity, and longer-term survival is associated with urinary GAG levels below a threshold of 100 mug/mg creatinine.

Adolescent↗
PubMed2005

G(M1)-ganglioside degradation and biosynthesis in human and murine G(M1)-gangliosidosis.

BACKGROUND: Gangliosides are building blocks of cell membranes and their biosynthesis and degradation have been extensively studied in the past. Regulation of the metabolism of these glycolipids controls fundamental cell functions. G(M1)-gangliosidosis, a neurodegenerative glycosphingolipid storage disease, is caused by deficiency of lysosomal beta-galactosidase with consequent disruption of the normal degradative pathway of G(M1)-ganglioside. We studied the impact of G(M1)-ganglioside accumulation on its biosynthetic enzyme in cells and tissues from human patients and from the G(M1)-gangliosidosis mouse model. METHODS: We tested the qualitative and quantitative pattern of gangliosides by thin layer chromatography and N-acetylneuraminic acid dosage, respectively. Regulation of G(M1)-ganglioside biosynthesis was evaluated by G(M1) synthase assay in human and murine samples. RESULTS: G(M1)-ganglioside accumulation has an inhibitory effect on the human but not on the mouse G(M1) synthase. We present evidence that G(M1) synthase activity in human and murine cells are regulated by different mechanisms. CONCLUSIONS: Alternative pathways in the mouse may account for these results and possibly explain some of the phenotypical differences between the human and mouse forms of this disorder.

Animals↗
PubMed2005

Ontogenetic changes in serum S100B in Down syndrome patients.

BACKGROUND: It has been shown that Down syndrome (DS) patients have elevated S100B levels in brain tissue. DESIGN: Measurements of S100B were performed in serum samples from 48 DS patients and 42 ostensibly healthy age-matched controls. RESULTS: We observed higher levels of S100B in the DS group than in the control group. Moreover, serum S100B in DS patients was not age-dependent as it is in normal individuals. CONCLUSION: The higher levels of S100B in DS patients may reflect a general and persistent increase in the extracellular space and may be associated with neurodegenerative lesions observed in DS patients.

Aging↗
PubMed2005

Direct comparison of measures of endurance, mobility, and joint function during enzyme-replacement therapy of mucopolysaccharidosis VI (Maroteaux-Lamy syndrome): results after 48 weeks in a phase 2 open-label clinical study of recombinant human N-acetylgalactosamine 4-sulfatase.

OBJECTIVE: Mucopolysaccharidosis VI (MPS VI; Maroteaux-Lamy syndrome) is a lysosomal storage disease caused by a deficiency of the enzyme N-acetylgalactosamine 4-sulfatase (ASB). This enzyme deficiency leads to a progressive disorder with multiple tissue and organ involvement. The disease is rare and is heterogeneous in its clinical presentation and progression. A potential treatment for this disease exists in the form of enzyme-replacement therapy (ERT) with recombinant human ASB (rhASB), and a phase 1/2 randomized, double-blind, 2-dose (0.2 and 1 mg/kg) study in 6 patients showed the treatment at 48 weeks to be well tolerated. Greater biochemical efficacy based on a urine glycosaminoglycan occurred in the high-dose (1 mg/kg) group, and functional improvement seemed greater in patients in the high-dose group with rapidly advancing disease. On the basis of the phase 1/2 results, a phase 2, open-label study in patients with rapidly advancing disease was initiated primarily to evaluate efficacy variables that measure endurance, mobility, and joint function in a larger group of patients. METHODS: This was an open-label, multinational study of 10 MPS VI patients who received 48 weekly intravenous treatments with 1.0 mg/kg rhASB and had assessments of biochemical and clinical responses at regular intervals. RESULTS: After 24 weeks of treatment, each patient on average experienced a 155-m (98%) improvement in the 12-minute walk, a 64-m (62%) improvement at the 6-minute time point of the 12-minute walk, and a 48-stair (110%) gain in the 3-minute stair climb versus the baseline mean values. Additional improvements after 48 weeks of treatment were observed, including mean values of 211 m (138%) in the 12-minute walk, 75 m (80%) at the 6-minute time point of the 12-minute walk, and 61-stair (147%) gain in the 3-minute stair climb versus the baseline mean values. Joint Pain and Stiffness Questionnaire scores improved by at least 50% by week 24 and were maintained at week 48, whereas there were only small improvements in active shoulder range of motion (<10 degrees ) and in the time taken to stand, walk, and turn starting from a seated position (Expanded Timed Get-Up and Go test). Improvement in pulmonary function based on forced vital capacity and forced expiratory volume at 1 minute in the absence of growth was observed in 3 of 6 patients, and the observed gains occurred in the 24- to 48-week treatment interval. A mean decrease of 76% in urinary excretion of glycosaminoglycans indicated that a satisfactory biochemical response was achieved and the ERT was well tolerated. CONCLUSIONS: The results suggest that a 12-minute walk extends the dynamic range of the conventional 6-minute walk and, along with the 3-minute stair climb, provide a robust approach to documenting the improvement in endurance in MPS VI patients who undergo ERT with rhASB.

Adolescent↗
PubMed2004

Specificity and sensitivity of S100B levels in amniotic fluid for Down syndrome diagnosis.

Down syndrome (DS) is the most common chromosomal abnormality and is associated with an extra copy of the chromosome 21. Although several markers are commonly used during pregnancy for the screening of DS, the definitive diagnosis is based on karyotype after amniocentesis, which is an expensive and laborious analysis. S100B is an astrocyte protein which had its gene mapped to the long arm of chromosome 21. Previous preliminary reports have found increased levels of this protein in the amniotic fluid of DS gestations. Aiming to achieve a simpler and cheaper test then karyotype to perform prenatal diagnosis of DS, here we have extended our previous studies and evaluated the real usefulness of amniotic S100B measurement for prenatal DS diagnosis. We have measured S100B in amniotic fluid of 96 pregnancies with DS and of 50 normal pregnancies. Pregnancies with DS presented significantly higher amniotic fluid S100B levels (M = 1.16 ng/mL; IQ = 0.83/1.78) than normal pregnancies (M = 0.51 ng/mL; IQ = 0.38/0.83) (p < 0.0001). A receiver operating characteristic (ROC) curve was performed to evaluate the sensitivity and specificity of S100B for DS diagnosis, and presented an area under the curve (AUC) of 0.82, indicating that S100B could be a reliable marker of DS. Moreover, values above 1.67 ng/mL were present only in DS fetuses, representing about 30% of affected pregnancies. However, as an overlap of values was observed between normal and DS gestations, we concluded that amniotic S100B alone is not a good test to discard DS diagnosis.

Adult↗
PubMed2004

Identification of a common mutation in mucopolysaccharidosis IVA: correlation among genotype, phenotype, and keratan sulfate.

Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disorder caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Mutation screening of the GALNS was performed by genomic PCR and direct sequence analyses in 20 MPS IVA patients from Latin America. In this study, 12 different gene mutations including nine unreported ones were identified in 16 severe and four attenuated patients and accounted for 90.0% of the unrelated mutant alleles. The gene alterations were missense mutations except one insertion. Six recurrent mutations, p.A75G, p.G116S, p.G139S, p.N164T, p.R380S, and p.R386C, accounted for 5.0, 10.0, 5.0, 7.5, 5.0, and 32.5% of the unrelated mutant alleles, respectively. The p.R386C mutation was identified in all Latin American populations studied. Eleven mutations correlated with a severe form, while one mutation, p.R380S, was associated with an attenuated form. MPS IVA patients had an elevation of urine and plasma keratan sulfate (KS) concentrations compared with those of the age-matched control. KS concentrations in severe patients were higher than those in attenuated patients. These data provide evidence for extensive allelic heterogeneity and presence of a common mutation in Latin American patients. Accumulation of mutations with clinical description and KS concentration will lead us to predict clinical severity of the patient more precisely.

Adolescent↗
PubMed2004

Allelic heterogeneity in the COH1 gene explains clinical variability in Cohen syndrome.

Cohen syndrome is a rare autosomal recessive disorder with a variable clinical picture mainly characterized by developmental delay, mental retardation, microcephaly, typical facial dysmorphism, progressive pigmentary retinopathy, severe myopia, and intermittent neutropenia. A Cohen syndrome locus was mapped to chromosome 8q22 in Finnish patients, and, recently, mutations in the gene COH1 were reported in patients with Cohen syndrome from Finland and other parts of northern and western Europe. Here, we describe clinical and molecular findings in 20 patients with Cohen syndrome from 12 families, originating from Brazil, Germany, Lebanon, Oman, Poland, and Turkey. All patients were homozygous or compound heterozygous for mutations in COH1. We identified a total of 17 novel mutations, mostly resulting in premature termination codons. The clinical presentation was highly variable. Developmental delay of varying degree, early-onset myopia, joint laxity, and facial dysmorphism were the only features present in all patients; however, retinopathy at school age, microcephaly, and neutropenia are not requisite symptoms of Cohen syndrome. The identification of novel mutations in COH1 in an ethnically diverse group of patients demonstrates extensive allelic heterogeneity and explains the intriguing clinical variability in Cohen syndrome.

Abnormalities, Multiple↗
PubMed2004

Development and testing of new screening method for keratan sulfate in mucopolysaccharidosis IVA.

Mucopolysaccharidosis IVA (MPS IVA), a progressive lysosomal storage disease, causes skeletal dysplasia through excessive storage of keratan sulfate (KS). We developed an ELISA-sandwich assay that used a MAb specific to KS. Forty-five blood and 59 urine specimens from MPS IVA patients (ages 1-65 y) were analyzed to determine whether KS concentration is a suitable marker for early diagnosis and longitudinal assessment of disease severity. Blood specimens were obtained from patients categorized as phenotypically severe (n = 36) and milder (n = 9). Urine specimens were also analyzed from patients categorized as severe (n = 56) and milder (n = 12), respectively. Blood KS levels (101-1525 ng/mL) in MPS IVA patients were two to eight times higher than those in age-matched controls (15-323 ng/mL). It was found that blood KS level varied with age and clinical severity. Blood KS levels in both MPS IVA and controls peaked between 5 and 10 y of age (mean, 776 versus 234 ng/mL, respectively). Blood levels in severe MPS IVA were 1.5 times higher than in the milder form. In contrast to blood, urine KS levels in both MPS IVA and controls peaked between 1 and 5 y (15.3 versus 0.26 mg/g creatinine), and thereafter declined with age. Urine KS level also varied with age and clinical severity, and the severe MPS IVA phenotype was associated with 6.7 times greater urine KS excretion than the milder one. These findings indicate that the new assay for blood or urine KS may be suitable for early diagnosis and longitudinal assessment of disease severity in MPS IVA.

Adolescent↗
PubMed2004

Metabolic effects and the methylenetetrahydrofolate reductase (MTHFR) polymorphism associated with neural tube defects in southern Brazil.

BACKGROUND: The importance of metabolic factors in neural tube defects (NTDs) has been the focus of many investigations. Several authors have suggested that abnormalities in homocysteine metabolism, such as hyperhomocysteinemia, folate deficiency, and low vitamin B12, may be responsible for these malformations and that both nutritional factors and genetic abnormalities are associated with them. METHODS: We conducted a case-control study to investigate the influence of biochemical and genetic factors in NTDs in infants in southern Brazil. Levels of folate, vitamin B12, total homocysteine (t-Hcy) and the 677C>T and 1298A>C polymorphisms of the MTHFR gene were analyzed in 41 NTD child-mother pairs and 44 normal child-mother control pairs. RESULTS: Subjects in the case group had a higher mean blood folate level than those in the control group. The level of vitamin B12 was lower in mothers in the NTD group than in control mothers (p = 0.004). The level of t-Hcy was not different in the two groups, but t-Hcy and vitamin B12 were correlated (p = 0.002). There was no difference in the genotype distribution for 677C>T and 1298A>C polymorphisms of MTHFR in the case and control pairs. The level of t-Hcy was correlated with 677TT. CONCLUSIONS: Despite the small sample in this study, we suggest that low vitamin B12 and, consequently, hyperhomocysteinemia are important risk factors for NTDs in our population.

Adolescent↗
PubMed2004

Investigation of lysosomal storage diseases in nonimmune hydrops fetalis.

OBJECTIVE: To investigate lysosomal storage diseases (LSD) in cases of nonimmune hydrops fetalis (NIHF). METHODS: Thirty-three cases of NIHF were investigated, 28 in the prenatal period and 5 in hydropic newborns. In addition to a general investigation for NIHF, specific enzymatic analyses for the detection of LSD were performed. RESULTS: In our sample, we detected five patients (15%) with LSD, each patient having one of the following diseases: mucolipidosis, Niemann-Pick disease, galactosialidosis, sialidosis and mucopolysaccharidosis type IV A. CONCLUSION: Although LSDs are rare disorders as a group, they should be considered as a possible cause of NIHF, even in the absence of consanguinity or of a previous family history. By excluding the more frequent causes of NIHF, an LSD investigation assists in clarifying the etiology of many hydropic cases, making more appropriate genetic counseling for parents possible.

Adult↗
PubMed2004

Biochemical study on beta-glucosidase in individuals with Gaucher's disease and normal subjects.

BACKGROUND: Gaucher's disease (GD) is a disorder caused by the deficiency of lysosomal beta-glucosidase, an enzyme that participates in the degradation of glycosphingolipids. Deficiency of this enzyme results in the accumulation of glucocerebrosides in macrophage lysosomes. No studies comparing the biochemical and kinetic behavior of this enzyme in leukocytes and fibroblasts from normal individuals and patients with Gaucher's disease are available. METHODS: We compared the activities of beta-glu and chitotriosidase between normal subjects and Gaucher disease patients, and characterized the behavior of beta-glu in terms of pH optimum, heat stability, Km and Vmax. RESULTS: The results showed a different behavior of the enzyme in the groups analyzed. CONCLUSIONS: This finding might be useful in cases in which the measurement of enzyme activity alone is not reliable for the establishment of the diagnosis of Gaucher's disease.

Case-Control Studies↗
PubMed2004

S100B content and SOD activity in amniotic fluid of pregnancies with Down syndrome.

OBJECTIVES: We measured S100B levels and superoxide dismutase (SOD) activity retrospectively in amniotic fluid samples from pregnancies with normal and Down syndrome (DS) fetuses. DESIGN AND METHODS: Samples from 26 normal and 71 Down syndrome fetuses were studied. S100B protein levels were determined using LIA-mat Sangtec kit, and SOD activity was measured with the RANSOD kit. RESULTS: We observed significantly higher levels of S100B in the Down group (median of 1.24 microg/l) than in the control group (median 0.69 microg/l). S100B concentration in DS samples increased from the 13th to the 18th week of gestation and was positively correlated with gestational age. The amniotic fluid SOD activity in the DS group (16.60 U/mg/prot) was significantly higher than in the normal one (10.78 U/mg/prot). CONCLUSIONS: This study indicates that S100B and SOD in amniotic fluid could be used as additional parameters for prenatal screening of trissomy 21 and that S100B values are associated with the gestational age.

Amniotic Fluid↗
PubMed2004

Biochemical characterization of chitotriosidase enzyme: comparison between normal individuals and patients with Gaucher and with Niemann-Pick diseases.

OBJECTIVES: The aim of the present study was to establish the range of chitotriosidase (CT) activity in normal individuals, patients with Gaucher disease (GD) and Niemann-Pick disease (NPD), types A or B. The kinetics of CT in these three groups was also investigated. DESIGN AND METHODS: CT activity, as well as Km, Vmax, optimum pH, and thermal stability of the enzyme were determined in the plasma of control, GD, and NPD subjects. RESULTS: CT activity in GD and NPD patients was, respectively, around 600-fold and 30-fold greater than in normal individuals. We observed significant differences in optimum pH, Vmax, and thermal stability between the various groups. Km was different in normal individuals relative to GD and NPD patients. However, there was no significant difference between Km values in patients with GD and with NPD. CONCLUSIONS: Based on the differences found in the biochemical parameters studied, our results may be important to help the identification of patients not only with GD but also with NPD.

Biological Assay↗
PubMed2004

The Latin-American network of human genetics.

The Latin-American Network of Human Genetics (RELAGH) is an internet-based federation of human and medical genetic societies of Latin America constituted in 2001. Member societies include the Mexican Association of Human Genetics, the Brazilian Society of Clinical Genetics, the Human Genetics Section of the Argentinean Society of Genetics, the Colombian Society of Human Genetics and the Panamanian Human Genetics Society. RELAGH is a full member of the steering committee of the International Federation of Human Genetics Societies. A core activity of RELAGH is to become a platform for the integration and collaboration of human geneticists across Latin America regarding training, services and research in medical genetics in the region.

Community Networks↗
PubMed2004

Newborn screening for congenital infectious diseases.

To estimate the prevalence of congenital toxoplasmosis, Chagas disease, cytomegalovirus, and rubella, blood samples on dried blood spot (DBS) from neonates (day 3-20 of life) were screened for immunoglobulin (Ig) M against Toxoplasma gondii, cytomegalovirus, rubella virus, and IgG against Trypanosoma cruzi by methods used for serum and adapted for use with DBS. Positive samples were further analyzed for IgM and IgG in serum from neonates and mothers. DBS samples from 364,130 neonates were tested for Toxoplasma gondii-specific IgM, and 15,873 neonates were also tested for IgM against cytomegalovirus and rubella virus and for Trypanosoma cruzi-specific IgG. A total of 195 were diagnosed with congenital toxoplasmosis, 16 with cytomegalovirus, and 11 with congenital rubella. One newborn had a confirmed result for Chagas disease, and 21 mothers had positive serum antibodies. These results suggest that infectious diseases should be considered for future inclusion in programs for newborn screening of metabolic diseases in disease-endemic areas.

Adult↗
PubMed2003

Nerve conduction studies, electromyography and sympathetic skin response in Fabry's disease.

We prospectively performed neurophysiologic studies in nine Fabry's Disease (FD) patients (8 male and 1 female) in order to describe the results of nerve conduction studies (NCS) and electromyography (EMG) and to verify whether the sympathetic skin response (SSR) is impaired in these patients. The investigation protocol included SSR, sensory and motor NCS and EMG. SSR was performed not only in FD patients, but also in 18 normal controls. All FD patients had normal nerve conduction studies and electromyography. SSR was present in all controls with a mean amplitude of 1453.6+/-682.3 microV. However, the SSR was absent in six and lower than 500 microV in the remaining FD patients. All patients had normal sensory and motor NCS and EMG. SSR, on the other hand, was significantly altered in all patients and this test could, therefore, be useful in the diagnostic evaluation of FD patients.

Adolescent↗
PubMed2003

Application of a protocol for the detection of disorders of sialic acid metabolism to 124 high-risk Brazilian patients.

Lysosomal storage disorders (LSD) present great clinical variability. Included in this group are sialic acid metabolism disorders (SAMD). In the present study, we describe the application of a 3-step protocol for the diagnosis of SAMD, including (1). oligosaccharide and sialyloligosaccharide chromatography; (2). quantitative determination of sialic acid; and (3). measurement of neuraminidase activity. Application of our protocol to 124 individuals at risk for SAMD led to the diagnosis of five affected patients, two with type I sialidosis, one with type II sialidosis, and two with galactosialidosis. Due to its simplicity and efficiency, we propose the use of this protocol for the diagnostic evaluation of patients with suspected SAMD, which could be specially useful to non-specialized laboratories and to services located in developing countries.

Adolescent↗