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Biomedical subjects

M Nicolino

Publications and source records attributed to M Nicolino.

At least 19 recordsLinked to original sources
PubMed2006

Recombinant human acid [alpha]-glucosidase: major clinical benefits in infantile-onset Pompe disease.

BACKGROUND: Pompe disease is a progressive metabolic neuromuscular disorder resulting from deficiency of lysosomal acid alpha-glucosidase (GAA). Infantile-onset Pompe disease is characterized by cardiomyopathy, respiratory and skeletal muscle weakness, and early death. The safety and efficacy of recombinant human (rh) GAA were evaluated in 18 patients with rapidly progressing infantile-onset Pompe disease. METHODS: Patients were diagnosed at 6 months of age and younger and exhibited severe GAA deficiency and cardiomyopathy. Patients received IV infusions of rhGAA at 20 mg/kg (n = 9) or 40 mg/kg (n = 9) every other week. Analyses were performed 52 weeks after the last patient was randomized to treatment. RESULTS: All patients (100%) survived to 18 months of age. A Cox proportional hazards analysis demonstrated that treatment reduced the risk of death by 99%, reduced the risk of death or invasive ventilation by 92%, and reduced the risk of death or any type of ventilation by 88%, as compared to an untreated historical control group. There was no clear advantage of the 40-mg/kg dose with regard to efficacy. Eleven of the 18 patients experienced 164 infusion-associated reactions; all were mild or moderate in intensity. CONCLUSIONS: Recombinant human acid alpha-glucosidase is safe and effective for treatment of infantile-onset Pompe disease. Eleven patients experienced adverse events related to treatment, but none discontinued. The young age at which these patients initiated therapy may have contributed to their improved response compared to previous trials with recombinant human acid alpha-glucosidase in which patients were older.

Dose-Response Relationship, Drug↗
PubMed2006

Bilateral anorchia in infancy: occurence of micropenis and the effect of testosterone treatment.

OBJECTIVE: To analyze the clinical and histological findings in boys with bilateral anorchia and the response to testosterone treatment on penis length. STUDY DESIGN: Patients were divided into two groups according to the absence (group A, n = 29) or the presence (group B, n = 26) of palpable intrascrotal or inguinal mass at first clinical examination. RESULTS: A micropenis was found in 46% of patients (n = 24) with a similar proportion in both groups. Testosterone treatment induced a mean penis length gain of 1.9 +/- 1.3 SDS (standard deviation score). However, micropenis persisted in six patients. Histological examination (n = 18) confirmed the absence of any testicular structure with deferent ducts being present unilaterally or bilaterally in all but three patients. In these three patients, a hemorrhagic testis, probably as a result of a mechanical torsion, was found. CONCLUSIONS: The presence of isolated micropenis in almost half of patients with bilateral anorchia strongly suggests that the testicular damage frequently occurs during the second half of gestation after male sexual differentiation. In most cases, testosterone treatment stimulates the penile growth. Although the pathogenesis of bilateral anorchia may be heterogeneous, our study suggests that gonads may have been functionally abnormal before they disappeared, and suggests that some patients have an intrinsic endocrine disorder.

Androgens↗
PubMed2006

Reinforced follow-up for children and adolescents with type 1 diabetes and inadequate glycaemic control: a randomized controlled trial intervention via the local pharmacist and telecare.

AIM: To evaluate the effectiveness and feasibility of reinforced follow-up via telecare mediated by the local pharmacist in contact with the hospital team to improve glycaemic control in children and adolescents with type 1 diabetes (DT1). METHODS: One hundred patients, aged 8 to 17 years, with a history of DT1 of more than 1 year, with HbA(1c) >=8%, were randomly assigned to either the "reinforced follow-up" group (RFG) or the "usual follow-up" group (UFG). The intervention consisted in downloading and then printing data stored in a glucometer every two weeks, by the local pharmacist. Printouts were faxed to the hospital team which then communicated adapted instructions for better glycemic control directly to the family. RESULTS: Fifty patients were assigned to each group. The two groups were comparable at the beginning. 71 children had a doctor's visit at 6 +/- 1 months (36 in RFG and 35 in UFG). At this date, there was no significant difference between the average HbA(1c) levels of the two groups (9.12 +/- 1.46 in RFG versus 9.27 +/- 1.20 in UFG). We had various difficulties setting up and gaining compliance with the intervention procedure, which explains why only 33 children in the RFG transmitted at least one fax. CONCLUSION: At this stage, the reinforced follow-up has not proved to be superior to the usual follow-up. However, it would be possible to make numerous improvements in order to make the former more feasible and probably more efficient.

Adolescent↗
PubMed2005

[Adrenal hypoplasia congenita: four new cases in children].

Adrenal hypoplasia congenita (AHC) is an extremely uncommon disease of early onset. This condition can be lethal in the absence of adapted treatment. Some of these diseases are related to changes in the gene DAX1 that encodes a member of the superfamily of hormone nuclear receptors. It is a transcriptional repressor that is central in the morphogenesis of the adrenals and the gonadic differentiation. Here we report on four cases of X- linked AHC. In the first two familial cases, mutations were identified and mothers were heterozygotes. Abnormally low levels of estriol were evidenced during the pregnancy leading to an early diagnosis and adapted care of the affected male neonates. These children are doing well with a 21-and 20 months follow-up with hormone replacement at the present time. The two last cases corresponded to a contiguous gene syndrome associating AHC to glycerol-kinase deficiency that was revealed respectively at six days and seven years of age by acute adrenal insufficiency.

Adolescent↗
PubMed2005

21-Hydroxylase deficiency: an exemplary model of the contribution of molecular biology in the understanding and management of the disease.

Congenital adrenal hyperplasia (CAH) is a family of autosomal recessive disorders caused by mutations in genes encoding the enzymes involved in one of the various steps of adrenal steroid synthesis. Steroid 21-hydroxylase deficiency (21-OHD) is responsible for over 95% of the 5 forms of CAH, and results due to enzymatic defect owing to mutation in the CYP21 gene. The disease has two major clinical presentations. The "classical" form is severe, and divided into a salt wasting (SW) and simple virilizing (SV) subgroups. In both, affected female fetuses undergo virilization of the external genitalia prenatally and present at birth with sexual ambiguity. In addition, in both sexes infants with SW CAH are at risk of life-threatening adrenal crisis without treatment. This is why it is so important to make a diagnosis and to counsel the families. The diagnosis is easy by measuring the plasma levels of 17-hydroxyprogesterone (17-OHP) in antenatal (amniotic fluid), or perinatal samples (peripheral blood). Confirmation by molecular genetic analysis is advised. The second form of 21-OHD is called "non classical" because the presentation is much less severe and the onset of clinical expression occurs long after birth, often in the peripubertal period, as non-specific symptoms of hyperandrogeny. The unambiguous diagnosis of the latter requires a simple short ACTH test, with the measurement of 17-OHP at 60 min. In both forms, the mutations on the gene CYP21 responsible for the disease are now well known and can be identified by molecular biology techniques. There is a good correlation between phenotypes and genotypes, due to variable amount of the 21-hydroxylase-enzyme activity left (null to 50-60%). SW, SV and NC forms are associated with distinct mutations or combination of mutations. Nowadays, by combining hormonal and molecular tests, it is possible to predict the clinical form of the disease in a given family in the context of a prenatal diagnosis, which can lead to a prenatal treatment. Therefore, 21-OHD genotyping also appears essential for a new approach of genetic counseling, prediction of clinical form after postnatal screening and to define the post-ACTH 17-OHP values indicating the cut-off lines between NC, heterozygote and normal subjects.

Chromosome Deletion↗
PubMed2003

High-risk genotype for type 1 diabetes: a new simple microtiter plate-based ELOSA assay.

The main contribution to genetic susceptibility for type 1 diabetes (T1D) is conferred by the HLA class II genes, with a major involvement of the DQB1*02 and 0302 alleles. The aim of our study was to develop a simple and rapid method suitable for identifying individuals with an HLA-associated T1D risk using whole blood as a source of DNA and reverse hybridization on microtiter plates (ELOSA). DNA was extracted from whole blood using various extraction methods. The PCR-amplified second exon of the DQB1 gene was hybridized at 37 degrees C for 1 hr to a set of 11 capture probes immobilized on a microtiter plate (eight-well strip per test) and corresponding to T1D susceptibility (S), protection (P), or neutral (N) alleles. Colorimetric analysis was then performed using specific oligonucleotides coupled to horseradish peroxidase and OrthoPhenyl Peroxidase (OPD) substrate. DNA samples corresponding to French (Rhône-Alpes area) T1D patients (n = 128) have been genotyped with the HLA-T1D prototype. A strong correlation is observed between susceptible genotypes and the disease, because 92.2% of the T1D individuals screened have at least one susceptible allele (DQB1*02 or *0302), thereby strengthening interest in analyzing DQB1 alleles as HLA-linked T1D markers in our Rhône-Alpes area population. Interestingly, clear T1D-associated genotyping results have been observed when using DNA samples extracted from dried blood spots, making it possible to envisage such genotyping in geographically dispersed affected families, for large-scale newborn screening, and for the inclusion of high-risk patients in clinical trials aimed at preventing the disease.

Alleles↗
PubMed2002

Combination of autoantibody markers and risk for development of type 1 diabetes: results from a large french cohort of family members.

BACKGROUND: The aims of the study were to characterize the relatives at high risk of progression to diabetes and to determine whether rate of progression to diabetes varied according to age, specific combination of antibodies and genetic markers of susceptibility. METHODS: Family members of type 1 diabetic patients were examined through a large medical network for the presence of specific antibodies to beta cell constituents and high risk DQB1 alleles. Antibodies to insulin, GAD and IA-2 as well as ICA were examined in 4,044 family members recruited in a large prospective family study in the Rhone-Alpes region (the GRADI study). Among them, 3,951 non diabetic first degree relatives have been tested on a median of 2.2 occasions and were followed for up to 16 years. RESULTS: Presence of antibodies to GAD (3.6%), IA-2 (4.9%), insulin (2.2%) and ICA at titers equal or above 20JDF units (1.1%) were noticed at the first determination and prevalence increased among ICA positive relatives versus ICA negative relatives. All combinations of markers resulted in specificities above 90%. The positive predictive value of antibodies was dependent on the number of positive antibodies. Combination of antibodies to GAD and IA-2 or GAD and IAA had higher predictive values and sensitivities than ICA titers above 20 JDF units. Additional positivity of IAA increased the predictive value but reduced the sensitivity of the screening procedure. Using a combi GAD/IA-2 assay increased the sensitivity of the screening up to 87.8% but reduced the predictive value to 13.8%. CONCLUSIONS: These data confirm in a large French cohort of first degree relatives of type 1 diabetic patients that combinations of antibodies to beta cell constituents can replace ICA in the first screening procedure. We report that combi GAD/IA-2 assay is well suited for screening purposes. However, time to diabetes in antibody positive relatives appears to be more heterogeneous to what has been described. The importance of genetic markers needs further evaluation.

Autoantibodies↗
PubMed2001

The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome.

In type I blepharophimosis/ptosis/epicanthus inversus syndrome (BPES), eyelid abnormalities are associated with ovarian failure. Type II BPES shows only the eyelid defects, but both types map to chromosome 3q23. We have positionally cloned a novel, putative winged helix/forkhead transcription factor gene, FOXL2, that is mutated to produce truncated proteins in type I families and larger proteins in type II. Consistent with an involvement in those tissues, FOXL2 is selectively expressed in the mesenchyme of developing mouse eyelids and in adult ovarian follicles; in adult humans, it appears predominantly in the ovary. FOXL2 represents a candidate gene for the polled/intersex syndrome XX sex-reversal goat.

Abnormalities, Multiple↗
PubMed2001

New insights into the postnatal growth of infants born 'idiopathic' small for gestational age.

Infants born small for gestational age (SGA) are defined as those with a birth weight and/or birth length below two standard deviations for gestational age. Postnatal catch-up growth is absent in 8-12% of children born SGA and these children achieve adult heights far below their target height. The objectives of our retrospective study were to confirm the prevalence of catch-up growth and to refine the kinetics of the catch-up process. The 'Lyon series' of patients consisted of 179 children with 'idiopathic' SGA, of whom 8% did not achieve catch-up growth (i.e. their height remained below -2 SD throughout the study). The number of days that the mother was hospitalized before delivery was found to be significantly correlated with lack of catch-up growth. Maternal hypertension, term delivery and postnatal parenteral nutrition were also associated with lack of catch-up growth, but the relationship was not significant. In addition, an oscillatory growth velocity pattern was observed in boys and girls born SGA, with alternating periods of growth acceleration and deceleration. This suggests that catch-up growth is regulated in a sophisticated way by the hypothetical 'Somatostat', although further confirmation of this process is needed.

Female↗
PubMed2001

[Intrauterine growth retardation, its consequences in infancy, in the child and long term].

The authors report the consequence of intra-uterine growth retardation on infancy and adult disease. During infancy in 7 to 10% of cases a growth retardation less than -2 DS, is observed and subsequently needs growth hormone treatment. In adult X syndrome (hypertension, diabetes of 2 types insulino resistant and cardiovascular disease) is observed 18 times more in subjects where the birth weight was low than 2.4 kg. Finally the authors give some recommendations to follow-up of the infants born with a growth restriction.

Adolescent↗
PubMed2000

Juvenile and adult-onset acid maltase deficiency in France: genotype-phenotype correlation.

OBJECTIVE: To characterize the phenotypes of patients with juvenile and adult-onset acid maltase deficiency (AMD) in the French population and correlate them with genetic defects. BACKGROUND: AMD is an autosomal recessive disorder caused by the absence of the enzyme acid a-glucosidase (GAA). Patients are generally compound heterozygotes for various mutations in the GAA gene. The most common mutant allele is a -13T to G transversion in intron 1. METHODS: The authors performed a clinical, biochemical, and genetic study on 21 unrelated patients with juvenile and adult-onset AMD. RESULTS: Although onset of progressive muscle weakness occurred during adulthood in all cases but one, presence of mild, nonprogressive muscular symptoms appearing during childhood was detected in 16 patients. Eighteen patients had a similar clinical pattern with pelvic girdle muscle weakness predominating in glutei and thigh adductors. Restrictive respiratory insufficiency with vital capacity less than 60% was noted in eight patients, and respiratory failure was the first manifestation in two cases. All patients but one were compound heterozygotes, and 17 carried the IVS1 (-13T ---> G) transversion (one patient was homozygous for this mutation). The two mutated alleles were identified in 10 cases, with 13 different mutations detected in the GAA gene. There was no clear correlation between the type of mutation and phenotype. CONCLUSIONS: This study shows a high genetic heterogeneity of juvenile and adult AMD in the French population. The absence of genotype-phenotype correlation suggests a complex physiopathology that requires further investigations.

Adolescent↗
PubMed2000

Oral insulin administration and residual beta-cell function in recent-onset type 1 diabetes: a multicentre randomised controlled trial. Diabète Insuline Orale group.

BACKGROUND: Oral administration of autoantigens can slow the progression of beta-cell destruction in non-obese diabetic mice. We investigated whether oral administration of recombinant human insulin could protect residual beta-cell function in recent-onset type 1 diabetes. METHODS: We enrolled 131 autoantibody-positive diabetic patients aged 7-40 years within 2 weeks of diagnosis (no ketoacidosis at diagnosis, weight loss <10%, polyuria for <6 weeks). They were randomly assigned 2.5 mg or 7.5 mg oral insulin daily or placebo for 1 year, in addition to subcutaneous insulin therapy. Serum C-peptide concentrations were measured in the fasting state and after stimulation, to assess beta-cell function. Autoantibodies to beta-cell antigens were assayed. Analyses were by intention to treat. FINDINGS: Baseline C-peptide and haemoglobin A1c concentrations were similar in the three groups. During follow-up, there were no differences between the groups assigned 2.5 mg or 7.5 mg oral insulin or placebo in subcutaneous insulin requirements, haemoglobin A1c concentrations, or measurements of fasting (mean at 12 months 0.18 [SD 0.17], 0.17 [0.17], and 0.17 [0.12] nmol/L) or stimulated C-peptide concentrations (glucagon-stimulated 0.39 [0.38], 0.37 [0.39], and 0.33 [0.24] nmol/L; meal-stimulated 0.72 [0.60], 0.49 [0.49], and 0.57 [0.51 nmol/L]. Neither age nor C-peptide concentration at entry influenced treatment effects. No differences were seen in the time-course or titres of antibodies to insulin, glutamic acid decarboxylase, or islet antigen 2. INTERPRETATION: At the doses used in this trial, oral administration of insulin initiated at clinical onset of type 1 diabetes did not prevent the deterioration of beta-cell function.

Administration, Oral↗