ABSTRACT
The authors describe the first mother-infant pair to complete an on-going, prospective, open-label, Phase 4 trial (ALIU) UU3, NCT00418821) determining the safety of laronidase enzyme replacement therapy (ERT) in pregnant women with mucopolysaccharidosis type I (MPS I) and their breastfed infants. The mother, a 32-year-old with attenuated MPS I (Scheie syndrome), received laronidase for three years and continued treatment throughout her second pregnancy and while lactating. A healthy 2.5 kg male was delivered by elective cesarean section at 37 weeks. He was breastfed for three months. No laronidase was detected in breast milk. The infant never developed anti-laronidase IgM antibodies, never had inhibitory antibody activity in a cellular uptake assay, and always had normal urinary glycosaminoglycan (GAG) levels. No drug-related adverse events were reported. At 2.5 years of age, the boy is healthy with normal growth and development. In this first prospectively monitored mother-infant pair, laronidase during pregnancy and breastfeeding was uneventful.
Subject(s)
Breast Feeding , Iduronidase , Milk, Human/drug effects , Mucopolysaccharidosis I , Pregnancy Complications , Adult , Drug Monitoring/methods , Enzyme Replacement Therapy/methods , Female , Glycosaminoglycans/urine , Humans , Iduronidase/administration & dosage , Iduronidase/adverse effects , Infant, Newborn , Male , Monitoring, Immunologic , Mucopolysaccharidosis I/diagnosis , Mucopolysaccharidosis I/drug therapy , Mucopolysaccharidosis I/metabolism , Mucopolysaccharidosis I/physiopathology , Pregnancy , Pregnancy Complications/diagnosis , Pregnancy Complications/drug therapy , Pregnancy Complications/metabolism , Pregnancy Complications/physiopathology , Pregnancy Outcome , Prospective StudiesABSTRACT
Fabry disease (FD) is an X-linked lysosomal storage disorder (LSD) caused by the deficiency of the enzyme α-galactosidase. It exhibits a wide clinical spectrum that may lead to a delayed or even missed diagnosis and the real incidence can be underestimated. We report the cases of two unrelated Italian families in whom FD was incidentally diagnosed in two females. In both families, the risk for other lysosomal disorders was known from other members affected by fucosidosis or mucopolysaccharidosis I Hurler/Scheie. Some subjects were simultaneously heterozygous for Fabry and the other lysosomal deficiency. Our study shows that the risk for more than one LSDs can occur in a family pedigree. The diagnosis of Fabry in female probands represents a diagnostic challenge, as symptoms and signs can be variably present because of the random X-chromosome inactivation.
Subject(s)
Fabry Disease/diagnosis , Fabry Disease/genetics , Mutation , alpha-Galactosidase/genetics , Adult , Aged, 80 and over , Fabry Disease/complications , Female , Fucosidosis/complications , Fucosidosis/genetics , Humans , Middle Aged , Mucopolysaccharidosis I/complications , Mucopolysaccharidosis I/genetics , Pedigree , alpha-Galactosidase/metabolismABSTRACT
Isolated angiokeratomas are common benign cutaneous lesions, generally deemed unworthy of further investigation. In contrast, diffuse angiokeratomas should alert the physician to a possible diagnosis of Fabry disease, a rare X-linked lysosomal storage disorder, characterized by α-galactosidase deficiency. Glycosphingolipids accumulate in cells throughout the body resulting in progressive multi-organ failure. Difficulties are encountered when trying to interpret the significance of angiokeratomas because they may also occur in other lysosomal storage disorders and rarely in an isolated manner in Fabry disease. We present an algorithm for the classification of angiokeratomas which might prove useful for the diagnosis and management of Fabry disease. Assessment of the clinical features and location of the lesions, personal and family history, skin biopsy, dermoscopy and electron microscopy imaging are sequential steps in the diagnostic process. Assessing the deficiency of α-galactosidase enzyme activity is essential to confirm the diagnosis in males, while mutation analysis is always needed in females. Potentially this algorithm can change the current approach to patients when Fabry disease is suspected, thus improving the diagnostic strategy and management of this disorder. It remains to be decided whether the use of an algorithm might reduce the number of genetic consultations. As evidence has shown the efficacy of enzyme replacement therapy in halting progression of the disease before the onset of irreversible organ damage, it is advisable to aim at an early diagnosis in order to achieve timely initiation of effective treatment with benefits for patients and appropriate use of medical resources.
Subject(s)
Angiokeratoma/etiology , Decision Support Techniques , Fabry Disease/pathology , Skin/pathology , Algorithms , Biopsy/methods , Dermoscopy , Fabry Disease/complications , Female , Humans , Lysosomal Storage Diseases, Nervous System/complications , Lysosomal Storage Diseases, Nervous System/pathology , Male , Microscopy, ElectronABSTRACT
Fabry disease: polymorphic haplotypes and a novel missense mutation in the GLA gene. Fabry disease (FD) is an X-linked lysosomal storage disorder with a heterogeneous spectrum of clinical manifestations that are caused by the deficiency of α-galactosidase A (α-Gal-A) activity. Although useful for diagnosis in males, enzyme activity is not a reliable biochemical marker in heterozygous females due to random X-chromosome inactivation, thus rendering DNA sequencing of the α-Gal-A gene, alpha-galactosidase gene (GLA), the most reliable test for the confirmation of diagnosis in females. The spectrum of GLA mutations is highly heterogeneous. Many polymorphic GLA variants have been described, but it is unclear if haplotypes formed by combinations of such variants correlate with FD, thus complicating molecular diagnosis in females with normal α-Gal-A activity. We tested 67 female probands with clinical manifestations that may be associated with FD and 110 control males with normal α-Gal-A activity. Five different combinations of GLA polymorphic variants were identified in 14 of the 67 females, whereas clearcut pathogenetic alterations, p.Met51Ile and p.Met290Leu, were identified in two cases. The latter has not been reported so far, and both mutant forms were found to be responsive to the pharmacological chaperone deoxygalactonojirimycin (DGJ; migalastat hydrochloride). Analysis of the male control population, as well as male relatives of a suspected FD female proband, permitted the identification of seven different GLA gene haplotypes in strong linkage disequilibrium. The identification of haplotypes in control males provides evidence against their involvement in the development of FD phenotypic manifestations.
Subject(s)
Fabry Disease/genetics , Haplotypes , Mutation, Missense , alpha-Galactosidase/genetics , Adult , Child , Female , Humans , Male , Middle Aged , PhenotypeABSTRACT
Fabry Disease (FD) is an X-linked multisystemic lysosomal disorder caused by mutations of alpha-galactosidase (GLA) gene. Only a few of the 450 genetic lesions identified so far have been characterised by in vitro expression studies. Thus the significance of newly identified GLA nucleotide variants in FD patients which lead to alpha-galactosidase (GAL-A) amino acid substitutions or intronic changes can be uncertain. We identified three GLA mutations, c.155G>A (p.C52Y), c.548G>C (p.G183A), c.647A>G (p.Y216C) in as many individuals (two male; one female) and performed in vitro expression studies and Western blot analysis in order to clarify their functional effects. Reduced GAL-A activity and normal or partially reduced mutant proteins were present in all overexpressed mutant systems in which three-dimensional structural analysis showed that the active site was not directly involved. We hypothesize that the three new mutations affect the GAL-A protein, leading to conformational FD. When mutant proteins overexpressed in COS-1 cells and in patients' lymphocytes were tested in the presence of the 1-deoxygalactonojirimicin (DGJ) chaperone, the p.G183A and p.Y216C systems showed increased GAL-A enzyme activities and protein stabilisation while p.C52Y was not responsive. We underline that genetic, biochemical and functional studies are helpful in clarifying the consequences of the missense genetic lesions detected in FD. ERT is the elective therapy for Fabry patients, but it is not always possible to issue the enzyme's active form in all involved organs. Our study endorses the hypothesis that an active site-specific chemical chaperone, which could be administered orally, might be effective in treating GAL-A conformational defects.
Subject(s)
Fabry Disease/genetics , Mutation , alpha-Galactosidase/genetics , Animals , COS Cells , Chlorocebus aethiops , Chromosome Mapping , DNA/genetics , DNA/isolation & purification , DNA Primers , Enzyme Replacement Therapy/methods , Fabry Disease/drug therapy , Fabry Disease/enzymology , Female , Humans , Male , Models, Molecular , Molecular Conformation , Mutagenesis, Site-Directed , Phenotype , Protein Conformation , Transfection , X Chromosome/genetics , alpha-Galactosidase/chemistrySubject(s)
Dosage Compensation, Genetic , Fabry Disease/genetics , Gene Silencing , Genetic Carrier Screening , Adolescent , Adult , Aged , Child , Fabry Disease/diagnosis , Female , Humans , Male , Pedigree , alpha-Galactosidase/geneticsABSTRACT
Mutation analysis performed on two Italian patients with alpha-mannosidosis allowed the identification of two new mutations, IVS20-2A>G and 322-323insA. The patients were both homozygous for these mutations. The first mutation causes skipping of exon 21, whereas the second causes a frameshift introducing a stop codon at position 160 of the amino acid sequence.
Subject(s)
Mutation , alpha-Mannosidase/genetics , alpha-Mannosidosis/genetics , Humans , alpha-Mannosidosis/etiologyABSTRACT
BACKGROUND: The main consequences of neurogenic bladder dysfunction are renal damage related to high intravesical pressure, vesicoureteral reflux (VUR) and urinary tract infections (UTIs). Neurologic impairment, UTIs and VUR are known to be linked with a potential for renal scarring. Of paramount importance as predisposing conditions for UTIs in neurogenic bladder are poor bladder drainage and detrusor-sphincter dyssynergy which cause further abnormalities on the internal bladder surface and, consequently, a bladder wall rich in glycosaminoglycans (GAGs). MATERIALS AND METHODS: The aim of this study is to investigate the correlation between GAG excretion and bladder wall degeneration in 43 patients affected by spina bifida (SB) and 40 healthy age-matched control children. RESULTS: The amounts of GAGs excreted vary greatly in SB patients aged from 0 to 5 years, and values are comparable to those observed in normal controls. They are significantly higher in children over 5 years of age. CONCLUSION: The increased excretion of GAGs in older SB patients is an important parameter in the evaluation of the physiopathological condition of the bladder wall and hence may be considered a possible marker for monitoring the beginning of bladder damage.
Subject(s)
Glycosaminoglycans/urine , Meningomyelocele/urine , Child , Child, Preschool , Female , Humans , Infant , MaleABSTRACT
OBJECTIVE: To determine variations in the amount of glycosaminoglycans (GAGs) excreted by patients with nocturnal enuresis and/or diurnal incontinence. PATIENTS, SUBJECTS AND METHODS: The study included 27 patients (aged 5-15 years) with nocturnal enuresis and/or diurnal incontinence, and 27 healthy age-matched children. Their urinary GAG excretion was assessed over 24 h using the sodium tetraborate-carbazole method. RESULTS: Patients with nocturnal enuresis and/or diurnal incontinence had higher mean values of urinary GAG excretion than age-matched controls. There were significant differences in GAG excretion between those with nocturnal enuresis and diurnal incontinence and those with nocturnal enuresis alone. CONCLUSIONS: GAG excretion in patients with nocturnal enuresis and/or diurnal incontinence was significantly higher than in normal children, suggesting that measuring urinary GAGs may be useful in evaluating physiopathological conditions of the bladder wall, and hence in monitoring potential damage in the bladder mucosa.
Subject(s)
Enuresis/urine , Glycosaminoglycans/urine , Urinary Incontinence/urine , Adolescent , Child , Child, Preschool , Enuresis/complications , Female , Humans , Male , Urinary Incontinence/complicationsABSTRACT
In this paper the possible application of an electronic nose to the analysis of urine is presented. In contrast with the conventional applications of sensors and biosensors operating in liquid, the approach discussed here makes use of gas sensors performing an analysis of the headspace. The application deals with urine samples from patients affected by kidney diseases; some of the samples contained traces of blood. Results show the possibility of distinguishing the samples containing blood from the others, and a linear correlation between the first three principal components and the blood content was found. Furthermore, the electronic nose matched with a suitable neural network showed good performance in measuring the pH and the specific weight of the samples.
Subject(s)
Hematuria/diagnosis , Urinalysis/methods , Adolescent , Algorithms , Child , Child, Preschool , Hematuria/etiology , Hematuria/urine , Humans , Hydrogen-Ion Concentration , Infant , Infant, Newborn , Kidney Diseases/complications , Reference Values , Sensitivity and Specificity , Urinalysis/instrumentationABSTRACT
We report a case of bladder obstruction in a patient with Hunter's syndrome, presenting with acute painful symptomatology, due to the impossibility of voiding, which was diagnosed with ultrasonography and cystometrography. Intermittent catheterization with intravesical oxybutynin chloride lead to successful functional resolution of the obstruction.
Subject(s)
Mucopolysaccharidosis II/complications , Urinary Bladder Neck Obstruction/diagnosis , Adult , Humans , Male , Mucopolysaccharidosis II/physiopathology , Ultrasonography , Urinary Bladder/diagnostic imaging , Urinary Bladder/physiopathology , Urinary Bladder Neck Obstruction/physiopathology , UrodynamicsABSTRACT
We describe our experience with 8 Italian patients having mucopolysaccharidosis type IV, diagnosed between 1 and 10 years of life, who presented odontoid hypoplasia causing cervical myelopathy. We discuss the possibility of cranio-cervical stabilization in order to reduce the neurological complications.
Subject(s)
Mucopolysaccharidosis IV/pathology , Muscular Atrophy, Spinal/pathology , Age of Onset , Child , Child, Preschool , Humans , Infant , Italy , Magnetic Resonance ImagingABSTRACT
A case of spondylo-epimetaphyseal dysplasia with joint laxity (SEMDJL) in an Italian girl is reported. This condition is mainly observed in the Afrikaans population of South Africa with an ancestral founder believed to be localized in West Germany. This case might support a link with the European origin of SEMDJL.
Subject(s)
Joint Instability/complications , Kyphosis/complications , Scoliosis/complications , Spinal Diseases/congenital , Child, Preschool , Epiphyses , Female , Humans , Kyphosis/diagnostic imaging , Radiography , Scoliosis/diagnostic imaging , Spinal Diseases/complications , Spinal Diseases/diagnostic imagingABSTRACT
1. The activities of some lysosomal hydrolases and the concentrations of their natural substrates were studied in the submandibular and sublingual glands of male and female rats using biochemical procedures. 2. In sublingual gland enzyme activities and substrate concentrations show the highest values. 3. The enzyme activities appear, in general, lower and the natural substrate concentrations higher in the females with respect to males. 4. In both glands beta-galactosidase shows the highest activity and beta-glucosidase the lowest. 5. These findings suggest that metabolic turnover of glycoproteins is slower in females than in males, probably because the oestrogens control the activity of lysosomal hydrolases.
Subject(s)
Glycoproteins/metabolism , Hydrolases/metabolism , Lysosomes/enzymology , Salivary Glands/enzymology , Animals , Female , Male , Rats , Rats, Inbred Strains , Sex CharacteristicsABSTRACT
1. A biochemical study was carried out on the protein-bound and lipid-bound sialic acid, and neuraminidase activity in the different tracts of the oviduct of the frog Rana esculenta during the reproductive cycle. 2. Plasma sexual steroids were also investigated by RIA. 3. Fluctuations in neuraminidase activity are related to that of glycoprotein sialic acid and plasma estradiol. Glycolipid sialic acid does not have a close relationship either with neuraminidase or plasma estradiol. 4. Very high plasma concentration of progesterone before ovulation and, on the contrary, its drop after ovulation were observed. 5. The results are discussed and hypotheses advanced to explain fluctuations of the studied parameters during the reproductive cycle.