ABSTRACT
Lysosomal storage diseases (LSDs) include a heterogeneous group of rare, inborn, metabolic diseases characterized by deficiency of lysosomal enzymes or of other proteins involved in lysosomal function, leading to multi organ system substrates accumulation, with consequent multi systemic clinical presentation. Cardiac disease is particularly important in some group of LSDs as glycogen storage diseases (Pompe), mucopolysaccharidoses and in glycosphingolipidoses (Anderson-Fabry disease and less frequently Gaucher disease). Various cardiac manifestations may be observed including hypertrophic and dilated cardiomyopathy, coronary artery disease and valvular disease. The availability of enzyme replacement therapy (ERT) has changed the natural history of some LSDs such as Pompe disease, thanks to the significant effects on cardiological involvement. In other LSDs such as MPSs or Fabry disease, ERT has been shown to stabilize or slow the progression of heart damage. This imposes the need for a timely diagnosis that allows a rapid onset of ERT.
Subject(s)
Fabry Disease , Heart Diseases , Lysosomal Storage Diseases , Enzyme Replacement Therapy , Fabry Disease/complications , Fabry Disease/diagnosis , Fabry Disease/drug therapy , Heart Diseases/etiology , Humans , Lysosomal Storage Diseases/diagnosis , Lysosomal Storage Diseases/drug therapyABSTRACT
Mucopolysaccharidosis type II or Hunter syndrome is an X-linked lysosomal storage disease caused by a mutation in the gene encoding the lysosomal enzyme iduronate-2-sulfatase. The consequent enzyme deficiency causes a progressive, multisystem accumulation of glycosaminoglycans, which is the cause of the clinical manifestations involving also Central Nervous System for patients with the severe form of disease. The limits of the currently available therapies for Hunter syndrome, hematopoietic stem cell transplantation and recombinant enzyme replacement therapy, mainly regarding brain achievement, have encouraged several studies which recognized gene therapy as a potential therapeutic option for this condition. In vitro studies firstly aimed at the demonstration that viral vector- mediated IDS gene expression could lead to high levels of enzyme activity in transduced cells. The encouraging results obtained allowed the realization of many preclinical studies investigating the utilization of gene therapy vectors in animal models of Mucopolysaccharidosis II, together with a phase I clinical trial approved for Hunter patients affected by the mild form of the disease. Together to in vivo studies in which recombinant vectors are directly administered, systematically or by direct injection into Central Nervous System, also ex vivo gene therapy, consisting in transplantation of autologous hematopoietic stem cells, modified in vitro, into the animal or patient, has been tested. A wider clinical application of the results obtained so far is essential to ensure that gene therapy can be definitively validated as a therapeutic option available and usable for this rare but life-threatening disorder.
Subject(s)
Genetic Therapy , Iduronate Sulfatase/genetics , Mucopolysaccharidosis II/genetics , Mucopolysaccharidosis II/therapy , Rare Diseases/genetics , Rare Diseases/therapy , Animals , Child, Preschool , Disease Models, Animal , Gene Transfer Techniques , Genetic Vectors/administration & dosage , Genetic Vectors/blood , Genetic Vectors/cerebrospinal fluid , Humans , Infant , Mutation , RetroviridaeABSTRACT
This corrects the article DOI: 10.1038/ejcn.2016.166.
ABSTRACT
BACKGROUND/OBJECTIVES: Phenylketonuria (PKU) is an autosomal recessive disease caused by deficient activity of phenylalanine hydroxylase. A low phenylalanine (Phe) diet is used to treat PKU. The diet is very restrictive, and dietary adherence tends to decrease as patients get older. Methods to improve dietary adherence and blood Phe control are continuously under investigation. SUBJECTS/METHODS: A new formula Phe-neutral amino acid (PheLNAA) has been tested in this study with the purpose of improving the compliance and lowering blood phenylalanine. The formula has been tested for nitrogen balance, and it is nutritionally complete. It is fortified with more nutritional additives that can be deficient in the PKU diet, such as B12, Biotin, DHA, Lutein and increased levels of large neutral amino acids to help lower blood Phe. The new formula has been tested on 12 patients with a loading test of 4 weeks. RESULTS: Fifty-eight percent of patients had a significant decline in blood Phe concentration from baseline throughout the study. The PheLNAA was well tolerated with excellent compliance and without illnesses during the study. CONCLUSIONS: In conclusion, the new formula is suitable for life-long treatment of PKU, and it offers the PKU clinic a new choice for treatment.
Subject(s)
Amino Acids, Neutral/administration & dosage , Food, Formulated , Food, Fortified , Phenylalanine/blood , Phenylketonurias/diet therapy , Adolescent , Female , Humans , Male , Patient Compliance/psychology , Phenylketonurias/blood , Phenylketonurias/psychology , Treatment OutcomeSubject(s)
Deafness/genetics , Growth Disorders/genetics , Hearing Loss, Sensorineural/genetics , Insulin-Like Growth Factor I/genetics , Mutation , Psychomotor Disorders/genetics , DNA Mutational Analysis , Deafness/metabolism , Growth Disorders/metabolism , Hearing Loss, Sensorineural/metabolism , Humans , Infant , Insulin-Like Growth Factor I/biosynthesis , Insulin-Like Growth Factor I/deficiency , Male , Polymorphism, Single-Stranded Conformational , Psychomotor Disorders/metabolismABSTRACT
OBJECTIVE: To evaluate the relative roles of endothelium and platelets in the pathogenesis of primary RP and RP secondary to SSc. METHODS: Endothelial derived ET-1, t-PA, PAI-1, and platelet derived beta-TG, PDGF, TGF-beta were measured in 36 patients with primary RP, 14 patients with RP secondary to SSc and 30 age and sex matched controls. RESULTS: A significative increase of ET-1, t-PA, PAI-1, TGF-beta, and beta-TG were the most relevant changes in patients with RP secondary to SSc with respect to the controls. Less relevant increases of t-PA, PAI-1, PDGF, and beta-TG levels were observed in patients with primary RP vs controls. CONCLUSIONS: These data seem to confirm the involvement of endothelial cells and platelets in the pathogenesis of RP, with mild changes in primary RP and more relevant changes in RP secondary to SSc.
Subject(s)
Biomarkers/blood , Endothelium/cytology , Platelet Activation , Raynaud Disease/physiopathology , Scleroderma, Systemic/complications , Adult , Endothelin-1/blood , Endothelium/pathology , Female , Humans , Male , Middle Aged , Plasminogen Activator Inhibitor 1/blood , Platelet-Derived Growth Factor/analysis , Tissue Plasminogen Activator/blood , Transforming Growth Factor beta/blood , beta-Thromboglobulin/analysisABSTRACT
Phenylketonuria (PKU) is an autosomal recessive disease caused by the deficiency of a liver-specific enzyme, phenylalanine hydroxylase (PAH). The pattern of PAH mutations in Mediterranean populations appears to be different from that observed in northern Europe and Asia. Our aim was to study the molecular basis of PKU in Campania and Calabria, two regions of southern Italy. We studied 99 unrelated alleles, detecting 75.8% of the mutations. Our results show that 57% of all the PKU alleles are caused by three different mutations: IVS10nt-546, R261Q and L48S, which display significant differences in their relative distribution across Italy. A novel mutation, a G-to-T transversion at the codon 257 (G257C), was also identified. This mutation results in a Gly-to-Cys change in the catalytic domain of the protein.
