Cardiogenetics 2013; 3(s1):exxxx [page 2] [Cardiogenetics 2013; 3(s1):e2] Cardiogenetics 2013; 3(s1):e2 Molecular basis, diagnosis and clinical management of mucopolysaccharidoses Rossella Parini, 1 Francesca Bertola, 2 Pierluigi Russo 3 1 UOS Malattie Metaboliche Rare, Department of Pediatrics, Fondazione MBBM, Azienda Ospedaliera San Gerardo, University of Milano-Bicocca; 2 Consortium for Human Molecular Genetics, University of Milano-Bicocca; 3 UO Department of Cardiology, Azienda Ospedaliera San Gerardo, Monza, Italy Abstract Mucopolysaccharidoses (MPSs) are a group of hereditary, monogenic disorders caused by lysosomal storage of glycosaminoglycans. Their incidence as a group is between 1:25,000 and 1:45,000. At present 11 different enzyme defi- ciencies are know to be responsible of 7 similar but distinct diseases. The diagnosis is suspected clinically but must be confirmed through bio- chemical, enzymatic and molecular analysis. Prenatal diagnosis is feasible for each disease. The phenotype worsens with age, due to pro- gressive storage, and mainly involves mucosal tissue, upper airways and lungs, bones and joints, central and peripheral nervous system, heart, liver, eye and ear. Any type of MPSs, is characterized by a wide variability of phenotype ranging from a severe fetal-neonatal disease to an attenuated form diagnosed in adult individu- als. Recently new treatments, like hematopoiet- ic stem cell transplantation and enzymatic replacement therapy, became available for many of these disorders entailing the urgency of early diagnosis to allow access to therapies. Thanks to therapies these patients have a longer life than in the past and this implies that also palliative treatments, of which the cardiological ones have a prominent part, must be undertaken diligently. The cardiologist may face, more frequently than expected, with the need to diagnose a patient with MPS who was not recognized by other spe- cialists. The echocardiographic features of these patients are typical and may help in the clinical diagnosis. The future probably deserves to these disorders other new treatments or combination therapies, which might further improve progno- sis of these diseases. Introduction The mucopolysaccharidoses (MPSs) are a group of monogenic disorders due to lysosomal storage of glycosaminoglycans (GAGs), previ- ously called mucopolysaccharides. 1 The defi- ciency of one of the enzymes participating in the GAGs degradation pathway causes progres- sive storage in the lysosomes and consequently in the cells and results in tissues and organs dysfunction. The damage is both direct or by activation of secondary and tertiary pathways among which a role is played by inflammation. 2 The incidence of MPSs as a group is reported between 1:25000 and 1:45000. 3 At present 11 dif- ferent enzyme deficiencies are involved in MPSs producing 7 distinct clinical phenotypes 1 (Table 1). 4 Depending on the enzyme deficien- cy, the catabolism of dermatan sulphate, heparan sulphate, keratan sulphate, chon- droitin sulphate, or hyaluronan may be impaired, singly or in combination. Diagnosis is suspected clinically and then confirmed by bio- chemical, enzymatic and molecular tests. For all the MPSs types prenatal diagnosis is available through enzymatic or molecular analysis. In contrast to a recent past when there was only palliative treatment for these diseases, now many specific treatments like hematopoi- etic stem cell transplantation (HSCT) in selected cases (severe MPS I) and enzyme replacement therapy (ERT) for MPS I, II, and VI are available. 5 These treatments are able to improve the clinical course of the disease mainly if started early. This brings along the responsibility for the clinician to recognize these diseases at the first signs to allow access to treatment before a severe damage has been established. In this respect pilot studies of newborn screening are ongoing. 6 In recent years, availability of specific treatments, gen- eral improvement of palliative medical care and improvement of recognition of mild cases presenting later in life, have produced a grow- ing number of adult MPSs patients in relative- ly good conditions who need to be cared after by adult services for metabolic diseases. Preparing the right setting for successful tran- sition of these patients from pediatric to adult service is a difficult task that all the centers for MPSs in Europe are dealing with. Diagnosis of mucopolysaccharidoses and prenatal diagnosis Diagnosis of MPSs is suspected clinically on the basis of a number of clinical features (red flags; Table 2), 1,4,7,8 but it needs a laboratory con- firmation. Urine GAGs analysis is a preliminary diagnostic test. There is a risk of false positive and negative results which is less frequent if a 24 h urine sample is collected and analyzed. There are patients with a normal GAGs urine concentration but an abnormal distribution of GAGs. The qualitative analysis is then suggest- ed. Diagnosis is established by enzyme assay in cultured fibroblasts, leukocytes or serum. In clinical laboratories residual enzyme activity is not accurately quantified and is thus not a valid predictor of disease outcome. 1 Conclusive diag- nosis is performed with molecular analysis con- firming results of enzyme activity and allowing an early prenatal diagnosis. When a patient is diagnosed with a MPS dis- order, genetic counseling is recommended. Genetic counseling can provide the family with information regarding the genetics, inheri- tance, and recurrence risks for the specific MPS condition in their family. When the mutations in the family are known, prenatal diagnosis can be performed by molecu- Correspondence: Rossella Parini, Department of Pediatrics, San Gerardo Hospital, Via Pergolesi 33, 20900 Monza, Italy. Tel. +39.039.2333286 - Fax: +39.039.2334364. E-mail: rossella.parini@unimib.it Key words: mucopolysaccharidoses (MPS), heart, heart and MPS, genetics and MPS. Acknowledgments: RP and PR acknowledge patients and their families and Drs. Andrea Imperatori and Lucia Boffi who collaborated in the clinical cardiological evaluation of MPSs patients. RP thanks Fondazione Pierfranco e Luisa Mariani of Milano for providing financial support for clinical assistance to metabolic patients and Mrs. Vera Marchetti, the secretary of the Metabolic Unit, for her very useful help in managing the patients. Contributions: RP, PR, manuscript preparation and first draft; FB, first draft of paragraph What are mucopolysaccharidoses for the molecular biol- ogist?; PR first draft of paragraph What are mucopolysaccharidoses for the cardiologist?; RP, other paragraphs and references writing. All authors reviewed the first draft and discussed the contained concepts. Conflict of interests: RP has received honoraria, travel grants and/or research grants from Shire HGT, Genzyme Corporation Inc. and BioMarin; FB has received travel grants from Genzyme Corporation Inc.; PR has received travel grants from BioMarin. Received for publication: 22 October 2012. Revision received: 1 January 2013. Accepted for publication: 11 January 2013. This work is licensed under a Creative Commons Attribution NonCommercial 3.0 License (CC BY- NC 3.0). ©Copyright R. Parini et al., 2013 Licensee PAGEPress, Italy Cardiogenetics 2013; 3(s1):e2 doi:10.4081/cardiogenetics.2013.s1.e2 Non-commercial use only