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Cardiogenetics 2013; 3(s1):exxxx3(s1):e2

Molecular basis, diagnosis storage of (GAGs), previ- ously called mucopolysaccharides.1 The defi- Correspondence: Rossella Parini, Department of and clinical management of ciency of one of the participating in Pediatrics, San Gerardo Hospital, Via Pergolesi mucopolysaccharidoses the GAGs degradation pathway causes progres- 33, 20900 Monza, Italy. sive storage in the lysosomes and consequently Tel. +39.039.2333286 - Fax: +39.039.2334364. E-mail: [email protected] Rossella Parini,1 Francesca Bertola,2 in the cells and results in tissues and organs 3 Pierluigi Russo dysfunction. The damage is both direct or by Key words: mucopolysaccharidoses (MPS), heart, 1UOS Malattie Metaboliche Rare, activation of secondary and tertiary pathways heart and MPS, genetics and MPS. 2 Department of Pediatrics, Fondazione among which a role is played by inflammation. The incidence of MPSs as a group is reported Acknowledgments: RP and PR acknowledge MBBM, Azienda Ospedaliera San between 1:25000 and 1:45000.3 At present 11 dif- patients and their families and Drs. Andrea Gerardo, University of Milano-Bicocca; ferent deficiencies are involved in Imperatori and Lucia Boffi who collaborated in 2Consortium for Human Molecular the clinical cardiological evaluation of MPSs MPSs producing 7 distinct clinical phenotypes1 Genetics, University of Milano-Bicocca; patients. RP thanks Fondazione Pierfranco e (Table 1).4 Depending on the enzyme deficien- 3UO Department of Cardiology, Azienda Luisa Mariani of Milano for providing financial cy, the catabolism of dermatan sulphate, support for clinical assistance to metabolic Ospedaliera San Gerardo, Monza, Italy heparan sulphate, keratan sulphate, chon- patients and Mrs. Vera Marchetti, the secretary of droitin sulphate, or hyaluronan may be the Metabolic Unit, for her very useful help in impaired, singly or in combination. Diagnosis is managing the patients. suspected clinically and then confirmed by bio- Abstract chemical, enzymatic and molecular tests. For all Contributions: RP, PR, manuscript preparation and first draft; FB, first draft of paragraph What the MPSs types prenatal diagnosis is available are mucopolysaccharidoses for the molecular biol- Mucopolysaccharidoses (MPSs) are a group through enzymatic or molecular analysis. ogist?; PR first draft of paragraph What are of hereditary, monogenic disorders caused by In contrast to a recent past when there was mucopolysaccharidoses for the cardiologist?; RP, lysosomal storage of glycosaminoglycans. Their only palliative treatment for these diseases, other paragraphs and references writing. All incidence as a group is between 1:25,000 and now many specific treatments like hematopoi- authors reviewed the first draft and discussed the 1:45,000. At present 11 different enzyme defi- etic stem cell transplantation (HSCT) in containedonly concepts. ciencies are know to be responsible of 7 similar selected cases (severe MPS I) and enzyme Conflict of interests: RP has received honoraria, but distinct diseases. The diagnosis is suspected replacement therapy (ERT) for MPS I, II, and travel grants and/or research grants from Shire 5 clinically but must be confirmed through bio- VI are available. These treatments are able to HGT, Genzyme Corporation Inc. and BioMarin; FB chemical, enzymatic and molecular analysis. improve the clinical course of the diseaseusehas received travel grants from Genzyme Prenatal diagnosis is feasible for each disease. mainly if started early. This brings along the Corporation Inc.; PR has received travel grants The phenotype worsens with age, due to pro- responsibility for the clinician to recognize from BioMarin. gressive storage, and mainly involves mucosal these diseases at the first signs to allow access tissue, upper airways and lungs, bones and to treatment before a severe damage has been Received for publication: 22 October 2012. Revision received: 1 January 2013. joints, central and peripheral nervous system, established. In this respect pilot studies of Accepted for publication: 11 January 2013. heart, liver, eye and ear. Any type of MPSs, is newborn screening are ongoing.6 In recent characterized by a wide variability of phenotype years, availability of specific treatments, gen- This work is licensed under a Creative Commons ranging from a severe fetal-neonatal disease to eral improvement of palliative medical care Attribution NonCommercial 3.0 License (CC BY- an attenuated form diagnosed in adult individu- and improvement of recognition of mild cases NC 3.0). als. Recently new treatments, like hematopoiet- presenting later in life, have produced a grow- ic stem cell transplantation and enzymatic ing number of adult MPSs patients in relative- ©Copyright R. Parini et al., 2013 Licensee PAGEPress, Italy replacement therapy, became available for many ly good conditions who need to be cared after Cardiogenetics 2013; 3(s1):e2 of these disorders entailing the urgency of early by adult services for metabolic diseases. doi:10.4081/cardiogenetics.2013.s1.e2 diagnosis to allow access to therapies. Thanks to Preparing the right setting for successful tran- therapies these patients have a longer life than sition of these patients from pediatric to adult in the past and this implies that also Non-commercialpalliative service is a difficult task that all the centers for treatments, of which the cardiological ones have MPSs in Europe are dealing with. GAGs. The qualitative analysis is then suggest- a prominent part, must be undertaken diligently. ed. Diagnosis is established by enzyme assay in The cardiologist may face, more frequently than cultured fibroblasts, leukocytes or serum. In expected, with the need to diagnose a patient clinical laboratories residual enzyme activity is with MPS who was not recognized by other spe- Diagnosis of not accurately quantified and is thus not a valid cialists. The echocardiographic features of these mucopolysaccharidoses predictor of disease outcome.1 Conclusive diag- patients are typical and may help in the clinical diagnosis. The future probably deserves to these and prenatal diagnosis nosis is performed with molecular analysis con- disorders other new treatments or combination firming results of enzyme activity and allowing therapies, which might further improve progno- Diagnosis of MPSs is suspected clinically on an early prenatal diagnosis. sis of these diseases. the basis of a number of clinical features (red When a patient is diagnosed with a MPS dis- flags; Table 2),1,4,7,8 but it needs a laboratory con- order, genetic counseling is recommended. firmation. Urine GAGs analysis is a preliminary Genetic counseling can provide the family with diagnostic test. There is a risk of false positive information regarding the genetics, inheri- Introduction and negative results which is less frequent if a tance, and recurrence risks for the specific MPS 24 h urine sample is collected and analyzed. condition in their family. The mucopolysaccharidoses (MPSs) are a There are patients with a normal GAGs urine When the mutations in the family are known, group of monogenic disorders due to lysosomal concentration but an abnormal distribution of prenatal diagnosis can be performed by molecu-

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lar analysis of tissue obtained by chorionic vil- mented in previous studies and present in of 653 amino acids.11 So far, more than 180 lus or amniocytes sampling. Enzymatic assay is homozygous state or in heterozygous state with mutations have been reported in MPS I often performed as well to guarantee the minor a second known severe mutation and when the patients spread along the entire coding and risk of misdiagnosis. If the mutations are not clinical phenotype is established according to splicing regions without appreciable mutation- completely known the prenatal diagnosis may standardized scoring index of severity. al hot spots. The two most common worldwide be performed with the enzymatic assay alone on Mutations resulting in large alterations of mutations are the nonsense p.W402X and chorionic villus sampling or amniocytes.1 sequence, as nonsense mutations or frame- p.Q70X associated to severe phenotype and shifts insertion/deletions, are generally identi- much frequent in North Europe. p.G51D and fied in patients affected by the severe form of p.P496R are specific Italian severe mutations the disease. Missense and splicing mutations whereas p.P533R, spread to Mediterranean What are are sometime compatible with some enzymatic countries, is associated to an intermediate- residual activity and then result in a wide range severe phenotype.12 mucopolysaccharidoses of phenotypes spanning the entire spectrum for the molecular biologist? from severe to attenuated.1 Mucopolysaccharidosis type II The updating of mutations identified is (MPS II) All MPSs have an autosomal recessive trans- available on Human Gene Mutation Database (http://www.hgmd.org). IDS gene maps to Xq28 and mission with the exception of MPS type II encodes for iduronate-2-sulphatase. Patients (Hunter syndrome) that is X-linked.9 Mucopolysaccharidosis type I are hemizygous males or, very rarely, females Most of MPSs have been identified and due to autosomal-X chromosomal transloca- cloned in the 90’s.10 Only HSGNAT gene, respon- (MPS I) tion or non-random X-chromosome inactiva- sible for MPS IIIC has been cloned later in tion, or in an only case homozygosis for a 2006.10 Although mutations are frequently novel IDUA gene maps to chromosome point mutation.13 or private mutations, genotype-phenotype cor- 4p16.3 More than 400 genetic alterations have been relations are feasible in around 50% of cases The gene contains 14 coding exons and described along the 9 exons and splicing when mutations identified are already docu- encodes for alfa-L-iduronidase, a polypeptide regions:only the most frequent mutations occur- use Table 1. Nomenclature and classification of mucopolysaccharidoses. Disease Defective enzyme GAG storage material Gene (localization) Estimated incidence* MPS I (Hurler, Hurler/Scheie, Scheie) a-L-iduronidase Dermatan sulphate, heparan sulphate IDUA (4p16.3) 1:84,000 MPS II (Hunter) Iduronate-2-sulphatase Dermatan sulphate, heparan sulphate IDS (Xq28) 1:196,000 MPS IIIA (Sanfilippo A) Heparan N-sulphatase Heparan sulphate SGSH (17q25.3) 1:92,000 MPS IIIB (Sanfilippo B) N-acetyl-a-glucosaminidase Heparan sulphate NAGLU (17q21.1) 1:157,000 MPS IIIC (Sanfilippo C) Acetyl-CoA: a-glucosamide Heparan sulphate HSGNAT (8p11.1) 1:714,000 N-acetyltransferase MPS IIID (Sanfilippo D) N-acetylglucosamine-6-sulphatase Heparan sulphate GNS (12q14) 1:1,000,000 MPS IVA (Morquio A) Galactose-6-sulphatase Keratan sulphate, chondroitin-6-sulphate GALNS (16q24.3) 1:131,000 MPS IVB (Morquio B) b-galactosidase Keratan sulphate GLB1 (3p21.33) 1:1,250,000 MPS VI (Maroteaux-Lamy) Arylsulphatase B Dermatan sulphate ARSB (5q11-q13) 1:120,000 MPS VII (Sly) b-glucuronidase Dermatan sulphate, heparan sulphate, GUSB (7q21.11) 1:588,000 Non-commercialchondroitin sulphate MPS IX Hyaluronan HYAL1 (3p21.3-p21.2) Only four cases reported *Mean incidence estimated by Muenzer, 2011.4 MPS, mucopolysaccharidoses; GAG, glycosaminoglycans.

Table 2. Red flags: warning signs for early diagnosis of mucopolysaccharidoses. Most frequent signs and symptoms of onset Most severe forms Attenuated forms Age of onset 0-2 years 3-8 years Organomegaly YN Heart valve disease YY Hernias Y Y/N Skeletal abnormalities Y (gibbus!) N Joint contractures NY Eye disease NY Y, yes; N, no.

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ring at the Arg468 codon were identified in beta-galactosidase (GLB1 gene, chromosome severe Hunter patients. 3p21.33). Both genes are fully characterized, What are Due to the presence of a distal pseudogene consisting in 14 and 16 exons respectively. Of mucopolysaccharidoses (IDS2) containing sequences highly homolo- overall near 170 mutations, missense muta- gous to IDS gene, complete or partial gene tions are the most prevalent in GALNS gene for the pediatrician? deletions and large rearrangements are fre- and p.I113F, p.G301C and p.R386C are the quently identified, in about 10% of patients most frequently identified in severe MPS IVA MPSs virtually affect all organs and tissues affected by the severe form. For this reason, patients.20 Mutations in GLB1 gene are about and show a progressive worsening with time. sequencing of genomic DNA is often followed 160 and give rise to two distinct lysosomal Most of the newborns appear healthy at birth by cDNA analysis.14 storage disorders, the MPS IVB and, in most and later, in the next months or years, they cases, the GM1 gangliosidosis. MPS IVB slowly develop the signs of the disease. Main Mucopolysaccharidosis type III patients are very rarely diagnosed and signs are skeletal abnormalities, short stature, organomegaly, heart valve defects, hearing (MPS III) p.W273L is considered a common mutation among only a little set of 20 mutations recog- deficits, corneal clouding, retinopathy, glauco- MPS III or Sanfilippo syndrome is classified nized so far.21 ma, brain involvement with progressive cogni- in 4 subtypes deriving from 4 different tive delay. Quality of life and life span are gen- enzyme defects involved in the degradation of 4,7 Mucopolysaccharidosis type VI erally substantially reduced. Although similar, the heparan sulphate. Four different genes each type of MPSs has a peculiar phenotypic encode each of these enzymes. (MPS VI) expression: MPS I is the prototype of MPSs and MPS IIIA is due to deficiency of the enzyme MPS VI, also known as Maroteaux-Lamy syn- includes all the signs and symptoms listed heparan N-sulphatase whose encoding gene drome, is caused by the deficiency of the aryl- above. MPS II is similar to MPS I but with a later is SGSH gene, localized to chromosome sulfatase B. This lysosomal enzyme is codified clinical onset of somatic signs in the severe 17q25.3 and consisting in 8 exons. The over by the ARSB gene, comprising 8 exons, located form and affecting only males. MPS VI is also 100 mutations identified to date produce phe- to chromosome 5q11-q13. Most of the near 140 affecting many organs and tissues and similar notype from severe to milder form. The most mutations identified so far are spread along to MPS I, but these patients do never have frank common mutation is the missense p.R245H ARSB gene. Despite the high incidence of rare cognitiveonly delay. MPS III presents in the classic associated to severe form as well as p.S66W, or private mutations, a panel of common muta- forms with very mild somatic involvement and p.R74C, c.1080delC, and p.Q380R. p.S298P tions has been profiled: p.Y210C associated to fast and profound mental decline. MPS IV has a results instead in milder phenotypes.15,16 the intermediate phenotype; p.L72R, p.R160X major skeletal involvement and short stature, MPS IIIB (enzyme N-acetyl-a-glucosa- and p.R315Q associated to the severe pheno- with preserved cognition. Both MPS III and 22 use minidase) is caused by mutations along the 6 type. MPS IV generally have a slower progression of exons of the NAGLU gene mapped to chromo- heart valve disease25 and survive longer than some 17q21.1. Near 140 mutations have been Mucopolysaccharidosis type VII severe MPS I, II and VI phenotypes. These dif- identified so far, most of them occurring once (MPS VII) ferences are at least partly due to the differ- or with low frequency. Only a small number of MPS VII or Sly syndrome is characterized by ences in the major accumulated substrate for common mutations have been identified in the deficiency of the enzyme beta-glu- each type of MPSs. For example those who have MPS IIIB patients: the p.R279X and p.R626X curonidase coded by GUSB gene. The gene, prevalent heparan sulphate excretion (MPS I, associated to a severe phenotype.17 located to chromosome 7q21.11, contains 12 II, III), are known to be at risk of mental delay MPS IIIC disorder is caused by deficiency of exons. Among the next to 50 mutations identi- in the severe forms.1 Besides, within the same acetyl-CoA:a-glucosamide N-acetyltransferase fied to date, the most prevalent are the mis- type of MPSs, the phenotypic spectrum is huge- caused by mutations in HSGNAT gene located sense mutations and the p.L176F is the most ly variable, as a result of the different severity of at chromosome 8p11.1 and composed by 18 representative associated to the attenuated mutations and overall genetic background of exons. From its recent cloning in 2006, only 60 phenotype. the single individual. mutations have been identified.18 Due to the presence of several pseudogenes, MPS IIID is the least common of the diagnostic techniques should be adopted first, Presenting signs and symptoms Sanfilippo syndromes. The defective enzyme is to allow the screening of correct exons and N-acetylglucosamine-6-sulphatase encodedNon-commercial by splicing regions of GUSB gene, second, to iden- Severe forms the gene GNS. It contains 14 exons and is 23 tify novel possible large rearrangements. Most frequently present in the first 2-3 years mapped to chromosome 12q14. Only near 20 of life with skeletal abnormalities (kyphosis mutations have been identified so far, with an Mucopolysaccharidosis type IX with lumbar gibbus between 6 and 12 months in unexpected high proportion of large deletions (MPS IX) severe MPS I (Figure 1), and others after the compared to other MPS III subtypes. For this MPS IX is the rarest form of MPS due to a first year of life in the other MPSs), often reason it is recommended to complete the deficiency of hyaluronidase enzyme implicat- accompanied by dysmorphic facies (Figure 2A), molecular diagnosis with quantitative tech- ed in degradation. The gene organomegaly (Figure 2B), multiple hernias niques if genomic analysis by sequencing implicated is HYAL1 consists in 3 coding (inguinal, umbilical), abnormally frequent and results negative.19 exons mapped to chromosome 3p21.31 where, severe upper airways infections, otitis and together with HYAL2 and HYAL3, constitutes a chronic rhinitis. Heart failure and severe valve Mucopolysaccharidosis type IV multigene family for lysosomal hyluronidase disease in the first year of life are reported as (MPS IV) genes. To date, only one patient diagnosed in the first presenting symptom in a minority of MPS IV or Morquio syndrome is classified 1996 and further three, belonging to a second cases with MPS I, MPS VI and in a MPS III in two forms: MPS IVA, due to the deficiency family in 2011, have been described world- patient.25-27 In other patients, mainly with MPS of N-acetylgalactosamine 6-sulphate sulfatase wide.24 Identification of other MPS IX patients III but also with MPS II, mental retardation at 2- (GALNS gene, chromosome 16q24.3) and will help to better define the clinical features 3 years may be the only, or most evident, pre- MPS IVB, resulting from the deficiency of and genotype phenotype correlation. senting sign.

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Attenuated forms Attenuated forms have widely variable clini- cal presentations with different presenting signs at different ages, often one or few organs only clinically manifest the disease.8,28 The most frequent signs of presentation are car- diac valve disease, eye disease, carpal tunnel syndrome and joints contractures.

Long-term evolution The disease invariably gets on in years with slow worsening of the first symptoms and addi- tion of others.

Severe and intermediate forms Severe and intermediate forms show coars- ening of facial appearance (prominent fore- head, scaphocephaly, flat nasal bridge with broad nose, abnormalities of dental shape and position and macroglossia) (Figures 3 and 4), persistence and often relapse after surgery, of multiple hernias, severe ear, nose, throat (ENT) involvement with obstructive sleep Figure 1. Early appearance of gibbus at 9 months of life and X-ray evolution after few years. apnea, noisy breathing, frequent middle ear infections and combined conductive-neu- only rosensory hearing loss. All this is sustained by enlarged tongue, redundant mucosal tissue, hyperplasia of adenoids and tonsils, deformi- ties of ossicles, narrow trachea (Figure 5), use thickened vocal cord. Treatments with continu- ous positive airways pressure during the night, adenotonsillectomy, ventilating ear tubes insertion and hearing aids may be needed.5 Heart signs and symptoms also worse with time and often pharmacological treatment and/or valvular replacement become necessary. Bone deformities become more and more evident (Figure 6): the term used to collective- ly indicate the typical skeletal deformities of MPSs is dysostosis multiplex.29 It includes short stature, scaphocephalic head, odontoid hypoplasia, anterior hypoplasia of lumbar ver- Figure 2. Coarse facies (A) and prominent abdomen (B) in a 2-month old infant affected tebrae with kyphosis, spade-like hands, by mucopolysaccharidosis type I Hurler. enlarged diaphyses of the long bones with irregular appearance of the metaphyses, small femoral heads and coxa valga, hipNon-commercial dislocation, short and thickened clavicles, oar-shaped ribs, tracheal deformities and joint contractures. Joint stiffness is a common and typical feature of all MPSs except for Morquio syndrome in which the joints tend to be hypermobile, sec- ondary to ligamentous laxity.4 The major risk of instability of the hypoplastic odontoid process is run by MPS IV and in the order MPS I, MPS VI and MPS II. It can result in life- threatening atlanto-axial subluxation.30 Spinal cord compression may also occur in the dorsal and lumbar spine.31 Magnetic resonance imag- ing of the cervical spine is recommended at the time of diagnosis and at regular intervals thereafter. Surgery to stabilize the spine by posterior fusion can be life saving. Both cen- Figure 3. A and B) Same patient, affected by mucopolysaccharidosis type I H/S at 2 and 8 years old. tral and peripheral nervous system are affect-

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Figure 5. Tracheal stenosis in mucopolysac- Figure 4. A and B) Progressive coarsening of facial appearance. Same patient with charidosis type II patient (multidetector mucopolysaccharidosis type II at 12 and 26 years of age respectively. computed tomography).

ed in the MPSs. Prominent perivascular spaces, hydrocephalus, brain atrophy, gliosis only and white matter changes are common32,33 (Figure 7). The communicating hydrocephalus that occurs in MPSs is usually slowly progres- sive, with mild or absent clinical symptoms. use Nerves entrapment syndromes, particularly of the carpal tunnel are common, but most patients lack typical symptoms until severe compression occurs.34 Seizures commonly occur in the oldest patients, and may be con- trolled by anti-epileptic drugs.35 Corneal cloud- ing in MPS I, IV, VI and VII may lead to signifi- cant visual disability. Glaucoma and cataracts have been reported in MPS I and MPS VI and in MPS III and IV respectively.36 In severe forms of MPS I and MPS II, and in MPS III profound developmental delay is the rule after the first years of life. Hyperactivity with developmental delay is often the first sign of disease in MPS III patients who, as already Figure 6. Generalized skeletal disease in mucopolysaccharidoses. mentioned, show very few somatic signs of MPS. This is particularly true for MPSNon-commercial IIIB37 (Figure 8).

Attenuated forms In the attenuated forms progression of signs and symptoms is much slower than in the severe ones. These patients may have a pres- entation apparently limited to one only organ and are often seen by a specialist for years before reaching the diagnosis.8,28 They are often followed by rheumatologists, orthopedics and cardiologists. Ocular symptoms and signs are common in the attenuated forms that may develop corneal clouding, glaucoma and retinal degeneration resulting in peripheral vision and night blindness. These patients usually do not have severe cognitive delay. Progressive Figure 7. Brain atrophy, gliosis, white matter changes in 10-year old mucopolysacchari- cord compression with resulting cervical dosis type I Hurler patient receiving only palliative treatment.

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myelopathy due to dura mater thickening has patients need surgery, they must be treated by MPSs are under evaluation: substrate degrada- been described in the mild forms of MPS I, II a well informed and skilled anesthesiological tion,42 site specific administration of ERT,43 and VI.30,38,39 team, aware of all risks of MPSs.40,41 chaperone administration44 and cell and gene- based therapeutic approaches.45-49 Anesthesiological risk Specific treatments MPSs patients are exposed to a major risk of ERT is presently available for MPS I, MPS II complications from general anesthesia and and MPS VI and is currently under evaluation What are intubation. The same patients who are at in a phase III international trial for MPS IV. mucopolysaccharidoses major risk of atlanto-axial instability have ERT does not cross the blood-brain barrier and major risk for anesthesia (MPS IV>MPS I and therefore is not effective in the brain. This is for the cardiologist? VI>MPS II). The risk is also directly related to the main reason why HSCT is strongly recom- the severity of the disease and increases with mended for severe MPS I. It is not recommend- Cardiac involvement in MPSs is mainly rep- age. Short neck, enlarged tongue, ENT abnor- ed for severe MPS II and MPS III as well resented by valve abnormalities, intramyocar- malities, vertebral malformations, and chest because results of HSCT in these diseases dial infiltration and accumulation (pseudo- deformities, concur together to increase tech- were discouranging.4 Besides the combined hypertrophy) (Figure 9), endocardial fibroelas- nical difficulties. Therefore when MPSs use of HSCT and ERT, other treatments for tosis, narrowing of coronary arteries and, in

only use

Figure 8. Adult mucopolysaccharidosis (MPS) type III B patient without typical Figure 9. Increased thickness of the interventricular septum in a 8-month old facial features of MPS. mucopolysaccharidosis type I patient. Non-commercial

Figure 10. Mucopolysaccharidosis type I in a 5-year old girl. Figure 11. Mucopolysaccharidosis type I in a 8-month old patient. Dilatation of the aortic root. Mitral valve involvement.

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rare cases, anomalies of the conduction tissue. patient, together with biochemical and molec- Tissue conduction anomalies Moreover, pulmonary hypertension may arise ular data will help in identifying the different There are some case reports documenting as a consequence of airways obstruction, diseases. the development of atrioventricular block.71 deformity of the ribs or the accumulation of Conduction abnormalities are rare in pediatric GAGs in the walls of pulmonary vessels.25,50-57 Coronary artery disease population, and might probably be prevented Thoracic and abdominal aorta arteriopathy A discrepancy has been reported between by enzyme replacement therapy or hematopoi- (Figure 10) and hypertension may represent the relatively frequent absence of symptoms etic stem cell transplantation. part of the clinical spectrum of the disease.51 It and the evidence of significant coronary is common opinion that the damage is more involvement at postmortem examination. This relevant and faster when dermatan sulphate is is believed to be due to the antithrombotic Therapy for valve disease in accumulated (type I, II, VI), because this GAG activity of dermatan sulphate and heparan sul- mucopolysaccharidoses naturally prevails in the valves and the vessel’s phate that avoid the formation of the thrombus As suggested by ACC/AHA 2008 guidelines for walls.58 Microscopically there is evidence of in the stenotic coronaries. On the other hand, the management of patients with valvular heart cytoplasmatic vacuoles in endothelial cells, the clinical picture may arise at any age. A case disease72 there is no indication supporting the myocytes and fibroblasts.59 There are fibro- of severe cardiac failure with fatal outcome in use of medications (i.e. ACE inhibitors or other blasts that appear enlarged and foamy and are a ten months infant has recently been vasodilatator drugs) in asymptomatic patients surrounded by collagen fibers.60 These, in the described.67 The autopsy showed the occlusion with various degrees of aortic or mitral regurgi- opinion of Braunlin et al.58 are engaged in of the left main coronary artery. A minimal tation and preserved left ventricular function. In attempted but ineffective valve repair. coronary involvement several years after patients with severe valve regurgitation and left hematopoietic stem cell transplantation has ventricular dilatation the use of diuretics and Valves abnormalities also been described.68 ACE-inhibitors is justified. Brain natriuretic Valves abnormalities are the most frequent peptide (BNP) and its precursor, NT-proBNP, cardiac findings: mitral valve is often involved Endocardial fibroelastosis may be of help to distinguish between cardiac (Figure 11), less frequently aortic valve, and in It is a rare sign that essentially occurs in and pulmonary dyspnoea, which is a frequent some cases tricuspid (Figure 12) and pul- infants. Typically, at echocardiography exami- diagnostic dilemma in MPS.73 Although MPS monary valve are involved too. only nation the endocardium appears fibrotic with patients have a high anesthesiological risk,40,41 69 The valve damage appears to have a typical dense echogenity. the current surgical approach is to follow gener- evolution, starting with valve insufficiency and al guidelines for valve disease. However, the progressing to stenosis during the disease Aortic artery involvement usedecision to perform a surgical intervention in course (Figure 13A-C). The natural history of Besides thoracic and abdominal aorta arteri- these patients besides severity of valve disease, the defect is probably sustained by deposition of opathy,51 dilatation and reduced elasticity of the will also take into consideration the age and 61 GAGs secondarily associated to inflamation ascending aorta has been described. It is proba- type of MPS, the current prognosis and specific and eventually followed by fibrosis. In the very bly related to the harmful effect of the GAGs on risk for the single patient and the expectations early phase the aspect of the valves is similar to the formation of tropoelastin for abnormal con- of the family. If the decision is taken to perform a mixomatous valve with a redundancy of the tent or abnormal structure of elastin.70 surgery, it will be done only in hospitals where thickened leaflets and consequent coaptation defect (Figure 13B). The pathogenesis of this precocious aspect has been attributed to the impaired degradation of the GAGs.62,63 Subsequently there is a defect of apposition (the first phase of normal valve closure in which the margins of the leaflets touch symmetrically between them) due to the irregular edge of the leaflets. This also happens very soon. With the progression of the disease, the leaflets become thickened and fibrous, often with a prevalent retraction of one of them and with anNon-commercial involve- ment of the subvalvular structure. In this phase, the apposition defect becomes the main mecha- nism of valve regurgitation. At the end, the cal- cification and the stiffness of the leaflets and the sub-valvular apparatus may occur and cause valve stenosis.64 Valve damage in MPS is quite typical, and differs from other common cardiological con- ditions, including mitral valve prolapse and rheumatic fever. Other lysosomal storage dis- eases like mucolipidosis type II and III (Figure 14)65 and Farber disease (Figure 15A and B) may show valve aspects similar to that of MPSs. In Fabry disease there may be mild valve damage but the main finding is the increased thickness of the ventricular walls.66 Figure 12. Tricuspid valve involvement in mucopolysaccharidosis type I. The comprehensive clinical evaluation of the

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Figure 15. A) Farber syndrome. Mitral valve aspect in a 1-year old boy; B) Mitraluse valve regurgitation.

Figure 13. A) Mitral valve with thickened, retracted leaflets in mucopolysaccharidosis type II; B) Mitral valve defect of apposi- tion and coaptation; C) Mitral regurgitation. Non-commercial

Figure 16. A) A 4-year old girl with mucopolysaccharidosis type Figure 14. A 21-year old boy affected by mucolipidosis type III: I. Increased thickness of interventricular septum (9 mm); B) Same the echocardiographic aspect of the aortic valve is similar to patient after 7-month enzymatic replacement therapy (interven- mucopolysaccharidosis valve disease. tricular septum 6 mm).

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the anesthesiological team is well aware of the world and results of pre-symptomatic diag- saminoglycan storage disorders: a review. risks and able to afford them.40,41 In the very nosis and early treatment will be available very Biochem Res Int 2012;2012:471325. young patients the policy is to postpone as soon. It is possible that they will even modify 11. Scott HS, Guo XH, Hopwood JJ, Morris CP. much as possible the time of intervention, in our convictions, for example about scarce effi- Structure and sequence of the human a-L- order to prevent the need of a second prosthesis cacy of HSCT in MPS II and III. iduronidase gene. Genomics 1992; 13: replacement later in follow-up. Improvement of traditional care, HSCT and 1311-3. Enzyme replacement therapy or hematopoi- ERT have already modified survival and quali- 12. Bertola F, Filocamo M, Casati G, et al. IDUA etic stem cell transplantation are effective on ty of life of MPSs patients: there are an mutational profiling of a cohort of 102 pseudohypertrophy (Figure 16A and B) but not increasing number of MPSs patients reaching European patients with mucopolysacchari- much on long term valve diseases.68,74 However adult age in good or at least discrete clinical dosis type I: identification and characteri- the valvular damage could be potentially conditions and expected to survive for a longer zation of 35 novel α-L-iduronidase (IDUA) reversible or limited during the initial phase of time than 20 years ago. Many organizational, alleles. Hum Mutat 2011;32:E2189-210. accumulation of GAGs, before the progression ethical and medical reasons drive to shifting 13. Scarpa M, Almássy Z, Beck M, et al. toward the retraction and distortion of the these kinds of patients to adult medical servic- Mucopolysaccharidosis type II: European leaflets occurs. es. Often both clinicians and patients are not recommendations for the diagnosis and ready to this change and transition to adult multidisciplinary management of a rare service may be impossible or very hard. It is disease. Orphanet J Rare Dis 2011;6:72. necessary that pediatric and adult centers for 14. Lualdi S, Regis S, Di Rocco M, et al. Conclusions and future lysosomal diseases prepare transition for the Characterization of iduronate-2-sulfatase perspectives next years, discussing procedures and modali- gene-pseudogene recombinations in eight ties, together with hospital administrations patients with Mucopolysaccharidosis type and patients’ organizations. II revealed by a rapid PCR-based method. MPSs, both in the severe and attenuated Hum Mutat 2005;25:491-7. forms, are devastating syndromes, substantially 15. Yogalingam G, Hopwood JJ. Molecular reducing quality and duration of life. In the last genetics of mucopolysaccharidosis type 20 years many achievements have been reached References IIIAonly and IIIB: Diagnostic, clinical, and bio- by the medical community in the knowledge of logical implications. Hum Mutat 2001;18: their genetic background and pathogenetic 1. Neufeld EF, Muenzer J. The mucopolysac- 264-81. mechanisms. The better understanding of inter- charidoses. In: Scriver CR et al., eds. The 16. Valstar MJ, Neijs S, Bruggenwirth HT, et and intracellular complex interactions, has metabolic and molecular bases of inherit-use al. Mucopolysaccharidosis type IIIA: clini- allowed developing ERT for most of them. ERT ed disease. New York: McGraw Hill; 2001. cal spectrum and genotype-phenotype cor- has been shown to stabilize or attenuate pro- pp. 3421-3452. relations. Ann Neurol 2010;68:876-87. 5 gression of signs and symptoms of the disease. 2. Clarke LA. Pathogenesis of skeletal and 17. Beesley CE, Jackson M, Young EP et al. When started very early ERT seems probably connective tissue involvement in the Molecular defects in Sanfilippo syndrome able even to substantially reduce the skeletal mucopolysaccharidoses: type B (mucopolysaccharidosis IIIB). J 75,76 burden in these patients. No effect has since storage is merely the instigator. Rheumato- Inherit Metab Dis 2005;28:759-67 . been demonstrated on the eye and mainly on logy (Oxford) 2011;50 Suppl 5:13-8. 18. Fedele AO, Hopwood JJ. Functional analy- central nervous system involvement. Efforts are 3. Nelson J, Crowhurst J, Carey B, Greed L. sis of the HGSNAT gene in patients with currently ongoing to set up treatments able to Incidence of the Mucopolysaccharidoses mucopolysaccharidosis IIIC (Sanfilippo C reach these sanctuaries: ERT local administra- in Western Australia. Am J Med Genet Syndrome). Hum Mutat 2010;31:E1574-86. tion, different preparations of ERT, small mole- 2003;123A;310-3. 19. Valstar MJ, Bertoli-Avella AM, Wessels MW, cules or cells or gene therapy reaching the CNS. 4. Muenzer J. Overview of the mucopolysac- et al. Mucopolysaccharidosis type IIID: 12 At present the only treatment reaching the CNS charidoses. Rheumatology 2011;50 Suppl new patients and 15 novel mutations. Hum and able to modify the cognitive evolution of 5:4-12. Mutat 2010;31:E1348-60. patients is HSCT, a procedure known since 5. Valayannopoulos V, Wijburg FA. Therapy for 20. Tomatsu S, Montaño AM, Nishioka T, et around 30 years and used so far to treat many the mucopolysaccharidoses. Rheumatology al. Mutation and polymorphism spectrum MPS I Hurler patients.77 Its harmfulnessNon-commercial and (Oxford) 2011;50 Suppl 5:49-59. of the GALNS gene in mucopolysacchari- related mortality have progressively slowed 6. Nakamura K, Hattori K, Endo F. Newborn dosis IVA (Morquio A). Hum Mutat 2005; down with years and recently HSCT has also screening for lysosomal storage disorders. 26:500-12. been proposed as a treatment for those Am J Med Genet C Semin Med Genet 2011; 21. Caciotti A, Garman SC, Rivera-Colón Y, et Hurler/Scheie patients who slowly develop men- 157:63-71. al. GM1 gangliosidosis and Morquio B dis- tal retardation.78 Unfortunately HSCT in Hunter 7. Muenzer, J. The mucopolysaccharidoses: a ease: an update on genetic alterations and (MPS II) and Sanfilippo (MPS III) syndromes heterogeneous group of disorders with clinical findings. Biochim Biophys Acta did not obtain good results in the past and is variable pediatric presentations. J Pediatr 2011;1812:782-90. then not recommended for these syndromes.77 2004;144: 527-34. 22. Karageorgos L, Brooks DA, Pollard A, et al. Although their benefits, both ERT and HSCT 8. Thomas JA, Beck M, Clarke JTR, Cox GF. Mutational analysis of 105 mucopolysac- are far from completely curing the MPSs. Childhood onset of Scheie syndrome, the charidosis type VI patients. Hum Mutat Therefore other promising treatments are cur- attenuated form of mucopolysaccharidosis 2007;28:897-903. rently under evaluation for a future use in I. J Inherit Metab Dis 2010;33:421-7. 23. Tomatsu S, Montaño AM, Dung VC, et al. humans, alone or in combination. However, as 9. Hopwood JJ, Bunge S, Morris, et al. Mutations and polymorphisms in GUSB it is clear that, whatever the treatment is, it Molecular basis of mucopolysaccharidosis gene in mucopolysaccharidosis VII (Sly may be more effective if started at the onset of type II: mutations in the iduronate-2-sul- Syndrome). Hum Mutat 2009;30:511-9. symptoms, neonatal screening for treatable phatase gene. Hum Mutat 1993;2:435-42. 24. Imundo L, Leduc CA, Guha S, et al. A com- MPSs disorders is ongoing in some regions of 10. Coutinho MF, Lacerda L, Alves S. Glyco- plete deficiency of Hyaluronoglucosa-

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minidase 1 (HYAL1) presenting as familial 40. Walker RWM, Ellwood J. The Management 54. Mohan UR, Hay AA, Cleary MA, et al. juvenile idiopathic arthritis. J Inherit of difficult intubation in children. Paediatr Cardiovascular changes in children with Metab Dis 2011;34:1013-22. Anesth 2009;19 Suppl 1:77-87. mucopolysaccharide disorders. Acta 25. Fesslovà V, Corti P, Sersale G, et al. The nat- 41. Ingelmo PM, Parini R, Grimaldi M, et al. Paediatr 2002;91:799-804. ural course and the impact of therapies of Multidetector computed tomography 55. Rigante D, Segni G. Cardiac structural cardiac involvement in the mucopolysac- (MDCT) for preoperative airway assess- involvement in mucopolysaccharidoses. charidoses. Cardiol Young 2009;19:170-8. ment in children with mucopolysacchari- Cardiology 2002; 98:18-20. 26. Hirth A, Berg A, Greve G. Successful treat- doses. Minerva Anestesiol 2011;77:774-80. 56. Scarpa M, Barone R, Fiumara A et al. ment of severe heart failure in an infant 42. Jakóbkiewicz-Banecka J, Piotrowska E, Mucopolysaccharidosis VI: the Italian with Hurler syndrome. J Inherit Metab Dis Gabig-Cimińska M, et al. Substrate reduc- experience. Eur J Pediatr 2009;168:1203-6. 2007;30:820. tion therapies for mucopolysaccharidoses. 57. Braunlin EA, Harmatz PR, Scarpa M, et al. 27. Hayflick S, Rowe S, Kavanaugh-McHugh A, Curr Pharm Biotechnol 2011;12:1860-5. Cardiac disease in patients with mucopoly- et al. Acute infantile cardiomyopathy as a 43. Chen A, Dickson P. Intrathecal enzyme saccharidosis: presentation, diagnosis and presenting feature of mucopolysaccharido- replacement therapy to treat spinal cord management. J Inherit Metab Dis 2011;34: sis VI. J Pediatr 1992;120:269-72. compression in mucopolysaccharidosis: 1183-97. 28. Munoz-Roja MV, Bay L, Sanchez L. Clinical Overview and rationale. J Pediatr Rehabil 58. Braunlin E, Tolar J, Mackey-Bojack S, et al. manifestations and treatment of mucopoly- Med 2010;3:7-11. Clear cells in the atrioventricular valves of saccharidosis type I patients in Latin 44. de Ruijter J, Valstar MJ, Wijburg FA. infants with severe human muchopolysac- America as compared with the rest of the Mucopolysaccharidosis type III (Sanfilippo charidosis (Hurler syndrome) are activated world J Inherit Metab Dis 2011;34:1029-37. Syndrome): emerging treatment strate- valvular interstitial cells. Cardiovascular 29. Gillespie JB, Siegling JA. Dysostosis multi- gies. Curr Pharm Biotechnol 2011;12:923- Pathol 2011;20:315-21. plex. J Bone Joint Surg Am 1940;22:171-5. 30. 59. Robbins S, Kumar V, Cotran R. Genetic dis- 30. White KK. Orthopaedic aspects of mucopo- 45. Langford-Smith A, Wilkinson FL, Langford- orders. In: Robins S, Kumar V, Kotran R, lysaccharidoses. Rheumatology (Oxford) Smith KJ, et al. Hematopoietic stem cell eds. Pathologic basis of disease. 4th edn. 2011;50 Suppl 5:26-33. and gene therapy corrects primary neu- Philadelphia: W.B. Saunders Company; 31. Kachur E, Del Maestro R. Mucopolysaccha- ropathology and behavior in mucopolysac- only1989. pp. 149-51. ridoses and spinal cord compression: case charidosis IIIA mice. Mol Ther 2012;20: 60. Marwick TH, Bastian B, Hughes CF, Bailey report and review of the literature with 1610-21. BP. Mitral stenosis in the Maroteaux-Lamy implications of bone marrow transplanta- 46. Smith LJ, Martin JT, O’Donnell P, et al. syndrome: a treatable cause of dyspnoea. tion. Neurosurgery 2000;47:223-9. Effect of neonatal gene therapy onuse lumbar Postgrad Med J 1992;68:287-8. 32. Rasalkar DD, Chu WCW, Hui J et al. spine disease in mucopolysaccharidosis VII 61. Simonaro CM. Cartilage and chondrocyte Pictorial review of mucopolysaccharidosis dogs. Mol Genet Metab 2012;107:145-52. pathology in the mucopolysaccharidoses: with emphasis on MRI features of brain 47. Visigalli I, Delai S, Politi LS, et al. Gene the role of glycosaminoglycan-mediated and spine. Br J Radiol 2011;84:469-77. therapy augments the efficacy of hemato- inflammation. J Pediatr Rehabil Med 2010; 33. Manara R, Priante E, Grimaldi M, et al. poietic cell transplantation and fully cor- 3:85-8. Brain and spine MRI features of Hunter rects mucopolysaccharidosis type I pheno- 62. Grande-Allen KJ, Griffin BP, Ratliff NB, et disease: frequency, natural evolution and type in the mouse model. Blood 2010;116: al. Glucosaminoglycan profiles of mixoma- response to therapy. J Inherit Metab Dis 5130-9. tous mitral leaflets and chorde parallel the 2011;34:763-80. 48. Tomanin R, Zanetti A, Zaccariotto E, et al. severity of mechanical alterations. J AM 34. White K, Kim T, Neufeld JA. Clinical Gene therapy approaches for lysosomal Coll Cardiol 2003;42:271-7. assessment and treatment of carpal tunnel storage disorders, a good model for the 63. Rabkin E, Aikawa M, Stone JR, et al. syndrome in the mucopolysaccharidoses. J treatment of mendelian diseases. Acta Actived interstizial myofibroblasts express Pediatr Rehabil Med 2010;3:57-62. Paediatr 2012;101:692-701. catabolic enzymes and mediate matrix 35. Muenzer J, Beck M, Eng CM, et al. 49. Pan D. Cell- and gene-based therapeutic remodeling in myxomatous heart valves. Multidisciplinary management of Hunter approaches for neurological deficits in Circulation 2001;104:2525-32. syndrome. Pediatrics 2009;124:e1228-39. mucopolysaccharidoses. Curr Pharm Bio- 64. Tan CT, Shaff HV, Miller Jr FA, et al. Valvular 36. Summers CG, Ashworth JL. OcularNon-commercial mani- technol 2011;12:884-96. heart disease in four patients with festations as key features for diagnosing 50. Nelson J, Shields MD, Mulholland HC. Maroteaux-Lamy syndrome. Circulation mucopolysaccharidoses. Rheumatology Cardiovascular studies in the mucopoly-sac- 1992;85:188-95. (Oxford) 2011;50 Suppl 5:34-40. charidoses. J Med Genet 1990;27:94-100. 65. Satoh Y, Sakamoto K, Fujibayashi Y, et al. 37. Moog U, van Mierlo I, van Schrojenstein 51. Taylor DB, Blaser SI, Burrows PE, et al. Cardiac involvement in mucolipidosis. Lantman-deValk HM, et al. Is Sanfilippo Arteriopathy and coarctation of the abdom- Importance of non invasive studies for type B in your mind when you see adults inal aorta in children with mucopolysac- detection of cardiac abnormalities. Jpn with mental retardation and behavioral charidosis: imaging findings. Am J Heart J 1983;24:145-5. problems? Am J Med Genet C Semin Med Roentgenol 1991;157:819-23. 66. Kampmann C, Linhart A, Baehner F, et al. Genet 2007;145C:293-301. 52. Wippermann CF, Beck M, Schranz D, et al. Onset and progression of the Anderson- 38. Modi M, Singla V, Khandelwal N, et al. Mitral and aortic regurgitation in 84 Fabry disease related cardiomyopathy. Int Maroteaux-Lamy syndrome (mucopolysac- patients with mucopolysaccharidoses. Eur J Cardiol 2008;130:367-73. charidosis VI) presenting as familial J Pediatr 1995;154:98-101. 67. van den Broek L, Baekx AP, Coolen H, et al. myelopathy. Int J Neurosci 2011;121:337-40. 53. Dangel JH. Cardiovascular changes in Fatal coronary artery disease in an infant 39. O’Brien DP, Cowie RA, Wraith JE. Cervical children with mucopolysaccharide storage with severe mucopolysaccharidosis tipe I. decompression in mild mucopolysacchari- diseases and related disorders - clinical Pediatrics 2011;127:e1343-6. dosis type II (Hunter syndrome). Childs and echocardiographic findings in 64 68. Braunlin EA, Stauffer NR, Peters CH, et al. Nerv Syst 1997;13:87-90. patients. Eur J Pediatr 1998;157:534-8. Usefulness of bone marrow transplanta-

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tion in the Hurler syndrome. Am J Cardiol Task Force on Practice Guidelines (Writing 75. Gabrielli O, Clarke LA, Bruni S, Coppa GV. 2003;92:882-6. Committee to revise the 1998 guidelines for Enzyme-replacement therapy in a 5- 69. Fong LV, Menahem S, Wraith JE. the management of patients with valvular month-old boy with attenuated presympto- Endocardial fibroelastosis in mucopolysac- heart disease). Endorsed by the Society of matic MPS I: 5-year follow-up. Pediatrics charidosis type VI. Clin Cardiol 1987;10: Cardiovascular Anesthesiologists, Society 2010;125:e183-7. 362-4. for Cardiovascular Angiography and 76. McGill JJ, Inwood AC, Coman DJ, et al. 70. Hinek A, Wilson SE. Impaired elastogene- Interventions, and Society of Thoracic Enzyme replacement therapy for muco- sis in Hurler disease. Dermatan sulfate Surgeons. J Am Coll Cardiol 2008;52:e1-142. polysaccharidosis VI from 8 weeks of age-a accumulation linked to deficiency in 73. McMurray JJ, Adamopoulos S, Anker SD. sibling control study. Clin Genet 2010;77: elastin- binding protein and elastic fiber ESC Guidelines for the diagnosis and treat- 492-8. assembly. Am J Pathol 2000;156:925-38. ment of acute and chronic heart failure 77. Rovelli AM. The controversial and chang- 71. Hishitani T, Wakita S, Isoda T et al. 2012: The Task Force for the Diagnosis and ing role of haematopoietic cell transplan- Sudden death in Hunter syndrome caused Treatment of Acute and Chronic Heart tation for lysosomal storage disorders: an by complete atrioventricular block. J Failure 2012 of the European Society of update. Bone Marrow Transplant 2008;41 Pediatr 2000;136:268-9. Cardiology. Developed in collaboration with Suppl 2:S87-9. 72. Bonow RO, Carabello BA, Chatterjee K, et al. the Heart Failure Association (HFA) of the 78. de Ru MH, Boelens JJ, Das AM, et al. En- 2008 focused update incorporated into the ESC. Eur J Heart Fail 2012;14:803-69. zyme replacement therapy and/or hemato- ACC/AHA 2006 guidelines for the manage- 74. Braunlin EA, Berry JM, Whitley CB. poietic stem cell transplantation at diagno- ment of patients with valvular heart disease: Cardiac findings after enzyme replace- sis in patients with mucopolysaccharidosis a report of the American College of ment therapy for mucopolysaccharidosis type I: results of a European consensus pro- Cardiology/American Heart Association type I. Am J Cardiol 2006;98:416-8. cedure. Orphanet J Rare Dis 2011;6:55.

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