A clinical study of 77 patients with mucopolysaccharidosis type II

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1 Acta Pædiatrica ISSN REGULAR ARTICLE A clinical study of 77 patients with mucopolysaccharidosis type II Ida VD Schwartz (ida.ez@terra.com.br) 1,2,Márcia G Ribeiro 3,João G Mota 4, Maria Betânia P Toralles 4, Patrícia Correia 5, Dafne Horovitz 5, Emerson S Santos 6, Isabella L Monlleo 6,7, Agnes C Fett-Conte 8, Ruy P Oliveira Sobrinho 9, Denise YJ Norato 9, Anna Carolina Paula 10, Chong A Kim 10, Andréa R Duarte 11, Raquel Boy 12, Eugênia Valadares 13, Maria De Michelena 14, Paulina Mabe 15, Cyro D Martinhago 16,João M Pina-Neto 16, Fernando Kok 17, Sandra Leistner-Segal 2, Maira G Burin 2, Roberto Giugliani 1,2 1.Department of Genetics, UFRGS, Porto Alegre, Brazil 2.Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Brazil 3.Clinical Genetics Service, IPPMG-UFRJ, Rio de Janeiro, Brazil 4.Department of Paediatrics, UFBA, Salvador, Brazil 5.Fernandes Figueira Institute, FIOCRUZ, Rio de Janeiro, Brazil 6.Department of Paediatrics, UNCISAL, Maceió, Brazil 7.Clinical Genetics Service, University Hospital, UFAL, Maceió, Brazil 8.Department of Molecular Biology, FAMERP, São José do Rio Preto, Brazil 9.Department of Medical Genetics, UNICAMP, Campinas, Brazil 10.Genetics Unit, Instituto da Criança, USP, São Paulo, Brazil 11.Medical Genetics Service, IMIP, Recife, Brazil 12.Mother and Child Department, UERJ, Rio de Janeiro, Brazil 13.Department of Propedeutics, Faculty of Medicine UFMG, Belo Horizonte, Brazil 14.Universidad Peruana Cayetano Heredia, Lima, Peru 15.Programa de Enfermedades Metabólicas, Hospital de Niños Dr Exequiel González Cortés, Santiago, Chile 16.Department of Genetics, School of Medicine, USP, Ribeirão Preto, Brazil 17.Child Neurology Service, School of Medicine, USP, São Paulo, Brazil Key Words Clinical findings, Hunter syndrome, Lysosomal storage diseases, Mucopolysaccharidosis type II, South America Correspondence IVD Schwartz, Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos, 2350, , Porto Alegre, RS, Brazil. Tel: Fax: ida.ez@terra.com.br DOI: /j x Abstract Aim: This study aims to assess the clinical features of 77 South American patients (73 Brazilian) with mucopolysaccharidosis type II (MPS II). Methods: Details of the patients and their disease manifestations were obtained from a review of medical records, interviews with the patients and/or their families, and physical examination of the patients. Results: Mean birth weight was 3360 g, median age at onset of symptoms was 18 months and median age at diagnosis was 6 years. For the whole sample (median age, 8.2 years; range, years), neurological degeneration, typical pebbly skin lesions, seizures and extensive dermal melanocytosis were found in 23.3, 13.0, 13.0 and 1.3% of the cases, respectively. The most frequently reported echocardiogram abnormality was mitral valve regurgitation. Refraction errors were the most common ophthalmological manifestation. The following characteristics were found to be associated with the severe form of MPS II: earlier age at biochemical diagnosis, higher levels of urinary glycosaminoglycans, language development delay, behavioural disturbances, poor school performance and mental retardation. Conclusion: Our results suggest that there is a considerable delay between the onset of signs and symptoms and the diagnosis of MPS II in Brazil (and probably in South America as well), and that many complications of this disease are underdiagnosed and undertreated. Therefore, the implementation of programmes aiming to increase the awareness of the disease, the availability of biochemical diagnostic tests and the provision of better support to affected patients is urgently needed. Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is an X-linked lysosomal storage disease caused by deficient activity of the enzyme iduronate-2-sulphatase (IDS). IDS is one of the enzymes responsible for the degradation of the glycosaminoglycans (GAGs) heparan sulphate and dermatan sulphate. In patients with MPS II, partially degraded GAGs accumulate inside lysosomes and are excreted in high amounts in the urine (1). Estimates of the incidence of this disease range from 1 in to 1 in male newborns (2 10) The papers by Young et al. (11,12) and Young and Harper (13,14) are the largest published studies describing the clinical presentation of MPS II. They conclude the following: 1. Although MPS II is associated with a broad spectrum of clinical severity, two main forms can be recognized (severe and mild/attenuated) 2. The differences between the severe and attenuated forms are mainly due to the progressive development of neurodegeneration in the severe form 3. The onset of neurodegeneration (developmental regression) was reported at a mean age of 8.0 years (mode, 6.5 years) C 2007 The Author(s)/Journal Compilation C 2007 Foundation Acta Pædiatrica/Acta Pædiatrica , pp

2 MPS II natural history Schwartz et al. 4. A low IQ in childhood does not necessarily predict the development of neurodegeneration 5. The age at onset of symptoms and the presence/absence of behavioural disturbances are predictive factors of ultimate disease severity in very young patients. With the advent of novel forms of treatment for MPS II, such as enzyme replacement therapy (15), the description of other large series of patients with MPS II is extremely important. The purpose of this study was to analyse 77 South American patients with MPS II, in order to better characterize the clinical presentation of this disorder and to identify factors associated with the development of neurodegeneration. METHODS This observational study was approved by the local Institutional Review Board and by the National Research Ethics Committee of Brazil. The study sample examined were all patients investigated at the Laboratory of Inborn Errors of Metabolism (LIEM) at the Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Brazil between 1982 and The LIEM is a reference laboratory for the diagnosis of lysosomal diseases in Brazil as well as for several other South American countries. Patients with MPS II and/or their legal representatives were contacted through their local physicians. Informed consent from the patient/legal representative was obtained before participation in the study. Following consent, a clinical assessment form was completed, based on a review of the medical records, an interview with the patient and/or family, and a physical examination of the patient. The following data were obtained mainly through an interview with the family: age at onset of symptoms, early clinical manifestations and presence of signs and symptoms of obstructive sleep apnoea, hypoacusia and delayed motor and language development. For patients who were deceased at the time of the study, information on the last physical examination recorded in the medical history was considered. In cases where there were serial evaluations of the same parameter, we considered the results of the most recent evaluation. The cases with known neurological outcomes were classified as either having the severe form (presence of neurodegeneration) or the attenuated form (patient older than 10 years of age with no neurodegeneration) of MPS II. Neurodegeneration was defined as the progressive loss of acquired neurological functions. Patients under the age of 10 years who did not show signs of neurodegeneration were considered as having an unknown neurological outcome. Only variables for which information was available from more than 50% of the patients were analysed. The curves of the National Center of Health Statistics (16) were used to define the percentiles of weight and length/height, and the curves of Nellhaus (17) were used to define the percentiles of head circumference. Categorical variables were summarized using frequencies and percentages. Continuous variables with a normal distribution were summarized using mean, standard deviation (SD) and maximum and minimum values. Continuous variables with asymmetric distribution were summarized using median, interquartile range (25 75th percentile) and maximum and minimum values. Student s t-test and the Mann Whitney U-test were used for the analysis of continuous variables with normal and asymmetric distribution, respectively. Analysis of categories of variables was conducted using the 2 -test or Fisher s exact test. Correlation between the continuous variables was made by Spearman s correlation coefficient. The level of statistical significance adopted was 5% (p = 0.05). RESULTS By 2003, 120 patients with MPS II had been diagnosed at the LIEM (one female, 119 male). We were able to contact 81 of these patients and 77 (one female, 76 male; 73 Brazilian, two Peruvian, one Chilean, one Argentinean) agreed to participate in this study (Table 1). The patients studied came from 59 unrelated families. None of the patients had received a bone marrow transplantation or enzyme replacement therapy. Median age at inclusion in the study was 8.2 years (range, years; female patient, 5.0 years). In total, 34.7% of the patients were 5 years of age, 32.3% were 6 10 years of age, 26.5% were years old and 6.5% were 21 years of age or older. Biochemical findings All patients presented with significantly reduced IDS activity in plasma, leukocytes or fibroblasts and normal activity of another sulphatase. The level of at least one other sulphatase was checked to exclude the diagnosis of multiple sulphatase deficiency. Median age at biochemical diagnosis was 6 years. Urinary GAG measurements had been conducted in 57 of the 77 patients and levels were found to be elevated in all of these patients. A significant inverse correlation between levels of urinary GAGs and age (r = 0.436, p = 0.001) was found (Fig. 1). Median plasma IDS activity was 5.9 nmoles/ 4 h/ml (interquartile range, nmoles/4 h/ml; reference values, nmoles/4 h/ml). No significant correlation was found between plasma IDS activity and urinary levels of GAGs (r = 0.067, p = 0.626). Birth data Intercurrent events were reported during the pre and/or perinatal period in 20 patients, the most frequently reported being maternal hypertension (in 5/20 patients). Mean birth weight was ± g (Table 1); 23.4% of patients weighed more than g at birth and 7.8% weighed more than g. Mean length at birth was 50.0 ± 2.1 cm. Extensive dermal melanocytosis at birth was reported in one patient. Clinical findings All patients, including the female patient, presented with the typical clinical features of MPS II. The clinical data obtained are summarized in Table 1. Interestingly, before the diagnosis of MPS II was confirmed, one of the patients was prescribed thyroxine for presumed hypothyroidism and another 64 C 2007 The Author(s)/Journal Compilation C 2007 Foundation Acta Pædiatrica/Acta Pædiatrica , pp

3 Schwartz et al. MPS II natural history Table 1 Characteristics of the 77 patients with mucopolysaccharidosis type II (MPS II) included in this study All patients (n = 77) Severe form (n = 18) Attenuated form (n = 17) p-value Age at onset of symptoms (months) Range Median (interquartile range) 18.0 ( ) 24.0 ( ) 39.0 ( ) Age at biochemical diagnosis (years) Range < Median (interquartile range) 6 (4 10) 7 (5 10) 14 (11 21) Age at last evaluation (years) Range < Median (interquartile range) 8.2 ( ) 9.6 ( ) 15.5 ( ) Alive (n) Mean age at death (years) (range) 15.1 ( ) 14.6 ( ) 17.0 ( ) 0.49 n Plasma IDS activity (nmoles/4 h/ml) Median (interquartile range) 5.9 ( ) 3.6 ( ) 4.7 ( ) 0.26 Urine GAGs level (mg/mmol creatinine) Median (interquartile range) 41.0 ( ) 40.0 ( ) 30.5 ( ) Mean weight at birth ± SD (kg) ± ± ± Symptoms of obstructive sleep apnoea 37/77 (48%) 8/18 (44.4%) 9/17 (53%) Hypoacusia 46/77 (59.7%) 8/18 (44.4%) 14/17 (82.3%) Seizures 10/77 (13%) 5/18 (27.7%) 1/17 (5.9%) Short stature (< 2 SD) 32/61 (52.5%) 13/14 (92.8%) 9/10 (90%) Macrocephaly (> 2SD) 27/68 (39.7%) 6/16 (37.5%) 5/12 (41.6%) Palpebral ptosis 17/77 (22.1%) 5/18 (27.7%) 6/17 (35.3%) Pebbly skin lesion 10/77 (13%) 3/18 (16.6%) 2/17 (11.7%) Poor school performance NE 18/18 (100%) 5/17 (29.4%) < Mental retardation NE 18/18 (100%) 2/17 (11.7%) < Motor development delay NE 12/16 (75.0%) 7/17 (41.1%) Language development delay NE 10/11 (90.9%) 6/17 (35.3%) Behavioural disturbances NE 11/11 (100%) 0/17 (0%) < Patients with the severe form of MPS II are defined as those who show neurodegeneration (not mental retardation). Patients with the attenuated form are defined as those who are older than 10 years of age with no neurodegeneration (see Section Methods ). GAGs, glycosaminoglycans; IDS, iduronate-2-sulphatase; NE, not evaluated. Reference values: nmoles/4 h/ml. Presence/absence based on the judgment of assistant physician, as no IQ test or formal neurological evaluation was performed. Data available only for patients classified as having the severe or the attenuated forms. Considered only for patients aged < 18 years. Urinary GAGs (mg/mmol creatinine) 130 Patients 120 Healthy control Age (years) Figure 1 Level of urinary glycosaminoglycans (GAGs) according to age in 57 patients with mucopolysaccharidosis type II (r = 0.436, p = 0.001). The open circles correspond to the upper normal limits for each age group. Reference values for upper normal limits according to age group (mg/mmol creatinine): < 6 months, 52.0; 6 months to < 1 year, 31.0; 1 year to < 2 years, 29.0; 2 years to < 3 years, 21.0; 3 years to < 14 years, 12.0; 14 years to < 16 years, 7.0 and > 16 years, 5.1. C 2007 The Author(s)/Journal Compilation C 2007 Foundation Acta Pædiatrica/Acta Pædiatrica , pp

4 MPS II natural history Schwartz et al. A SD Weight (kg) SD Age (years) B 65 Head circumference (cm) SD 2 SD Age (years) C Height (cm) SD SD Age (years) Figure 2 (A) Weight according to age in 60 patients with mucopolysaccharidosis type II. Reference values are plotted according to Hamill et al. (16). (B) Head circumference according to age in 68 patients with mucopolysaccharidosis type II. Reference values are plotted according to Nellhaus (17). (C) Height according to age in 61 patients with mucopolysaccharidosis type II. Reference values are plotted according to Hamill et al. (16). was prescribed penicillin for prevention of suspected recurrent rheumatic fever. The charts for weight, head circumference and height at the last evaluation for patients under 18 years are presented in Figure 2. Weight records show that some children weighed more than 2 SD above the mean until the age of 5 years (Fig. 2A). Between 5 and 10 years of age, for most children weight remained between ± 2 SD of the mean. After 10 years 66 C 2007 The Author(s)/Journal Compilation C 2007 Foundation Acta Pædiatrica/Acta Pædiatrica , pp

5 Schwartz et al. MPS II natural history of age, however, for most children, values recorded were more than 2 SD below the mean. Measurement of head circumference showed that macrocephaly was common at all ages (Fig. 2B). Records of height show that height was above 2 SD for most patients until approximately 7.8 years of age. After this age, height was between 2 and 6 SD of the mean for the majority of patients (Fig. 2C). The median age at the onset of symptoms was 18.0 months (interquartile range, months) (Table 1). Joint contractures, macrocephaly, coarsened facial features and increased abdominal volume/hepatosplenomegaly were the most frequently reported early clinical manifestations. Twenty-four of the 77 patients were receiving medication at the time of the evaluation: the main reasons for this were respiratory/pulmonary problems (9), behavioural disturbances (7), seizures (5) and cardiac insufficiency (4). No patient was taking medication for joint pain, glaucoma or arterial hypertension. At the time of this study, nine of the patients had died. Mean age at death was 15.1 years (range, years) (Table 1). The causes of death reported were: sudden death (one case), cachexia (one case), cardiomyopathy (one case), pneumonia (one case), bleeding during surgical intervention (one case), aspiration (one case) and unknown (three cases). Follow-up with other specialists Of the 77 patients evaluated, 40 had undergone at least one ophthalmological evaluation. The results of this examination were reported to be abnormal in 14 patients. The most frequently found abnormalities were refraction errors (13 cases). Corneal clouding was present in one patient and papilloedema was described in one patient with hydrocephalus. Signs and symptoms of obstructive sleep apnoea were reported by 37 of the 77 patients; however, sleep studies had only been conducted in ten patients. The results of the sleep evaluations were abnormal in seven of the ten patients; however, only four of these patients were using continuous positive airway pressure. Hypoacusia was reported by patients/relatives in 46 of the 77 cases; however, one or more audiometric tests had only been conducted in 26 patients. The results of these tests were reported as abnormal in 23 patients. Most patients presented with a combined conductive and sensorineural hearing disorder. Only four of these 23 patients were using a hearing aid. Seizures were reported by ten, and hydrocephalus by three, of the 77 patients. An echocardiogram had been performed once or more in 38 of the patients. Table 2 lists the echocardiogram findings. Mitral valve regurgitation was the most frequent finding (n = 24), and was reported to be mild in 14 patients (median age, 11.5 years; interquartile range, ) and moderate in five patients (median age, 11.0 years; interquartile range, ). Information regarding the severity of mitral valve regurgitation was not available for the remaining five patients. Table 2 Echocardiogram findings in 38 patients with mucopolysaccharidosis type II Severe Attenuated Not Total (%) form form classified Findings (n = 38) (n = 7) (n = 11) (n = 20) Normal echocardiogram 5 (13.1) Valve regurgitation Mitral 24 (63.1) Aortic 15 (35.5) Tricuspid 4 (10.5) Pulmonary 2 (5.3) Valve thickening Mitral 14 (36.8) Aortic 11 (28.9) Tricuspid 2 (5.3) Pulmonary 2 (5.3) Valve stenosis Mitral 1 (2.6) Aortic 2 (5.3) Pulmonary Tricuspid LV dilatation 5 (13.1) LVH and/or interventricular 4 (10.5) septal thickening LV relaxation deficit 2 (5.3) Left atrial dilatation 2 (5.3) Pulmonary hypertension 2 (5.3) Reduced ejection fraction Other Small ventricular septal 2 (5.3) defect Small atrial septal defect 1 (2.6) Persistent arterial duct 1 (2.6) Bicuspid aortic valve 1 (2.6) Median age of patients, 7.0 years; range, years; interquartile range, years (n = 38); median age for the severe form, 11.0 years; median age for the attenuated form, 16.0 years; median age for patients not classified, 4.5 years. LV, left ventricular; LVH, LV hypertrophy. Analysis of cases with known neurological outcome Classification of the clinical severity of MPS II was possible for 35 of the 77 patients. Those patients with a history of neurological degeneration were considered as having the severe form of MPS II (n = 18), whereas patients older than 10 years of age with no history of neurological degeneration (n = 17) were considered to have the attenuated form (see Section Methods ). The patients with severe disease were unrelated, while the 17 patients with the attenuated form of the disease came from 13 different families. A comparison between these two groups is presented in Table 1. The groups differed significantly. Patients with the severe form of the disease were younger at biochemical diagnosis (p < 0.001) and at their last evaluation (p < 0.001). They also had a higher level of urinary GAGs (p = 0.042) and were more likely to have a history of behavioural disorders (p < 0.001), poor school performance (p < 0.001), mental retardation (p < 0.001) language development delay (p = 0.006). Hypoacusia was more frequent in patients with the attenuated form (p = 0.049). The onset of symptoms was before 2.5 years of age for 86.6% of patients with the severe C 2007 The Author(s)/Journal Compilation C 2007 Foundation Acta Pædiatrica/Acta Pædiatrica , pp

6 MPS II natural history Schwartz et al. form and 43.7% of patients with the attenuated form. In the severe form, the mean age at the onset of neurological degeneration was 6.2 years (range, years), and the mean age at death was 14.6 years. The most frequently reported behavioural disturbances among patients with the severe form of MPS II were hyperactivity (eight cases), aggression (three cases) and temper tantrums (two cases). None of the patients with the severe form of MPS II attended regular school. Of the 17 patients with the attenuated form, five presented with poor school performance; three of these patients had never attended regular school and were classified by their physicians as mentally retarded. The remaining two patients were not classified as mentally retarded and their poor performance was, presumably, a result of hypoacusia and socioeconomic deprivation. Three of the patients with the attenuated form of MPS II were deceased at the time of the study (mean age at death, 17.0 years). Records show that these three patients performed poorly at school and two were reported to be mentally retarded. Patients with the severe and attenuated forms of MPS II also differed in terms of early clinical presentation. In patients with severe MPS II, the most frequently reported first signs of the disease were macrocephaly, delayed motor development, language development and behavioural problems. For patients with the attenuated form, the first reported signs were joint contractures, skeletal alterations and increased abdominal volume/hepatosplenomegaly. DISCUSSION This is the largest series of South American patients with MPS II reported to date. Our data show clearly that MPS II is an early-onset disease. The reported median age of onset of signs and symptoms (all patients, 18 months; severe form, 24 months; attenuated form, 39 months) appears to be earlier than the mean values found by Young and Harper (severe form, 2.47 years; attenuated form, 4.30 years) (13,14). Review of the medical records showed evidence of much earlier manifestations. Some patients had presented with hernias at birth and many had undergone surgery for umbilical/inguinal hernia during their first year of life. This type of manifestation, however, is not usually recognized by physicians and family members as an early manifestation of MPS II. Thus, the age at onset of symptoms may be earlier than indicated in the current study. Despite the many early clinical manifestations, the diagnosis of MPS II was obtained a long time after the onset of symptoms (median age, 6 years). We consider that the delay in diagnosis was mainly due to the structure of the public health systems in Brazil and other South American countries, which are not set up appropriately for the diagnosis of rare diseases such as MPS II. In these countries, most patients depend on the public health system, whose priority is the management of more frequent pathologies, such as infectious diseases and those resulting from malnutrition. Thus, there are few specialists in the field of metabolic diseases, few laboratories able to perform diagnostic tests and limited access to these scarce facilities. As to survival, it is interesting to point out that 67% of our sample was younger than 10 years of age, and that only 6.5% were older than 20 years of age. We believe this difference in age distribution is due to the higher frequency of the severe form of MPS II in our population, and to the fact that death in this form usually takes place between 10 and 15 years of age (1). According to Young et al. (13), the severe form of MPS II is 3.38 times more frequent than the attenuated form. The following are additional aspects to be highlighted. (1) Although the mean birth weights found for the total Brazilian sample (data not shown) and for the patients with the severe form of the disease (Table 1), who were all Brazilians, were not significantly higher than that reported by Nóbrega (18) for Brazilian male newborns, 23.4% of MPS II patients weighed more than the 90th percentile ( g) at birth. High birth weight has been described previously in the severe form of MPS I (19). (2) Five of the 38 (13.1%) MPS II patients investigated by echocardiogram presented with minor heart malformations (Table 2). The association of these alterations with MPS II may be coincidental, as congenital heart disease occurs in approximately 6 per 1000 total live births, being the most common congenital malformation (20). However, Wippermann et al. (21) and Mohan et al. (22) have reported the occurrence of minor heart malformations in three out of 84 (3.6%) and four out of 99 (4%) patients with MPS, respectively, values that are higher than would be expected if there was no association. (3) One of our patients presented with extensive dermal melanocytosis (also known as extensive Mongolian spots) at birth. Several authors have reported the occurrence of this type of alteration in lysosomal storage diseases, especially in the severe form of MPS I and in GM1 gangliosidosis (for review, see Ref. 23). To date, we are aware of another eight patients with MPS II and extensive dermal melanocytosis (24,25). The possible higher birth weight and frequency of minor heart malformations and extensive dermal melanocytosis observed in our sample suggest that the IDS deficiency has effects in the early prenatal period, interfering with the normal processes of organogenesis and histogenesis. Our findings for head circumference and height curves are similar to those published by Young and Harper (13,14). However, we have not found other publications in the literature that include weight curves for patients with MPS II. The lack of complementary investigations carried out by appropriate specialists following diagnosis is striking. Although there are no international guidelines for the followup of patients with MPS disorders, it seems clear that, due to the high frequency of hypoacusia, obstructive sleep apnoea, and ophthalmological and cardiological problems, these patients should be evaluated periodically by cardiologists and ophthalmologists, and that appropriate sleep studies and audiometric assessments should also be carried out (1,15,26,27). The lack of complementary investigations of these patients is reflected in the small number of patients that 68 C 2007 The Author(s)/Journal Compilation C 2007 Foundation Acta Pædiatrica/Acta Pædiatrica , pp

7 Schwartz et al. MPS II natural history are receiving symptomatic treatment. For example, although 46 patients complained of hypoacusia, only four made use of a hearing aid. The results from echocardiogram and ophthalmological evaluations are in accordance with the literature. The most frequent echocardiographic alteration reported was mitral valve regurgitation (21,22). Corneal clouding and glaucoma seem rare in MPS II (1,26). Comparison of the severe and attenuated forms of MPS II At present, the factors responsible for the neurodegeneration that characterizes the severe form of MPS II are not fully understood. Several studies have tried to attribute the clinical variability to the genotype and consequent residual activity of the enzyme; however, most of these studies have been unsuccessful (1,28,29). Our analysis showed that patients with the severe and attenuated forms of MPS II do not differ in terms of levels of plasma IDS activity, weight at birth, median age at the onset of symptoms, history of seizures, presence of symptoms of obstructive sleep apnoea and delay in motor development, or the presence of macrocephaly, pebbly skin lesions, palpebral ptosis and short stature. Statistically significant differences were found in the levels of urinary GAGs and rate of occurrence of hypoacusia, behavioural disorders, poor school performance and mental retardation. The difference found in levels of urinary GAGs may be due to the fact that there is a significant negative correlation between the level of urinary GAGs and age in normal healthy persons until about 16 years of age (30), and that the median age of patients with the attenuated form was higher than that of patients with the severe form; however, we do not know whether the pattern of urinary excretion of GAGs in individuals with MPS is similar to that found for healthy individuals. We believe that the absence of a statistically significant difference between the two groups in terms of the median age at the onset of symptoms, could be partly explained by biased parental memory, as this difference was reported by Young et al. (12). Mean age at death for patients with the severe form (mean, 14.6 years; range, years) appears to be similar to that reported in the literature (mean, 11.7 years; range, years) (14). On the basis of the CNS involvement in patients with the severe form of MPS II it might be expected that motor delay would be more marked in this group than in those with the attenuated form. We believe that the absence of a difference between the two forms of MPS II in terms of motor delay may be because both groups present with joint contractures during infancy/childhood. The higher frequency of hypoacusia found in individuals with the attenuated form could be explained by the fact that this complication is more easily noticeable in this group of individuals. CONCLUSION As reported by Young et al. (12) the severe form of the disease seems to be evident earlier than the attenuated form, hindering the development of the cognitive skills of patients, causing behavioural disorders during childhood. Neurodegeneration is typically observed around the age of 4 10 years. Delay in motor development may happen in both forms. However, mental retardation, language delay, behavioural disorders and seizures are infrequent in patients with the attenuated form. Our data analysis clearly shows that there is a lack of awareness of MPS II among health professionals and a lack of structure for the follow-up and treatment of these patients in Brazil. Improvement in conditions for clinical and biochemical diagnosis and the introduction of novel drugs should take place alongside the development of centres qualified for the management of MPS patients. The establishment of guidelines for the follow-up and treatment of these patients is essential. ACKNOWLEDGEMENTS This study was conducted with the support of the National Organization for Rare Disorders (grant from the Roscoe Brady Program) and CAPES/Brazil. It is dedicated to all South American families with MPS. Conflict of Interests Statement All of the authors have declared no conflict of interest. References 1. Neufeld E, Muenzer J. The mucopolysaccharidoses. 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