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Pediatrics International (2014) 56, 520–525
doi: 10.1111/ped.12281
Original Article
Mucopolysaccharidosis type VI in Russia, Kazakhstan, and Central and Eastern Europe Agnieszka Jurecka,1,4 Ekaterina Zakharova,6 Loreta Cimbalistiene,7 Nina Gusina,8 Vera Malinova9, Agnieszka Róz˙dz˙yn´ska-S´wia˛tkowska,2 Adam Golda,5 Anna Kulpanovich,8 Gulnara Kaldenovna Abdilova,10 Elena Voskoboeva6 and Anna Tylki-Szyman´ska3 1 Department of Medical Genetics, 2Anthropology Laboratory, 3Department of Pediatrics, Nutrition and Metabolic Diseases, Children’s Memorial Health Institute, Warsaw, 4Department of Genetics, University of Gdan´sk, Gdan´sk, 5Department of Cardiology, Gliwice General Hospital, Gliwice, Poland, 6Department of Inherited Metabolic Diseases, Research Center for Medical Genetics, Moscow, Russian Federation, 7Center for Medical Genetics, Santariskiu Klinikos, Vilnius University Hospital, Vilnius, Lithuania, 8Genetics Unit, National Medical Center “Mother and Child”, Minsk, Belarus, 9Department of Pediatrics and Adolescence Medicine, First Faculty of Medicine, General University Hospital, Charles University, Prague, Czech Republic and 10Department of Pediatrics, Research Center of Pediatrics and Pediatric Surgery, Almaty, Kazakhstan Abstract
Background: The aim of this study was to describe the natural clinical course, incidence and prevalence of mucopolysaccharidosis type VI (MPS VI) in Russia, Kazakhstan, and Central and Eastern Europe. Methods: Patients (n = 49) were identified by retrieving the data from eight international centers for MPS VI. Results: A large number of patients presented with an attenuated phenotype (33%). Height and genotype were related to the severity of the disease, while no clear trend was observed between height and urinary glycosaminoglycan level. A high prevalence of the p.R152W mutation was observed both in the whole series (42%) as well as in Russian patients (43%). The incidence rate ranged from 0.0363 to 0.64 per 100 000 live births in Poland and Lithuania, respectively. Conclusions: The observed high p.R152W carrier frequency in the Lithuanian population may indicate a possible founder effect in this region. The high prevalence of this mutation observed in the whole series, as well as the Slavic origin of the majority of patients homozygous for this mutation, suggest that p.R152W may be of Slavic, not Lithuanian origin. Resettlement of the Polish population after World War II resulted in dilution of the prevalence of carriers in Poland and a very low MPS VI incidence.
Key words genotype–phenotype analysis, incidence, Maroteaux–Lamy syndrome, natural history, prevalence, urinary glycosaminoglycan.
Mucopolysaccharidosis type VI or Maroteaux–Lamy syndrome (MPS VI; MIM 253200) is a rare autosomal recessive lysosomal storage disorder caused by deficient activity of N-acetylgalactosamine-4-sulfatase (4-sulfatase, arylsulfatase B; ARSB; EC 3.1.6.12), an enzyme involved in the degradation of dermatan sulfate.1 The reported birth prevalence of MPS VI varies, ranging from 1 in 43 261 to 1 in 1 505 160 live births.2,3 The rate of clinical progression of MPS VI varies considerably, generating a wide continuous clinical spectrum from severe to relatively attenuated.1,4 The most prominent and debilitating manifestations usually arise in the musculoskeletal, cardiorespiratory, and nervous systems, but individual cases vary considerably in the timing of symptom onset, the pattern of organ involvement, and the rate of disease progression.1,4–6 In MPS VI,
Correspondence: Agnieszka Jurecka, MD PhD, Department of Genetics, University of Gdan´sk, ul. Wita Stwosza 59, 80-308 Gdan´sk, Poland. Email: [email protected] Received 19 September 2013; revised 13 November 2013; accepted 19 December 2013.
© 2013 Japan Pediatric Society
central nervous system involvement is absent in both severe and attenuated phenotypes. Investigations of allelic heterogeneity in MPS VI were facilitated by the isolation and characterization of the full-length cDNA encoding the human arylsulfatase B protein and the genomic arylsulfatase B sequence.7–9 To date, approximately 150 different mutations have been identified. Allele frequencies of the different mutations are very low, and most mutations are unique. The allelic heterogeneity is thought to cause a wide spectrum of clinical phenotypes observed in MPS VI, mainly characterized by a remarkable variability in the rate of progression.1,4 Extensive knowledge on the variability, progression, and natural history of MPS VI is scarce, although needed to increase awareness of the disease and to evaluate clinical efficacy of the therapy. In this study we report the largest unbiased cohort of MPS VI patients from Russia, Kazakhstan, Central and Eastern Europe and Belarus. The present study was conducted with the aims of providing details on the clinical history to clarify phenotypic
Mucopolysaccharidosis type VI variability and to specify the prevalence and incidence rates for MPS VI in Poland, Lithuania, Belarus, and Estonia.
Methods
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Gdansk (Poland, n = 248) and Vilnius (Lithuania, n = 172), were screened. The presence of wild-type or mutant alleles was detected on PCR followed by restriction enzyme digestion (the mutation causes the loss of Msp I restriction endonuclease site).
Study design
The study objectives were as follows: (i) to describe the natural history of MPS VI (n = 49) with regard to clinical manifestations of the disease, growth patterns, and relationship between height, glycosaminoglycan (GAG) level and severity of the disease; (ii) to analyze the ARSB mutations in MPS VI patients from Russia (n = 13), Kazakhstan (n = 2), Czech Republic (n = 2) and Poland (n = 1); (iii) to assess the frequency of the p.R152W mutation among the Russian patients (n = 17) and in the whole series (n = 49); (iv) to assess the MPS VI prevalence and incidence rates in Poland, Lithuania, Belarus and Estonia; and (v) to assess the carrier frequency of p.R152W mutation in the ARSB gene in the Polish and Lithuanian population
Data analysis for incidence and prevalence
The initial diagnosis of MPS VI was based on the demonstration of accumulated substrates (glycosaminoglycans) in body fluids using electrophoresis. Definite diagnosis was made on confirmation of the deficiency of the relevant enzyme and/or the presence of pathogenic mutation. Sequencing of the ARSB alleles was performed for all patients in Warsaw, Poland, using genomic DNA extracted from whole blood, DNA amplification of coding region on polymerase chain reaction (PCR), and automated sequencing as described previously.10
The live birth numbers in Poland were obtained from a Central Statistical Office.11 Data for Belarus, Estonia, and Lithuania were obtained from public statistics sources,12–14 while information on the demographics of these three countries was obtained from Wikipedia. For the years 1970–1990 in Poland the live births number was available every 5 years; for the years 1990–2009 the live births number was available annually. The missing live births data were calculated using linear interpolation for the years 1983 to 1989 and using the least squares approach to estimate the values for the years 2010–2011 for Poland, 2011 for Lithuania, and 2010–2011 for Estonia. The calculations of incidence rates with specification of the confidence interval were conducted using Windows Microsoft Excel 2007. For epidemiological analysis, the incidence rates were calculated by dividing the total number of diagnosed MPS VI cases in the years 1983–2011 by the total number of live births from this time period and presented as a number per 100 000 live births. Calculation of MPS VI prevalence was done by dividing the number of diagnosed MPS VI patients by the averaged number of the population within the analyzed time period in the country and presented as a number per 100 000 inhabitants. Data on country population were obtained from government public Internet sources.11,12,14
Patient enrollment and data collection
Ethics consideration
All patients with MPS VI diagnosed in Russia, Kazakhstan, Belarus and Central and Eastern Europe (Poland, Lithuania, Latvia, Estonia, Czech Republic), between 1 January 1983 and 31 December 2011 (a 28 year interval) were included. The lists of diagnosed patients were provided by eight diagnostic centers for MPS VI (Moscow, Warsaw, Vilnius, Riga, Tartu, Prague, Minsk and Almaty), and compared to information provided by the Russian, Polish, Belarusian and Lithuanian MPS Societies. Presumed to be exhaustive, the patient list was then used for data collection. Clinical classification was based on the age of onset and clinical manifestations, and defined as previously reported.4 Forty-two MPS VI families (14 Russian, nine Belarusian, seven Lithuanian, five Polish, three Czech, two Estonian, and two Kazakh) were studied. All patients were naïve to enzyme replacement therapy at the time of the study.
The protocol was approved by the human-subjects institutional review board at the participating diagnostic centers.
Diagnosis of MPS VI
Molecular analysis
The ARSB gene was analyzed by direct sequencing using a method described previously.10 Eighteen new patients were studied (13 Russian, two Kazakh, two Czech, one Polish). Carrier frequency of p.R152W mutation in the ARSB gene
To evaluate the carrier frequency of p.R152W mutation in the ARSB gene, 420 samples of genomic DNA extracted from the blood of healthy, anonymous individuals from two regions:
Results Clinical evaluation
Table S1 summarizes the demographic, clinical, biochemical, and molecular data for the 49 patients studied. A remarkably large variability in the course of the disease was detected ranging from severe through intermediate to attenuated. Severe phenotype
The classical severe phenotype of MPS VI was present in the minority (n = 9; 18%) of the present patients. First signs and symptoms and diagnosis. These patients developed symptoms very early in life (all within the first 12 months of life), and the mean age at onset of symptoms was 9.5 months (range, 6 months–1 year; median, 9.5 months). The main symptom at presentation, seen in the majority of patients, was umbilical hernia and recurrent infections as well as growth arrest starting after the first year of life. The mean age at diagnosis was 5 years (range, 2–10 years; median, 5 years). The mean of delay in diagnosis (the period between age at onset of symptoms and age at diagnosis) was 3.2 years (range, 1–4.5 years; median, 4.2 years). © 2013 Japan Pediatric Society
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Growth. Later in life, these patients presented with short stature, significant skeletal malformations, and other clinical abnormalities. To compare patients of different ages and different gender z-scores, body height was calculated for each individual. The observed mean z-score ± SD was −4.88 ± 1.23 (min, −6.52; max, −2.83; Fig. 1). This value was statistically different from the general population (P = 0.0001), but it was also statistically different from the mean z-score for patients with intermediate (P = 0.016) and attenuated (P = 0.003) phenotype. Adult height in these patients was 130 cm. All patients were alive at the time of the study. Their median age was 15 years (range, 3–40 years).
−1 −2 −3 −4 −5 −6 −7
Severe Intermediate Attenuated Phenotype
Fig. 1 Mean z-score of body height vs mucopolysaccharidosis type VI phenotype. , mean; , mean ± SEM; , mean ± SD. Due to the huge diversity of the analyzed group, all individual data for body height were standardized for age and gender using the World Health Organization body growth reference charts to show actual degree of deviation. © 2013 Japan Pediatric Society
Growth. In these patients height was only slightly decreased. For body height the observed mean z-score ± SD was −1.95 ± 1.13 (min, −3.8; max, −0.16; Fig. 1). This value was statistically different from the general population (P = 0.0009). Adult height in these patients was >145 cm. Age at death and cause of death. Two of the patients were deceased at the time of the study. They had died at the ages of 24 and 38 years due to spinal cord compression and heart failure, respectively. The median age of the live patients was 33 years (range, 17–47 years).
Mucopolysaccharidosis type VI Mutational analysis. In this group of patients the most common mutation detected was a missense mutation (p.R152W) found in a homozygous state (almost 70% of this group) or in heterozygosity with other missense mutations (p.R160Q, p.L360P). Additionally, three patients were heterozygous for p.Y210C mutation. Height and urinary GAG
No clear trend between height and urinary GAG level was observed. ARSB mutations in MPS VI patients
Molecular analysis of some of the patients has been reported previously elsewhere.10,15,16 In the present study, 18 additional MPS VI patients from Russia (n = 13), Kazakhstan (n = 2), Czech Republic (n = 2) and Poland (n = 1) were genotyped. In this group, 11 different disease-causing mutations were found. Four novel mutations included two missense mutations p.L72P and p.C91Y, deletion del C247_248, and insertion insA262. We also report seven previously described mutations (p.Q88X, p.T92K, p.R152W, p.R160Q, p.Y210C, p.R315X, p.C521Y). Among Russian MPS VI patients, the frequency of the most common mutations was 43% for p.R152W, 21% for p.C521Y, and 7% for p.Y210C and p.R315X. Altogether, these mutations were represented on 78% of ARSB alleles. In the whole series consisting of patients from Russia, Kazakhstan, and Central and Eastern Europe, the frequency of the most common mutations was 42% for p.R152W, 8% for p.C521Y, 7.1% for p.Y266S, 5.9% for p.T92K and p.Y210C, and 4.8% for p.Q88X. Altogether, these mutations were represented on 73.7% of ARSB alleles. Rare or private mutations comprised only 23.8% of ARSB lesions identified. Assessment of carrier frequency of p.R152W
Among 420 analyzed samples, one carrier of the mutation p. R152W was found originating from the Lithuanian population.
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The other 419 tested samples were homozygous for the wild-type allele. The observed overall p.R152W carrier frequency was 0.2% (1/420), while the observed carrier frequency in the Lithuanian population was 0.6% (1/172). Based on estimates of MPS VI incidence in the Caucasian population—ranging from 1 in 238 095 to 1 in 1 300 00017—we can estimate that 1/244 to 1/570 people are heterozygous carriers of any disease causing mutant allele in the ARSB gene. The observed carrier frequency for the mutation p.R152W in the Lithuanian population (0.6%) is significantly different from estimated frequency of carriers of any mutation in the ARSB gene (0.2–0.4%). Unfortunately, this calculation is based on a very small number of samples and therefore, further studies are needed in order to confirm a high carrier frequency for the mutation p.R152W in the Lithuanian population. Incidence and prevalence rates
In the given years 1983–2011 there were 13 788 511 live births in Poland, 3 442 454 in Belarus, 1 242 224 in Lithuania and 499 312 in Estonia. In the analyzed period of time there were 13 patients diagnosed with MPS VI in Belarus, eight in Lithuania, five in Poland, and twp in Estonia. To date, no individuals in the Latvian population have been conclusively diagnosed with MPS VI. The mean population of Poland in the analyzed period of time was 37 936 476 inhabitants; in Belarus, 9 808 332; in Lithuania, 3 401 017; and in Estonia, 1 419 367. Comparison of incidence rates by country is given in Table 1.
Discussion In this study, we describe the natural history of MPS VI diagnosed in Russia, Kazakhstan, Belarus, and Central and Eastern Europe between the years 1983–2011 and provide a complete and unbiased overview of the clinical course. Additionally, we present the incidence and prevalence rates of MPS VI in this region.
Table 1 Incidence rates of MPS VI Region Northern Ireland Poland Denmark Sweden Norway British Columbia, Canada Netherlands Germany Western Australia Belarus Estonia Australia Lithuania Turkish population in Germany
Years 1958–1985 1983–2011 1975–2004 1975–2004 1979–2004 1972–1996 1970–1990 1980–1995 1969–1996 1983–2011 1983–2011 1980–1996 1983–2011 1980–1995
No. MPS VI patients 0 5 2 2 1 1 6 31 2 13 2 18† 8 16
Incidence per 100,000 live births 0 0.036 0.05 0.07 0.07 0.1 0.15 0.23 0.31 0.378 0.400 0.43 0.644 2.3
Incidence rate per total live births No patients in 840 000 1 in 2 757 702 NA 1 in 1 505 160 1 in 1 455 813 1 in 1 035 816 NA 1 in 432 610 1 in 320 589 1 in 264 800 1 in 249 656 1 in 248 372 1 in 155 280 1 in 43 261
Reference 16
Present study 2 2 2 18 19 3 16
Present study Present study 20
Present study 3
Bold, MPS VI incidence in Central and Eastern European countries; †includes pre- and postnatal data. MPS IV, mucopolysaccharidosis type VI; NA, not available.
© 2013 Japan Pediatric Society
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Clinical evaluation
Frequency of ARSB mutations
Patients included in this study had the same general pattern of disease progression as observed in MPS VI patients reported in the literature,1,4,21 with three major clinical phenotypes: severe (18%), intermediate (49%), and relatively attenuated (33%). A remarkably large number of patients in the present cohort had an attenuated phenotype, with regression later in life and prolonged survival. The first clinical signs in these attenuated patients were observed at a median age of 10.3 years, and the main symptom was only slightly decreased joint range of motion. Within the first decade of life, these patients did not present typical MPS VI features, their height was only slightly decreased, and diagnosis of MPS VI was frequently made almost 13 years after the appearance of the first symptoms. Despite classification as attenuated, these patients developed serious manifestations of the disease including joint degeneration, cardiac valve disease, sleep apnea, decrease in pulmonary function and reduced endurance. Several parameters have been suggested as useful for the differentiation of phenotypes. Body height is a very sensitive parameter, reflecting any kind of error in the process of ontogenesis.19 The average z-score for body height in the present patients was below the WHO reference charts. The lowest deviation from the norm was observed for patients with the attenuated phenotype, while the greatest deviation was noted for patients with the severe phenotype (Fig. 1). The mean z-score for the intermediate phenotype was between these two groups. Individuals with the severe phenotype were not taller than 130 cm, while individuals with an attenuated form of MPS VI grew to a relatively normal height, reaching >145 cm. This shows that body height is directly related to the severity of the disease. Similarly, genotype–phenotype correlation was observed. Missense mutations p.R152W (in homozygosity) and p.Y210C were associated with a relatively attenuated MPS VI phenotype, while heterozygosity for p.R152W mutation yielded an intermediate phenotype. Some missense (p.L72P, p.T92K, and p.Y266S in homozygosity) and nonsense mutations (p.R160X, p.R313X, p.Y513X) were associated with a severe MPS VI phenotype.
In our previous study, we observed a high frequency of p.R152W mutation in Poland, Belarus and Baltic States.10 In the present study, a high prevalence of the p.R152W mutation was also observed in the Russian patients (43%) as well as in the whole series (42%). Interestingly, in 14 unrelated Russian families, four mutations (p.R152W, p.C521Y, p.Y210C and p.R315X) were represented on almost 80% of ARSB alleles. Similarly, in the whole series of 42 unrelated families, three mutations (p.R152W, p.C521Y, p.Y266S) were represented on almost 60% of ARSB alleles, while private mutations comprised only a very small portion of ARSB lesions identified. So far mutation p.R152W has been reported only in Russia and Central and Eastern Europe.10,16,22
Height and urinary GAG
Unlike the Swiedler et al. study, we did not observe a clear trend between phenotype and urinary GAG level.18 There are several problems with using urinary GAG level as a parameter for the prediction of MPS VI disease severity. First, the majority of methods used for urinary GAG measurements assess all GAG semi-quantitatively, not only dermatan sulfate and chondroitin sulfate. Second, using the GAG/creatinine ratio assumes that patients have normal kidney function. And last, the excretion of GAG in urine decreases significantly with age in both healthy individuals and in MPS patients.18,20 Therefore, in our opinion, any conclusions about the supposed course of the disease made on the basis of urinary GAG level measured in a child would be very risky. © 2013 Japan Pediatric Society
Incidence and prevalence rates
In the present study we found a relatively high incidence of MPS VI in Lithuania, Estonia and Belarus, and a very low incidence in Poland. In fact, the incidence rates for these three countries are the highest in Europe to be reported so far. Poland had the lowest incidence rate published, apart from the Nelson et al. data.23 The observed high p.R152W carrier frequency (0.6%) in the Lithuanian population may indicate a possible founder effect in this region. The high prevalence of this mutation observed in the whole series as well as the Slavic origin of the majority of patients homozygous for this mutation, suggest that p.R152W may be of Slavic, not Lithuanian origin. The precise estimation of incidence in the case of orphan diseases such as MPS VI can be difficult given that patients with attenuated phenotype may stay symptom free and undiagnosed for a long time. The high frequency of the p.R152W mutation associated with an attenuated MPS VI phenotype10,15 may additionally lead to an underestimation of the frequency of this type in this region. Conclusions
First, when compared with the published literature, a larger number of patients in the current study presented with an attenuated phenotype (33%). Second, height and genotype were related to the severity of the disease, while no clear trend was observed between height and urinary GAG. Third, high prevalence of the p.R152W mutation was observed both in the whole series (42%) as well as in Russian patients (43%). Fourth, the MPS VI incidence rates in the countries studied were within the wide range reported in the literature, but the values for Poland were among the lowest, while the values for Lithuania were among the highest from all previously published incidence rates. Fifth, this can be explained by a high prevalence of the mutation p.R152W in the analyzed population, indicating a possible founder effect in this region. And sixth, the high prevalence of this mutation observed in the whole series, as well as the Slavic origin of the majority of patients homozygous for this mutation, suggest that p.R152W may be of Slavic, not Lithuanian origin.
Mucopolysaccharidosis type VI Acknowledgments The authors thank the Polish MPS Society (Stowarzyszenie Chorych na Mukopolisacharydoze˛ i Choroby Rzadkie) and, in particular, its president, Teresa Matulka, for their permanent support and encouragement. We would like to express our gratitude for inviting Lithuanian and Belarusian patients to the society’s annual meeting, which allowed us to collect the data and examine the patients. The authors thank Dr Barbara Czartoryska (Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland) for performing urinary GAG measurements. The authors would also like to thank Professor Vaidutis Kucinskas (Center for Medical Genetics, Vilnius University Hospital) for providing the samples and Ms Patrycja Juchniewicz (Department of Molecular Biology, University of Gdan´sk) for her work related to the carrier frequency studies. The authors would also like to express their gratitude to Professor Katrin Õunap (Department of Pediatrics, University of Tartu) for providing clinical information about her patients. The authors acknowledge help from the patients and their families, who gave their time and participated in this study. We also thank all study personnel. There was no potential, perceived, or real conflict of interest. There were no study sponsors. No honorarium, grant, or other form of payment was given to produce the manuscript.
References 1 Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS (eds). The Metabolic and Molecular Basis of Inherited Disease. McGraw-Hill, New York, 2001; 3421– 52. 2 Baehner F, Schmiedeskamp C, Krummenauer F et al. Cumulative incidence rates of the mucopolysaccharidoses in Germany. J. Inherit. Metab. Dis. 2005; 28: 1011–17. 3 Malm G, Lund AM, Mansson JE, Heiberg A. Mucopolysaccharidoses in the Scandinavian countries: Incidence and prevalence. Acta Paediatr. 2008; 97: 1577–81. 4 Valayannopoulos V, Nicely H, Harmatz P, Turbeville S. Mucopolysaccharidosis VI. Orphanet J. Rare Dis. 2010; 5: 5. 5 Golda A, Jurecka A, Tylki-Szymanska A. Cardiovascular manifestations of mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome). Int. J. Cardiol. 2011; 158: 6–11. 6 Golda A, Jurecka A, Opoka-Winiarska V, Tylki-Szymanska A. Mucopolysaccharidosis type VI: A cardiologist’s guide to diagnosis and treatment. Int. J. Cardiol. 2013; 167: 1–10. 7 Litjens T, Baker EG, Beckmann KR, Morris CP, Hopwood JJ, Callen DF. Chromosomal localization of ARSB, the gene for human N-acetylgalactosamine-4-sulphatase. Hum. Genet. 1989; 82: 67–8. 8 Paterson DE, Harper G, Weston HJ, Mattingley J. MaroteauxLamy syndrome, mild form: MPS VI B. Br. J. Radiol. 1982; 55: 805–12. 9 Pilz H, von Figura K, Goebel HH. Deficiency of arylsulfatase B in 2 brothers aged 40 and 38 years (Maroteaux-Lamy syndrome, type B). Ann. Neurol. 1979; 6: 315–25.
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10 Jurecka A, Piotrowska E, Cimbalistiene L et al. Molecular analysis of mucopolysaccharidosis type VI in Poland, Belarus, Lithuania and Estonia. Mol. Genet. Metab. 2012; 105: 237–43. 11 GUS Central Statistical Office. Births in the period 1970–2009. [Cited 19 July 2013.] Available from URL: http://www.stat.gov.pl/ gus/5840_646_PLK_HTML.htm 12 National Statistical Committee of the Republic of Belarus. Population of the Republic of Belarus. [Cited 19 July 2013.] Available from URL: http://www.belstat.gov.by/homep/en/main.html 13 Main demographic indicators. Births, deaths and natural increase. [Cited 19 July 2013.] Available from URL: http://pub.stat.ee/px -web.2001/I_Databas/Population/01Population_indicators_and _composition/02Main_demographic_indicators/02Main_demographic _indicators.asp 14 LS Statistics Lithuania. Number of population, live births, deaths by month. [Cited 19 July 2013.] Available from URL: http://db1 .stat.gov.lt/statbank/SelectTable/omrade0.asp?SubjectCode=S3& PLanguage=1&ShowNews=OFF 15 Jurecka A, Golda A, Opoka-Winiarska V, Piotrowska E, Tylki-Szymanska A. Mucopolysaccharidosis type VI (MaroteauxLamy syndrome) with a predominantly cardiac phenotype. Mol. Genet. Metab. 2011; 104: 695–99. 16 Voskoboeva E, Krasnopol’skaia KD, Peters K, von Figura K. [Identification of mutations in the arylsulfatase B gene in Russian mucopolysaccharidosis type VI patients]. Genetika 2000; 36: 837–43. 17 Giugliani R, Harmatz P, Wraith JE. Management guidelines for mucopolysaccharidosis VI. Pediatrics 2007; 120: 405– 18. 18 Azevedo A, Schwartz IV, Kalakun L et al. Clinical and biochemical study of 28 patients with mucopolysaccharidosis type VI. Clin. Genet. 2004; 66: 208–13. 19 Marucha J, Jurecka A, Syczewska M, Rozdzynska-Swiatkowska A, Tylki-Szymanska A. Restricted joint range of motion in MPS II patients: Correlation with height, age and functional status. Acta Paediatr. 2012; 101: e183–88. 20 Swiedler SJ, Beck M, Bajbouj M et al. Threshold effect of urinary glycosaminoglycans and the walk test as indicators of disease progression in a survey of subjects with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). Am. J. Med. Genet. A 2005; 134A: 144–50. 21 Gallegos-Arreola MP, Machorro-Lazo MV, Flores-Martinez SE et al. Urinary glycosaminoglycan excretion in healthy subjects and in patients with mucopolysaccharidoses. Arch. Med. Res. 2000; 31: 505–10. 22 Thumler A, Miebach E, Lampe C et al. Clinical characteristics of adults with slowly progressing mucopolysaccharidosis VI: A case series. J. Inherit. Metab. Dis. 2012; 35: 1071–9. 23 Nelson J, Crowhurst J, Carey B, Greed L. Incidence of the mucopolysaccharidoses in Western Australia. Am. J. Med. Genet. A 2003; 123A: 310–13.
Supporting Information Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Table S1 Clinical phenotype and genotype in 49 MPS VI patients.
© 2013 Japan Pediatric Society
Pediatrics International (2014) 56, 520–525
doi: 10.1111/ped.12281
Original Article
Mucopolysaccharidosis type VI in Russia, Kazakhstan, and Central and Eastern Europe Agnieszka Jurecka,1,4 Ekaterina Zakharova,6 Loreta Cimbalistiene,7 Nina Gusina,8 Vera Malinova9, Agnieszka Róz˙dz˙yn´ska-S´wia˛tkowska,2 Adam Golda,5 Anna Kulpanovich,8 Gulnara Kaldenovna Abdilova,10 Elena Voskoboeva6 and Anna Tylki-Szyman´ska3 1 Department of Medical Genetics, 2Anthropology Laboratory, 3Department of Pediatrics, Nutrition and Metabolic Diseases, Children’s Memorial Health Institute, Warsaw, 4Department of Genetics, University of Gdan´sk, Gdan´sk, 5Department of Cardiology, Gliwice General Hospital, Gliwice, Poland, 6Department of Inherited Metabolic Diseases, Research Center for Medical Genetics, Moscow, Russian Federation, 7Center for Medical Genetics, Santariskiu Klinikos, Vilnius University Hospital, Vilnius, Lithuania, 8Genetics Unit, National Medical Center “Mother and Child”, Minsk, Belarus, 9Department of Pediatrics and Adolescence Medicine, First Faculty of Medicine, General University Hospital, Charles University, Prague, Czech Republic and 10Department of Pediatrics, Research Center of Pediatrics and Pediatric Surgery, Almaty, Kazakhstan Abstract
Background: The aim of this study was to describe the natural clinical course, incidence and prevalence of mucopolysaccharidosis type VI (MPS VI) in Russia, Kazakhstan, and Central and Eastern Europe. Methods: Patients (n = 49) were identified by retrieving the data from eight international centers for MPS VI. Results: A large number of patients presented with an attenuated phenotype (33%). Height and genotype were related to the severity of the disease, while no clear trend was observed between height and urinary glycosaminoglycan level. A high prevalence of the p.R152W mutation was observed both in the whole series (42%) as well as in Russian patients (43%). The incidence rate ranged from 0.0363 to 0.64 per 100 000 live births in Poland and Lithuania, respectively. Conclusions: The observed high p.R152W carrier frequency in the Lithuanian population may indicate a possible founder effect in this region. The high prevalence of this mutation observed in the whole series, as well as the Slavic origin of the majority of patients homozygous for this mutation, suggest that p.R152W may be of Slavic, not Lithuanian origin. Resettlement of the Polish population after World War II resulted in dilution of the prevalence of carriers in Poland and a very low MPS VI incidence.
Key words genotype–phenotype analysis, incidence, Maroteaux–Lamy syndrome, natural history, prevalence, urinary glycosaminoglycan.
Mucopolysaccharidosis type VI or Maroteaux–Lamy syndrome (MPS VI; MIM 253200) is a rare autosomal recessive lysosomal storage disorder caused by deficient activity of N-acetylgalactosamine-4-sulfatase (4-sulfatase, arylsulfatase B; ARSB; EC 3.1.6.12), an enzyme involved in the degradation of dermatan sulfate.1 The reported birth prevalence of MPS VI varies, ranging from 1 in 43 261 to 1 in 1 505 160 live births.2,3 The rate of clinical progression of MPS VI varies considerably, generating a wide continuous clinical spectrum from severe to relatively attenuated.1,4 The most prominent and debilitating manifestations usually arise in the musculoskeletal, cardiorespiratory, and nervous systems, but individual cases vary considerably in the timing of symptom onset, the pattern of organ involvement, and the rate of disease progression.1,4–6 In MPS VI,
Correspondence: Agnieszka Jurecka, MD PhD, Department of Genetics, University of Gdan´sk, ul. Wita Stwosza 59, 80-308 Gdan´sk, Poland. Email: [email protected] Received 19 September 2013; revised 13 November 2013; accepted 19 December 2013.
© 2013 Japan Pediatric Society
central nervous system involvement is absent in both severe and attenuated phenotypes. Investigations of allelic heterogeneity in MPS VI were facilitated by the isolation and characterization of the full-length cDNA encoding the human arylsulfatase B protein and the genomic arylsulfatase B sequence.7–9 To date, approximately 150 different mutations have been identified. Allele frequencies of the different mutations are very low, and most mutations are unique. The allelic heterogeneity is thought to cause a wide spectrum of clinical phenotypes observed in MPS VI, mainly characterized by a remarkable variability in the rate of progression.1,4 Extensive knowledge on the variability, progression, and natural history of MPS VI is scarce, although needed to increase awareness of the disease and to evaluate clinical efficacy of the therapy. In this study we report the largest unbiased cohort of MPS VI patients from Russia, Kazakhstan, Central and Eastern Europe and Belarus. The present study was conducted with the aims of providing details on the clinical history to clarify phenotypic
Mucopolysaccharidosis type VI variability and to specify the prevalence and incidence rates for MPS VI in Poland, Lithuania, Belarus, and Estonia.
Methods
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Gdansk (Poland, n = 248) and Vilnius (Lithuania, n = 172), were screened. The presence of wild-type or mutant alleles was detected on PCR followed by restriction enzyme digestion (the mutation causes the loss of Msp I restriction endonuclease site).
Study design
The study objectives were as follows: (i) to describe the natural history of MPS VI (n = 49) with regard to clinical manifestations of the disease, growth patterns, and relationship between height, glycosaminoglycan (GAG) level and severity of the disease; (ii) to analyze the ARSB mutations in MPS VI patients from Russia (n = 13), Kazakhstan (n = 2), Czech Republic (n = 2) and Poland (n = 1); (iii) to assess the frequency of the p.R152W mutation among the Russian patients (n = 17) and in the whole series (n = 49); (iv) to assess the MPS VI prevalence and incidence rates in Poland, Lithuania, Belarus and Estonia; and (v) to assess the carrier frequency of p.R152W mutation in the ARSB gene in the Polish and Lithuanian population
Data analysis for incidence and prevalence
The initial diagnosis of MPS VI was based on the demonstration of accumulated substrates (glycosaminoglycans) in body fluids using electrophoresis. Definite diagnosis was made on confirmation of the deficiency of the relevant enzyme and/or the presence of pathogenic mutation. Sequencing of the ARSB alleles was performed for all patients in Warsaw, Poland, using genomic DNA extracted from whole blood, DNA amplification of coding region on polymerase chain reaction (PCR), and automated sequencing as described previously.10
The live birth numbers in Poland were obtained from a Central Statistical Office.11 Data for Belarus, Estonia, and Lithuania were obtained from public statistics sources,12–14 while information on the demographics of these three countries was obtained from Wikipedia. For the years 1970–1990 in Poland the live births number was available every 5 years; for the years 1990–2009 the live births number was available annually. The missing live births data were calculated using linear interpolation for the years 1983 to 1989 and using the least squares approach to estimate the values for the years 2010–2011 for Poland, 2011 for Lithuania, and 2010–2011 for Estonia. The calculations of incidence rates with specification of the confidence interval were conducted using Windows Microsoft Excel 2007. For epidemiological analysis, the incidence rates were calculated by dividing the total number of diagnosed MPS VI cases in the years 1983–2011 by the total number of live births from this time period and presented as a number per 100 000 live births. Calculation of MPS VI prevalence was done by dividing the number of diagnosed MPS VI patients by the averaged number of the population within the analyzed time period in the country and presented as a number per 100 000 inhabitants. Data on country population were obtained from government public Internet sources.11,12,14
Patient enrollment and data collection
Ethics consideration
All patients with MPS VI diagnosed in Russia, Kazakhstan, Belarus and Central and Eastern Europe (Poland, Lithuania, Latvia, Estonia, Czech Republic), between 1 January 1983 and 31 December 2011 (a 28 year interval) were included. The lists of diagnosed patients were provided by eight diagnostic centers for MPS VI (Moscow, Warsaw, Vilnius, Riga, Tartu, Prague, Minsk and Almaty), and compared to information provided by the Russian, Polish, Belarusian and Lithuanian MPS Societies. Presumed to be exhaustive, the patient list was then used for data collection. Clinical classification was based on the age of onset and clinical manifestations, and defined as previously reported.4 Forty-two MPS VI families (14 Russian, nine Belarusian, seven Lithuanian, five Polish, three Czech, two Estonian, and two Kazakh) were studied. All patients were naïve to enzyme replacement therapy at the time of the study.
The protocol was approved by the human-subjects institutional review board at the participating diagnostic centers.
Diagnosis of MPS VI
Molecular analysis
The ARSB gene was analyzed by direct sequencing using a method described previously.10 Eighteen new patients were studied (13 Russian, two Kazakh, two Czech, one Polish). Carrier frequency of p.R152W mutation in the ARSB gene
To evaluate the carrier frequency of p.R152W mutation in the ARSB gene, 420 samples of genomic DNA extracted from the blood of healthy, anonymous individuals from two regions:
Results Clinical evaluation
Table S1 summarizes the demographic, clinical, biochemical, and molecular data for the 49 patients studied. A remarkably large variability in the course of the disease was detected ranging from severe through intermediate to attenuated. Severe phenotype
The classical severe phenotype of MPS VI was present in the minority (n = 9; 18%) of the present patients. First signs and symptoms and diagnosis. These patients developed symptoms very early in life (all within the first 12 months of life), and the mean age at onset of symptoms was 9.5 months (range, 6 months–1 year; median, 9.5 months). The main symptom at presentation, seen in the majority of patients, was umbilical hernia and recurrent infections as well as growth arrest starting after the first year of life. The mean age at diagnosis was 5 years (range, 2–10 years; median, 5 years). The mean of delay in diagnosis (the period between age at onset of symptoms and age at diagnosis) was 3.2 years (range, 1–4.5 years; median, 4.2 years). © 2013 Japan Pediatric Society
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Growth. Later in life, these patients presented with short stature, significant skeletal malformations, and other clinical abnormalities. To compare patients of different ages and different gender z-scores, body height was calculated for each individual. The observed mean z-score ± SD was −4.88 ± 1.23 (min, −6.52; max, −2.83; Fig. 1). This value was statistically different from the general population (P = 0.0001), but it was also statistically different from the mean z-score for patients with intermediate (P = 0.016) and attenuated (P = 0.003) phenotype. Adult height in these patients was 130 cm. All patients were alive at the time of the study. Their median age was 15 years (range, 3–40 years).
−1 −2 −3 −4 −5 −6 −7
Severe Intermediate Attenuated Phenotype
Fig. 1 Mean z-score of body height vs mucopolysaccharidosis type VI phenotype. , mean; , mean ± SEM; , mean ± SD. Due to the huge diversity of the analyzed group, all individual data for body height were standardized for age and gender using the World Health Organization body growth reference charts to show actual degree of deviation. © 2013 Japan Pediatric Society
Growth. In these patients height was only slightly decreased. For body height the observed mean z-score ± SD was −1.95 ± 1.13 (min, −3.8; max, −0.16; Fig. 1). This value was statistically different from the general population (P = 0.0009). Adult height in these patients was >145 cm. Age at death and cause of death. Two of the patients were deceased at the time of the study. They had died at the ages of 24 and 38 years due to spinal cord compression and heart failure, respectively. The median age of the live patients was 33 years (range, 17–47 years).
Mucopolysaccharidosis type VI Mutational analysis. In this group of patients the most common mutation detected was a missense mutation (p.R152W) found in a homozygous state (almost 70% of this group) or in heterozygosity with other missense mutations (p.R160Q, p.L360P). Additionally, three patients were heterozygous for p.Y210C mutation. Height and urinary GAG
No clear trend between height and urinary GAG level was observed. ARSB mutations in MPS VI patients
Molecular analysis of some of the patients has been reported previously elsewhere.10,15,16 In the present study, 18 additional MPS VI patients from Russia (n = 13), Kazakhstan (n = 2), Czech Republic (n = 2) and Poland (n = 1) were genotyped. In this group, 11 different disease-causing mutations were found. Four novel mutations included two missense mutations p.L72P and p.C91Y, deletion del C247_248, and insertion insA262. We also report seven previously described mutations (p.Q88X, p.T92K, p.R152W, p.R160Q, p.Y210C, p.R315X, p.C521Y). Among Russian MPS VI patients, the frequency of the most common mutations was 43% for p.R152W, 21% for p.C521Y, and 7% for p.Y210C and p.R315X. Altogether, these mutations were represented on 78% of ARSB alleles. In the whole series consisting of patients from Russia, Kazakhstan, and Central and Eastern Europe, the frequency of the most common mutations was 42% for p.R152W, 8% for p.C521Y, 7.1% for p.Y266S, 5.9% for p.T92K and p.Y210C, and 4.8% for p.Q88X. Altogether, these mutations were represented on 73.7% of ARSB alleles. Rare or private mutations comprised only 23.8% of ARSB lesions identified. Assessment of carrier frequency of p.R152W
Among 420 analyzed samples, one carrier of the mutation p. R152W was found originating from the Lithuanian population.
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The other 419 tested samples were homozygous for the wild-type allele. The observed overall p.R152W carrier frequency was 0.2% (1/420), while the observed carrier frequency in the Lithuanian population was 0.6% (1/172). Based on estimates of MPS VI incidence in the Caucasian population—ranging from 1 in 238 095 to 1 in 1 300 00017—we can estimate that 1/244 to 1/570 people are heterozygous carriers of any disease causing mutant allele in the ARSB gene. The observed carrier frequency for the mutation p.R152W in the Lithuanian population (0.6%) is significantly different from estimated frequency of carriers of any mutation in the ARSB gene (0.2–0.4%). Unfortunately, this calculation is based on a very small number of samples and therefore, further studies are needed in order to confirm a high carrier frequency for the mutation p.R152W in the Lithuanian population. Incidence and prevalence rates
In the given years 1983–2011 there were 13 788 511 live births in Poland, 3 442 454 in Belarus, 1 242 224 in Lithuania and 499 312 in Estonia. In the analyzed period of time there were 13 patients diagnosed with MPS VI in Belarus, eight in Lithuania, five in Poland, and twp in Estonia. To date, no individuals in the Latvian population have been conclusively diagnosed with MPS VI. The mean population of Poland in the analyzed period of time was 37 936 476 inhabitants; in Belarus, 9 808 332; in Lithuania, 3 401 017; and in Estonia, 1 419 367. Comparison of incidence rates by country is given in Table 1.
Discussion In this study, we describe the natural history of MPS VI diagnosed in Russia, Kazakhstan, Belarus, and Central and Eastern Europe between the years 1983–2011 and provide a complete and unbiased overview of the clinical course. Additionally, we present the incidence and prevalence rates of MPS VI in this region.
Table 1 Incidence rates of MPS VI Region Northern Ireland Poland Denmark Sweden Norway British Columbia, Canada Netherlands Germany Western Australia Belarus Estonia Australia Lithuania Turkish population in Germany
Years 1958–1985 1983–2011 1975–2004 1975–2004 1979–2004 1972–1996 1970–1990 1980–1995 1969–1996 1983–2011 1983–2011 1980–1996 1983–2011 1980–1995
No. MPS VI patients 0 5 2 2 1 1 6 31 2 13 2 18† 8 16
Incidence per 100,000 live births 0 0.036 0.05 0.07 0.07 0.1 0.15 0.23 0.31 0.378 0.400 0.43 0.644 2.3
Incidence rate per total live births No patients in 840 000 1 in 2 757 702 NA 1 in 1 505 160 1 in 1 455 813 1 in 1 035 816 NA 1 in 432 610 1 in 320 589 1 in 264 800 1 in 249 656 1 in 248 372 1 in 155 280 1 in 43 261
Reference 16
Present study 2 2 2 18 19 3 16
Present study Present study 20
Present study 3
Bold, MPS VI incidence in Central and Eastern European countries; †includes pre- and postnatal data. MPS IV, mucopolysaccharidosis type VI; NA, not available.
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Clinical evaluation
Frequency of ARSB mutations
Patients included in this study had the same general pattern of disease progression as observed in MPS VI patients reported in the literature,1,4,21 with three major clinical phenotypes: severe (18%), intermediate (49%), and relatively attenuated (33%). A remarkably large number of patients in the present cohort had an attenuated phenotype, with regression later in life and prolonged survival. The first clinical signs in these attenuated patients were observed at a median age of 10.3 years, and the main symptom was only slightly decreased joint range of motion. Within the first decade of life, these patients did not present typical MPS VI features, their height was only slightly decreased, and diagnosis of MPS VI was frequently made almost 13 years after the appearance of the first symptoms. Despite classification as attenuated, these patients developed serious manifestations of the disease including joint degeneration, cardiac valve disease, sleep apnea, decrease in pulmonary function and reduced endurance. Several parameters have been suggested as useful for the differentiation of phenotypes. Body height is a very sensitive parameter, reflecting any kind of error in the process of ontogenesis.19 The average z-score for body height in the present patients was below the WHO reference charts. The lowest deviation from the norm was observed for patients with the attenuated phenotype, while the greatest deviation was noted for patients with the severe phenotype (Fig. 1). The mean z-score for the intermediate phenotype was between these two groups. Individuals with the severe phenotype were not taller than 130 cm, while individuals with an attenuated form of MPS VI grew to a relatively normal height, reaching >145 cm. This shows that body height is directly related to the severity of the disease. Similarly, genotype–phenotype correlation was observed. Missense mutations p.R152W (in homozygosity) and p.Y210C were associated with a relatively attenuated MPS VI phenotype, while heterozygosity for p.R152W mutation yielded an intermediate phenotype. Some missense (p.L72P, p.T92K, and p.Y266S in homozygosity) and nonsense mutations (p.R160X, p.R313X, p.Y513X) were associated with a severe MPS VI phenotype.
In our previous study, we observed a high frequency of p.R152W mutation in Poland, Belarus and Baltic States.10 In the present study, a high prevalence of the p.R152W mutation was also observed in the Russian patients (43%) as well as in the whole series (42%). Interestingly, in 14 unrelated Russian families, four mutations (p.R152W, p.C521Y, p.Y210C and p.R315X) were represented on almost 80% of ARSB alleles. Similarly, in the whole series of 42 unrelated families, three mutations (p.R152W, p.C521Y, p.Y266S) were represented on almost 60% of ARSB alleles, while private mutations comprised only a very small portion of ARSB lesions identified. So far mutation p.R152W has been reported only in Russia and Central and Eastern Europe.10,16,22
Height and urinary GAG
Unlike the Swiedler et al. study, we did not observe a clear trend between phenotype and urinary GAG level.18 There are several problems with using urinary GAG level as a parameter for the prediction of MPS VI disease severity. First, the majority of methods used for urinary GAG measurements assess all GAG semi-quantitatively, not only dermatan sulfate and chondroitin sulfate. Second, using the GAG/creatinine ratio assumes that patients have normal kidney function. And last, the excretion of GAG in urine decreases significantly with age in both healthy individuals and in MPS patients.18,20 Therefore, in our opinion, any conclusions about the supposed course of the disease made on the basis of urinary GAG level measured in a child would be very risky. © 2013 Japan Pediatric Society
Incidence and prevalence rates
In the present study we found a relatively high incidence of MPS VI in Lithuania, Estonia and Belarus, and a very low incidence in Poland. In fact, the incidence rates for these three countries are the highest in Europe to be reported so far. Poland had the lowest incidence rate published, apart from the Nelson et al. data.23 The observed high p.R152W carrier frequency (0.6%) in the Lithuanian population may indicate a possible founder effect in this region. The high prevalence of this mutation observed in the whole series as well as the Slavic origin of the majority of patients homozygous for this mutation, suggest that p.R152W may be of Slavic, not Lithuanian origin. The precise estimation of incidence in the case of orphan diseases such as MPS VI can be difficult given that patients with attenuated phenotype may stay symptom free and undiagnosed for a long time. The high frequency of the p.R152W mutation associated with an attenuated MPS VI phenotype10,15 may additionally lead to an underestimation of the frequency of this type in this region. Conclusions
First, when compared with the published literature, a larger number of patients in the current study presented with an attenuated phenotype (33%). Second, height and genotype were related to the severity of the disease, while no clear trend was observed between height and urinary GAG. Third, high prevalence of the p.R152W mutation was observed both in the whole series (42%) as well as in Russian patients (43%). Fourth, the MPS VI incidence rates in the countries studied were within the wide range reported in the literature, but the values for Poland were among the lowest, while the values for Lithuania were among the highest from all previously published incidence rates. Fifth, this can be explained by a high prevalence of the mutation p.R152W in the analyzed population, indicating a possible founder effect in this region. And sixth, the high prevalence of this mutation observed in the whole series, as well as the Slavic origin of the majority of patients homozygous for this mutation, suggest that p.R152W may be of Slavic, not Lithuanian origin.
Mucopolysaccharidosis type VI Acknowledgments The authors thank the Polish MPS Society (Stowarzyszenie Chorych na Mukopolisacharydoze˛ i Choroby Rzadkie) and, in particular, its president, Teresa Matulka, for their permanent support and encouragement. We would like to express our gratitude for inviting Lithuanian and Belarusian patients to the society’s annual meeting, which allowed us to collect the data and examine the patients. The authors thank Dr Barbara Czartoryska (Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland) for performing urinary GAG measurements. The authors would also like to thank Professor Vaidutis Kucinskas (Center for Medical Genetics, Vilnius University Hospital) for providing the samples and Ms Patrycja Juchniewicz (Department of Molecular Biology, University of Gdan´sk) for her work related to the carrier frequency studies. The authors would also like to express their gratitude to Professor Katrin Õunap (Department of Pediatrics, University of Tartu) for providing clinical information about her patients. The authors acknowledge help from the patients and their families, who gave their time and participated in this study. We also thank all study personnel. There was no potential, perceived, or real conflict of interest. There were no study sponsors. No honorarium, grant, or other form of payment was given to produce the manuscript.
References 1 Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS (eds). The Metabolic and Molecular Basis of Inherited Disease. McGraw-Hill, New York, 2001; 3421– 52. 2 Baehner F, Schmiedeskamp C, Krummenauer F et al. Cumulative incidence rates of the mucopolysaccharidoses in Germany. J. Inherit. Metab. Dis. 2005; 28: 1011–17. 3 Malm G, Lund AM, Mansson JE, Heiberg A. Mucopolysaccharidoses in the Scandinavian countries: Incidence and prevalence. Acta Paediatr. 2008; 97: 1577–81. 4 Valayannopoulos V, Nicely H, Harmatz P, Turbeville S. Mucopolysaccharidosis VI. Orphanet J. Rare Dis. 2010; 5: 5. 5 Golda A, Jurecka A, Tylki-Szymanska A. Cardiovascular manifestations of mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome). Int. J. Cardiol. 2011; 158: 6–11. 6 Golda A, Jurecka A, Opoka-Winiarska V, Tylki-Szymanska A. Mucopolysaccharidosis type VI: A cardiologist’s guide to diagnosis and treatment. Int. J. Cardiol. 2013; 167: 1–10. 7 Litjens T, Baker EG, Beckmann KR, Morris CP, Hopwood JJ, Callen DF. Chromosomal localization of ARSB, the gene for human N-acetylgalactosamine-4-sulphatase. Hum. Genet. 1989; 82: 67–8. 8 Paterson DE, Harper G, Weston HJ, Mattingley J. MaroteauxLamy syndrome, mild form: MPS VI B. Br. J. Radiol. 1982; 55: 805–12. 9 Pilz H, von Figura K, Goebel HH. Deficiency of arylsulfatase B in 2 brothers aged 40 and 38 years (Maroteaux-Lamy syndrome, type B). Ann. Neurol. 1979; 6: 315–25.
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10 Jurecka A, Piotrowska E, Cimbalistiene L et al. Molecular analysis of mucopolysaccharidosis type VI in Poland, Belarus, Lithuania and Estonia. Mol. Genet. Metab. 2012; 105: 237–43. 11 GUS Central Statistical Office. Births in the period 1970–2009. [Cited 19 July 2013.] Available from URL: http://www.stat.gov.pl/ gus/5840_646_PLK_HTML.htm 12 National Statistical Committee of the Republic of Belarus. Population of the Republic of Belarus. [Cited 19 July 2013.] Available from URL: http://www.belstat.gov.by/homep/en/main.html 13 Main demographic indicators. Births, deaths and natural increase. [Cited 19 July 2013.] Available from URL: http://pub.stat.ee/px -web.2001/I_Databas/Population/01Population_indicators_and _composition/02Main_demographic_indicators/02Main_demographic _indicators.asp 14 LS Statistics Lithuania. Number of population, live births, deaths by month. [Cited 19 July 2013.] Available from URL: http://db1 .stat.gov.lt/statbank/SelectTable/omrade0.asp?SubjectCode=S3& PLanguage=1&ShowNews=OFF 15 Jurecka A, Golda A, Opoka-Winiarska V, Piotrowska E, Tylki-Szymanska A. Mucopolysaccharidosis type VI (MaroteauxLamy syndrome) with a predominantly cardiac phenotype. Mol. Genet. Metab. 2011; 104: 695–99. 16 Voskoboeva E, Krasnopol’skaia KD, Peters K, von Figura K. [Identification of mutations in the arylsulfatase B gene in Russian mucopolysaccharidosis type VI patients]. Genetika 2000; 36: 837–43. 17 Giugliani R, Harmatz P, Wraith JE. Management guidelines for mucopolysaccharidosis VI. Pediatrics 2007; 120: 405– 18. 18 Azevedo A, Schwartz IV, Kalakun L et al. Clinical and biochemical study of 28 patients with mucopolysaccharidosis type VI. Clin. Genet. 2004; 66: 208–13. 19 Marucha J, Jurecka A, Syczewska M, Rozdzynska-Swiatkowska A, Tylki-Szymanska A. Restricted joint range of motion in MPS II patients: Correlation with height, age and functional status. Acta Paediatr. 2012; 101: e183–88. 20 Swiedler SJ, Beck M, Bajbouj M et al. Threshold effect of urinary glycosaminoglycans and the walk test as indicators of disease progression in a survey of subjects with mucopolysaccharidosis VI (Maroteaux-Lamy syndrome). Am. J. Med. Genet. A 2005; 134A: 144–50. 21 Gallegos-Arreola MP, Machorro-Lazo MV, Flores-Martinez SE et al. Urinary glycosaminoglycan excretion in healthy subjects and in patients with mucopolysaccharidoses. Arch. Med. Res. 2000; 31: 505–10. 22 Thumler A, Miebach E, Lampe C et al. Clinical characteristics of adults with slowly progressing mucopolysaccharidosis VI: A case series. J. Inherit. Metab. Dis. 2012; 35: 1071–9. 23 Nelson J, Crowhurst J, Carey B, Greed L. Incidence of the mucopolysaccharidoses in Western Australia. Am. J. Med. Genet. A 2003; 123A: 310–13.
Supporting Information Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Table S1 Clinical phenotype and genotype in 49 MPS VI patients.
© 2013 Japan Pediatric Society
