Clinical manifestations in female carriers of mucopolysaccharidosis type II: a spanish cross-sectional study

Orphanet Journal of Rare Diseases

Olga Alonso-Luengo¹  Enrique Galán-Gómez²  María Luz Couce³  Ramón Cancho-Candela⁵  Carlos Alcalde-Martín⁵  María Rosario Domingo-Jiménez⁶  Encarna Guillén-Navarro⁴ 

[1] Sección de Neuropediatría, Hospital Universitario Virgen del Rocio, Sevilla, Spain;Unidad de Genética Clínica. Servicio de Pediatría. Hospital Materno Infantil Infanta Cristina. Facultad de Medicina, Universidad de Extremadura, Badajoz. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER. U724), Badajoz, Spain;Unidad de Errores Innatos del Metabolismo. Servicio de Neonatología, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain;Unidad de Genética Médica. Servicio de Pediatría, Hospital Clínico Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain;Servicio de Pediatría, Hospital Universitario Rio Hortega, Valladolid, Spain;Sección de Neuropediatría, Hospital Clínico Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain

关键词: Glycosaminoglycans;    Iduronate 2-sulfatase;    X- inactivation;    Heterozygotes;    Carriers;    Mucopolysaccharidosis type II;    Hunter syndrome;   

Others  :  863691
DOI  :  10.1186/1750-1172-8-92

 received in 2013-03-12, accepted in 2013-06-20,  发布年份 2013

【 摘 要 】

Background

Mucopolysaccharidosis type II (MPS II) is an inherited X-linked disease associated with a deficiency in the enzyme iduronate 2-sulfatase due to iduronate 2-sulfatase gene (IDS) mutations. Recent studies in MPS II carriers did not find clinical involvement, but these were mainly performed by anamnesis and patients’ self-reported description of signs and symptoms. So although it is rare in heterozygous carriers, investigations in other types of inherited X-linked disorders suggest that some clinical manifestations may be a possibility. The aim of this study was to evaluate the clinical pattern in female carriers of MPS II and to determine whether clinical symptoms were associated with the X-chromosome inactivation (XCI) pattern and age.

Methods

Female carriers of MPS II were genetically identified by molecular analysis of IDS. The clinical evaluation protocol included pedigree analysis, a comprehensive anamnesis, complete physical examination, ophthalmological evaluation, brain-evoked auditory response, electrocardiogram, echocardiogram, pulmonary function tests, abdominal sonogram, skeletal survey, neurophysiological studies, blood cell counts and biochemistry, urine glycosaminoglycan (GAGs) quantification, karyotype and pattern of XCI.

Results

Ten women were included in the study. The mean age of the participants was 40.2 ± 13.1 years. Six carriers presented a skewed XCI pattern, 3 of whom (aged 38, 42 and 52 years) had increased levels of GAGs in the urine and showed typical MPS II clinical manifestations, such as skeletal anomalies, liver abnormalities, carpal tunnel syndrome, recurrent ear infection, hypoacusia and more frequent severe odontological problems without coarse facial features.

Conclusions

This is the first study performing a comprehensive evaluation of heterozygous MPS II carriers. Our results provide evidence of possible progressive, age-dependent, mild clinical manifestations in MPS II female carriers with a skewed XCI pattern, most likely affecting the normal allele. Further comparative studies with systematized clinical examinations in larger age-stratified populations of MPS II female carriers are required.

【 授权许可】

   
2013 Guillén-Navarro et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Machili G, Barbujani G, Danieli GA, Hermann FH: Segregation and sporadic cases in families with Hunter’s syndrome. J Med Genet 1991, 28:398-401.
• [2]Nelson J, Crowhust J, Carey B, Greed L: Incidence of the mucopolysaccharidosis in Western Australia. Am J Med Genet 2003, 123A:310-313.
• [3]Scarpa M, Almássy Z, Beck M, Bodamer O, Bruce IA, De Meirleir L, Guffon N, Guillén-Navarro E, Hensman P, Jones S, Kamin W, Kampmann C, Lampe C, Lavery CA, Teles EL, Link B, Lund AM, Malm G, Pitz S, Rothera M, Stewart C, Tylki-Szymańska A, van der Ploeg A, Walker R, Zeman J, Wraith JE: Hunter Syndrome Europena Expert Council Mucopolysaccharidosis type II: European recommendations for the diagnosis and multidisciplinary management of a rare disease. Orphanet J Rare Dis 2011, 6:72. BioMed Central Full Text
• [4]Pinto LL, Vieira TA, Giugliani R, Schwartz IV: Expression of the disease on female carriers of X-linked lysosomal disorders: a brief review. Orphanet J Rare Dis 2010, 5:14. BioMed Central Full Text
• [5]Lyon MF: Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature 1961, 190:372-373.
• [6]Busque L, Mio R, Brais E, Blais N, Lalonde Y, Maragh M, Gilliand DG: Nonrandom X inactivation patterns in normal females: lyonization ratios vary with age. Blood 1996, 88:59-65.
• [7]Minks J, Robinson WP, Brown CJ: A skewed view of X chromosome inactivation. J Clin Invest 2008, 118(1):20-23.
• [8]Schwartz IVD, Pinto LLC, Ribeiro MG, Mota JG, Acosta AX, Correia P, Horovitz D, Porciuncula CGG, Lipinski-Figueiredo E, Fett-Conte A, Oliveira Sobrinho RP, Norato DYJ, Paula AC, Kim CA, Duarte AR, Boy R, Leistner-Segal S, Burin MG, Giugliani R: Clinical and Biochemical Studies in Mucopolysaccharidosis type II Carriers. J Inherit Metab Dis 2009, 32(6):732-738.
• [9]Piña-Aguilar RE, Zaragoza-Arévalo GR, Rau I, Gal A, Alcántara-Ortigoza MA, López-Martínez MS, Santillán-Hernández Y: Mucopolysaccharidosis type II in a female carrying a heterozygous stop mutation of the iduronate-2-sulfatase gene and showing a skewed X chromosome inactivation. Eur J Med Genet 2013, 56(3):159-162.
• [10]Clarke JT, Greer WL, Strasberg PM, Pearce RD, Skomorowski MA, Ray PN: Hunter disease (Mucopolisaccharidosis Type II) associated with unbalanced inactivation of the X-chromosomes in a karyotypically normal girl. Am J Hum Gen 1991, 49:289-297.
• [11]Mossman J, Blunt S, Stephens R, Jones EE, Pembrey M: Hunter’s disease in a girl: association with X:5 chromosomal translocation disrupting the Hunter gene. Arch Dis Child 1983, 58(11):911-915.
• [12]Sukegawa K, Song XQ, Masuno M, Fukao T, Shimozawa N, Fukuda S, Isogai K, Nishio H, Matsuo M, Tomatsu S, Kondo N, Orii T: Hunter disease in a girl caused by R468Q mutation in the iduronate-2-sulfatase gene and skewed inactivation of the X chromosome carrying the normal allele. Hum Mutat 1997, 10(5):361-367.
• [13]Tuschl K, Gal A, Paschke E, Kircher S, Bodamer OA: Mucopolysaccharidosis Type II in Females: Case Report and Review of Literature. Pediatr Neurol 2005, 32(4):270-272.
• [14]Winschester B, Young E, Geddes S, Genet S, Hurst J, Middleton-Price H, Williams N, Webb M, Habel A, Malcolm S: Female twin with Hunter Disease due to nonrandom inactivation of the X-chromosome: a consequence of twinning. Am J Med Genet 1992, 44(6):834-838.
• [15]Cudry S, Tigaud I, Froissart R, Bonnet V, Maire I, Bozon D: MPS II in females: molecular basis of two different cases. J Med Genet 2000, 37(10):E29.
• [16]Broadhead DM, Kirk JM, Burt AJ, Gupta V, Ellis PM, Besley GT: Full expression of Hunter’s disease in a female with an X-chromosome deletion leading to non-random inactivation. Clin Genet 1986, 30(5):392-398.
• [17]Kloska A, Jakóbkiewicz-Banecka J, Tylki-Szymanska A, Czartoryska B, Wergrzyn G: Female Hunter syndrome caused by a single mutation and familial XCI skewing: implication for other X-linked disorders. Clin Genet 2011, 80(5):459-465.
• [18]Jurecka A, Krumina Z, Żuber Z, Różdżyńska-Świątkowska A, Kłoska A, Czartoryska B, Tylki-Szymańska A: Mucopolysaccharidosis type II in females and response to enzyme replacement therapy. Am J Med Genet A 2012, 158A(2):450-454.
• [19]De Camargo Pinto LL, Maluf S, Leistner-Segal S, Zimmer da Silva C, Brusius-Facchin A, Burin MG, Brustolin S, Llerena J, Moraes L, Vedolin L, Schuch A, Giugliani R, Schwartz IVD: Are MPS II heterozygotes actually asymptomatic? A study based on clinical and biochemical data, X-inactivation analysis and imaging evaluations. Am J Med Genet 2011, 155:50-57. Part A
• [20]Wilcox WR, Oliveira JP, Hopkin RJ, Ortiz A, Banikazemi M, Feldt-Rasmussen U, Sims K, Waldek S, Pastores GM, Lee P, Eng CM, Marodi L, Stanford KE, Breunig F, Wanner C, Warnock DG, Lemay RM, Germain DP, Fabry R: Females with Fabry disease frequently have major organ involvement: lessons from the Fabry Registry. Mol Genet Metab 2008, 93(2):112-128.
• [21]Houtkooper RH, Rodenburg RJ, Thiels C, Van Lenthe H, Stet F, Poll-The BT, Stone JE, Steward CG, Wanders RJ, Smeitink J, Kulik W, Vaz FM: Cardiolipin and monolysocardiolipin analysis in fibroblasts, lymphocytes, and tissues using high-performance liquid chromatography-mass spectrometry as a diagnostic test for Barth syndrome. Anal Biochem 2009, 387(2):230-237.
• [22]Del T-R: Seguimiento de pacientes con síndrome de Hunter: el registro HOS (Hunter Outcome Survey). Rev Neurol 2007, 44(Supl 1):S13-S17.
• [23]Stone JE: Urine analysis in the diagnosis of mucopolysaccharide disorders. Ann Clin Biochem 1998, 35:207-225.
• [24]Yunis JJ: High resolution of human chromosomes. Science 1976, 191(4233):1268-1270.
• [25]Allen RC, Zoghbi HY, Moseley AB, Belmont JW: Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet 1992, 51:1220-1239.
• [26]Salsano E, Tabano S, Sirchia SM, Colapietro P, Castellotti B, Gellera C, Rimoldi M, Pensato V, Mariotti C, Pareyson D, Miozzo M, Uziel G: Preferential expression of mutant ABCD1 allele is common in adrenoleukodystrophy female carriers but unrelated to clinical symptoms. Orphanet J Rare Dis 2012, 7:10. BioMed Central Full Text
• [27]Cardiff University: The Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff. 2013. http://www.hgmd.cf.ac.uk/ac/index.php webcite
• [28]Migeon BR: The role of X inactivation and cellular mosaicism in women’s health and sex specific diseases. JAMA 2006, 295:22-29.
• [29]Migeon BR, Pappas K: Females are mosaics: X inactivation and sex differences in disease. 1e. New York & London: Oxford University Press; 2007:271.
• [30]Desnick RJ, Ioannou YA, Eng CM, et al.: A galactosidase A deficiency: Fabry disease. In The metabolic and molecular basis of inherited disease, Volume Volume III. 8th edition. Edited by Scriver CR, Beaudet AL, Sly WS. New York: McGraw-Hill; 2001:3773-3774.
• [31]Bruhl K, Gal A, Bunge S, Beck M: Anderson-Fabry disease: clinical manifestations of the disease in female heterozygotes. J Inherit Metab Dis 2001, 24:715-724.
• [32]Mehta A, Ricci R, Widmer U, Dehout F, De Garcia Lorenzo A, Kapmann C, Linhart A, Sunder-Plasmann G, Ries M, Beck M: Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin Invest 2004, 34:236-342.
• [33]Chabas A, Happle R: Understanding the biology of X linked diseases. Acta Paediatr 2006, 451(Suppl 95):9-10.
• [34]Sharp A, Robinson D, Jacobs P: Age- and tissue-specific variation of X chromosome inactivation ratios in normal women. Hum Genet 2000, 107(4):343-349.
• [35]Dobyns WB, Filauro A, Tomson BN, Chan AS, Ho AW, Ting NT, Osterwijk JC, Ober C: Inheritance of most X-linked traits is not dominant or recessive, just X-linked. Am J Med Genet 2004, Part A 129A:136-143.
• [36]The World Factbook. 2013. https://www.cia.gov/library/publications/the-world-factbook/geos/sp.html webcite
• [37]Bolduc V, Chagnon P, Provost S, Dubé MP, Belisle C, Gingras M, Mollica L, Busque L: No evidence that skewing of X chromosome inactivation patterns is transmitted to offspring in humans. J Clin Invest 2008, 118(1):333-341.
• [38]Knudsen GP, Pedersen J, Klingenberg O, Lygren I, Ørstavik KH: Increased skewing of X chromosome inactivation with age in both blood and buccal cells. Cytogenet Genome Res 2007, 116(1–2):24-28.
• [39]Kristiansen M, Knudesen GP, Bathum L, Naumova AK, Sorensen TI, Brix TH, Svendsen AJ, Christensen K, Kyvik KO, Orstavik KH: Twin study of genetic and aging effects on X chromosome inactivation. Eur J Hum Genet 2005, 13:599-606.