Mucopolysaccharidosis and Adulthood: Genetics, Inheritance, and Reproductive Options

Abstract

The mucopolysaccharide diseases are a group of heterogeneous, inherited conditions that are characterized by the deficiency of specific lysosomal enzymes. These lysosomal enzymes are responsible for the breakdown of glycosaminoglycans (GAGs), which are a key component of connective tissue. When lysosomal enzymes are deficient, the resultant build-up of GAGs impacts on cellular functioning. The resultant clinical manifestations are multisystemic, progressive, and life-limiting. Although each condition is characterized by its own constellation of symptoms; there is a great deal of heterogeneity and overlap in the clinical manifestations (both within and between mucopolysaccharidosis [MPS] subtypes). Increasing understanding of the genetic and biochemical basis of the MPS diseases has paved the way for a wave of exciting developments in their treatment and management. New treatments have changed the face of many of the MPS diseases; and as a result, management has moved beyond the pediatric clinic into the adult clinic. For the first time, individuals with MPS are living into adulthood with fewer limitations than the natural course of their disease would predict. It is essential that in this new age of MPS disease management, early diagnosis achieved and those at risk of having a child affected by one of these conditions are appropriately counseled in relation to their reproductive options. It is also important that individuals with MPS are counseled independently, at an appropriate age (or when they have capacity) about the basis of their disease and what this means for them. Here we discuss the diagnosis and inheritance of the MPS conditions; specifically focusing on genetic counseling requirements. We also discuss the outcomes of a research study, undertaken by the UK Mucopolysaccharide Disease Society, into the experiences of women with MPS who have had successful pregnancies.

Keywords

mucopolysaccharide - genetic counseling - inheritance - prenatal - preimplantation genetic diagnosis - pregnancy

^* deceased in December 2017

• References

• 1 Platt FM, Boland B, van der Spoel AC. The cell biology of disease: lysosomal storage disorders: the cellular impact of lysosomal dysfunction. J Cell Biol 2012; 199 (05) 723-734
• 2 Wraith JE. The mucopolysaccharidoses: a clinical review and guide to management. Arch Dis Child 1995; 72 (03) 263-267
• 3 Muenzer J. The mucopolysaccharidoses: a heterogeneous group of disorders with variable pediatric presentations. J Pediatr 2004; 144 (5, Suppl): S27-S34
• 4 Hopwood JJ, Morris CP. The mucopolysaccharidoses. Diagnosis, molecular genetics and treatment. Mol Biol Med 1990; 7 (05) 381-404
• 5 Meikle PJ, Hopwood JJ. Lysosomal storage disorders: emerging therapeutic options require early diagnosis. Eur J Pediatr 2003; 162 (1, Suppl 1): S34-S37
• 6 Beck M. Therapy for lysosomal storage disorders. IUBMB Life 2010; 62 (01) 33-40
• 7 Clarke LA. The mucopolysaccharidoses: a success of molecular medicine. Expert Rev Mol Med 2008; 18: 10e1
• 8 Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS. , et al, eds. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw Hill; 2001: 3421-3452
• 9 Meikle PJ, Fietz MJ, Hopwood JJ. Diagnosis of lysosomal storage disorders: current techniques and future directions. Expert Rev Mol Diagn 2004; 4 (05) 677-691
• 10 Hopwood JJ, Harrison JR. High-resolution electrophoresis of urinary glycosaminoglycans: an improved screening test for the mucopolysaccharidoses. Anal Biochem 1982; 119 (01) 120-127
• 11 Kresse H, von Figura K, Klein U, Glössl J, Paschke E, Pohlmann R. Enzymic diagnosis of the genetic mucopolysaccharide storage disorders. Methods Enzymol 1982; 83: 559-572
• 12 Gelb MH, Turecek F, Scott CR, Chamoles NA. Direct multiplex assay of enzymes in dried blood spots by tandem mass spectrometry for the newborn screening of lysosomal storage disorders. J Inherit Metab Dis 2006; 29 (2–3): 397-404
• 13 Zhang XK, Elbin CS, Turecek F. , et al. Multiplex lysosomal enzyme activity assay on dried blood spots using tandem mass spectrometry. Methods Mol Biol 2010; 603: 339-350
• 14 Ruijter GJ, Boer M, Weykamp CW. , et al. External quality assurance programme for enzymatic analysis of lysosomal storage diseases: a pilot study. J Inherit Metab Dis 2005; 28 (06) 979-990
• 15 Mardis E. Next-Generations DNA Sequencing Methods. Ann Rev Genomics HumGenet 2008; 9: 387-402
• 16 Fonda Allen J, Stoll K, Bernhardt BA. Pre- and post-test genetic counseling for chromosomal and Mendelian disorders. Semin Perinatol 2016; 40 (01) 44-55
• 17 Baldwin EE, Boudreault P, Fox M, Sinsheimer JS, Palmer CG. Effect of pre-test genetic counseling for deaf adults on knowledge of genetic testing. J Genet Couns 2012; 21 (02) 256-272
• 18 Resta R, Biesecker BB, Bennett RL. , et al; National Society of Genetic Counselors' Definition Task Force. A new definition of genetic counselling: national Society of genetic counsellors' task force report. J Genet Couns 2006; 15 (02) 77-83
• 19 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 (04) 270-272
• 20 Winchester B, Young E, Geddes S. , et al. Female twin with Hunter disease due to nonrandom inactivation of the X-chromosome: a consequence of twinning. Am J Med Genet 1992; 44 (06) 834-838
• 21 Clarke JT, Greer WL, Strasberg PM, Pearce RD, Skomorowski MA, Ray PN. Hunter disease (mucopolysaccharidosis type II) associated with unbalanced inactivation of the X chromosomes in a karyotypically normal girl. Am J Hum Genet 1991; 49 (02) 289-297
• 22 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
• 23 Murphy AM, Lambert D, Treacy EP, O'Meara A, Lynch SA. Incidence and prevalence of mucopolysaccharidosis type 1 in the Irish republic. Arch Dis Child 2009; 94 (01) 52-54
• 24 Murphy AM. Disease frequency of inborn errors of metabolism in the Irish Traveller Community. Ulster Med J 2008; 77 (01) 69
• 25 Lake BD, Young EP, Winchester BG. Prenatal diagnosis of lysosomal storage diseases. Brain Pathol 1998; 8 (01) 133-149
• 26 Fowler DJ, Anderson G, Vellodi A, Malone M, Sebire NJ. Electron microscopy of chorionic villus samples for prenatal diagnosis of lysosomal storage disorders. Ultrastruct Pathol 2007; 31 (01) 15-21
• 27 Benn PA, Chapman AR. Ethical challenges in providing noninvasive prenatal diagnosis. Curr Opin Obstet Gynecol 2010; 22 (02) 128-134
• 28 Powledge TM, Fletcher J. Guidelines for the ethical, social and legal issues in prenatal diagnosis. A report from the Genetics Research Group of the Hastings Center, Institute of Society, Ethics and the Life Sciences. N Engl J Med 1979; 300 (04) 168-172