Lysosomale Speichererkrankungen – Update und neue therapeutische Optionen

Zusammenfassung

Lysosomale Speichererkrankungen repräsentieren eine Gruppe von über 50 genetisch bedingten Erkrankungen. Durch einen genetischen Defekt eines lysosomalen Enzyms oder Aktivatorproteins kommt es zur Akkumulation spezifischer Substrate mit konsekutiv z. T. schwersten Funktionsstörungen verschiedener Organsysteme. Lysosomale Speichererkrankungen sind derzeit nicht heilbar. Aufgrund ihres progredienten Verlaufs weisen viele von ihnen eine dramatische Morbidität und Mortalität auf, eine möglichst frühzeitige Behandlung zur Erhaltung wesentlicher Körperfunktionen ist essenziell. Während lange Zeit als alleinige therapeutische Option die symptomatische Therapie zur Verfügung stand, stellen der Ersatz des fehlenden lysosomalen Enzyms (ERT) bzw. die Substratreduktion kausale Therapieansätze dar. Viele lysosomale Speichererkrankungen sind durch pathognomonische Augenbefunde gekennzeichnet. Insofern bietet die ophthalmologische Untersuchung die Möglichkeit einer frühzeitigen und nicht invasiven Diagnostik, sodass ggf. eine wirksame Therapie frühzeitig eingeleitet werden kann. Diese Zusammenfassung soll einen Überblick über die geläufigsten Speichererkrankungen insbesondere in Hinblick auf ophthalmologische Veränderungen geben sowie neue therapeutische Ansätze näher erläutern.

Abstract

Lysosomal storage diseases represent a group of about 50 genetic disorders. The deficiencies of lysosomal and non-lysosomal proteins cause an accumulation of compounds which are normaly degraded within the lysosome. There are currently no therapeutic options to cure patients suffering from a lysosomal storage disease. Due to their progressive nature there is considerable morbidity and mortality. Thus, an early treatment to maintain major systemic functions is of utmost importance. While so far only symptomatic therapies are in use, the newly available enzyme replacment therapies offer a real causal approach for selected storage diseases. Many of these disorders are characterised by pathognomonic eye findings. Therefore, the ophthalmological examination provides the opportunity for an early and non-invasive diagnosis and a chance to initiate early treatment. This review is intended to give a survey of the most common lysosomal storage diseases, particularly with regard to ophthalmological changes as well as illustrate new therapeutic options.

Schlüsselwörter

Kinderophthalmologie - Genetik - lysosomale Speichererkrankung

Key words

paediatric ophthalmology - genetics - lysosomal storage diseases

Literatur

• 1 Abraham F A, Yatziv S, Russell A. et al . Electrophysiological and psychophysical findings in Hunter syndrome.  Arch Ophthalmol. 1974;  91 181-186
• 2 Accardo A P, Pensiero S, Perissutti P. Saccadic analysis for early identification of neurological involvement in Gaucher disease.  Ann N Y Acad Sci. 2005;  1039 503-507
• 3 Alroy J, Haskins M, Birk D E. Altered corneal stromal matrix organization is associated with mucopolysaccharidosis I, III and VI.  Exp Eye Res. 1999;  68 523-5230
• 4 Arbisser A I, Murphree A L, Garcia C A. et al . Ocular findings in mannosidosis.  Am J Ophthalmol. 1976;  82 (3) 465-471
• 5 Ashworth J L, Biswas S, Wraith E. et al . Mucopolysaccharidoses and the eye.  Surv Ophthalmol. 2006;  51 (1) 1-17
• 6 Ashworth J L, Biswas S, Wraith E. et al . The ocular features of the mucopolysaccharidoses.  Eye. 2006;  20 (5) 553-563
• 7 Associaton of Delaware Valley .National Tay-Sachs & Allied Diseases. http://www.tay-sachs.org
• 8 Baehner F, Schmiedeskamp C, Krummenauer F. et al . Cumulative incidence rates of the mucopolysaccharidoses in Germany.  J Inherit Metab Dis. 2005;  28 1011-1017
• 9 Barbey F, Hayoz D, Widmer U. et al . Efficacy of enzyme replacement therapy in Fabry disease.  Curr Med Chem Cardiovasc Hematol Agents. 2004;  2 (4) 277-286
• 10 Berg T, Riise H M, Hansen G M. et al . Spectrum of mutations in alpha-mannosidosis.  Am J Hum Genet. 1999;  64 (1) 77-88
• 11 Beutler E. Enzyme replacement in Gaucher disease.  PLoS Med. 2004;  1 (2) e21, Epub 2004 Nov 30
• 12 Cheng Y, Verp M S, Knutel T. et al . Mucopolysaccharidosis type VII as a cause of recurrent non-immune hydrops fetalis.  J Perinat Med. 2003;  31 (6) 535-537
• 13 Clarke L A. The mucopolysaccharidoses: a success of molecular medicine.  Expert Reviews in molecular medicine. 2008;  10 1-18
• 14 Cogan D G, Chu F C, Gittinger J. et al . Fundal abnormalities of Gaucher’s disease.  Arch Ophthalmol. 1980;  98 (12) 2202-2203
• 15 Collins M L, Traboulsi E I, Maumenee I H. Optic nerve head swelling and optic atrophy in the systemic mucopolysaccharidoses.  Ophthalmology. 1990;  97 (11) 1445-1449
• 16 Dehout F, Roland D, Treille de Granseigne S. et al . Relief of gastrointestinal symptoms under enzyme replacement therapy in patients with Fabry disease.  J Inherit Metab Dis. 2004;  27 (4) 499-505
• 17 Desnick R J, Brady R, Barranger J. et al . Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy.  Ann Intern Med. 2003;  138 (4) 338-346
• 18 Fahnehjelm K T, Törnquist A L, Malm G. et al . Ocular findings in four children with mucopolysaccharidosis I-Hurler (MPS I-H) treated early with haematopoietic stem cell transplantation.  Acta Ophthalmol Scand. 2006;  84 (6) 781-785
• 19 Falke K, Büttner A, Schittkowski M. et al . The microstructure of cornea verticillata in Fabry disease and amiodarone-induced keratopathy: a confocal laser-scanning microscopy study.  Graefes Arch Clin Exp Ophthalmol. 2009;  247 (4) 523-534
• 20 FDA. First treatment for Pompe disease.  Consum. 2006;  40 (4) 3
• 21 Fernandes Filho J A, Shapiro B E. Tay-Sachs Disease.  Arch Neurol. 2004;  61 (9) 1466-1468
• 22 Ghosh M, Hunter W S, Wedge C. Corneal changes in Tay-Sachs disease.  Can J Ophthalmol. 1990;  25 (4) 190-192
• 23 Guemes A, Kosmorsky G S, Moodie D S. et al . Corneal opacities in Gaucher disease.  Am J Ophthalmol. 1998;  126 (6) 833-835
• 24 Herskhovitz E, Young E, Rainer J. et al . Bone marrow transplantation for Maroteaux-Lamy syndrome (MPS VI): long-term follow-up.  J Inherit Metab Dis. 1999;  22 (1) 50-62
• 25 Hoffmann B, Garcia de Lorenzo A, Mehta A. et al . Effects of enzyme replacement therapy on pain and health related quality of life in patients with Fabry disease: data from FOS (Fabry Outcome Survey).  J Med Genet. 2005;  42 (3) 247-252
• 26 Käsmann-Kellner B, Weindler J, Pfau B. et al . Ocular changes in mucopolysaccharidosis IV A (Morquio A syndrome) and long-term results of perforating keratoplasty.  Ophthalmologica. 1999;  213 (3) 200-205
• 27 Kakkis E D, Schuchman E, He X. et al . Enzyme-replacement therapy in mucopolysaccharidosis I.  Mol Genet Metab. 2001;  72 (3) 199-208
• 28 Koseoglu S T, Harmatz P, Turbeville S. et al . Reversed papilledema in an MPS VI patient with galsulfase (Naglazyme®) therapy.  Int Ophthalmol. 2008;  17 Epub ahead of print
• 29 Leavitt J A, Kotagal S. The „cherry red” spot.  Pediatr Neurol. 2007;  37 (1) 74-75
• 30 Lengyel D, Weissert M, Schmid L. et al . Eye movement abnormalities as a sign for the diagnosis in Niemann-Pick disease type C.  Klin Monatsbl Augenheilkd. 1999;  214 (1) 50-52
• 31 Maegawa G H, Stockley T, Tropak M. et al . The natural history of juvenile or subacute GM 2 gangliosidosis: 21 new cases and literature review of 134 previously reported.  Pediatrics. 2006;  118 (5) e1550-e1562
• 32 Martin R, Beck M, Eng C. et al . Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome).  Pediatrics. 2008;  121 377-386
• 33 McDonnell J M, Green W R, Maumenee I H. Ocular histopathology of systemic mucopolysaccharidosis, type II-A (Hunter syndrome, severe).  Ophthalmology. 1985;  92 (12) 1772-1779
• 34 McGovern M M, Wasserstein M P, Aron A. et al . Ocular manifestations of Niemann-Pick disease type B.  Ophthalmology. 2004;  111 (7) 1424-1427
• 35 Meyer A, Kossow K, Gal A. et al . Scoring evaluation of the natural course of mucopolysaccharidoses type III A (Sanfilippo syndrome type a).  Pediatrics. 2007;  120 1255-1261
• 36 Miano M, Lanino E, Gatti R. et al . Four year follow-up of a case of fucosidosis treated with unrelated donor bone marrow transplantation.  Bone Marrow Transplant. 2001;  27 (7) 747-751
• 37 Mistry P, Germain D P. Therapeutic objectives in Gaucher disease.  Rev Med Interne. 2007;  28 (Suppl 2) S171-S175
• 38 Narita A S, Russell-Eggitt I. Bilateral epiretinal membranes: a new finding in Hunter syndrome.  Ophthalmic Genet. 1996;  17 (2) 75-78
• 39 Natowicz M R, Short M P, Wang Y. et al . Clinical and biochemical manifestations of hyaluronidase deficiency.  N Engl J Med. 1996;  335 (14) 1029-1033
• 40 Neufeld E F, Muenzer J. The Mucopolysaccharidoses. Scriver CR, Beaudet AL, Sly WS and Valle D The Metabolic and Molecular Bases of Inherited Diseases New York; 2001 Volume II, Eighth edition: 3421-3452
• 41 Nguyen T T, Gin T, Nicholls K. et al . Ophthalmological manifestations of Fabry disease: a survey of patients at the Royal Melbourne Fabry Disease Treatment Centre.  Clin Experiment Ophthalmol. 2005;  33 (2) 164-168
• 42 Palmer M, Green W R, Maumenee I H. et al . Niemann-Pick disease – type C. Ocular histopathologic and electron microscopic studies.  Arch Ophthalmol. 1985;  103 (6) 817-822
• 43 Paschke E, Milos I, Kreimer-Erlacher H. et al . Mutation analyses in 17 Patients with deficiency in acid &beta-galactosidase: three novel point mutations and high correlation of mutation W 273L with Morquio disease type B.  Huma Genet. 2001;  109 159-166
• 44 Patterson M C, Vecchio D, Prady H. et al . Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study.  Lancet Neurol. 2007;  6 765-772
• 45 Pitz S, Ogun O, Arash L. et al . Does enzyme replacement therapy influence the ocular changes in type VI mucopolysaccharidosis?.  Graefes Arch Clin Exp Ophthalmol. 2009;  247 (7) 975-980
• 46 Pitz S, Ogun O, Bajbouj M. et al . Ocular changes in patients with mucopolysaccharidosis I receiving enzyme replacement therapy: a 4-year experience.  Arch Ophthalmol. 2007;  125 (10) 1353-1356
• 47 Reczek D, Schwake M, Schröder J. et al . LIMP-2 is a receptor for lysosomal mannose-6-phsophate – independent targeting of β-Glucocerebrosdidase.  Cell. 2007;  131 770-783
• 48 Shrier E M, Barr C C, Grabowski G A. Vitreous opacities and retinal vascular abnormalities in Gaucher disease.  Arch Ophthalmol. 2004;  122 (9) 1395-1398
• 49 Pokorny K S, Ritch R, Friedman A H. et al . Ultrastructure of the eye in fetal type II glycogenosis (Pompe’s disease).  Invest Ophthalmol Vis Sci. 1982;  22 (1) 25-31
• 50 Prall F R, Drack A, Taylor M. et al . Ophthalmic manifestations of Danon disease.  Ophthalmology. 2006;  113 (6) 1010-1013
• 51 Sato S, Maeda N, Watanabe H. et al . Multiple iridociliary cysts in patients with mucopolysaccharidoses.  Br J Ophthalmol. 2002;  86 933-934
• 52 Schorderet D F, Cottet S, Lobrinus J A. et al . Retinopathy in Danon disease.  Arch Ophthalmol. 2007;  125 (2) 231-236
• 53 Schumacher R G, Brzezinska R, Schulze-Frenking G. et al . Sonographic ocular findings in patients with mucopolysaccharidoses I, II and VI.  Pediatr Radiol. 2008;  38 (5) 543-550, Epub 2008 Feb 26
• 54 Sévin M, Lesca G, Baumann N. et al . The adult form of Niemann-Pick disease type C.  Brain. 2007;  130 (Pt 1) 120-133
• 55 Sodi A, Ioannidis A S, Mehta A. et al . Ocular manifestations of Fabry’s disease: data from the Fabry Outcome Survey.  Br J Ophthalmol. 2007;  91 (2) 210-214, Epub 2006 Sep 14
• 56 Snodgrass M B. Ocular findings in a case of fucosidosis.  Br J Ophthalmol. 1976;  60 (7) 508-511
• 57 Springer C, Gutschalk A, Meinck H M. et al . Late-onset retinal dystrophy in alpha-mannosidosis.  Graefes Arch Clin Exp Ophthalmol. 2005;  243 (12) 1277-1279, Epub 2005 Jun 17
• 58 Stark H. Eye changes in Gaucher’s disease.  Klin Monatsbl Augenheilkd. 1983;  183 (3) 216-220
• 59 Steinlin M, Thun-Hohenstein L, Boltshauser E. Congenital oculomotor apraxia. Presentation – developmental problems – differential diagnosis.  Klin Monatsbl Augenheilkd. 1992;  200 (5) 623-625
• 60 Suvarna J C, Hajela S A. Cherry – red spot.  J Postgrad Med. 2008;  54 (1) 54-57
• 61 Takada G, Satoh W, Komatsu K. et al . Transitory type of sphingomyelinase deficient Niemann-Pick disease: clinical and morphological studies and follow-up of two sisters.  Tohoku J Exp Med. 1987;  153 (1) 27-36
• 62 Tsukadaira A, Hirose Y, Aoki H. et al . Diagnosis of fucosidosis through a skin rash.  Intern Med. 2005;  44 (8) 907-908
• 63 Valstar M J, Ruijter G JG, Diggelen O P. et al . Sanfilippo syndrome: a mini-review.  J Inherit Metab Dis. 2008;  31 240-252
• 64 Vellodi van A, Young E P, Cooper A. et al . Bone marrow transplantation for mucopolysaccharidosis type I: experience of two British centres.  Arch Dis Child. 1997;  76 (2) 92-99
• 65 Walkley S U, Haskins M E, Shull R M. Alterations in neuron morphology in mucopolysaccharidosis type I. A Golgi study.  Acta Neuropathol. 1988;  75 (6) 611-620
• 66 Wang T J, Chen M S, Shih Y F. et al . Fundus abnormalities in a patient with type I Gaucher’s disease with 12-Year follow-up.  Am J Ophthalmol. 2005;  139 (2) 359-362
• 67 Wraith J E, Scarpa M, Beck M. et al . Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy.  Eur J Pediatr. 2008;  167 (3) 267-277
• 68 Zhu M, Lovell K L, Patterson J S. et al . Beta-mannosidosis mice: a model for the human lysosomal storage disease.  Hum Mol Genet. 2006;  15 (3) 493-500