Hereditäre Linsenluxation

Zusammenfassung

Eine Linsenluxation ist, wenn nicht traumatisch bedingt, meist hereditär. Sie ist ein Hauptsymptom mehrerer komplexer syndromaler Erkrankungen, wie z. B. dem Marfan-Syndrom oder der Homocystinurie. Auch bei anderen Bindegewebserkrankungen ist das Risiko für eine Linsenluxation erhöht. Weiterhin kann auch eine isoliert vorliegende Linsenluxation genetisch bedingt sein, wie z. B. bei Vorliegen von Mutationen im ADAMTSL4-Gen. Je nach genetischer Veränderung, die der Linsenluxation zugrunde liegt, ergeben sich für den Patienten unterschiedliche Konsequenzen: Zum einen können Begleitsymptome auftreten, die spezifische Vorsorge- und Behandlungskonsequenzen haben können. Zum anderen können nur durch den Mutationsnachweis der genaue Erbgang und somit die Risiken für weitere Familienmitglieder determiniert werden. Diese Arbeit gibt einen Überblick über die verschiedenen Formen und Ursachen der syndromalen und isolierten Linsenluxation, deren Genetik und ggf. therapeutische Konsequenzen, sowie einen Algorithmus für sinnvolle genetische Diagnostik.

Abstract

If not due to trauma, ectopia lentis is usually caused genetically. It is a main symptom of several syndromal disorders such as Marfan syndrome or homocystinuria. Also other connective tissue disorders convey an elevated risk for ectopia lentis. Isolated ectopia lentis is frequently caused by genetic alterations as well, most commonly due to mutations in ADAMTSL4. Depending on the molecular basis, the consequences for the management of patients may differ significantly: On the one hand, possible accompanying symptoms may require a specific surveillance and treatment. Also, the risk for other family members to develop ectopia lentis or accompanying symptoms can only be determined if the genetic cause and thus inheritance pattern are known. This review describes the different types and genetic causes of syndromal and isolated ectopia lentis as well as possible consequences for the patients; also it presents a sensible algorithm for the molecular diagnostic approach.

Schlüsselwörter

Genetik - Katarakt - Glaukom - Kinderophthamologie

Key words

genetics - cataract - glaucoma - paediatric ophthalmology

• Literatur

• 1 Anteby I, Isaac M, BenEzra D. Hereditary subluxated lenses: visual performances and long-term follow-up after surgery. Ophthalmology 2003; 110: 1344-1348
• 2 Loeys BL, Dietz HC, Braverman AC et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet 2010; 47: 476-485
• 3 Drolsum L, Rand-Hendriksen S, Paus B et al. Ocular findings in 87 adults with Ghent-1 verified Marfan syndrome. Acta Ophthalmol 2014; [Epub ahead of print]
• 4 Maumenee IH. The eye in the Marfan syndrome. Birth Defects Orig Artic Ser 1982; 18: 515-524
• 5 Radke RM, Baumgartner H. Diagnosis and treatment of Marfan syndrome: an update. Heart 2014; 100: 1382-1391
• 6 Callewaert B, Malfait F, Loeys B et al. Ehlers-Danlos syndromes and Marfan syndrome. Best Pract Res Clin Rheumatol 2008; 22: 165-189
• 7 Dietz HC, Cutting GR, Pyeritz RE et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 1991; 352: 337-339
• 8 Neptune ER, Frischmeyer PA, Arking DE et al. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet 2003; 33: 407-411
• 9 Gallo EM, Loch DC, Habashi JP et al. Angiotensin II-dependent TGF-beta signaling contributes to Loeys-Dietz syndrome vascular pathogenesis. J Clin Invest 2014; 124: 448-460
• 10 Groenink M, den Hartog AW, Franken R et al. Losartan reduces aortic dilatation rate in adults with Marfan syndrome: a randomized controlled trial. Eur Heart J 2013; 34: 3491-3500
• 11 Faivre L, Collod-Beroud G, Loeys BL et al. Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study. Am J Hum Genet 2007; 81: 454-466
• 12 Turner CL, Emery H, Collins AL et al. Detection of 53 FBN1 mutations (41 novel and 12 recurrent) and genotype-phenotype correlations in 113 unrelated probands referred with Marfan syndrome, or a related fibrillinopathy. Am J Med Genet A 2009; 149?A: 161-170
• 13 Chu BS. Weill-Marchesani syndrome and secondary glaucoma associated with ectopia lentis. Clin Exp Optom 2006; 89: 95-99
• 14 Jensen AD, Cross HE, Paton D. Ocular complications in the Weill-Marchesani syndrome. Am J Ophthalmol 1974; 77: 261-269
• 15 Young ID, Fielder AR, Casey TA. Weill-Marchesani syndrome in mother and son. Clin Genet 1986; 30: 475-480
• 16 Pimienta AL, Wilcox WR, Reinstein E. More than meets the eye: The evolving phenotype of Weill-Marchesani syndrome-diagnostic confusion with geleophysic dysplasia. Am J Med Genet A 2013; 161?A: 3126-3129
• 17 Faivre L, Dollfus H, Lyonnet S et al. Clinical homogeneity and genetic heterogeneity in Weill-Marchesani syndrome. Am J Med Genet A 2003; 123?A: 204-207
• 18 Dagoneau N, Benoist-Lasselin C, Huber C et al. ADAMTS10 mutations in autosomal recessive Weill-Marchesani syndrome. Am J Hum Genet 2004; 75: 801-806
• 19 Faivre L, Gorlin RJ, Wirtz MK et al. In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani syndrome. J Med Genet 2003; 40: 34-36
• 20 Morales J, Al-Sharif L, Khalil DS et al. Homozygous mutations in ADAMTS10 and ADAMTS17 cause lenticular myopia, ectopia lentis, glaucoma, spherophakia, and short stature. Am J Hum Genet 2009; 85: 558-568
• 21 Hubmacher D, Apte SS. Genetic and functional linkage between ADAMTS superfamily proteins and fibrillin-1: a novel mechanism influencing microfibril assembly and function. Cell Mol Life Sci 2011; 68: 3137-3148
• 22 Kutz WE, Wang LW, Bader HL et al. ADAMTS10 protein interacts with fibrillin-1 and promotes its deposition in extracellular matrix of cultured fibroblasts. J Biol Chem 2011; 286: 17156-17167
• 23 Farias FH, Johnson GS, Taylor JF et al. An ADAMTS17 splice donor site mutation in dogs with primary lens luxation. Invest Ophthalmol Vis Sci 2010; 51: 4716-4721
• 24 Yap S. Classical homocystinuria: vascular risk and its prevention. J Inherit Metab Dis 2003; 26: 259-265
• 25 Yap S, Rushe H, Howard PM et al. The intellectual abilities of early-treated individuals with pyridoxine-nonresponsive homocystinuria due to cystathionine beta-synthase deficiency. J Inherit Metab Dis 2001; 24: 437-447
• 26 Adam S, Almeida MF, Carbasius Weber E et al. Dietary practices in pyridoxine non-responsive homocystinuria: a European survey. Mol Genet Metab 2013; 110: 454-459
• 27 Hubmacher D, Cirulis JT, Miao M et al. Functional consequences of homocysteinylation of the elastic fiber proteins fibrillin-1 and tropoelastin. J Biol Chem 2010; 285: 1188-1198
• 28 Moat SJ, Bao L, Fowler B et al. The molecular basis of cystathionine beta-synthase (CBS) deficiency in UK and US patients with homocystinuria. Hum Mutat 2004; 23: 206
• 29 Skovby F, Gaustadnes M, Mudd SH. A revisit to the natural history of homocystinuria due to cystathionine beta-synthase deficiency. Mol Genet Metab 2010; 99: 1-3
• 30 Liberfarb RM, Levy HP, Rose PS et al. The Stickler syndrome: genotype/phenotype correlation in 10 families with Stickler syndrome resulting from seven mutations in the type II collagen gene locus COL2A1. Genet Med 2003; 5: 21-27
• 31 Parke DW. Stickler syndrome: clinical care and molecular genetics. Am J Ophthalmol 2002; 134: 746-748
• 32 Khan AO, Aldahmesh MA, Mohamed JY et al. The distinct ophthalmic phenotype of Knobloch syndrome in children. Br J Ophthalmol 2012; 96: 890-895
• 33 Sniderman LC, Koenekoop RK, OʼGorman AM et al. Knobloch syndrome involving midline scalp defect of the frontal region. Am J Med Genet 2000; 90: 146-149
• 34 Menzel O, Bekkeheien RC, Reymond A et al. Knobloch syndrome: novel mutations in COL18A1, evidence for genetic heterogeneity, and a functionally impaired polymorphism in endostatin. Hum Mutat 2004; 23: 77-84
• 35 Ades LC, Holman KJ, Brett MS et al. Ectopia lentis phenotypes and the FBN1 gene. Am J Med Genet A 2004; 126?A: 284-289
• 36 Chandra A, Patel D, Aragon-Martin JA et al. The Revised Ghent Nosology; Reclassifying Isolated Ectopia Lentis. Clin Genet 2014; [Epub ahead of print]
• 37 Robinson PN, Booms P, Katzke S et al. Mutations of FBN1 and genotype-phenotype correlations in Marfan syndrome and related fibrillinopathies. Hum Mutat 2002; 20: 153-161
• 38 Ahram D, Sato TS, Kohilan A et al. A homozygous mutation in ADAMTSL4 causes autosomal-recessive isolated ectopia lentis. Am J Hum Genet 2009; 84: 274-278
• 39 Chandra A, Aragon-Martin JA, Hughes K et al. A genotype-phenotype comparison of ADAMTSL4 and FBN1 in isolated ectopia lentis. Invest Ophthalmol Vis Sci 2012; 53: 4889-4896
• 40 Neuhann TM, Artelt J, Neuhann TF et al. A homozygous microdeletion within ADAMTSL4 in patients with isolated ectopia lentis: evidence of a founder mutation. Invest Ophthalmol Vis Sci 2011; 52: 695-700
• 41 Christensen AE, Fiskerstrand T, Knappskog PM et al. A novel ADAMTSL4 mutation in autosomal recessive ectopia lentis et pupillae. Invest Ophthalmol Vis Sci 2010; 51: 6369-6373
• 42 Chandra A, Jones M, Cottrill P et al. Gene expression and protein distribution of ADAMTSL-4 in human iris, choroid and retina. Br J Ophthalmol 2013; 97: 1208-1212
• 43 Gabriel LA, Wang LW, Bader H et al. ADAMTSL4, a secreted glycoprotein widely distributed in the eye, binds fibrillin-1 microfibrils and accelerates microfibril biogenesis. Invest Ophthalmol Vis Sci 2012; 53: 461-469
• 44 Ali M, McKibbin M, Booth A et al. Null mutations in LTBP2 cause primary congenital glaucoma. Am J Hum Genet 2009; 84: 664-671
• 45 Khan AO, Aldahmesh MA, Alkuraya FS. Congenital megalocornea with zonular weakness and childhood lens-related secondary glaucoma – a distinct phenotype caused by recessive LTBP2 mutations. Mol Vis 2011; 17: 2570-2579
• 46 Haji-Seyed-Javadi R, Jelodari-Mamaghani S, Paylakhi SH et al. LTBP2 mutations cause Weill-Marchesani and Weill-Marchesani-like syndrome and affect disruptions in the extracellular matrix. Hum Mutat 2012; 33: 1182-1187
• 47 Desir J, Sznajer Y, Depasse F et al. LTBP2 null mutations in an autosomal recessive ocular syndrome with megalocornea, spherophakia, and secondary glaucoma. Eur J Hum Genet 2010; 18: 761-767