Morbus Fabry

Zusammenfassung

Die Morbus Fabry Erkrankung ist eine seltene, X-chromosomal vererbbare, lysosomale Speichererkrankung, bedingt durch eine Mutation im α-Galaktosidase-A-Gen (GLA). Bei betroffenen Patienten kommt es dadurch zu einem Mangel des lysosomalen Enzyms α-Galaktosidase A, welches unter normaler Konzentration beim Abbauprozess von zellmembranständigem Globotriaosyceramid (Gb3) beteiligt ist. Dieser Enzymmangel führt zur sukzessiven Akkumulation von Gb3 in zahlreichen Organen. Die Folge ist eine nachhaltige Parenchym- und Funktionsschädigung der betroffenen Organsysteme.

Das Spektrum klinischer Symptome ist vielfältig und reicht von den im Kindes- und Jugendalter oft diagnostizierten Akroparästhesien, Hypohidrosis, Angiokeratomen und Hornhauttrübungen bis hin zu schweren pathologischen Veränderungen in Nieren, Herz, ZNS sowie anderen Organen im Erwachsenenalter. Morbus Fabry Patienten leiden unter einer erhöhten Morbidität und Mortalität, und haben unbehandelt eine verminderte Lebenserwartung (Männer ca. 20 Jahre, Frauen ca. 15 Jahre). Der klinische Phänotyp ist sehr variabel: während Männer unbehandelt im Verlauf meistens schwer erkranken, treten die Symptome bei Frauen zeitlich verzögert und milder auf. Aufgrund der mutationsbedingt individuellen Krankheitsverläufe wird die Diagnose in erster Linie aufgrund der klinischen Symptome gestellt und durch einen laborchemischen Nachweis einer verminderten α-Galaktosidase-A-Aktivität im Blut sowie durch eine genetische Mutationsanalyse gesichert. Neben einer symptomorientierten, konservativen Therapie ist durch die Einführung der Enzymersatztherapie (EET) seit 2001 eine kausale Behandlung des M. Fabry möglich. Nach heutigen Erkenntnissen bewirkt die EET eine Stabilisierung bzw. zum Teil sogar eine Verbesserung von Symptomen und Lebensqualität und hat zugleich das Potenzial, die Mortalität zu verringern. Um Organschäden zu verhindern bzw. zu mildern, ist eine frühe Diagnose und Behandlung erstrebenswert.

Abstract

Fabry disease is an inherited X-linked lysosomal storage disease due to a genetic defect of the GLA gene which encodes the protein of the enzyme α-galaktosidase A. Under normal concentrations this lysosomal enzyme is involved in degradation and catabolism processes of membrane glycosphingolipids in almost all cells of the human organism. The enzyme deficiency leads to a progessive accumulation of globotriaosylceramide (Gb3) in various tissues and organ systems and is responsible for the large variability of the clinical signs and symptoms of the disease.

First signs and symptoms such as painful neuropathy (acroparethesia), hypo- or unhidrosis and gastrointestinal disturbances can be found already in childhood and mainly affect quality of life. In the following decades of life, renal cardiac, and cerebrovascular complications occur in hemizygous males and with some delay in a part of heterozygous females as well. If not treated, these complications result in increased morbidity and premature mortality.

With the introduction of the enzyme replacement therapy (ERT) in 2001 a causal treatment is available. Published data from clinical trials and observational studies demonstrated that ERT mitigates signs and symptoms of the disease as well as quality of life, and has the potential to reduce mortality. The efficacy of ERT seems to be less pronounced in severe cases of the disease, which makes an early diagnosis and treatment more important in order to prevent or improve the progression of the disease.

Morbus Fabry - α-Galaktosidase A - Glykosphingolipide

Fabry disease - α-galactosidase A - glycosphingolipids

Literatur

• 1 Anderson W. A case of „angio-keratoma”.  Br J Dermatol. 1898;  10 113-117
• 2 Baehner F, Kampmann C, Whybra C, Miebach E, Wiethoff C M, Beck M. Enzyme replacement therapy in heterozygous females with Fabry disease: results of a phase IIIB study.  J Inherit Metab Dis. 2003;  26 617-627
• 3 Banikazemi M, Bultas J, Waldek S. et al . Agalsidase-beta therapy for advanced Fabry disease.  Ann Intern Med. 2007;  146 77-86
• 4 Beck M, Ries M. Morbus Fabry - Clinical manifestation, diagnosis and therapy. OCC Europe Ltd London 2002
• 5 Beck M, Ricci R, Widmer U. et al . Fabry disease: overall effects of agalsidase alfa treatment.  Eur J Clin Invest. 2004;  34 838-844
• 6 Becker A E, Schoorl R, Balk A G, van der Heide R M. Cardiac manifestations of Fabry’s disease. Report of a case with mitral insufficiency and electrocardiographic evidence of myocardial infarction.  Am J Cardiol. 1975;  36 829-835
• 7 Bekri S, Lidove O, Jaussaud R, Knebelmann B, Barbey F. The role of ceramide trihexoside (globotriaosylceramide) in the diagnosis and follow-up of the efficacy of treatment of fabry disease: a review of the literature.  Cardiovasc Hematol Agents Med Chem. 2006;  4 289-297
• 8 Breunig F, Weidemann F, Strotmann J, Knoll A, Wanner C. Clinical benefit of enzyme replacement therapy in Fabry disease.  Kidney Int. 2006;  69 1216-1221
• 9 Cybulla M, Schaefer E, Wendt S. et al . Chronic renal failure and proteinuria in adulthood: Fabry disease predominantly affecting the kidneys.  Am J Kidney Dis. 2005;  45 e82-89
• 10 Cybulla M, Walter k, Neumann H PH. et al .Morbus Fabry: Demographische Übersicht seit Einführung der Enzymersatztherapie. Dtsch Med Wochenschr 2007: 1505-1509
• 11 Desnick R JIY, Eng C M. alpha-Galactosidase A deficiency: Fabry disease. 7th ed. McGraw-Hill, Inc New York 1995
• 12 Desnick R J, Wasserstein M P. Fabry disease: clinical features and recent advances in enzyme replacement therapy.  Adv Nephrol Necker Hosp. 2001;  31 317-339
• 13 Desnick R J, Brady R O. Fabry disease in childhood.  J Pediatr. 2004;  144 (5 Suppl) S20-26
• 14 Elliott P M, Kindler H, Shah J S. et al . Coronary microvascular dysfunction in male patients with Anderson-Fabry disease and the effect of treatment with alpha galactosidase A.  Heart. 2006;  92 357-360
• 15 Eng C M, Guffon N, Wilcox W R. et al . Safety and efficacy of recombinant human alpha-galactosidase A - replacement therapy in Fabry’s disease.  N Engl J Med. 2001;  345 9-16
• 16 Eng C M, Banikazemi M, Gordom R E. et al . A phase 1/2 clinical trial of enzyme replacement in Fabry disease: pharmacokinetic, substarte clearance, and safety studies.  Am J Hum Genet. 2001;  68 711-722
• 17 Fabry J. Ein Beitrag Zur Kenntnis der Purpura haemorrhagica nodularis (Purpura papulosa hemorrhagica Hebrae).  Arch Derm Syph. 1898;  43 187-200
• 18 Fachinformation Replagal. November 2006
• 19 Fachinformation Fabrazyme. August 2006
• 20 Fellgiebel A, Muller M J, Mazanek M, Baron K, Beck M, Stoeter P. White matter lesion severity in male and female patients with Fabry disease.  Neurology. 2005;  65 600-602
• 21 Ferrans V J, Hibbs R G, Burda C D. The heart in Fabry’s disease. A histochemical and electron microscopic study.  Am J Cardiol. 1969;  24 95-110
• 22 Germain D P. A new phenotype of Fabry disease with intermediate severity between the classical form and the cardiac variant.  Contrib Nephrol. 2001;  136 234-240
• 23 Hilz M J, Brys M, Marthol H, Stemper B, Dutsch M. Enzyme replacement therapy improves function of C-, Adelta-, and Abeta-nerve fibers in Fabry neuropathy.  Neurology. 2004;  62 1066-1072
• 24 Hoffmann B, Reinhardt D, Koletzko B. Effect of enzyme-replacement therapy on gastrointestinal symptoms in Fabry disease.  Eur J Gastroenterol Hepatol. 2004;  16 1067-1069
• 25 Hoffmann B, Garcia de Lorenzo A, Mehta A, Beck M, Widmer U, Ricci R. 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;  42 247-252
• 26 Kalliokoski R J, Kantola I, Kalliokoski K K. et al . The effect of 12-month enzyme replacement therapy on myocardial perfusion in patients with Fabry disease.  J Inherit Metab Dis. 2006;  29 112-118
• 27 Kampmann C, Wiethoff C M, Perrot A, Beck M, Dietz R, Osterziel K J. The heart in Anderson Fabry disease.  Z Kardiol. 2002;  91 786-795
• 28 Kampmann C RM, Bähner F, Kim K S, Bajbouj M, Beck M. Influence of enzyme replacement therapy on Anderson-Fabry disease associated hypertrophic infiltrative cardio-myopathy.  Eur J Pediatr. 2002;  161 R165
• 29 Kampann C. Enzyme replacement therapy and the heart.  In: Metha A, Beck M, Sunder-Plassmann G (eds) Fabry disease: Perspectives from 5 years of FOS. PharmaGenesis Ltd Oxford 2006: 257-262
• 30 Larralde M, Boggio P, Amartino H, Chamoles N. Fabry disease: a study of 6 hemizygous men and 5 heterozygous women with emphasis on dermatologic manifestations.  Arch Dermatol. 2004;  140 1440-1446
• 31 Lidove O, Jaussaud R, Aracting S. Dermatological and soft-tissue manifestations of Fabry disease: characteristics and response to enzyme replacement therapy. In: Metha A, Beck M, Sunder-Plassmann G (eds) Fabry disease: Perspectives from 5 years of FOS. PharmaGenesis Ltd Oxford 2006: 233-240
• 32 Liston E H, Levine M D, Philippart M. Psychosis in Fabry disease and treatment with phenoxybenzamine.  Arch Gen Psychiatry. 1973;  29 402-403
• 33 Lockmann L A, D B H, Krivit W, Desnick R J. Relief of pain of Fabry’s disease by diphenylhydantoin.  Neurology. 1973;  28 871-879
• 34 Lyon M F. X-chromosome inactivation: a repeat hypothesis.  Cytogenet Cell Genet. 1998;  80 133-137
• 35 MacDermot K, Brown A, Jones Y, Zuckerman J. Enzyme replacement therapy reverses cardiomyopathy of Fabry disease; results of a randomized, double blind, placebo controlled trial.  Eur J Hum Gen. 2001;  9 S92
• 36 MacDermot K D, Holmes A, Miners A H. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females.  J Med Genet. 2001;  38 769-775
• 37 MacDermot K D, Holmes A, Miners A H. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males.  J Med Genet. 2001;  38 750-760
• 38 Meikle P J, Hopwood J J, Clague A E, Carey W F. Prevalence of lysosomal storage disorders.  Jama. 1999;  281 249-254
• 39 Mendez M F, Stanley T M, Medel N M, Li Z, Tedesco D T. The vascular dementia of Fabry’s disease.  Dement Geriatr Cogn Disord. 1997;  8 252-257
• 40 Mitsias P, Levine S R. Cerebrovascular complications of Fabry’s disease.  Ann Neurol. 1996;  40 8-17
• 41 Mohrenschlager M, Ring J, Abeck D. Skin manifestations of Fabry disease.  Jama. 2001;  286 1315
• 42 Moore D F, Altarescu G, Ling G S, Jeffries N, Frei K P, Weibel T. et al . Elevated cerebral blood flow velocities in Fabry disease with reversal after enzyme replacement.  Stroke. 2002;  33 525-531
• 43 Müller M J. Neuropsychatric and psychsocial aspects of Fabry disease. In: Metha A, Beck M, Sunder-Plassmann G (eds) Fabry disease: Perspectives from 5 years of FOS. PharmaGenesis Ltd Oxford 2006: 281-294
• 44 O’Brien B D, Shnitka T K, McDougall R B. et al . Pathophysiologic and ultrastructural basis for intestinal symptoms in Fabry’s disease.  Gastroenterology. 1982;  82 957-962
• 45 Ramaswami U, Whybra C, Parini R. et al . Clinical manifestations of Fabry disease in children: data from the Fabry Outcome Survey.  Acta Paediatr. 2006;  95 86-92
• 46 Ries M, Ramaswami U, Parini R. et al . The early clinical phenotype of Fabry disease: a study on 35 European children and adolescents.  Eur J Pediatr. 2003;  162 767-772
• 47 Ries M, Gupta S, Moore D F. et al . Pediatric Fabry disease.  Pediatrics. 2005;  115 e344-355
• 48 Ries M, Clarke J T, Whybra C. et al . Enzyme-replacement therapy with agalsidase alfa in children with Fabry disease.  Pediatrics. 2006;  118 924-932
• 49 Rolfs A, Bottcher T, Zschiesche M. et al . Prevalence of Fabry disease in patients with cryptogenic stroke: a prospective study.  Lancet. 2005;  366 1794-1796
• 50 Schiffmann R, Murray G J, Treco D. et al . Infusion of alpha-galactosidase A reduces tissue globotriaosylceramide storage in patients with Fabry disease.  Proc Natl Acad Sci USA. 2000;  97 365-370
• 51 Schiffmann R, Moore D F. Neurological manifestations of Fabry disease. In: Metha A, Beck M, Sunder-Plassmann G (eds) Fabry disease: Perspectives from 5 years of FOS. PharmaGenesis Ltd Oxford 2006: 215-225
• 52 Schiffmann R, Kopp J B, Austin 3rd  H A. et al . Enzyme replacement therapy in Fabry disease: a randomized controlled trial.  JAMA. 2001;  285 2743-2749
• 53 Schiffmann R, Ries M, Timmons M, Flaherty J T, Brady R O. Long-term therapy with agalsidase alfa for Fabry disease: safety and effects on renal function in a home infusion setting.  Nephrol Dial Transplant. 2006;  21 345-354
• 54 Schwarting A, Dehout F, Feriozzi S, Beck M, Mehta A, Sunder-Plassmann G. Enzyme replacement therapy and renal function in 201 patients with Fabry disease.  Clin Nephrol. 2006;  66 77-84
• 55 Sher N A, Letson R D, Desnick R J. The ocular manifestations in Fabry’s disease.  Arch Ophthalmol. 1979;  97 671-676
• 56 Sheth K J, Bernhard G C. The arthropathy of Fabry disease.  Arthritis Rheum. 1979;  22 781-783
• 57 Sheth K J, Roth D A, Adams M B. Early renal failure in Fabry’s disease.  Am J Kidney Dis. 1983;  2 651-654
• 58 Sodi A, Ioannidis A, Pitz S. Ophtalmological manifestations of Fabry disease. In: Metha A, Beck M, Sunder-Plassmann G (eds) Fabry disease: Perspectives from 5 years of FOS. PharmaGenesis Ltd Oxford 2006: 249-262
• 59 Spada M, Pagliardini S, Yasuda M. et al . High incidence of later-onset fabry disease revealed by newborn screening.  Am J Hum Genet. 2006;  79 31-40
• 60 Spaeth G L, Frost P. Fabry’s disease. Its ocular manifestations.  Arch Ophthalmol. 1965;  74 760-769
• 61 Spinelli L, Pisani A, Sabbatini M. et al . Enzyme replacement therapy with agalsidase beta improves cardiac involvement in Fabry’s disease.  Clin Genet. 2004;  66 158-165
• 62 Sunder-Plassmann G. Renal manifestations of Fabry disease. In: Metha A, Beck M, Sunder-Plassmann G (eds) Fabry disease: Perspectives from 5 years of FOS. PharmaGenesis Ltd Oxford 2006: 203-214
• 63 Thurberg B L, Rennke H, Colvin R B. et al . Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types after enzyme replacement therapy.  Kidney Int. 2002;  62 1933-1946
• 64 Weidemann F, Breunig F, Beer M. et al . Improvement of cardiac function during enzyme replacement therapy in patients with Fabry disease: a prospective strain rate imaging study.  Circulation. 2003;  108 1299-1301
• 65 Wilcox W R, Banikazemi M, Guffon N. et al . Long-term safety and efficacy of enzyme replacement therapy for Fabry disease.  Am J Hum Genet. 2004;  75 65-74
• 66 Schiffmann R, Askari H, Timmons M. et al . Weekly enzyme replacement therapy may slow decline of renal function in patients with Fabry Disease who are on longterm biweekly dosing.  J Am Soc Nephrol. 2007;  18 1576-1583