Clin Genet 2015: 88: 499–501 Printed in Singapore. All rights reserved
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12585
Letter to the Editor
Fabry disease in a geriatric population To the Editor, Fabry disease (FD, OMIM 301 500) is an X-linked lysosomal storage disorder caused by an 𝛂-galactosidase A enzyme deficiency leading to accumulation of glycosphingolipids. The classical phenotype (no residual enzymatic activity) emerges during childhood and adolescence and includes acroparesthesia, angiokeratoma, hypohidrosis, and gastrointestinal problems. In adults, disease progression results in cerebrovascular and cardiovascular manifestations, and chronic kidney disease (CKD), leading to premature death (1). A mutation-dependent atypical phenotype (low residual enzymatic activity) with a prominent cardiac involvement has also been described (2). Enzyme replacement therapy (ERT; agalsidase-alfa, Shire HGT and agalsidase-beta, Sanofi-Genzyme) is the only specific approved treatment for FD, although the use of this expensive therapy in a geriatric population (≥75 years) has not yet been evaluated. The clinical characteristics of six elderly (one male/five females) with FD are presented in Table 1. The male patient was diagnosed at the age of 73 based on left ventricular hypertrophy (LVH), and the mutation c.352C>T conferred the atypical phenotype. Because of a moderate disease severity, ERT was introduced at a low dose. Three of the five females were diagnosed after 70 years of age based on a positive familial history and a classical phenotype. Nervous system manifestations included transient ischemic attack (TIA) and/or stroke (2/5), diffuse and supra-normal white-matter lesions (2/5), and bilateral hearing loss (4/5). A moderate or severe LVH was systematically observed, associated with conduction anomalies (4/5), history of coronaropathy (2/5) and/or significant valvular anomalies (3/5). Microalbuminuria/proteinuria was detected in all females. One female was on hemodialysis and three others had CKD. Each female patient showed a severe level of involvement of the brain, heart, and/or kidney. The clinical impact of their disease was therefore as severe as that observed in younger hemizygous male patients. Males with the classical form of FD do not normally reach old age, but our male patient with the atypical form, had a moderate LVH at the age of 75 years, but normal renal function and no history of TIA/stroke. In fact, patients with the atypical form do not have glycosphingolipid deposits in their endothelial and vascular smooth muscle cells in contrast to the classical phenotype (2). The preservation of the vascular conduits in these patients may explain their better long-term prognosis.
Life expectancy is reduced in FD, with a mean of 58.2 years for males and 75.4 years for females (1). Recent studies using long-term ERT in male adults affected with the classical form showed that once cardiovascular remodeling is well established, ERT did not prevent disease progression i.e. a decline in renal function, increase in cardiac mass and/or fibrosis, sudden death, and new TIA/strokes (3, 4). However, the risk of developing a first or second renal, cardiac or cerebral complication declined with increasing treatment duration (3). In long-term treated females, renal function was usually normal and cardiac mass remained stable or even decreased slightly, but ERT did not prevent new TIA/stroke occurrence (3, 4). Two of three of our untreated females, with a severe LVH, died of sudden death at the age of 77 and 87 years, respectively, i.e. within a normal life expectancy range. The two treated women, with comparable disease severity, received ERT at the age of 65 and 73 years, respectively. However, the effectiveness of ERT in severe FD is considered to be limited (3, 4), particularly in patients with CKD (5). The use of ERT in newly diagnosed elderly males with a moderate atypical form of FD is also questionable. Before considering ERT treatment in geriatric patients with FD, nephroprotection strategies and the prevention of severe arrhythmia with pace-makers or defibrillators should also be considered. Addressing quality of life, care of co-morbidities, as well as these alternative interventions is crucial in patients where ERT treatment is not recommended. The introduction of ERT in geriatric patients (≥75 years) with classical and atypical forms of FD appears to be of poor benefit in terms of life expectancy and cost effectiveness. This strengthens the importance of early diagnosis for more effective therapy. F. Barbeya D. Jolyb E. Noelc O. Drouineaud P.-A. Krayenbühle O. Lidovef,g a Centre of Molecular Diseases, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland b Department of Nephrology, Necker Hospital, Paris, France c Department of Internal Medicine, Centre Hospitalier Universitaire, Strasbourg, France d Department of Internal Medicine, Hospital Dieppe, Dieppe, France
499
500
75/M 73 Negative 4.7 nmol/h/mg (normal range 15.6–45.0) c.352C > T WML Bilateral SNHL Acroparesthesia
LVH
Normal eGFR and urinary analysis Hypertension Angiokeratoma GSL depositsa GI pain Tiredness Hypothyroidism
Age (last follow-up)/Sex M/F Age at diagnosis (years) Familial history α-galactosidase activity
Heart
Kidney
1 year/Alive
Duration of ERT(years)/Outcome
11 years/Alive Pacemaker at age 71
Agalsidase-alfa 0.2 mg/kg body weight since 2003 Enalapril Spironolactone Altizide Aspirin
GI symptoms Corneal dystrophy
Normal eGFR Microalbuminuria Hypertension
Agalsidase-beta 1 mg/kg body weight since 2008 Coumadine Amiodarone Perindopril Pravastatine
Asthma
No ERT/Sudden death 6 years/Alive at the age of 77 Hemodialysis
Carbamazepine Amitriptyline Clopidogrel Verapamil
Breast cancer
GI symptoms Corneal dystrophy
Angiokeratoma
Telangiectasia Corneal dystrophy Sicca syndrome Osteoporosis
Hypertension
LVH Ischemic (stents) and valvular cardiopathy Auricular fibrillation; LBBB
Q327K Bilateral SNHL
79/F 77 Positive Low
4
CKD stage 2 K/DOQI Proteinuria
– Vertigo Bilateral SNHL Acroparesthesia Hypohidrosis LVH
c.283 T > G TIA at age 71 Bilateral SNHL Trigeminal neuralgia LVH Aortic stricture
77/F 40 Positive Low
3
75/F 37 Positive Low
2
No ERT/Alive
Lisinopril Artovastatin Phenprocoumone
Urinary bladder carcinoma
Hypothyroidism
No angiokeratoma
CKD stage 3 K/DOQI Proteinuria
g.2962–5871del2.9 kb Anterior stroke Vascular dementia WML Bilateral SNHL LVH Pacemaker
83/F 72 Positive ND
5
Aspirin Digoxine Simvastatine Candesartan Torasemide No ERT/Sudden death at 87
GI symptoms GSL depositsa Tiredness Osteoporosis Raynaud’s phenomenon
LVH Ischemic (CABG) and valvular cardiopathy Aortic stricture surgery at age 76 Auricular fibrillation LBBB CKD stage 3 K/DOQI Proteinuria Hypertension Angiokeratoma
c.389insT Vertigo Acroparesthesia Trigeminal neuralgia
87/F 78 Positive Low
6
CABG, coronary artery bypass grafting; eGFR, estimated glomerular filtration rate; ERT, enzyme replacement therapy; ESRD, end stage renal disease; GSL, glycosphingolipid; LBBB, left bundle block branch; LVH, left ventricular hypertrophy; SNHL, sensorineural hearing loss; TIA, transient ischaemic attack; WML, white-matter lesions. a Ultrastructural study.
Other therapies
Agalsidase-beta 0.3 mg/kg body weight since 2013 Losartan Artovastatin Aspirin Levothyroxin
Enzyme replacement therapy
Co-morbidities
Other symptoms
Skin
Type of mutation Nervous system
1
Patient
Table 1. Characteristics of the patients at baseline and outcome
Letter to the Editor
Letter to the Editor e Department
of Medicine, Linth Hospital, Uznach, Switzerland, and f Department of Internal Medicine and Rheumatology, Croix Saint Simon Hospital, Paris, France g INSERM-UMRS 974, University Pierre ete Marie Curie, Paris, France References 1. Waldek S, Patel MR, Banikazemi M et al. Life expectancy and cause of death in males and females with Fabry disease. Genet Med 2009: 11: 790–796. 2. Elleder M, Bradová V, Smíd F et al. Cardiocyte storage and hypertrophy as a sole manifestation of Fabry’s disease. Virchows Arch 1990: 417: 449–455.
3. Rombach SM, Smid BE, Bouwman MG et al. Long term ERT for Fabry disease: effectiveness on kidney, heart and brain. Orphanet J Rare Dis 2013: 8: 47. 4. Weidemann F, Niemann M, Störk S et al. Long-term outcome of ERT in advanced Fabry disease: evidence for disease progression towards serious complications. J Intern Med 2013: 274: 331–41. 5. Banikazemi M, Bultas J, Waldek S et al. Agalsidase-beta therapy for advanced Fabry disease: a randomized trial. Ann Intern Med 2007: 146: 77–86.
Correspondence Frédéric Barbey, Centre of Molecular Diseases, Centre Hospitalier Universitaire Vaudois, Pierre Decker 2 av, 1011 Lausanne, Switzerland. Tel.: +41 79 556 50 41; fax: +41 21 314 35 46; e-mail: [email protected]
501
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd CLINICAL GENETICS doi: 10.1111/cge.12585
Letter to the Editor
Fabry disease in a geriatric population To the Editor, Fabry disease (FD, OMIM 301 500) is an X-linked lysosomal storage disorder caused by an 𝛂-galactosidase A enzyme deficiency leading to accumulation of glycosphingolipids. The classical phenotype (no residual enzymatic activity) emerges during childhood and adolescence and includes acroparesthesia, angiokeratoma, hypohidrosis, and gastrointestinal problems. In adults, disease progression results in cerebrovascular and cardiovascular manifestations, and chronic kidney disease (CKD), leading to premature death (1). A mutation-dependent atypical phenotype (low residual enzymatic activity) with a prominent cardiac involvement has also been described (2). Enzyme replacement therapy (ERT; agalsidase-alfa, Shire HGT and agalsidase-beta, Sanofi-Genzyme) is the only specific approved treatment for FD, although the use of this expensive therapy in a geriatric population (≥75 years) has not yet been evaluated. The clinical characteristics of six elderly (one male/five females) with FD are presented in Table 1. The male patient was diagnosed at the age of 73 based on left ventricular hypertrophy (LVH), and the mutation c.352C>T conferred the atypical phenotype. Because of a moderate disease severity, ERT was introduced at a low dose. Three of the five females were diagnosed after 70 years of age based on a positive familial history and a classical phenotype. Nervous system manifestations included transient ischemic attack (TIA) and/or stroke (2/5), diffuse and supra-normal white-matter lesions (2/5), and bilateral hearing loss (4/5). A moderate or severe LVH was systematically observed, associated with conduction anomalies (4/5), history of coronaropathy (2/5) and/or significant valvular anomalies (3/5). Microalbuminuria/proteinuria was detected in all females. One female was on hemodialysis and three others had CKD. Each female patient showed a severe level of involvement of the brain, heart, and/or kidney. The clinical impact of their disease was therefore as severe as that observed in younger hemizygous male patients. Males with the classical form of FD do not normally reach old age, but our male patient with the atypical form, had a moderate LVH at the age of 75 years, but normal renal function and no history of TIA/stroke. In fact, patients with the atypical form do not have glycosphingolipid deposits in their endothelial and vascular smooth muscle cells in contrast to the classical phenotype (2). The preservation of the vascular conduits in these patients may explain their better long-term prognosis.
Life expectancy is reduced in FD, with a mean of 58.2 years for males and 75.4 years for females (1). Recent studies using long-term ERT in male adults affected with the classical form showed that once cardiovascular remodeling is well established, ERT did not prevent disease progression i.e. a decline in renal function, increase in cardiac mass and/or fibrosis, sudden death, and new TIA/strokes (3, 4). However, the risk of developing a first or second renal, cardiac or cerebral complication declined with increasing treatment duration (3). In long-term treated females, renal function was usually normal and cardiac mass remained stable or even decreased slightly, but ERT did not prevent new TIA/stroke occurrence (3, 4). Two of three of our untreated females, with a severe LVH, died of sudden death at the age of 77 and 87 years, respectively, i.e. within a normal life expectancy range. The two treated women, with comparable disease severity, received ERT at the age of 65 and 73 years, respectively. However, the effectiveness of ERT in severe FD is considered to be limited (3, 4), particularly in patients with CKD (5). The use of ERT in newly diagnosed elderly males with a moderate atypical form of FD is also questionable. Before considering ERT treatment in geriatric patients with FD, nephroprotection strategies and the prevention of severe arrhythmia with pace-makers or defibrillators should also be considered. Addressing quality of life, care of co-morbidities, as well as these alternative interventions is crucial in patients where ERT treatment is not recommended. The introduction of ERT in geriatric patients (≥75 years) with classical and atypical forms of FD appears to be of poor benefit in terms of life expectancy and cost effectiveness. This strengthens the importance of early diagnosis for more effective therapy. F. Barbeya D. Jolyb E. Noelc O. Drouineaud P.-A. Krayenbühle O. Lidovef,g a Centre of Molecular Diseases, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland b Department of Nephrology, Necker Hospital, Paris, France c Department of Internal Medicine, Centre Hospitalier Universitaire, Strasbourg, France d Department of Internal Medicine, Hospital Dieppe, Dieppe, France
499
500
75/M 73 Negative 4.7 nmol/h/mg (normal range 15.6–45.0) c.352C > T WML Bilateral SNHL Acroparesthesia
LVH
Normal eGFR and urinary analysis Hypertension Angiokeratoma GSL depositsa GI pain Tiredness Hypothyroidism
Age (last follow-up)/Sex M/F Age at diagnosis (years) Familial history α-galactosidase activity
Heart
Kidney
1 year/Alive
Duration of ERT(years)/Outcome
11 years/Alive Pacemaker at age 71
Agalsidase-alfa 0.2 mg/kg body weight since 2003 Enalapril Spironolactone Altizide Aspirin
GI symptoms Corneal dystrophy
Normal eGFR Microalbuminuria Hypertension
Agalsidase-beta 1 mg/kg body weight since 2008 Coumadine Amiodarone Perindopril Pravastatine
Asthma
No ERT/Sudden death 6 years/Alive at the age of 77 Hemodialysis
Carbamazepine Amitriptyline Clopidogrel Verapamil
Breast cancer
GI symptoms Corneal dystrophy
Angiokeratoma
Telangiectasia Corneal dystrophy Sicca syndrome Osteoporosis
Hypertension
LVH Ischemic (stents) and valvular cardiopathy Auricular fibrillation; LBBB
Q327K Bilateral SNHL
79/F 77 Positive Low
4
CKD stage 2 K/DOQI Proteinuria
– Vertigo Bilateral SNHL Acroparesthesia Hypohidrosis LVH
c.283 T > G TIA at age 71 Bilateral SNHL Trigeminal neuralgia LVH Aortic stricture
77/F 40 Positive Low
3
75/F 37 Positive Low
2
No ERT/Alive
Lisinopril Artovastatin Phenprocoumone
Urinary bladder carcinoma
Hypothyroidism
No angiokeratoma
CKD stage 3 K/DOQI Proteinuria
g.2962–5871del2.9 kb Anterior stroke Vascular dementia WML Bilateral SNHL LVH Pacemaker
83/F 72 Positive ND
5
Aspirin Digoxine Simvastatine Candesartan Torasemide No ERT/Sudden death at 87
GI symptoms GSL depositsa Tiredness Osteoporosis Raynaud’s phenomenon
LVH Ischemic (CABG) and valvular cardiopathy Aortic stricture surgery at age 76 Auricular fibrillation LBBB CKD stage 3 K/DOQI Proteinuria Hypertension Angiokeratoma
c.389insT Vertigo Acroparesthesia Trigeminal neuralgia
87/F 78 Positive Low
6
CABG, coronary artery bypass grafting; eGFR, estimated glomerular filtration rate; ERT, enzyme replacement therapy; ESRD, end stage renal disease; GSL, glycosphingolipid; LBBB, left bundle block branch; LVH, left ventricular hypertrophy; SNHL, sensorineural hearing loss; TIA, transient ischaemic attack; WML, white-matter lesions. a Ultrastructural study.
Other therapies
Agalsidase-beta 0.3 mg/kg body weight since 2013 Losartan Artovastatin Aspirin Levothyroxin
Enzyme replacement therapy
Co-morbidities
Other symptoms
Skin
Type of mutation Nervous system
1
Patient
Table 1. Characteristics of the patients at baseline and outcome
Letter to the Editor
Letter to the Editor e Department
of Medicine, Linth Hospital, Uznach, Switzerland, and f Department of Internal Medicine and Rheumatology, Croix Saint Simon Hospital, Paris, France g INSERM-UMRS 974, University Pierre ete Marie Curie, Paris, France References 1. Waldek S, Patel MR, Banikazemi M et al. Life expectancy and cause of death in males and females with Fabry disease. Genet Med 2009: 11: 790–796. 2. Elleder M, Bradová V, Smíd F et al. Cardiocyte storage and hypertrophy as a sole manifestation of Fabry’s disease. Virchows Arch 1990: 417: 449–455.
3. Rombach SM, Smid BE, Bouwman MG et al. Long term ERT for Fabry disease: effectiveness on kidney, heart and brain. Orphanet J Rare Dis 2013: 8: 47. 4. Weidemann F, Niemann M, Störk S et al. Long-term outcome of ERT in advanced Fabry disease: evidence for disease progression towards serious complications. J Intern Med 2013: 274: 331–41. 5. Banikazemi M, Bultas J, Waldek S et al. Agalsidase-beta therapy for advanced Fabry disease: a randomized trial. Ann Intern Med 2007: 146: 77–86.
Correspondence Frédéric Barbey, Centre of Molecular Diseases, Centre Hospitalier Universitaire Vaudois, Pierre Decker 2 av, 1011 Lausanne, Switzerland. Tel.: +41 79 556 50 41; fax: +41 21 314 35 46; e-mail: [email protected]
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