Evidence-Based Management of Patients with Fabry Disease

*Schiffmann R, et al. Kidney Int. 2017;91:284-293.3

Signs and Symptoms

Signs and symptoms of Fabry disease can include skin lesions (angiokeratomas), pain and burning in the hands and feet (acroparaesthesia), fatigue, impaired sweating, and gastrointestinal problems. Corneal opacities that progress to a characteristic "whorled" pattern are found in the vast majority of hemizygotes, but generally do not impact vision. There is a high degree of clinical variability both among patients from the same family and among those from unrelated families with the same mutation. Many of these symptoms are observed during childhood and adolescence, and tend to be observed in hemizygous males. X-chromosome inactivation impacts the phenotype and natural history of Fabry disease in females.12 In heterozygous females, random X-inactivation may result in expression of α-gal A activity in the plasma or leucocytes within the normal range in up to 60% of women.3,13 Heterozygous females are not just asymptomatic carriers, and can develop either a partial or full spectrum of clinical manifestations associated with Fabry disease.14 Late onset/cardiac mutation variants of Fabry disease are typically milder and/or clinically restricted to heart disease.15

Kidney disease and Fabry disease

Kidney disease is a major complication of Fabry disease and is thought to be related to glycosphingolipid accumulation throughout the nephron.1 Clinical kidney disease has been reported in children as young as 16 years of age, but is more common in adult Fabry patients. By the age of 35 years about 50% of men and 20% of women with classic Fabry mutations have proteinuria in the presence of Fabry disease.1 GL3 accumulation in the kidney occurs preferentially in the glomeruli (especially podocytes but also in endothelial, mesangial, and parietal epithelial cells), distal tubular cells, and vascular smooth muscle cells. The predilection for podocytes and the correlation of podocyte GL3 accumulation and increased podocyte foot process width may explain the early renal manifestations of proteinuria.15,16 Within the glomerulus, the largest amount of lipid material is seen in podocytes, followed by the parietal epithelial, mesangial, and glomerular endothelial cells (Figures 1 and 2).17 Podocyte loss in the urine (podocyturia) is increased in patients with Fabry disease and correlates with the clinical severity of kidney disease, suggesting that podocyte loss may be important in the progression of Fabry nephropathy.16,18

Figure 1: Kidney pathology in Fabry disease*

*Light Microscopy -- Kidney pathology in Fabry disease. (A) Glomerulus showing extensive inclusion bodies of glycolipid in podocytes (arrowhead), and mild mesangial widening (PAS stain; magnification, ×80). (B) Plastic embedded tissue showing in-site deposition of glycolipid in glomerular podocytes (arrowhead; toluidine blue stain; magnification, ×80). (C) Plastic embedded renal tissue demonstrating glycolipid inclusion bodies in distal tubules (asterisk), with relative sparing of proximal tubules, and interstitial fibrosis (toluidine blue stain; magnification, ×80). (D) Deposition of glycolipid in endothelial cells of peritubular capillaries (asterisk; toluidine blue stain; magnification, ×200). (E) Urine showing vacuolated urinary epithelial cells (oval fat bodies) in a Fabry patient (Papanicolaou stain; magnification, ×160). Alroy J, et al. J Am Soc Nephrol. 2002;13(Suppl 2):S134-S138.17

Figure 2: Kidney pathology in Fabry disease*

*Electron microscopy: GL-3 inclusions, most with typical "zebra body" appearance in podocytes (yellow arrow), endothelial cells (red arrow) and mesangial cells (orange arrow) in a glomerulus (provided by M Mauer and B Najafian)15

Evaluation of Fabry Disease

Onset of the signs and symptoms associated with Fabry disease should warrant prompt steps for diagnosis and intervention. Some features such as the corneal and skin changes are virtually diagnostic, especially with a positive family history, but laboratory confirmation is often needed. Also, observed signs and symptoms are heterogeneous among many patients, making timely diagnosis a challenge. In addition, some symptoms can resemble other more common diseases. Overall diagnostic delays have been estimated at ~15 years for both genders.2,19It is therefore important to begin with a comprehensive medical and family history, and to include Fabry disease in the differential diagnosis according to the hallmark clinical and familial features in Table 2.

Table 2: When to consider Fabry disease as a diagnosis*

Test ANY patient who has:
In the absence of above two factors, test patients with at least two of the features below:
*Adapted from Laney D, et al. J Genet Counsel. 2013;22:555-564.5

Initial Evaluation

An initial evaluation should consist of the following:16

  • History: neuropathic pain, heat intolerance, decreased tear/saliva/sweat production, diarrhea, abdominal pain, angiokeratomas, foamy urine, history of transient ischemic attack (TIA) / cerebrovascular accident (CVA) and myocardial disease
  • Family History of relatives with unexplained neurologic disease, or kidney failure, heart failure, or early stroke, transmitted X-linked
  • Physical Exam: angiokeratomas, telangiectasias, hypo-or anhydrosis, corneal opacity, edema, abnormal cardiac examination (evidence of left ventricular hypertrophy (LVH), arrhythmia), corneal opacities, retinal and conjunctival vascular tortuosity
  • Urine sediment and measurement of kidney function (albumin and protein excretion rates and GFR)
  • Electrocardiogram (EKG) to evaluate for LVH and conduction defects

Evaluation of Family Members

Evaluation of family members should consist of the following:16

  • Symptomatic male relatives of an affected individual: screen with testing for α-Gal A activity (blood or leukocyte) even in asymptomatic; if deficient enzyme activity, then send for genetic analysis unless the mutation is already identified in affected relative
  • In females, there is high false negative rate of α-Gal A, therefore genetic testing should be strongly considered
  • In late onset/cardiac variants α-Gal A enzyme activity may not be in the diagnostic range in males and females and mutation analysis will then be needed.4

Appropriate biochemical and/or genetic confirmation could be considered for confirmation if physical and clinical examination raises a suspicion of Fabry disease (Figure 3).20,21 Assays of plasma alpha-galactosidase activity may be less sensitive than in leukocytes.3,22 Mutation analysis of the GLA gene is needed to diagnose females (unless the woman is an obligate heterozygote, i.e., the father is known to have Fabry disease), and in males and females with atypical presentations or marginal α-Gal A levels.4

Figure 3: Fabry Testing Roadmap*

*Standard sequencing of GLA will not detect large deletions, large duplications, some intronic mutations, and mutations  in the promoter or other regulatory regions. Results must be  interpreted in the context of an individual's clinical and/or biochemical profile. Laney D, et al. J Genet Counsel. 2013;22:555-564.5

Regular assessments of kidney function in Fabry patients should include glomerular filtration rate (GFR), urine albumin excretion.1,3,23 Generally, the diagnosis of early decline of GFR in patients with Fabry disease and chronic kidney disease (CKD) is hampered by inaccuracy of creatinine-based GFR measurements. Overestimation of true GFR may be especially relevant in many male Fabry patients. A baseline carefully done using measured GFR and serum creatinine can allow for better subsequent eGFR interpretations, especially with normal or near normal measured GFR. Fabry disease should be considered and tested in patients with CKD with no definitive cause of nephropathy and when no biopsy has been performed, especially in familial cases.3 The diagnosis is rarely made by skin or kidney biopsy, however, Fabry disease may be found incidentally if a kidney biopsy is performed to diagnose proteinuria CKD.16,24

Management of Fabry Disease

Fabry disease is a chronic, slowly progressive disease with a broad heterogeneous presentation. Therefore, management of Fabry disease is life-long and can involve multiple disciplines, including genetic counseling, dermatology, cardiology, neurology, and nephrology. Management of patients with Fabry disease also involves comprehensive therapy, including conventional/supportive treatment and enzyme replacement therapy (ERT). Conventional/supportive management typically consists of pain relief, blood pressure control/nephroprotection, antiarrhythmic agents, gastrointestinal medicines, and lifestyle modifications. Renal replacement therapy (dialysis or kidney transplantation) is available for patients with kidney failure.

Fabry disease patients experiencing neuropathic pain can benefit from avoiding any possible triggers of their acute pain attacks. Various medications have been recommended for pain management (Table 3).25,26,27,28,29,30,31 Certain antidepressants and anticonvulsants can be considered. Generally, studies agree upon starting the medication at low dose, and evaluating tolerability and effectiveness after 2-3 weeks.32 To reduce the likelihood of side-effects from polypharmacy, the dosage of each drug prescribed should be titrated to the highest tolerated dose providing significant pain control before other pain-modulating agents are added.25 Analgesics are also an option, but nonsteroidal anti-inflammatory drugs (NSAIDs) are generally not considered effective and can negatively impact kidney function.1,33 In addition, nonpharmacologic approaches including psychological and physical treatments have been proven effective in the relief of pain and the treatment of comorbid disorders including anxiety and depression.26,34

Table 3: Supportive treatment of chronic neuropathic pain in Fabry disease*

Agent
Dose
Cardiac Restrictions
Renal Restrictions
Clinical Evidence

Carbamazepine

250-800 mg/day

May interfere with activity of other drugs (e.g., warfarin)

None

Filling-Katz et al. 1989

Gabapentin

Slowly titrated from 100 mg/day to a max of 2400 mg/day

None

Yes (with precautions in cases of renal insufficiency):
CrCl 30-59: 400-1400 mg/day
CrCl 15-29 200-700 mg/day
CrCl <15 100-300 mg/day

Ries et al. 2003

Phenytoin

300 mg/day

None

None

Lockman et al. 1973

Pregabalin

75-300 mg/day

None
Yes (with precautions in cases of renal insufficiency):
CrCl 30-60: 75-300 mg day
CrCl 15-30: 25-150 mg/day
CrCl <15: 25-75 mg/day

Tricyclic antidepressants

12.5-150 mg/day

Avoid due to risk of Arrythmias
Unknown

Serotonin-norepinephrine reuptake inhibitors

 
 

Sommer et al. 2013
Finnerup et al. 2015

Duloxetine

60-120 mg/day

None
None

Venlafaxine

150-225 mg ER/day

QT-interval prolongation
Dose adjustment according to renal function.
Mild to moderate renal impairment: Reduce total daily dose by 25%
Hemodialysis: Reduce total daily dose by 50%
*Adapted from Politei et al.26
Package inserts

Treatments for gastrointestinal symptoms can include changes in eating habits (e.g., smaller, more frequent meals), H-2 blockers, and metoclopramide.2

Cardiovascular complications account for the majority of deaths in Fabry disease.3,35,36 Heart failure may have multifactorial causes that need to be addressed. Hypertension is not common during earlier onset of Fabry disease and low blood pressure is considered more typical in this patient population.37 However, hypertension is more common as the renal disease progresses.1,38,39 Hypertension, along with LVH, is most strongly associated with cardiovascular events in Fabry disease patients.40 Hypertension should be managed when present. Many patients might not tolerate beta blockers.3 Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) can be considered, particularly in the presence of proteinuria, given their ability to act as antiproteinuric agents.1,40,23

Enzyme replacement therapy (ERT) addresses the underlying metabolic cause of Fabry disease – deficient α-Gal A activity. Agalsidase beta is a recombinant human α-Gal A enzyme with a similar amino acid sequence as the native enzyme. It is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian cell expression system. Agalsidase beta is administered 1 mg/kg via an intravenous(IV) infusion every two weeks. Infusions usually take several hours. Agalsidase beta is available in the United States. Agalsidase alfa (0.2 mg/kg IV every 2 weeks) is another human recombinant α-gal for use as ERT in Fabry patients, but it is available outside of the United States.

Studies have shown that ERT with agalsidase beta normalizes GL3 levels in a multiple organs and tissues.41,42 A Phase III clinical trial showed that 11 infusions of agalsidase beta at a dose of 1 mg/kg over a 20-week period safely and effectively cleared the abnormalities in the capillary endothelium of the kidneys, heart, and skin of patients with classic Fabry's disease.42 Kidney capillary endothelial cells were (nearly) completely cleared of Gb3 within 98% of patients in the study. In contrast to endothelial cells, podocytes, arterial smooth muscle cells and to a lesser extent, distal tubular epithelial cells in the kidney are more resistant to ERT and only partially clear from GL-3 or it takes longer duration (compared to endothelial cells) to completely clear them from GL-3 inclusions.43,44,45 The efficacy of ERT in clearing podocytes from GL-3 inclusions appears to be dose-dependent.45,46,47 Thus, 0.2 mg/kg every other week agalsidase alfa or doses less than 1 mg/kg every other week agalsidase beta may not be enough to clear podocytes from GL-3 inclusions.45,46,47

Data also shows that early facilitation of long-term treatment with agalsidase beta can preserve kidney function patients with Fabry disease.48 Thus, long term administration of agalsidase beta in patient with less than 0.5 g/g urine protein creatinine ratio and/or less than 50% global glomerulosclerosis on biopsy preserved GFR, while this did not halt progressive GFR decline in those with more than 0.5 g/day proteinuria and/or 50% or more global glomerulosclerosis on biopsy. A study by Tøndel et al indicates that early treatment with ERT at 1 mg/kg every other week may partially to completely clear podocytes from GL3 inclusions in young patients and reduce albuminuria.49 Transient mild-to-moderate infusion reactions (e.g., rigors, fever/chills) was found to occur in ~60% of patients, which may diminish over time.42 Reducing the infusion rate, administering preventive medications (i.e., diphenhydramine, steroids, acetaminophen), or both measures controlled these reactions.41,42

ACEI or ARBs in combination with ERT was shown to decrease the rate of proteinuria, if ERT was initiated at a younger age and urine protein to creatinine ratio (UPCR) was maintained at or below 0.5 g/g with antiproteinuric therapy.50 ERT alone, in the absence of ACEIs or ARBs has not been shown to substantially decrease proteinuria in Fabry patients.50

Tables 4 and 5 outline recommendations for the initiation of pediatric and adult patients with Fabry disease.51,52 The decision to initiate ERT should be based on the full range of available diagnostic tests and a thorough dialogue with patients and/or their families regarding the implications of treatment.

Table 4: Initiating ERT in pediatric patients with Fabry disease*

Symptomatic male or female pediatric patient
Asymptomatic male patients with classical (severe) mutations
Asymptomatic female patients and asymptomatic male patients with late-onset mutations or variants of unknown significance
*Adapted from: Hopkin R, et al. Mol Genet Metab. 2016;117:104-113.

Table 5: Recommendations for initiation of ERT in adult male and female patients with classic or later onset mutations of GLA, variants of unknown significance (GLA VUS)*

Classic Fabry mutation: Male patient, symptomatic or asymptomatic
Classic Fabry mutation: Female patient, symptomatic
Classic Fabry mutation: Female patient, asymptomatic
Later-onset Fabry mutation or missense GLA variant of unknown significance (VUS): Male and female patients
* Treatment decisions may be influenced by advanced elderly age of the patient and severe comorbidity. Treatment decisions in female patients may be guided by the X chromosome inactivation profile, if assessed. Predominant expression of the mutant GLA allele is generally associated with rapid disease progression, requiring closer monitoring and early therapeutic intervention. Adapted from Ortiz A, et al. Mol Genet Metab. 2018;123:416-427.
* Treatment decisions may be influenced by advanced elderly age of the patient and severe comorbidity. Treatment decisions in female patients may be guided by the X chromosome inactivation profile, if assessed. Predominant expression of the mutant GLA allele is generally associated with rapid disease progression, requiring closer monitoring and early therapeutic intervention. Adapted from Ortiz A, et al. Mol Genet Metab. 2018;123:416-427.

Novel Therapies

A number of therapeutic alternatives for Fabry disease have been undergoing investigation, including chaperones, substrate reduction therapy (SRT), stem cell transplant, and gene therapy.10 Migalastat hydrochloride is an oral pharmacologic chaperone that binds to and stabilizes specific mutant forms of alpha-galactosidase facilitating trafficking to lysosomes. In pre-clinical studies, migalastat has been shown to reduce the storage of GL-3 in vitro and in vivo (Fabry transgenic mice).54,55,56 In humans, 6 months treatment with migalastat has been shown to reduce GL-3 accumulation in kidney peritubular capillary endothelial cells and in podocytes.57,58 In August 2018, migalastat received US Food and Drug Administration (FDA) approval for the treatment of adults with Fabry disease who have a genetic mutation determined to be responsive ("amenable") to treatment based on in vitro assay data.

References

  1. Sunder-Plassmann G, Fӧdinger M, Kain R. Fabry Disease. In: Gilbert S, Weiner D, Gipson D, Perazella M, Tonelli M., eds. National Kidney Foundation. Primer on kidney diseases. 6th ed. Philadelphia, PA: Saunders Elsevier; 2014.
  2. Germain D. Fabry disease. Orphanet J Rare Dis. 2010;5:30.
  3. Schiffmann R, Hughes D, Linthorst G, et al. Screening, diagnosis, and management of patients with Fabry disease: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference. Kidney Int. 2017;91:284-293.
  4. Desnick R, Ioannou Y, Eng C. Alpha-galactosidase A deficiency: Fabry disease. In: Valle D, Beaudet A, Vogelstein B, Kinzler K, et al., eds. The Online Metabolic and Molecular Bases of inherited disease. New York, NY: McGraw-Hill; 2014.
  5. Laney D, Bennett R, Clarke V, et al. Fabry disease practice guidelines: recommendations of the National Society of Genetic Counselors. J Genet Counsel. 2013;22:555-564.
  6. De Francesco P, Mucci J, Ceci R, Fossati C, Rozenfeld P. Higher apoptotic state in Fabry disease peripheral blood mononuclear cells: effect of globotriaosylceramide. Mol Genet Metab. 2011;104:319- 324.
  7. Das A, Naim H. Biochemical basis of Fabry disease with emphasis on mitochondrial function and protein trafficking. Adv Clin Chem. 2009;49:57-71.
  8. Choi L, Vernon J, Kopach O, et al. The Fabry disease-associated lipid Lyso-Gb3 enhances voltage-gated calcium currents in sensory neurons and causes pain. Neurosci Lett. 2015;594:163-168.
  9. Liebau M, Braun F, Höpker K, et al. Dysregulated autophagy contributes to podocyte damage in Fabry's disease. PLoS One. 2013;8:e63506.
  10. Alipourfetrati S, Saeed A, Norris J, Sheckley F, Rastogi A. A Review of current and future treatment strategies for Fabry disease: a model for treating lysosomal storage diseases. J Pharmacol Clin Toxicol. 2015;3:1051.
  11. Vedder A, Strijland A, vd Bergh Weerman M, Florquin S, Aerts J, Hollak C. Manifestations of Fabry disease in placental tissue. J Inherit Metab Dis. 2006;29:106-111.
  12. Echevarria L, Benistan K, Toussaint A, et al. X-chromosome inactivation in female patients with Fabry disease. Clin Genet. 2016;89:44-54.
  13. Gupta S, Ries M, Kotsopoulos S, et al. The relationship of vascular glycolipid storage to clinical manifestations of Fabry disease: a crosssectional study of a large cohort of clinically affected heterozygous women. Medicine (Baltimore). 2005;84:261–268.
  14. Wang R, Lelis A, Mirocha J et al. Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life. Genet Med. 2007;9:34-45.
  15. Najafian B, Svarstad E, Bostad L, et al. Progressive podocyte injury and globotriaosylceramide (GL-3) accumulation in young patients with Fabry disease. Kidney Int. 2011;79:663-670.
  16. Mauer M, Kopp J, Schiffmann R. Curhan G, Glassock R, Lam A (Eds.). Fabry disease: Clinical features and diagnosis. UptoDate, Waltham MA. Accessed June 29, 2018.
  17. Alroy J, Sabnis S, Kopp J. Renal pathology in Fabry disease. J Am Soc Nephrol. 2002;13(Suppl 2):S134-S138.
  18. Fall B, Scott C, Mauer M, et al. Urinary podocyte loss is increased in patients with Fabry disease and correlates with clinical severity of Fabry nephropathy. PLoS One. 2016;11:e0168346.
  19. Wilcox W, Oliveira J, Hopkin R, et al. Females with Fabry disease frequently have major organ involvement: lessons from the Fabry Registry. Mol Genet Metab 2008;93:112-128.
  20. Linthorst G, De Rie M, Tjiam K, et al. Misdiagnosis of Fabry disease: importance of biochemical confirmation of clinical or pathological suspicion. Br J Dermatol. 2004;150:575-577.
  21. Laney D, Bennett R, Clarke V, et al. Fabry disease practice guidelines: recommendations of the National Society of Genetic Counselors. J Genet Counsel. 2013;22:555-564.
  22. Andrade J, Waters P, Singh R, et al. Screening for Fabry disease in patients with chronic kidney disease: limitations of plasma alpha-galactosidase assay as a screening test. Clin J Am Soc Nephrol. 2008;3:139-145.
  23. Ortiz A, Oliveira J, Wanner C et al. Recommendations and guidelines for the diagnosis and treatment of Fabry nephropathy in adults. Nat Clin Pract Nephrol. 2008;4:327-336.
  24. Warnock D. Fabry disease: diagnosis and management, with emphasis on the renal manifestations. Curr Opin Nephrol Hypertens. 2005;14:87-95.
  25. Kidney Disease: Improving Global Outcomes. KDIGO Conference on Diagnosis and Management of Patients with Fabry Nephropathy . October 15-17, 2015. Dublin, Ireland. www.kdigo.org. Accessed June 29, 2018.
  26. Politei J, Bouhassira D, Germain D, et al. Pain in fabry disease: Practical recommendations for diagnosis and treatment. CNS Neurosci Ther. 2016;22:568-576.
  27. Filling-Katz M, Merrick H, Fink J, Miles R, Sokol J, Barton N. Carbamazepine in Fabry's disease: effective analgesia with dose-dependent exacerbation of autonomic dysfunction. Neurology. 1989;39:598-600.
  28. Ries M, Mengel E, Kutschke G, et al. Use of gabapentin to reduce chronic neuropathic pain in Fabry disease. J Inherit Metab Dis. 2003;26:413-414.
  29. Lockman L, Hunninghake D, Krivit W, Desnick R. Relief of pain of Fabry's disease by diphenylhydantoin. Neurology. 1973;23:871-875.
  30. Finnerup N, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol. 2015;14:162-173.
  31. Sommer C, Uc_eyler N, Duning T, et al. Pain therapy for Fabry's disease. Internist (Berl). 2013;54:121-122.
  32. Schuller Y, Linthorst G, Hollak C, Van Schaik I, Biegstraaten M. Pain management strategies for neuropathic pain in Fabry disease - a systematic review. BMC Neurol. 2016;16:25.
  33. Perazella M, Shirali A. Kidney disease caused by therapeutic agents. In: Gilbert S, Weiner D, Gipson D, Perazella M, Tonelli M., eds. National Kidney Foundation. Primer on kidney diseases. 6th ed. Philadelphia, PA: Saunders Elsevier; 2014.
  34. Zeltzer L, Palermo T, Krane E. Pain management. In: Kliegman R, Stanton B, St. Geme J, Schor N, edS. Nelson Textbook of Pediatrics, 20th edn, Philadelphia, PA: Elsevier; 2015.
  35. Mehta A, Clarke J, Giugliani R, et al. Natural course of Fabry disease: changing pattern of causes of death in FOS - Fabry Outcome Survey. J Med Genet. 2009;46:548-552.
  36. Waldek S, Patel M, Banikazemi M, et al. Life expectancy and cause of death in males and females with Fabry disease: findings from the Fabry Registry. Genet Med. 2009;11:790-796.
  37. Terryn W, Deschoenmakere G, De Keyser J, et al. Prevalence of Fabry disease in a predominantly hypertensive population with left ventricular hypertrophy. Int J Cardiol. 2013;167:2555-2560.
  38. Kleinert J, Dehout F, Schwarting A, et al. Prevalence of uncontrolled hypertension in patients with Fabry disease. Am J Hypertens. 2006;19:782-787.
  39. Ortiz A, Oliveira J, Waldek S, Warnock D, Cianciaruso B, Wanner C. Nephropathy in males and females with Fabry disease: cross-sectional description of patients before treatment with enzyme replacement therapy. Nephrol Dial Transplant. 2008,23:1600-1607.
  40. Patel M, Cecchi F, Cizmarik M, et al. Cardiovascular events in patients with Fabry disease natural history data from the Fabry registry. J Am Coll Cardiol. 2011;1:1093-1099.
  41. Schiffmann R, Kopp J, Austin H, et al. Enzyme replacement therapy in Fabry disease: a randomized controlled trial. JAMA. 2001;285:2743-2749.
  42. Eng C, Guffon N, Wilcox W, et al. Safety and efficacy of recombinant human α-galactosidase A - replacement therapy in Fabry's disease. N Engl J Med. 2001;345:9-16.
  43. Thurberg B, Rennke H, Colvin R, et al. Globotriaosylceramide accumulation in the Fabry kidney is cleared from multiple cell types after enzyme replacement therapy. Kidney Int. 2002;62:1933-1946.
  44. Najafian B, Tøndel C, Svarstad E, Sokolovkiy A, Smith K, Mauer M. One year of enzyme replacement therapy reduces globotriaosylceramide inclusions in podocytes in male adult patients with Fabry disease. PLoS One. 2016;11:e0152812.
  45. Skrunes R, Tøndel , Leh , et al. Long-term dose-dependent agalsidase effects on kidney histology in Fabry disease. Clin J Am Soc Nephrol. 2017;12:1470-1479.
  46. Skrunes R, Svarstad E, Kampevold Larsen K, Leh S, Tøndel C. Reaccumulation of globotriaosylceramide in podocytes after agalsidase dose reduction in young Fabry patients. Nephrol Dial Transplant. 2017;32:807-813.
  47. Warnock D, Mauer M. Fabry disease: dose matters. J Am Soc Nephrol. 2014;25:653-655.
  48. Germain D, Waldek S, Banikazemi M, et al. Sustained, long-term renal stabilization after 54 months of agalsidase beta therapy in patients with Fabry disease. J Am Soc Nephrol. 2007;18:1547-1557
  49. Tøndel C, Bostad L, Larsen K, et al. Agalsidase benefits renal histology in young patients with Fabry disease. J Am Soc Nephrol. 2013;24:137-418.
  50. Warnock D, Thomas C, Vujkovac B, et al. Antiproteinuric therapy and Fabry nephropathy: factors associated with preserved kidney function during agalsidase-beta therapy. J Med Genet. 2015;52:860-866.
  51. Hopkin R, Jefferies J, Laney D, et al; Fabry Pediatric Expert Panel. The management and treatment of children with Fabry disease: A United States-based perspective. Mol Genet Metab. 2016;117:104-113.
  52. Ortiz A, Germain D, Desnick R, et al. Fabry disease revisited: Management and treatment recommendations for adult patients. Mol Genet Metab. 2018;123:416-427.
  53. Mauer M, Glynn E, Svarstad E, et al. Mosaicism of podocyte involvement is related to podocyte injury in females with Fabry disease. PLoS One. 2014;9:e112188.
  54. Benjamin E, Flanagan J, Schilling A, et al. The pharmacological chaperone 1-deoxygalactonojirimycin increases alpha- galactosidase A levels in Fabry patient cell lines. J Inherit Metab Dis. 2009;32:424-440.
  55. Ishii S, Chang H, Yoshioka H, et al. Preclinical efficacy and safety of 1-deoxygalactonojirimycin in mice for Fabry disease. J Pharmacol Exp Ther. 2009;328:723-731.
  56. Young-Gqamana B, Brignol N, Chang H, et al. Migalastat HCl reduces globotriaosylsphingosine (lyso-Gb3) in Fabry transgenic mice and in the plasma of Fabry patients. PLoS One. 2013;8:57631.
  57. Mauer M, Sokolovskiy A, Barth J, et al. Reduction of podocyte globotriaosylceramide content in adult male patients with Fabry disease with amenable GLA mutations following 6 months of migalastat treatment. J Med Genet. 2017;54:781-786.
  58. Germain D, Hughes D, Nicholls K, et al. Treatment of Fabry's disease with the pharmacologic chaperone migalastat. N Engl J Med. 2016;375:545-555.