Fabry disease

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Fabry disease

Lindsay A. Eminger and Rhonda E. Schnur

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

(From Lebwohl MG. The Skin and Systemic Disease: A Color Atlas, 2nd edn. Churchill Livingstone 2003, with permission of Elsevier.)

Fabry disease (or Anderson–Fabry disease, OMIM 301500) is a progressive, X-linked lysosomal storage disorder caused by the deficiency or absence of the enzyme α-galactosidase A (GLA). This results in the accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids within lysosomes. Systemic manifestations of Fabry disease include renal dysfunction, cardiomyopathy and arrhythmias, cerebrovascular complications, corneal and lenticular opacities, tinnitus and hearing loss, gastrointestinal disturbances, pulmonary disease, osteopenia, and depression. Causes of death include end-stage renal disease (ESRD), cardiac disease, or stroke. Males are more severely affected, but female carriers may exhibit symptoms depending on the pattern of X-chromosome inactivation (lyonization). Atypical variants associated with only cardiac or renal disease are also part of the spectrum of Fabry disease. To date, more than 600 GLA mutations have been reported.

This chapter will focus on the treatment of Fabry disease as it relates to the skin. Cutaneous manifestations of Fabry disease include angiokeratomas, hypohidrosis, telangiectasias, lymphedema, and acroparesthesias. Angiokeratomas are hyperkeratotic, dark red to blue-black telangiectatic papules that are associated with Fabry and other lysosomal storage diseases including fucosidosis, sialidosis, aspartylglucosaminuria, and β-galactosidase deficiency. They symmetrically cluster around the umbilicus, hips, back, thighs, buttocks, penis, and scrotum. Angiokeratomas increase in number and size over time, and correlate with the severity of the systemic manifestations of disease. They are seen in about two-thirds of males and more than one-third of females with Fabry disease.

Acroparesthesias are a debilitating symptom of Fabry disease. Episodic burning, severe pain, and a constant tingling of the palms and soles are characteristic features. Abdominal or flank pain mimicking appendicitis or renal colic may also occur. Pain crises result from glycolipid accumulation in the autonomic nervous system and vascular endothelium. A similar mechanism underlies Fabry-associated hypohidrosis, an early and nearly universal finding. Less commonly, hyperhidrosis may occur.

Management strategy

Comprehensive medical therapy for Fabry disease requires a multi-disciplinary approach that includes a combination of enzyme replacement therapy (ERT) and conventional medical treatment. Because of the rapid advances in treatment, Fabry disease is now proposed as a candidate for newborn screening test panels.

Traditionally, angiokeratomas have been treated with surgical excision, electrocoagulation, and cryosurgery. These procedures can be associated with pain, bleeding, scarring, and recurrence, often necessitating repeated treatments. Laser therapy is the treatment of choice for multiple angiokeratomas. Various lasers have been utilized, including the CO2, argon, copper vapor, and flashlamp–pumped-dye lasers. Copper vapor lasers are superior to argon because of their wavelength specificity for hemoglobin. However, the flashlamp–pumped-dye laser may produce less pain and bleeding, results in a shorter healing time, and has a reduced risk of pigment changes and scarring. Intense pulsed light has also been utilized. Local anesthetics are useful when pre-treating sensitive areas (e.g., penile skin).

Neuropathic pain and acroparesthesias may benefit from avoidance of triggers, including physical exertion and temperature changes. Diphenylhydantoin, carbamazepine, gabapentin, topiramate and tricyclic anti-depressants are used for analgesia. Non-steroidal anti-inflammatory drugs (NSAIDs) are generally ineffective and narcotics should be avoided if possible.

Hemodialysis and renal transplantation are utilized for patients with renal failure. Renal transplantation also arrests the development of new cutaneous lesions, relieves acroparesthesias, and may improve sweating ability.

Gastrointestinal complications including delayed gastric emptying and dyspepsia have been treated with metoclopramide, pancrelipase, loperamide, and H2 blockers. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers reduce proteinuria. Hearing aids assist in moderate hearing loss, while profound deafness requires cochlear implantation. Aspirin or clopidigrel is recommended for cardiovascular disease prophylaxis. Conventional treatments are also utilized in the management of cardiovascular symptoms in Fabry disease.

ERT has revolutionized the treatment of Fabry disease. Two human enzyme products have been utilized: agalsidase-β (Fabrazyme, Genzyme Corporation) and agalsidase-α (Replagal, Shire Genetic Therapies). Both were approved by the European Agency for Evaluation of Medical Products in 2001, but only agalsidase-β is approved by the FDA. The enzymes are administered intravenously bi-weekly at a dose of 0.2 mg/kg for agalsidase-α and 1.0 mg/kg for agalsidase-β. No clear difference in clinical effect between the two preparations was demonstrated in a randomized, controlled, prospective study.

ERT normalizes levels of Gb3 in multiple organs, resulting in a number of symptomatic benefits. ERT stabilizes or slows progression of renal and cardiac disease, reduces neuropathic pain, stabilizes hearing loss, improves sweat function and quality of life. ERT has not been demonstrated to reduce stroke. Patients treated with ERT have a slowing of progression to “major” clinical events (ESRD, myocardial infarction, stroke or death).

Today, ERT remains the only FDA-approved medicinal therapy for the direct treatment of Fabry disease. However, new approaches are actively being studied. A promising therapeutic strategy involves small molecules called ‘active site-specific chaperones’ that may be useful with certain types of mutations. In Fabry disease, missense mutations can cause misfolding of the mutant GLA enzyme and retention of the misfolded enzyme in the endoplasmic reticulum. The retained enzyme is then degraded, rather than being trafficked to the appropriate location in the cell, the lysosome. Chaperones are orally active molecules that selectively bind to the misfolded enzyme, promote correct folding and aid in delivery to lysosomes. 1-Deoxygalactonojirimycin (DGJ), also known as migalastat hydrochloride (Amigal, Amicus Therapeutics, NJ, USA), is a molecular chaperone that is currently undergoing phase III clinical trials.

Substrate reduction therapy is an alternative investigative approach that involves inhibiting the production of Gb3 that accumulates as a result of GLA deficiency. A glucosylceramide synthase inhibitor slows the rate of Gb3 synthesis, thus decreasing storage within the lysosomes. Eliglustat tartrate (Genz 112638) is an immunosugar analog under investigation as a glucosylceramide synthase inhibitor for treating Gaucher disease and other lysosomal storage disorders including Fabry disease.

To date, gene therapy trials have been limited to mice, but have shown promising therapeutic results.

Specific investigations

First-line therapies

imageEnzyme replacement therapy A
imageLaser therapy E
imageIntense pulsed light E
imageSurgical excision E
imageDiphenylhydantoin B
imageCryotherapy E

Third-line and future therapies

imageSite-specific molecular chaperone therapy (AT1001, 1-deoxygalactonojirimycin, DGJ, N-butyldeoxynojirimycin, NB-DNJ) B
imageSubstrate reduction therapy (eliglustat tartrate, Genz 112638)  
imageGene replacement therapy  
imageRenal transplantation/hemodialysis C

Co-administration with the pharmacological chaperone AT1001 increases recombinant human α-galactosidase A tissue uptake and improves substrate reduction in Fabry mice.

Benjamin ER, Khanna R, Schilling A, Flanagan JJ, Pellegrino LJ, Brignol N, et al. Mol Ther 2012; 20: 717–26.

This study evaluated the efficacy of combined ERT and chaperone therapy. Co-incubation of Fabry fibroblasts with recombinant human α-galactosidase A (rhα-Gal A) and AT1001 (1-deoxygalactonojirimycin, migalastat hydrochloride) resulted in up to fourfold higher levels of cellular α-Gal A and approximately 30% greater Gb3 reduction compared to ERT alone. In rats, AT1001 increased the circulating half-life of rhα-Gal A by >2.5-fold, and in GLA knockout mice resulted in up to fivefold higher α-Gal A levels and fourfold greater GL-3 reduction.

Clinical trials of Amigal (TM) for Fabry disease.

http://www.amicustherapeutics.com, Cranbury NJ. Accessed August 26, 2012.

Migalastat hydrochloride (AT1001, 1-deoxygalactonojirimycin, DGJ, Amigal) is a chemical chaperone that selectively binds to and stabilizes proteins. Amicus Therapeutics presented preliminary data in 2010 from its phase II extension study of Amigal™ (migalastat HCl) for Fabry disease and from preclinical studies evaluating the combination of pharmacological chaperones and ERT for Fabry disease. During the extension study, treatment with migalastat HCl was generally well-tolerated, with no drug-related serious adverse events. Renal function measured via estimated glomerular filtration rate and quantitation of proteinuria remained stable out to 2–3 years in the extension study of migalastat HCl for all subjects. A phase III study commenced in 2009. In pre-clinical studies evaluating the combination of ERT and migalastat HCl in the Fabry mouse model, there was prolonged half-life of ERT in the circulation, increased cellular enzyme activity and greater substrate reduction in target tissues compared to results with ERT alone.

[/level-membership-for-dermatology-category][not-level-membership-for-dermatology-category]

Fabry disease

Lindsay A. Eminger and Rhonda E. Schnur

Evidence Levels:  A Double-blind study  B Clinical trial ≥ 20 subjects  C Clinical trial < 20 subjects  D Series ≥ 5 subjects  E Anecdotal case reports

image

(From Lebwohl MG. The Skin and Systemic Disease: A Color Atlas, 2nd edn. Churchill Livingstone 2003, with permission of Elsevier.)

Fabry disease (or Anderson–Fabry disease, OMIM 301500) is a progressive, X-linked lysosomal storage disorder caused by the deficiency or absence of the enzyme α-galactosidase A (GLA). This results in the accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids within lysosomes. Systemic manifestations of Fabry disease include renal dysfunction, cardiomyopathy and arrhythmias, cerebrovascular complications, corneal and lenticular opacities, tinnitus and hearing loss, gastrointestinal disturbances, pulmonary disease, osteopenia, and depression. Causes of death include end-stage renal disease (ESRD), cardiac disease, or stroke. Males are more severely affected, but female carriers may exhibit symptoms depending on the pattern of X-chromosome inactivation (lyonization). Atypical variants associated with only cardiac or renal disease are also part of the spectrum of Fabry disease. To date, more than 600 GLA mutations have been reported.

This chapter will focus on the treatment of Fabry disease as it relates to the skin. Cutaneous manifestations of Fabry disease include angiokeratomas, hypohidrosis, telangiectasias, lymphedema, and acroparesthesias. Angiokeratomas are hyperkeratotic, dark red to blue-black telangiectatic papules that are associated with Fabry and other lysosomal storage diseases including fucosidosis, sialidosis, aspartylglucosaminuria, and β-galactosidase deficiency. They symmetrically cluster around the umbilicus, hips, back, thighs, buttocks, penis, and scrotum. Angiokeratomas increase in number and size over time, and correlate with the severity of the systemic manifestations of disease. They are seen in about two-thirds of males and more than one-third of females with Fabry disease.

Acroparesthesias are a debilitating symptom of Fabry disease. Episodic burning, severe pain, and a constant tingling of the palms and soles are characteristic features. Abdominal or flank pain mimicking appendicitis or renal colic may also occur. Pain crises result from glycolipid accumulation in the autonomic nervous system and vascular endothelium. A similar mechanism underlies Fabry-associated hypohidrosis, an early and nearly universal finding. Less commonly, hyperhidrosis may occur.

Management strategy

Comprehensive medical therapy for Fabry disease requires a multi-disciplinary approach that includes a combination of enzyme replacement therapy (ERT) and conventional medical treatment. Because of the rapid advances in treatment, Fabry disease is now proposed as a candidate for newborn screening test panels.

Traditionally, angiokeratomas have been treated with surgical excision, electrocoagulation, and cryosurgery. These procedures can be associated with pain, bleeding, scarring, and recurrence, often necessitating repeated treatments. Laser therapy is the treatment of choice for multiple angiokeratomas. Various lasers have been utilized, including the CO2, argon, copper vapor, and flashlamp–pumped-dye lasers. Copper vapor lasers are superior to argon because of their wavelength specificity for hemoglobin. However, the flashlamp–pumped-dye laser may produce less pain and bleeding, results in a shorter healing time, and has a reduced risk of pigment changes and scarring. Intense pulsed light has also been utilized. Local anesthetics are useful when pre-treating sensitive areas (e.g., penile skin).

Neuropathic pain and acroparesthesias may benefit from avoidance of triggers, including physical exertion and temperature changes. Diphenylhydantoin, carbamazepine, gabapentin, topiramate and tricyclic anti-depressants are used for analgesia. Non-steroidal anti-inflammatory drugs (NSAIDs) are generally ineffective and narcotics should be avoided if possible.

Hemodialysis and renal transplantation are utilized for patients with renal failure. Renal transplantation also arrests the development of new cutaneous lesions, relieves acroparesthesias, and may improve sweating ability.

Gastrointestinal complications including delayed gastric emptying and dyspepsia have been treated with metoclopramide, pancrelipase, loperamide, and H2 blockers. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers reduce proteinuria. Hearing aids assist in moderate hearing loss, while profound deafness requires cochlear implantation. Aspirin or clopidigrel is recommended for cardiovascular disease prophylaxis. Conventional treatments are also utilized in the management of cardiovascular symptoms in Fabry disease.

ERT has revolutionized the treatment of Fabry disease. Two human enzyme products have been utilized: agalsidase-β (Fabrazyme, Genzyme Corporation) and agalsidase-α (Replagal, Shire Genetic Therapies). Both were approved by the European Agency for Evaluation of Medical Products in 2001, but only agalsidase-β is approved by the FDA. The enzymes are administered intravenously bi-weekly at a dose of 0.2 mg/kg for agalsidase-α and 1.0 mg/kg for agalsidase-β. No clear difference in clinical effect between the two preparations was demonstrated in a randomized, controlled, prospective study.

ERT normalizes levels of Gb3 in multiple organs, resulting in a number of symptomatic benefits. ERT stabilizes or slows progression of renal and cardiac disease, reduces neuropathic pain, stabilizes hearing loss, improves sweat function and quality of life. ERT has not been demonstrated to reduce stroke. Patients treated with ERT have a slowing of progression to “major” clinical events (ESRD, myocardial infarction, stroke or death).

Today, ERT remains the only FDA-approved medicinal therapy for the direct treatment of Fabry disease. However, new approaches are actively being studied. A promising therapeutic strategy involves small molecules called ‘active site-specific chaperones’ that may be useful with certain types of mutations. In Fabry disease, missense mutations can cause misfolding of the mutant GLA enzyme and retention of the misfolded enzyme in the endoplasmic reticulum. The retained enzyme is then degraded, rather than being trafficked to the appropriate location in the cell, the lysosome. Chaperones are orally active molecules that selectively bind to the misfolded enzyme, promote correct folding and aid in delivery to lysosomes. 1-Deoxygalactonojirimycin (DGJ), also known as migalastat hydrochloride (Amigal, Amicus Therapeutics, NJ, USA), is a molecular chaperone that is currently undergoing phase III clinical trials.

Substrate reduction therapy is an alternative investigative approach that involves inhibiting the production of Gb3 that accumulates as a result of GLA deficiency. A glucosylceramide synthase inhibitor slows the rate of Gb3 synthesis, thus decreasing storage within the lysosomes. Eliglustat tartrate (Genz 112638) is an immunosugar analog under investigation as a glucosylceramide synthase inhibitor for treating Gaucher disease and other lysosomal storage disorders including Fabry disease.

To date, gene therapy trials have been limited to mice, but have shown promising therapeutic results.