1McMaster University, Hamilton, ON, Canada
2Baywood Dermatology, Ajax, ON, Canada
3CCA Medical Research, Ajax, ON, Canada
4St. Michael’s Hospital, Toronto, ON, Canada
5Division of Dermatology, Department of Medicine, University of Toronto, Toronto, ON, Canada
6Probity Medical Research, Waterloo, ON, Canada
Conflict of interest:
BC has no conflicts to disclose. DNA has been an advisory board member, investigator, speaker, consultant, or received honoraria from AbbVie, Actelion, Amgen, Boehringer, Celgene, Coherus, Dermira, Eli Lilly, Galderma, Incyte, Janssen, Leo, Novartis, Pfizer, Regeneron, Sanofi Genzyme, UCB, and Valeant.
Fabry disease (FD) is an X-linked lysosomal storage disease. A lack of alpha-galactosidase activity results in the accumulation of globotriaosylceramide in cells of various systems, leading to multi-systemic effects. The cutaneous hallmark of FD is a specific distribution of angiokeratoma. Other common symptoms include cornea verticillata, acroparesthesia, and sweating abnormalities. FD-specific symptoms, history, as well as examination of angiokeratoma can assist in the differential diagnosis. Enzyme replacement therapy is the current mainstay of treatment.
enzyme replacement therapy, Fabry disease, alpha-galactosidase A, symptoms, treatment
Fabry disease (FD) is an X-linked lysosomal storage disease, affecting glycosphingolipid metabolism. The cause of FD is a variety of mutations in the GLA gene on the X chromosome (Xq22.1), resulting in a deficiency of the lysosomal enzyme alpha-galactosidase A (AGAL). This leads to the progressive accumulation of globotriaosylceramide (GL3) in cells throughout the body, causing multi-systemic effects.1 The incidence of FD in the general population is estimated to be 1:117,000.2
The classical variant of FD results from a complete loss of alphagalactosidase A function. Its symptoms include acroparesthesia, sweating abnormalities (hypo/hyperhidrosis), cornea verticillata, and angiokeratoma, as well as cardiovascular, cerebrovascular, and renal disorders such as cardiomyopathy, arrhythmia, stroke, and proteinuria.1 Non-classical or atypical variants of FD involve residual enzyme activity. Symptoms are generally milder, may be restricted to one organ, and have a later onset of 40 to 60 years of age. The severity of FD also depends on sex, with males being more severely affected than females.3 FD in heterozygous females has a wider spectrum, likely due to lyonization, where one X chromosome is randomly inactivated in female embryos.4
Facial dysmorphism has also been described in FD. The “Fabry facies” is characterized by periorbital fullness, bushy eyebrows, recessed forehead, pronounced nasal angle, bulbous nasal tip, prominent supraorbital ridges, shallow midface, full lips, prominent nasal bridge, broad alar base, coarse features, posteriorly rotated ears, and prognathism. Although there is no single facial feature to characterize FD, it is possible that these facial features may become more prominent with age due to the accumulation of GL3. Non-facial physical features that may indicate FD include broad fingertips, short fingers, and a small anterior-posterior chest diameter.5
Other Signs and Symptoms
The incidence of pain in FD has been reported in 81.4% of male patients and 65.3% of female patients. The average age of onset of pain has been found to be 14.8 years for males and 19.8 years for females.6 Pain is possibly caused by the deposition of GL3 in the dorsal root ganglia and sympathetic ganglia, or by small fiber neuropathy. Generally, the pain is either chronic or episodic. Episodic pain in FD, termed “Fabry crises,” typically begins in the extremities and radiates proximally, and may be triggered by exercise, illness, temperature changes, or other physical and emotional stresses. This neuropathic pain is also associated with a lack of temperature perception.7
Hypohidrosis is prevalent in FD patients, with reported incidence of 53% in males and 28% in females. Anhidrosis has been observed in 25% of males and 4% of females. Hyperhidrosis occurs less frequently, with 6% of males and 12.6% of females reporting this symptom.8
Cornea verticillata are whorl-like corneal opacities, resulting from changes in the subepithelial layers of the cornea.9 It is the most common ocular manifestation of FD, observed in 76.9% of females and 73.1% of males. Other less common ocular manifestations include vessel tortuosity and Fabry cataracts. Cornea verticillata may also be pathognomonic for FD, as its differential diagnosis only includes specific medications, such as amiodarone and aminoquinolines. However, it does not have predictive value with regards to disease severity.10
Angiokeratoma (AGK) is the most common cutaneous manifestation of FD, and has been reported in 66% of males and 36% of females.8 In FD, AGKs appear as non-blanching, red to blue-black lesions ranging from 1 to 5 mm in diameter.11
The age of onset for AGKs is typically 5-10 years in males.12 The distribution of AGK in males with FD is mainly on the penis, scrotum, inner thighs, lower back, buttocks, and the umbilicus. In females, AGKs are mainly found on the trunk and limbs.11 While patients with FD generally describe an increasing number of cutaneous lesions over time, no correlation has been found between age and the extent or number of lesions.8 It is possible older patients are more observant of their skin and, therefore, report more AGKs.
The distribution of AGKs in FD differs from AGK in other diseases. Angiokeratoma of Fordyce usually appears after age 30 and is found on the genitals, angiokeratoma of Mibelli generally presents on the extensor surfaces of hands and feet, and angiokeratoma circumscriptum naeviformis is concentrated on the trunk and extremities.1, 13 Idiopathic AGK is also possible without any specific localization.13
Diffuse AGK has also been observed in other lysosomal storage diseases, including fucosidosis, sialidosis, GM1 gangliosidosis, galactosialidosis, beta-mannosidosis, Schindler disease type II, and aspartylglucosaminuria.1, 11
AGK histology reveals a vascular proliferation inside the papillary dermis. The overlying epidermis is acanthotic and orthokeratotic. The vascular channels are occasionally plugged with erythrocytes. Dermoscopy of AGK shows red to bluish black vascular lacunae
with clear borders. Occasionally, overlying yellow keratotic areas are also observed.11
Currently, it is unclear whether AGK can be used as a biomarker for disease progression or as a measure of efficacy of enzyme replacement therapy.14 However, when stratified by age, male and female FD patients with cutaneous vascular lesions (angiokeratomas and telangiectasiae) were shown to more likely have major organ involvement.8
For both males and females, at least one of the following is required for a definite FD diagnosis: FD-specific distribution of AGK or neuropathic pain, cornea verticillata, or increased plasma GL3. For males, a GLA mutation resulting in less than 5% leukocyte AGAL enzyme activity is also required for diagnosis. Family history of FD can be predictive, and urinalysis can be used to detect proteinuria. However, in the presence of a non-FD-specific distribution of AGK, pain, or cornea verticillata, and a GLA mutation of unknown significance, a definitive FD diagnosis cannot be established and alternative diagnoses should be considered.13
Dermoscopy can identify multiple lesions when they are not visible to the naked eye or when multiple AGKs are surrounding one distinct lesion.11
Enzyme Replacement Therapy
Standard treatment for FD is enzyme replacement therapy (ERT). Currently, there are two forms of recombinant alpha-galactosidase A: agalsidase alfa, which is produced by continuous human cell lines, and agalsidase beta, which has been produced by Chinese hamster ovary cells transduced with the AGAL gene. According to a 2016 Cochrane Review, ERT has been shown to significantly alleviate the cardiac, renal, and neuropathic effects of FD.15 The US FDA has only approved agalsidase beta for FD,15 whereas both agalsidase alfa and beta are approved for FD in Canada. The Canadian Fabry Disease Initiative is a nation-wide study that is currently comparing the efficacy of the two ERT treatments.16 The recommended dose is 0.2 mg/kg of body weight administered every 2 weeks for agalsidase alfa and 1 mg/kg of body weight every 2 weeks for agalsidase beta.15
Six randomized controlled trials (RCT) examining the effect of agalsidase beta on skin GL3 deposition have been performed. A 20-week long RCT in 1999 involving 58 patients with skin-GL3 deposits as a secondary endpoint found significantly lower GL3 deposits in skin, kidney, and heart biopsies, with 20 of 29 patients who received treatment experiencing clearance of renal capillary endothelial GL3 deposits (a score of 0 on a scale of 0-3).17 In the subsequent 6-month open-label study, all patients in the former placebo group and 98% of patients in the former treatment group had scores of 0.18 In the same cohort of patients enrolled in an open-label trial, complete clearance of GL3 skin deposits was reported in 98% of patients at 30 months and 86% of patients at 54 months.19 Another RCT involving the same cohort examined dermatologic biopsies and found similar results, with scores of 0 (GL3 clearance) in superficial dermal capillary endothelial cells in 100% of adult patients, in deep dermal vascular endothelial cells in 85%, in vascular smooth muscle cells in 33%, and in the perineurium in 4%.20 A 48-week open-label study from 2002 to 2005 with patients aged 8 to 16 years found clearance of GL3 deposits in superficial dermal capillary endothelial cells at 24 and 48 weeks, and a reduction from moderate/severe GL3 accumulation to mild/cleared GL3 accumulation in deep dermal capillary endothelial cells at 24 and 48 weeks.21 Another openlabel study from 2003 to 2006 examining skin and kidney GL3 deposits administered the standard dose of 1 mg/kg every 2 weeks of agalsidase beta to 21 adult patients for 6 months, and then a reduced dose of 0.3 mg/kg every 2 weeks for 18 months. Ninety-five percent of patients had a score of 0 (no GL3 skin deposits) at week 24, compared to 24% at baseline. During the low dose period, only 70-80% of patients had scores of 0, with seven patients experiencing increasing scores and two patients experiencing new spontaneous AGK.22
A retrospective analysis involving 134 adult patients investigated the effects of immunoglobulin G (IgG) antibodies against agalsidase beta during treatment. No correlation was found between IgG titers and the onset of clinical events, renal function, or plasma GL3. However, a correlation was found between IgG titers and GL3 deposits in dermal capillary endothelial cells, with a larger proportion of patients with GL3 deposits in the highest titer subgroup.23 The clinical significance of the possible effect of these antibodies is still unknown.
FD is a multisystem X-linked lysosomal storage disease. The most common cutaneous manifestation is diffuse angiokeratomas. Family history of FD and common symptoms, including cornea verticillata, neuropathic pain, and sweating abnormalities, can be used to confirm an FD diagnosis. ERT has shown to be an effective form of treatment to alleviate cardiac, renal, and cutaneous effects of FD. Overall, dermatologists should always consider FD as a potential diagnosis in the presence of angiokeratomas, and ERT administered promptly upon confirmation of FD as the causative disease.
- Desnick RJ, Ioannou YA, Eng CM. Chapter 150: α-Galactosidase A deficiency: Fabry disease. In: Valle D, Beaudet AL, Vogelstein B, et al., eds. The online metabolic and molecular bases of inherited disease. New York, NY: McGraw-Hill; 2014. Available at ommbid.mhmedical.com/content.aspx?bookid=971&Sectionid=62644837. Accessed January 14, 2018.
- Meikle PJ, Hopwood JJ, Clague AE, et al. Prevalence of lysosomal storage disorders. JAMA. 1999 Jan 20;281(3):249-54.
- Arends M, Wanner C, Hughes D, et al. Characterization of classical and nonclassical Fabry disease: a multicenter study. J Am Soc Nephrol. 2017 May;28(5):1631-41.
- Lyon MF. X-chromosome inactivation and human genetic disease. Acta Paediatr Suppl. 2002 91(439):107-12.
- Ries M, Moore DF, Robinson CJ, et al. Quantitative dysmorphology assessment in Fabry disease. Genet Med. 2006 Feb;8(2):96-101.
- Hoffmann B, Beck M, Sunder-Plassmann G, et al. Nature and prevalence of pain in Fabry disease and its response to enzyme replacement therapy–a retrospective analysis from the Fabry Outcome Survey. Clin J Pain. 2007 Jul-Aug;23(6):535-42.
- Schiffmann R, Scott LJ. Pathophysiology and assessment of neuropathic pain in Fabry disease. Acta Paediatr Suppl. 2002 91(439):48-52.
- Orteu CH, Jansen T, Lidove O, et al. Fabry disease and the skin: data from FOS, the Fabry outcome survey. Br J Dermatol. 2007 Aug;157(2):331-7.
- Sher NA, Letson RD, Desnick RJ. The ocular manifestations in Fabry’s disease. Arch Ophthalmol. 1979 Apr;97(4):671-6.
- Sodi A, Ioannidis AS, Mehta A, et al. Ocular manifestations of Fabry’s disease: data from the Fabry Outcome Survey. Br J Ophthalmol. 2007 Feb;91(2):210-4.
- Zampetti A, Orteu CH, Antuzzi D, et al. Angiokeratoma: decision-making aid for the diagnosis of Fabry disease. Br J Dermatol. 2012 Apr;166(4):712-20.
- Kanitakis J, Allombert C, Doebelin B, et al. Fucosidosis with angiokeratoma. Immunohistochemical & electronmicroscopic study of a new case and literature review. J Cutan Pathol. 2005 Aug;32(7):506-11.
- van der Tol L, Cassiman D, Houge G, et al. Uncertain diagnosis of Fabry disease in patients with neuropathic pain, angiokeratoma or cornea verticillata: consensus on the approach to diagnosis and follow-up. JIMD Rep. 2014 17:83-90.
- Ries M, Schiffmann R. Fabry disease: angiokeratoma, biomarker, and the effect of enzyme replacement therapy on kidney function. Arch Dermatol. 2005 Jul;141(7):904-5; author reply 5-6.
- El Dib R, Gomaa H, Carvalho RP, et al. Enzyme replacement therapy for Anderson-Fabry disease. Cochrane Database Syst Rev. 2016 Jul 25;7:CD006663.
- Embrett M, Mackinnon NJ. Qualitative evaluation of the Canadian Fabry Disease Initiative. Can Pharm J (Ott). 2012 May;145(3):136-41 e3.
- Eng CM, Guffon N, Wilcox WR, et al. Safety and efficacy of recombinant human alpha-galactosidase A replacement therapy in Fabry’s disease. N Engl J Med. 2001 Jul 5;345(1):9-16.
- Wilcox WR, Banikazemi M, Guffon N, et al. Long-term safety and efficacy of enzyme replacement therapy for Fabry disease. Am J Hum Genet. 2004 Jul;75(1):65-74.
- Germain DP, 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 May;18(5):1547-57.
- Thurberg BL, Randolph Byers H, Granter SR, et al. Monitoring the 3-year efficacy of enzyme replacement therapy in Fabry disease by repeated skin biopsies. J Invest Dermatol. 2004 Apr;122(4):900-8.
- Wraith JE, Tylki-Szymanska A, Guffon N, et al. Safety and efficacy of enzyme replacement therapy with agalsidase beta: an international, open-label study in pediatric patients with Fabry disease. J Pediatr. 2008 Apr;152(4):563-70, 70 e1.
- Lubanda JC, Anijalg E, Bzduch V, et al. Evaluation of a low dose, after a standard therapeutic dose, of agalsidase beta during enzyme replacement therapy in patients with Fabry disease. Genet Med. 2009 Apr;11(4):256-64.
- Benichou B, Goyal S, Sung C, et al. A retrospective analysis of the potential impact of IgG antibodies to agalsidase beta on efficacy during enzyme replacement therapy for Fabry disease. Mol Genet Metab. 2009 Jan;96(1):4-12.