On-line version ISSN 1806-4841
An. Bras. Dermatol. vol.84 no.4 Rio de Janeiro July/Aug. 2009
Paula BoggioI; Paula Carolina LunaII; María Eugenia AbadIII; Margarita LarraldeIV
Assistant of Pediatric Dermatology Division, Department of Dermatology, Hospital
General de Agudos J.M. Ramos Mejía - Buenos Aires, Argentina
IIDermatologist, Assistant of Pediatric Dermatology Division, Department of Dermatology, Hospital General de Agudos J.M. Ramos Mejía, and Department of Dermatology, Hospital Churruca - Buenos Aires, Argentina
IIIDermatologist, Assistant of Pediatric Dermatology Division, Department of Dermatology, Hospital General de Agudos J.M. Ramos Mejía, and Department of Dermatology, Hospital Alemán - Buenos Aires, Argentina
IVDermatologist, Ph.D. in Medicine, Universidade de Buenos Aires (UBA) and Associate Professor of Dermatology, UBA. Head of Pediatric Dermatology Division, Department of Dermatology, Hospital General de Agudos J.M. Ramos Mejía -, Buenos Aires, Argentina
Fabry disease is an uncommon, X-linked lysosomal storage disorder, caused by partial or complete deficiency of the enzyme a-galactosidase A. The defect leads to accumulation of uncleaved globotriaosylceramide on the vascular endothelium and visceral tissues, being the skin, heart, kidneys and central nervous system the most affected organs. We performed review of the literature related to the disease and emphasized that early recognition of angiokeratomas and hypohidrosis are key diagnostic signs of this serious disease. We also addressed the need of multidisciplinary assessment of these patients.
Keywords: Alpha-galactosidase; Angiokeratoma; Fabry disease
Anderson-Fabry disease, also named Fabry disease (DF) or angiokeratoma corporis diffusum universale (OMIM #301500), was reported independently and almost simultaneously by dermatologists William Anderson in England and Johannes Fabry in Germany, in 1898 1-3.
FD is considered a lysosomal storage disease. It is an inborn error of glycosphingolipid metabolism produced by mutations of the gene that codifies the lysosome enzyme α-galactosidase A (α-GAL). Reduction or absence of the activity of this enzyme leads to progressive accumulation of neutral glycosphingolipid with terminal residues of α-galactosyl (especially in the form globotriaosylceramide or GL-3) in the plasma and in the lysosome of endothelial cells of varied organs, especially the skin, kidneys, heart, eye and brain, leading to the onset of disease 4-7.
FD heritage is X-linked. The affected gene is named GALA and is found in the region Xq22.1 of chromosome X. GALA is about 12 kb long and contains about 7 exons that range from 92 to 291 base pairs 8. The genetic defect that produces the disease is extremely heterogeneous and current more than 300 mutations have been identified 4,8. Most families have "private mutations", that is, specific mutations to a specific family 4,9.
In male homozygote patients, Fabry gene has high penetration and most have the classical phenotype of the disease. In female heterozygous patients, the disease has variable expressiveness because of the random inactivation of one X chromosome (Lyon hypothesis). Currently, heterozygous are not considered simple carriers, given that most have systemic abnormalities related to the disease and increase of morbidity and mortality. Therefore, FD transmission of X-linked recessive form should be disregarded 10-12.
The correlation grade between genotype and phenotype of the disease is reason for controversy. For example, different mutations are associated with similar phenotypes, whereas family members that shared the same mutation have different phenotypes 7,13.
If we suspect of the diagnosis of FD, the family history investigation is highly important, given that most cases occur as hereditary. However, absence of positive family data does not invalidate the diagnosis, given that de novo mutations have been documented 4,5,11.
Enzymatic defect of FD leads to accumulation of uncleaved glycosphingolipid (particularly GL-3) in plasma and in lysosome of innumerous cell types: endothelial cells, pericytes, smooth cells in blood vessels, cardiac myocytes, epithelial cells of renal glomeruli and tubules, ganglionary cells of autonomic nervous system, corneal cells, histiocytes and connective tissue cells 5,14. GL-3 deposits in endothelial cells lysosome, pericytes and blood smooth muscle cells produce protuberances of the vessel lumen that cause narrowing and dilations that progress to ischemia and infarction 14, as well as accumulation in other type of cells that lead to increase in cell size with onset of organomegalias and visceral dysfunction 15. This pathophysiological mechanism explains the multisystemic nature of this disease.
In some specific tissues, other additional mechanisms contribute to the onset of the disease. For example, it is believed that in the heart, the signaling pathways determining hypertrophy, apoptosis, necrosis and fibrosis would be activated and in the nervous system the abnormal reaction of vascularization and the activation of the coagulation cascade would be involved 16-18.
FD is more frequent in Caucasians, but it may affect all races. It is estimated that the incidence of the disease is one case to each 40,000 men or 1 in each 117,000 live births, which means it is the second most frequent disease by lysosome accumulation in human beings 15,19. The incidence might be underestimated because of the existence of an intermediate variant of the disease, the post mortem diagnosed cases and those diagnosed within the context of an affected family member 5.
Clinical signs and symptoms of FD are very heterogeneous and subtle at first, which hinders or delays the diagnosis in many situations.
Homozygote: in general, there is total loss of enzyme function and they have the classical form of the disease. At first, symptoms occur in childhood and adolescence, including chronic paresthesia and episodes of acral and/or abdominal pain (Fabry crisis), heat intolerance, reduction or absence of sudoresis, presence of angiokeratomas (AK) on the skin and/or mucosa and cornea verticilata. Between the third and fourth decades of life, there is increase in previously mentioned symptoms and there are also reports of progressive systemic impairment (heart, renal and brain abnormalities) 4,5. In the absence of family history, diagnosis takes long time to be made (mean age of 29 years), when there is irreversible visceral damage 4. Milder forms of the disease, which are manifested later with primary affection of renal or cardiovascular systems, are known as renal or heart variant, respectively, or atypical forms of FD and occur in patients with detectable enzymatic activity 20-22. Forms of intermediate severity, between the classical phenotype and renal or heart variants were described and are named intermediate forms.
Heterozygote: clinical presentation of the disease in women is variable and it may range from asymptomatic status to as severe presentations as those in men 19.
Patients that have blood antigen B have clinical manifestations that are relatively more severe, given that degradation of this antigen is also dependent on enzyme α-GAL.23
The most characteristic findings of FD are cutaneous disseminated angiokeratomas, or, AK corporis diffusum. AK are vascular lesions that comprehend one or more dilated blood vessels on the upper dermis, directly under the epidermis, which are normally followed by epidermal reactions characterized by acanthosis and/or hyperkeratosis 24. Clinically, they are presented as innumerous papules of varied color, from red to black, with slightly keratosic surface and variable size between 1 to 10 mm in diameter. They tend to be arranged in groups and normally they have symmetrical distribution preferably on the skin area that goes from the navel to the tights (distribution named "bathing suit") (Figures 1, 2 and 3)4,6. Occurrence of AK in areas of trauma, such as the waist, elbows, extensor surface of the arms and the spine, indicates that this mechanical factor would act as a possible trigger (Koëbner phenomenon) (Figure 4) 4,5. AK's onset is at teenager years in homozygote, but the onset in women is not clearly established yet, but it normally takes place in more advanced years 19,25. Almost all men with the classical phenotype of FD will have AK, but it may be absent in the heart and renal variants of the disease. Up to 30% of the heterozygote patients will develop these characteristic cutaneous manifestations, but they are normally isolated lesions in atypical locations 5,10. The number and size of AK increases as time goes by 24,26,, and they are not always directly related with systemic morbidity 4,5,27. They are persistent lesions, but some AK may progress to thrombosis and disappear spontaneously 28.
Mucosas can also be affected in FD. As a result of disease advance, we can commonly see AK in the mucosas, especially in the oral mucosa, affecting the anterior portion of jugal mucosa or labial mucosa, displaying a telangiectasic aspect (Figure 5) 4,5.
The most common sign reported by patients was reduction of sudoresis. It is frequently presented in children or adolescents with dry skin and it is translated into intolerance to heat and exercise, and sometimes into fever without apparent cause 4,5. It is suggested that hypohidrosis or anhidrosis is secondary to selective damage of autonomic nerves, deposits of GL-3 on sweat glands and/or ischemia owing to impairment of blood vessels that nourish both autonomic nerves and sweat glands 29-31. There are reports of patients with FD that have hyperhidrosis, especially palmar-plantar, which seems to be more common than previously believed, and it is more prevalent in women 16, 32-34.
Body hair may be affected in FD as diffuse body hypotrichosis, by direct built-up of GL-3 in hair follicles, and also caused by vascular abnormalities of irrigation 33.
Other common affection detected in the dermatological physical examination is the presence of edema of eyelids and extremities 15. Lymphaedema of the legs is common, and it is produced by GL-3 deposits in the lymphatic vessel 35. It is rarely responsible for onset of recurrent stasis ulcers, which might be initial manifestations of the disease 36.
There is one isolated report of a homozygote patient with FD who presented painful hypodermal nodules that were diagnosed as cutaneous nodous polyartheritis 37.
Neurological: The key symptom of FD is chronic paresthesia, which occurs especially in homozygote patients, affects hands and feet, starts in infant years and persists until adult life. It is burning pain followed by tingling, which can be intermittent or continuous, and can radiate to neighboring areas 4,5. Acroparesthesias are the main cause of morbidity of the disease during the two first decades of your life, and in some cases, they lead to depression and even to suicide attempts 29,38. The pain can be interrupted by the so-called "Fabry crises", which are episodes of acute pain that last from minutes to days, which may be followed by fatigue, low grade fever and arthralgia 4,5. They can be triggered by stress, fatigue, disease, and external temperature increase and/or physical exercise 4,5. Acroparesthesias and crises tend to disappear with time, possibly owing to complete destruction of nerves fibers 39,40. In adult age, the occurrence of cerebral vascular accident (CVA) is on average at 34 years of age in homozygote and 40 in heterozygote subjects, and it is essentially caused by occlusion of microvasculature or embolism 55. Cerebrovascular diseases indicate poor prognosis and, together with cardiovascular affections, they represent the main causes of death of these patients 41. Other neurological affections include auditory affections (hearing loss), sensorial and vestibular affections (vertigo and tinnitus) 39.
Ophthalmological: There are conjunctival abnormalities that consist of vascular dilations and tortuosities that are particularly evident in the inferior bulbar conjunctiva (Figure 6) 4,15. Retinal abnormalities are similar to the previous ones and can be exacerbated by the presence of renal disease and high blood pressure, which is a very common finding in homozygote 29,42,43. Lens lesions are less frequent and consist of built-up of granular material and anterior subcapsular cataract 44. The most common ocular findings of FD is cornea verticilata (yellowish opacities characterized by one or more lines radiating from a point close to the corneal core), present in almost all homozygote subjects and in about 70% to 90% of heterozygote subjects. This affection does not impact sight.
Given that this ocular finding is very frequent, slit lamp ophthalmoscopy is an important tool to support the diagnosis of women with FD when there is no access to molecular studies 44,45. There may be also xerophthalmia of variable grade because of reduction of tear production 15.
Renal: Presence of polyuria because of defective concentration may be an early manifestation of renal impairment, but it is normally ignored. Most of the patients with classical forms develop proteinuria in late adolescent years, and this is the moment that renal damage is actually recognized 4,5. It is progressive, normally leads to chronic renal failure, which is manifested between the third to fifth decades of life and it is treated with chronic dialysis or with renal transplantation 7,46. After the transplantation, graft enzyme activity manages to metabolize GL-3 avoiding impairing the transplanted kidney. Logically, heterozygote women are not candidates to donation 5. Before that, when dialysis and renal transplantation were not performed, chronic renal failure was the main cause of death in FD and life expectancy was 41 years 16. In the so-called renal variant of FD, patients develop failure in similar ages to those that have the classical phenotype, but in the absence of other disease manifestations 20.
Cardiological: Heart impairment is constant in FD. It is caused by GL-3 deposits in the myocardium, in valves and in the conduction system, which explains the diversity of symptoms, whose expression depends on gender and age 5,47. The most common manifestations are: left ventricle hypertrophy (LVH), mitral failure, arrhythmia, and arterial coronary disease 14,47. LVH that coexists with valve abnormalities are associated with the most severe form of the disease and are important prognostic factors of severity in general 48.
Some subjects with low residual levels of enzyme α-GAL develop a variant of the disease that has only heart expression, named cardiac variant of FD. It is estimated that 3-6% of men with non-obstructive hypertrophic cardiomyopathy, considered idiopathic, have this FD variant 49.
Another less known manifestation of this disease is lipid profile abnormality that consists of slightly increased total cholesterol, HDL cholesterol increase, and normal levels of LDL cholesterol and triglycerides 50.
Heltianu et al. checked the correlation between FD and eNOS gene abnormality. This gene is responsible for synthesizing nitric oxide, an essential molecule for the physiological functions of vascular system, which is exclusively produced by endothelial cells. eNOS mutations may lead to greater predisposition or intensification of cardiovascular diseases, such as for example, FD. It is an additional mechanism that explains why only one allele for FD causes different phenotypes among holders 51.
Gastrointestinal: Episodes of diarrhea, vomiting, post-prandial pain and malabsorption are the most common complaints and are especially disabling in children. Other findings are pancreatic failure, jejunal diverticuli and achalasia. These abnormalities are due to accumulation of GL-3 in intestinal blood vessels and autonomic ganglia 52.
Face: Some patients have facial dysmorphy of different grades. The findings are: prominent ear lobes, thick eyebrows, depressed forehead, prominent nasal angle, large nose, prominent supraorbital bridge, widened nasal basis and unclear features 53,54.
Stomatological: Oral cavity findings, in addition to AK, include: xerostomia (by reduction of salivary secretion), erythema and edema of fungiform papillae, glossitis, en-block tongue, granulomatous keilitis, and increase in prevalence of cysts and pseudocysts of maxillary sinuses 54.
Psychiatric: Depression, suicidal ideation and dementia. 5,15,55
Others: presence of AK in the respiratory and digestive tract mucosa 15, greater incidence of subclinical hypothyroidism, airway obstruction, osteopenia up to osteoporosis, anemia, and others 5.
Clinical suspicion of FD should be confirmed as follows:
Homozygote: diagnosis is based on the determination of α-GAL levels in tears, plasma, leukocytes, cutaneous fibroblast culture, or as recently described, in drops of dry blood collected in filter paper 56. The presence of GL-3 in urinary sediment, plasma or fibroblast culture 9.
Heterozygote: in some cases diagnosis may be made similarly to homozygote subjects. But normally this test is not appropriate to screen women, given that they may have random inactivation of chromosome X between the cells, which would mean enough production of enzyme in plasma and in tissues. Therefore, definite diagnosis in heterozygote requires the identification of specific family mutation in gene α-GAL based on molecular biology studies 57,58.
Many studies have demonstrated that definite diagnosis of FD is made on average 15 years after the onset of symptoms 5.
Given that GL-3 starts early in intrauterine life, it is possible to have prenatal diagnosis through demonstration of low activity of α-GAL in biopsy of chorionic villi or in the culture of amniotic fluid, if they are fetus with XY karyotype 59. In the case of family mutation of α-GAL already known, the molecular study may exceed or confirm the enzymatic diagnosis.
In biopsy of different tissues of FD patients, histopathological findings consist of the presence of cytoplasmatic vacuoli that contain accumulated lipids (previous preservation of tissues by freezing or fixating it in calcium formol 1%) under light microscopy 5. Under electron microscopy we can see the presence of lysosome inclusions, with typical concentric lamelar configuration (alternating clear and dark bands each 4-6 mm), called zebra-similar inclusion bodies 5,60. When these findings are not conclusive, we can resort to immunoelectron microscopy with anti-GL antibodies 5,61.
DERMATOLOGICAL DIFFERENTIAL DIAGNOSIS
Differential diagnosis of isolated AK is made with: vulgaris wart, senile or rubi angioma, pyogenic granuloma, Spitz nevus, pigmented seborrheic keratosis, and melanoma 24. They should also be differentiated from other types of AK (Chart 1) 62.
Disseminated AK is strongly suggestive of FD, but they are not pathognomonic. For this reason, we should exclude a broad range of lysosome storage diseases, in addition to a form of AK corporis diffusum not associated with known enzymatic abnormalities, called idiopathic or cutaneous variant of AK corporis diffusum (Chart 2).24,26,63
Once the diagnosis of FD is confirmed, the patient and the family should receive genetic counseling. All daughters of the homozygote will inherit the disease, once they will get the X that has the mutation from the father, and none of the sons will get the disease, given that they get the Y chromosome from the father. Half of the sons and half of the daughters of a heterozygote will be affected, given that she has one X with mutation and one without 5,64.
The treatment of this complex disease requires a multidisciplinary team formed by clinicians, dermatologists, neurologists, cardiologists, nephrologists, and geneticists, all experienced in the topic.
a. Non-specific therapy:
It is support care, directed only to controlling the symptoms and signs present and it normally complements specific therapy.
Angiokeratomas: may be destroyed by different methods: electrocoagulation, cryotherapy, surgical exeresis or laser (Neodymium-YAG, pulsed dye, and others). Laser therapy is the therapy of choice 33.
Acroparesthesias, Fabry crisis: We ask the patients to identify and avoid predisposing symptoms. Partial improvement of pain is obtained with diphenylhydantoine, carbamazepine, gabapentine, oxacarbazepine or topiramate 5,16,65.
Cerebral and retinal vascular disease: prevention is made with antineoplastic or anti-coagulant agents. Vascular protection may be enhanced with inhibitors of angiotensin conversion enzyme, statins and folic acid 5,65.
Renal disease: control of arterial hypertension, dialysis, and even renal transplant 5. Aggressive treatment is indicated with angiotensin converting enzyme inhibitor or with blockers of angiotensin receptors to reduce proteinuria 16,66
Cardiac disease: control of arrhythmia with anti-arrhythmia drugs, pacemakers (if indicated), up to heart transplantation. The patients with coronary disease can be candidates to coronary revascularization 67.
b. Specific Therapy:
Enzymatic replacement therapy (ERT)
This strategy of treatment is based on the discovery that cells can incorporate an enzyme into the extracellular medium and use it for its normal metabolism. ERT for FD was approved in Europe in 2001 and in the United States in 2003. Currently, there are two human α-GAL available in the market: alpha algasidase (Replagal®, Transkaryotic Therapies Inc., Cambridge, Massachusetts), produced by human fibroblast cultures added by active promoters for gene transcription of α-GAL, approved in Europe, and beta algasidase (Fabrazyme®, Genzyme Corp., Cambridge, Massachusetts), obtained from recombinant therapy of hamsters' ovaries, approved in Europe and USA 5,68. Both proteins are structurally and functionally similar, without specific comparable activity and are administered by intravenous via every 15 days. Doses are variable depending on the preparation: 0.2 mg/kg/dose of alpha algasidase and 1 mg/kg/dose of beta algasidase.
ERT is a treatment to be used for their entire life, given that the amount of plasmatic enzyme is rapidly depleted, requiring constant infusions 68. Tolerance to ERT is normally good, except for mild or moderate reactions associated with infusion, product of formation of non-neutralizing IgG antibodies.
It is clear that ERT reverses metabolic abnormalities and many pathological affections of FD. The purpose of implementation is to prevent the development of the disease in young patients and to avoid or reverse the progression of organic dysfunction in older patients 68. Therefore, current recommendations to start ERT are: 16,69
- below 16 years:
as soon as there are signs and symptoms
- over 16 years: upon diagnosis
Heterozygote: when there are significant symptoms or key organ impairment.
Clinical trials with both enzymatic preparations show reduction in frequency of pain episodes, heart masses, and GL-3 deposits in kidneys (with stabilization or improvement of renal function in cases of mild impairment) and on the skin. There is evidence that ERT improves sudoresis, gastrointestinal symptoms, pulmonary and auditory disorders 5,16. However, there is no information about the long-term impact of ERT in FD mortality.
Gene therapy: This technique aims at adding normal gene of α-GAL to normal gene of the patient's DNA, which starts to producing normal enzyme. The methods used to introduce foreign genes in cells are basically classified as viral systems (they use viral vectors such as oncoretroviruses, lentiviruses or adenoviruses) and non-viral systems (liposome containing DNA). Both delivery systems have been tested in FD. Gene therapy proposes definite cure of the disease, but it is still at experimental stage 70.
Others: There are specific modalities under study to treat FD:
Chaperone: it is a new strategy of enzymatic enhancement, useful to patients that have unstable variants of mutant α-GAL, which owing to quality defects it is retained in the endoplasmatic reticulum but maintain residual enzymatic activity. Small synthetic molecules that act as chaperone retrieve residual α-GAL transporting it to lysosome. This therapy is administered by oral route and offers an excellent complementation to ERT 71,72.
Reversible competitive α-GAL inhibitors: it is the use of powerful competitive α-GAL inhibitors, and when inside the cells, they determine increase of enzyme activity. At the same time, these substances seem to speed up transportation, maturation and stability of mutating enzyme 73,74. They would behave as pharmacological chaperons, useful only to patients with residual enzymatic activity.
Substrate deprivation: it is based on inhibition of early stages of glycosphingolipid synthesis with consequent reduction of formation and accumulation of Gb3 75.
FD is a severe multisystemic disease. Current availability of specific treatment forces us to make the diagnosis as early as possible. Dermatologically speaking, we should recognize that AK and hypohidrosis are the two signs that support the diagnosis.
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How to cite this article: Boggio P, Luna PC, Abad ME, Larralde M. Doença de Fabry. An Bras Dermatol. 2009;84(4):367-76.