Clinical manifestations

Presentation and course

Patients with Fabry disease are typically divided into a severe, classic phenotype, which is caused by mutations that are associated with no (or less than 3%) residual alpha-galactosidase A activity and a generally milder nonclassical phenotype with variant, atypical, or late-onset mutations associated with definite residual activity of up to 30% of mean normal values (134; 06).

In affected hemizygous males with the classic phenotype, clinical symptoms usually begin in late childhood or adolescence with the development of neuropathic pain in the extremities (acroparesthesia), poor heat and exercise tolerance, angiokeratoma, hypohidrosis, corneal and lenticular opacities (cornea verticillata), and psychosocial problems (111). Because of the storage of glycolipid in the vascular system, progressive cardiac, renal, and cerebral involvement follows, mostly during the second to fourth decades. Late complications of the disease include deafness and tinnitus, stroke, cardiac conduction disturbances, hypertrophic cardiomyopathy with left ventricular hypertrophy, valvular heart disease, gastrointestinal problems, and chronic renal failure.

Nonclassical Fabry disease is characterized by a more variable disease course, in which patients are generally less severely affected, disease onset is delayed, and disease manifestations may be limited to a single organ (06; 29). Patients with Fabry disease identified in screening studies of individuals with stroke, renal failure, or cardiomyopathy often have the nonclassical phenotype (06).

Despite the X-linked inheritance pattern of Fabry disease, women often have signs and symptoms of Fabry disease due to skewed X chromosome inactivation, although they are usually less severely affected than men (84; 43; 06).

Dermatologic findings. Angiokeratomas consist of clusters of individual ectatic blood vessels covered by a few layers of skin. These lesions are flat or slightly raised, dark red to blue in color, and are usually located in the groin, buttocks, upper legs, and umbilical regions. The angiokeratomas become apparent in childhood and gradually increase in size and number over the years. Angiectasias may also occur in the oral mucosa, pinna of the ear, conjunctiva, and retina.

Cardiac findings. Glycosphingolipid accumulation within myocardium, heart valves, conduction pathways, and coronary vessels occurs in hemizygous males. Hypertrophic cardiomyopathy may occur without other clinical manifestations of Fabry disease in hemizygous males (100). On the other hand, diastolic dysfunction can occur prior to the presence of left ventricular hypertrophy (153). Mitral valve insufficiency is a common occurrence, and arrhythmias and electrocardiogram changes are often noted. Small vessel myocardial ischemia and infarction are frequent late manifestations of this disorder (28). Sudden cardiac death is the more common cause of death in patients with Fabry disease (09).

Pulmonary findings. Respiratory symptoms are usually not considered prominent manifestations of Fabry disease, but with age patients complain of dyspnea, cough, and wheezing that is independent of their smoking status (20). This population also has higher incidence of spontaneous pneumothorax and, occasionally, hemoptysis. The pulmonary symptoms are postulated to be due to fixed narrowing of airways from glycosphingolipid accumulation.

Renal findings. Progressive glycosphingolipid accumulation within the renal glomeruli and tubules and the vasculature is associated with proteinuria and gradual renal failure. Inspection of the urine with polarized light will often demonstrate casts and “Maltese crosses,” which are birefringent lipid globules. Deterioration of renal function develops, with azotemia and death occurring in the third to fifth decades, unless treatment with chronic hemodialysis or renal transplantation is provided (18; 119).

Ophthalmological findings. Corneal opacity that can be seen only by slit-lamp examination is usually the first ocular abnormality. These corneal changes (present in essentially all hemizygous Fabry patients) first appear as a mild generalized clouding in the subepithelial corneal layer and may progress to form whorled streaks ("cornea verticillata.")

Cornea verticillata (also called vortex keratopathy, whorl keratopathy, or Fleischer vortex) describes a whorl-like pattern of golden brown or gray opacities in the corneal epithelium. "Verticillata" is from the Latin noun “verticillus,” meaning "whorl.” Usually asymptomatic, it is caused by the deposition of metabolic substrates or disease byproducts in the basal epithelial layer of the cornea in Fabry disease. Cornea verticillata is not specific to Fabry disease, however, as it may also occur with other diseases (eg, multiple myeloma, neurotrophic keratitis, Lisch corneal dystrophy, epidemic keratoconjunctivitis, and iron deposition after radial keratotomy) and as a complication of some drugs (eg, amiodarone, atovaquone, chloroquine/hydroxychloroquine, gentamicin, gold salts, indomethacin, meperidine, perhexiline maleate, phenothiazines such as chlorpromazine, suramin, tamoxifen, tilorone, and the tyrosine kinase inhibitors vandetanib and osimertinib) (116). Nevertheless, cornea verticillata is most often associated with Fabry disease or amiodarone use. Chloroquine and hydroxychloroquine increase the intralysosomal pH and may cause corneal pathology by reducing the activity of the alpha-galactosidase A enzyme (69).

Lenticular opacities may occur in approximately 30% of affected males and consist of granular anterior capsular and subcapsular deposits, or a characteristic posterior capsular spoke-like opacity, or “Fabry cataract” (15). The corneal and lenticular opacities, however, do not interfere with vision.

Retinal and conjunctival lesions, manifesting as tortuous and dilated vessels, may occur as part of a diffuse systemic vascular involvement. Ischemic optic neuropathy may occur secondary to cilioretinal artery occlusion or central retinal artery occlusion (49).

Peripheral nervous system findings. Patients with Fabry disease suffer from a length-dependent small-fiber neuropathy (130; 83; 21). Dorsal root ganglia may become swollen (21).

The most dramatic symptom in males, and often in females, affected with Fabry disease is pain in the extremities (98; 84). This is usually described as an intense burning or lancinating pain in the fingers or toes. There may also be mild persistent numbness and paresthesias in the extremities (acroparesthesia), interspersed with the episodic excruciating pain. The painful crises may last for several days and may be associated with fever and an increased erythrocyte sedimentation rate. Decreased cold perception, and, to a lesser extent, warm perception, is a hallmark of this neuropathy (83). Exposure to cold is particularly painful (63). Autonomic nervous system dysfunction commonly manifests as chronic diarrhea, constipation, nausea, exaggerated gastrocolic reflex, reduced cutaneous flare response, and hypohidrosis (24). Priapism has been described in some patients, mostly children; it may be due to increased neuronal nitric oxide synthase (and probably endothelial nitric oxide synthase) content and the consequent elevated nitric oxide production and high arterial blood flow in the penis (88).

Cochleovestibular findings. Hearing impairment and vertigo are common findings, especially in males with Fabry disease (112).

Central nervous system findings. The symptoms related to the cerebrovascular complications of Fabry disease are no different than stroke symptoms from any other etiology. They include hemiparesis, vertigo, diplopia, dysarthria, nystagmus, headache, ataxia, memory loss, and hemisensory loss (101). The vertebrobasilar system was affected in 67% of hemizygotes and 60% of heterozygotes, with elongation and tortuosity of vertebral and basilar vessels noted angiographically (53). A study using MR angiography showed that the basilar artery is enlarged in male patients with Fabry disease as a whole (53). MR angiography often shows that the basilar artery is enlarged and tortuous (dolichoectasia) in male patients with Fabry disease (53; 142; 50).

In a quantitative MRI study of 50 Fabry hemizygotes, progressive cerebrovascular involvement in small- to medium-size vessels occurred over time (31). In this study, there were no patients younger than 26 years of age who had cerebrovascular disease, but all patients over 54 years of age had cerebrovascular disease, although usually these lesions were clinically silent. Stroke can be the presenting symptom and can occur in female heterozygotes as well (101; 133).

White matter lesions on MRI are common and are not typically accompanied by neurologic or cognitive abnormalities (80). Cerebral microbleeds were found by brain MRI in 30% of patients (77). In addition, these white matter lesions do not regress with enzyme replacement therapy (137). Asymptomatic white matter lesions on brain MRI were found in 16% of children with Fabry disease (85).

Heterozygous females. Heterozygous females may have variable manifestations of Fabry disease that can range from asymptomatic to as severe as a male with classic Fabry disease (109; 68; 07; 43; 16; 65; 64; 62; 145). Approximately 70% to 80% of affected females will have corneal opacities, but only rarely will cataracts be noted. In approximately 30% of females, a few angiokeratomas may be present in the characteristic location. Intermittent pain and paresthesia may occur and, rarely, cardiac and renal symptoms may develop. A few heterozygotes have had clinical symptoms comparable to those found in affected males, thought to be due to skewed X-inactivation (43). In a female monozygotic twin pair, wherein one girl was affected with Fabry disease and the other was asymptomatic, uneven X-inactivation and discordant gene expression were found to explain the clinical differences in these identical siblings (109).

Prognosis and complications

The majority of untreated hemizygous males die by 40 to 50 years of age. The median survival age of males with Fabry disease is 50 to 55 years (18; 119). Death is usually a consequence of renal failure, heart disease, or sometimes stroke (18); however, myocardial ischemia may also cause fatal complications (28). Heterozygous females have mild symptoms and a wide spectrum of disease complications. Clinical manifestations of Fabry disease can range between subtle subclinical manifestations such as corneal opacities and classic Fabry disease as described before. MRI abnormalities in the kidneys have been observed in affected males and in female carriers, however, this latter group presents a lower incidence than classically affected males (60). Cerebrovascular manifestations have been observed in carrier females (133). Therefore, Fabry disease in heterozygotes is, in itself, a wide spectrum in which many of them might require enzyme replacement due to the extent of their clinical disease therapy (61).

Clinical vignette

A 12-year-old boy presented to the child neurology clinic with a history of painful extremities after exercising on warm days. This began 1 to 2 years earlier and was similar to what his sister and mother had experienced at the same age. Both mother and sister, however, had milder symptoms, and at the age of 43 years, the mother was no longer troubled by this symptom. The child had complained also of diarrhea and cramping following meals. The family history was significant for a maternal uncle who died at the age of 47 and grandfather who died at the age of 54 from complications of myocardial infarctions and multiple strokes. The clinical examination revealed a painful peripheral neuropathy affecting distal lower extremities. Three angiokeratomas were present around the umbilicus, groin, and buttock.

Examination of the eyes demonstrated a slight clouding of the corneas, but no lenticular opacities were observed. Because of the possibility of an X-linked disease, the pathological studies obtained from the maternal uncle were reviewed. Tissue taken from the dorsal root ganglia showed an accumulation of lipids in the small sensory neurons consistent with Fabry disease in the uncle.

Leukocyte alpha-galactosidase A enzyme activity from the boy was low, thus, confirming the diagnosis of Fabry disease.

Biological basis

Etiology and pathogenesis

Fabry disease is caused by a deficiency of the enzyme alpha-galactosidase A.

Although Fabry disease is often regarded as an X-linked recessive disorder, the observation that female heterozygotes are frequently affected, albeit usually less severely than affected males (84; 68; 07; 43; 06; 16; 65; 64; 62; 145), argues that Fabry disease could be considered X-linked dominant with reduced penetrance. As with many other X chromosome disorders, it has also been argued that Fabry disease should be characterized as inherited in an X-linked manner, without distinction as to being recessive or dominant (41).

Pathological findings. Multiple organs are affected in Fabry disease, but the major pathological alterations occur in the cardiovascular and renal systems secondary to glycosphingolipid accumulation.

Skin. The skin lesions consist of superficial telangiectasias and angiomas. Larger angiomas may be associated with elevation, hypertrophy, and hyperkeratosis, explaining the use of the term “angiokeratoma”. Other pathological changes may include atrophy or reduction in the number of sweat and sebaceous glands, as well as lipid accumulation in sweat glands (59).

Heart. Glycosphingolipid accumulation occurs in myocardial cells and valvular fibrocytes (36), causing the hypertrophy of the chamber walls, along with valvular involvement. Coronary vessels are also affected by lipid storage within their endothelial cells.

Lungs. Pathological studies have demonstrated laminated inclusions in ciliated epithelial cells, goblet cells, capillary endothelium, type II pneumocytes, and in pulmonary and bronchial smooth muscles (20).

Kidney. The first lipid deposition in Fabry kidney begins in endothelial and epithelial cells of the glomerulus and later affects proximal tubules and interstitial cells (95). Eventually, renal vessels also show glycosphingolipid accumulation.

Eye. The eye demonstrates glycosphingolipid deposits within the ocular vessels, iris, and connective tissue of the lens and cornea (54). A corneal dystrophy is seen, thought to be secondary to subepithelial ridges or reduplication of the basement membrane (54).

Nervous system. The CNS is affected by a cerebral vasculopathy (119) and accumulates lipids in several groups of neurons, many belonging to the autonomic nervous system. These areas involved include the supraoptic, preoptic, and paraventricular nuclei, nucleus basalis of amygdala, anterior thalamus, subiculum of hippocampus, Edinger-Westphal nucleus, mesencephalic nucleus of the fifth cranial nerve, substantia nigra, salivary nuclei, dorsal nucleus of the vagus, nucleus gracilis and cuneatus, reticular substance of pons and medulla, and intermediolateral cell columns of the thoracic cord (106; 73; 38). Peripheral nervous system structures that show lipid accumulation include the small ganglion cells in dorsal horn and loss of small myelinated and unmyelinated nerves (98; 23).

See Table 1 below for chemical storage.

Table 1. Glycosphingolipids that Accumulate in Fabry Disease

Globotriaosylceramide accumulates in many tissues, including kidney, aorta, spleen, liver, autonomic ganglia, lymph nodes, striated muscle, and prostate (38). Within the central and peripheral nervous systems, histologic lipid staining is caused by storage of globotriaosylceramide (73). Using immunocytochemical techniques with a monoclonal antibody to globotriaosylceramide, more widespread neuronal storage of this lipid could be demonstrated in layers 5 and 6 of the neocortex, pigmented neurons in the substantia nigra, substantia gelatinosa, and motor neurons (40). Despite this neuronal “accumulation,” Fabry disease is not a primary neuronal disorder. Typically, the only evident CNS neuronal dysfunction or loss occurs secondarily in association with ischemic lesions (90). Galabiosylceramide (digalactosylceramide) appears to be more tissue-specific because it is stored primarily in kidney, pancreas, right heart structures, lung, and urinary sediment (38). Patients with blood groups B or AB, who possess the blood group B antigen, were previously thought to have a more severe form of Fabry disease, but more recent studies dispelled this notion (81).

Biochemistry of alpha-galactosidase A. The biochemical defect in Fabry disease is the deficiency of the alpha-galactosidase A enzyme.

The glycosphingolipids (such as globotriaosylceramide, digalactosylceramide, and galabiosylceramide) have in common a terminal alpha-galactosyl moiety that is cleaved by the alpha-galactosidase A enzyme.

Thus, a deficiency or defect in the enzyme results in the accumulation of various glycosphingolipids with terminal alpha-D-galactosyl residues, including globotriaosylceramide and digalactosylceramide.

The mature enzyme is a 46 kd protein that forms a homodimeric structure of approximately 101 kd and functions optimally with an artificial substrate at a pH of 4.6. The C-terminal region of the alpha-galactosidase A is important for the regulation of the enzyme because a deletion of 12 or more amino acids from the C-terminus results in a complete loss of enzyme activity (89). The enzyme requires the presence of saposin B, a sphingolipid activator protein also known as sphingolipid activator protein-1. Saposin B, one of a family of activator proteins encoded by the same gene on chromosome 10, acts as a detergent for the protein-lipid complex (97). Saposin B is also required for the function of two other lysosomal enzymes, beta-galactosidase (deficient in GM1 gangliosidosis) and arylsulfatase-A (deficient in metachromatic leukodystrophy) in addition to stimulating the hydrolysis of over 20 glycolipids.

Molecular genetics of alpha-galactosidase A. The gene encoding alpha-galactosidase A, GLA, is localized to Xq22.1 (144). The gene is 12 kbp in length and contains seven exons (ranging from 92-291 bp) and six introns (ranging from 0.2 to 3.8 kbp). The full-length cDNA has 1437 bp encoding a mature 398 amino acid subunit and a 31 amino acid signal peptide (79). The gene is unusual as it does not have a 3' untranslated region and has 12 Alu repetitive elements that represent about 30% of the 12 kbp gene (14). Despite this abundance of Alu repeat elements, there has been only one reported deletion caused by an Alu-Alu recombination (78). In the first exon, there is a 60 bp 5' untranslated sequence prior to the initiation codon containing three polymorphic variants (32).

Defects in the GLA gene in Fabry disease. In a study of 130 Fabry families, six rearrangements of the gene encoding alpha-galactosidase A were identified by Southern blot analysis (12). Five of these abnormalities were deletions (4 in exon 2) and one was caused by a duplication. At present, over 500 mutations, including deletions, insertions, partial duplications, splice junction consensus sight alterations, complex mutations involving more than one mutational event, and single base substitutions causing nonsense or missense mutations, have been reported (The Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff). In asymptomatic or mildly affected cardiac variants, however, only missense mutations that expressed residual alpha-galactosidase A activity were identified (37). A genotype-phenotype correlation has been difficult to establish, but some mutations such as the p.N215S mutation seen in asymptomatic and mild cardiac variants and the p.D264V noted in patients with pulmonary symptoms suggest that some genotypes may predict the clinical course. Although most of the mutations are ‘private’, or confined to a single family, some common mutations such as p.R227Q and p.R227X were identified (45). A very large kindred in Nova Scotia with the p.L143P mutation has been described (39). Common sites for point mutations include CpG dinucleotide regions (46). Codons 111 to 122 appear to be a deletion "hot spot" (48). Exon 7 appears to a region prone to gene rearrangements (45). The IVS4 + 919G > A mutation, a highly prevalent splice mutation among Han Chinese, has mainly cardiac consequences, but its clinical expression may depend in part on heart-related modifier genes (71). In Taiwan, this mutation has a prevalence of 1 of 875 in males and 1 of 399 in females. Despite the existence of some geographic and ethnic regions with founder mutations, new private mutations continue to be discovered, suggesting significant heterogeneity in the molecular mutations causing Fabry disease in various families (122).

Although disease-associated point mutations in protein-coding gene regions usually cause translational perturbations and result in premature chain termination, amino acid substitutions, or overall altered sequence alterations downstream from the mutation site, nucleotide exchanges at the border between introns and exons can affect splicing behavior and lead to abnormal pre-mRNA processing (01). For example, exonic mutations c.194G>T and c.358C>G lead to the use of alternative donor splice sites at exon 1 and exon 2, respectively, and the mutations c.548G>T and c.638A>T lead to significant exon 4 skipping (01).

In some families, there may be considerable phenotypic heterogeneity even with the same mutation (143).

Pathophysiology of Fabry disease. Most glycosphingolipids are synthesized in the liver or bone marrow. Globotriaosylceramide appears to be transported from hepatocytes by low- and high-density lipoproteins and taken up by other cells through high-affinity lipoprotein receptors. Globoside, a major precursor of globotriaosylceramide, is produced to a large extent from the senescence of erythrocyte membranes. The turnover of membrane glycosphingolipids is a major substrate burden in Fabry disease. In many organs, such as the vascular endothelium, muscle, and kidney, glycosphingolipid storage may occur either from endogenous production or, less likely, secondarily through active uptake and diffusion of circulating glycolipids. Globotriaosylceramide accumulation also occurs in nervous system structures with permeable blood-brain barriers such as the choroid plexus, circumventricular organs, and dorsal root ganglion (73). Other cerebral nuclei that do not have a permeable blood-brain barrier are hypothesized to store globotriaosylceramide, because of either site-specific differences in metabolism or selective uptake and transfer of this lipid (73; 40).

A prothrombotic state was identified in Fabry disease (33) in association with dysfunction of endothelial nitric oxide synthase and increased release of reactive oxygen species associated with cerebral hyperperfusion at rest (92; 93). Hyperperfusion at rest was confirmed in an arterial spin-labeling MRI study (102). A general inflammatory state is common (75).

Epidemiology

Fabry disease is an X-linked recessive disorder (or X-linked dominant with variable penetrance in females) that maps to Xq22 (144). Many patients are not diagnosed because of the nonspecific nature of the complications and the involvement of only one organ system (“atypical Fabry disease”).

The disease is relatively rare, with an estimated prevalence of 1 in 40,000 (38). Although most reported cases have occurred in Caucasians, a variety of ethnic groups have been affected with the disease. Findings in newborn screening studies suggest that the prevalence of Fabry disease may be as high as 1 in 4600 births (135). A newborn screening study of 219,973 samples in Illinois found an estimated prevalence of Fabry disease of 1 in 8454, including the p.A143T variant, and 1 in 10,000 without including this variant (22); the p.A143T variant was by far the most common. In a newborn screening program in Western Japan, no patients with the A143T variant were identified (118). Some studies have reported the prevalence of Fabry disease among patients with stroke, patients undergoing dialysis, and patients with hypertrophic cardiomyopathy (114). A re-analysis of 63 studies that screened 51,363 patients corrected for real pathogenic mutations: the revised prevalence estimates were 0.21% for male and 0.15% for female hemodialysis patients; 0.94% for males and 0.90% for females with hypertrophic cardiomyopathy; and finally, 0.13% for male and 0.14% for female stroke patients (42). Fabry disease is not common among patients with other forms of heart disease (127).

Certain geographical areas have a high number of patients due to a founder effect; these include Nova-Scotia (76) and possibly also Taiwan (27).

Prevention

Because of the low prevalence of the disease in the general population, carrier testing is not routinely performed. Screening of patients at risk has been proposed (08). In affected families, however, alpha-galactosidase enzyme analysis will diagnose hemizygous males, but only genetic analyses for GLA mutations can identify heterozygous females. It was previously thought that urinary glycolipid measurements could be used to determine carrier status in females by comparing the ratio of globotriaosylceramide and galabiosylceramide to hydroxy fatty acid glucosylceramide (25). However, globotriaosylceramide is also elevated in the urine of patients with heart disease who do not have any clinical, genetic, or biochemical evidence of Fabry disease (121). Interestingly, elevated levels of this glycosphingolipid along with elevation of other lipids are a risk factor for death in patients with common heart disease (121). The recognition of the disease or carrier status in different family members can then lead to appropriate genetic counseling. Because the disease is inherited as an X-linked disorder, hemizygous males are unable to pass the disease to their sons, but all of their daughters will be carriers. Heterozygous mothers can expect to have 50% of their sons be affected with the disease and 50% of their daughters be carriers.

Differential diagnosis

Confusing conditions

The complete clinical syndrome of Fabry disease in males, including angiokeratoma, painful peripheral neuropathy, and corneal dystrophy beginning in childhood, is characteristic. Other diseases, however, may be associated with angiokeratoma. Four dermatologic conditions have angiokeratoma as a major manifestation: (1) solitary or multiple angiokeratomas usually occur on the lower extremities following trauma; (2) angiokeratoma circumscriptum is usually characterized by a large solitary hyperkeratotic plaque that is first noted at birth or in early childhood and is more frequent in males; (3) angiokeratoma of Mibelli is more common in females, with childhood onset of hyperkeratotic vascular lesions over bony prominences; (4) the lesions of angiokeratoma of Fordyce are confined to the scrotum, although similar lesions have been described on the labia of older women (67). Angiokeratoma can also be seen in other metabolic disorders, such as neuraminidase deficiency, galactosialidosis, fucosidosis, GM1 gangliosidosis, and aspartylglucosaminuria (38).

Cornea verticillata is most often associated with Fabry disease or amiodarone use. It may also occur with other diseases (eg, multiple myeloma, neurotrophic keratitis, Lisch corneal dystrophy, epidemic keratoconjunctivitis, and iron deposition after radial keratotomy) and as a complication of some drugs (eg, atovaquone, chloroquine/hydroxychloroquine, gentamicin, gold salts, indomethacin, meperidine, perhexiline maleate, phenothiazines such as chlorpromazine, suramin, tamoxifen, tilorone, and the tyrosine kinase inhibitors vandetanib and osimertinib) (149; 69; 116).

Renal disease consisting of proteinuria, lipiduria, and electron-dense lysosomal granules, which mimic the renal manifestations of Fabry disease, may be induced by exposure to silica (11).

Diagnostic workup

A diagnostic algorithm has been proposed, which utilizes clinical features, such as early-onset symptoms, late-onset symptoms, and very specific symptoms (ie, cornea verticillata and angiokeratomas) or family history of Fabry disease to dictate further testing of enzyme activity in males or gene mutation analysis in females (50).

The diagnostic approach varies for male and female patients (03).

To date, female patients have been underrecognized and undertreated in several countries (117).

Analysis of enzyme activity and accumulating metabolites. The most effective method of diagnosing Fabry disease is measurement of alpha-galactosidase A enzyme activity in males. This enzyme may be measured in plasma, tears, leukocytes, cultured fibroblasts, or transformed lymphoblasts (35). Affected hemizygous males typically have no detectable galactosidase A activity whereas others have enzyme activity up to 30% to 35% of mean normal. Female heterozygotes can have low or normal enzyme activity, and they do often have elevated globotriaosylceramide levels in the urine, but definitive diagnosis of Fabry disease in an affected female can only be done via mutation analysis of the GLA gene (61).

Demonstration of elevated globotriaosylceramide using mass spectroscopy is critical. Urinary sediment analysis demonstrates glycolipid excretion of large quantities of globotriaosylceramide and galabiosylceramide in affected individuals (25). CSF is remarkable for the presence of large quantities of globotriaosylceramide (74). Skin biopsies will also show intralysosomal lipid deposition in clinically normal areas of skin (139).

Mutation analysis of the GLA gene. Molecular based diagnostic testing can be performed quickly by using polymerase chain reaction amplification of exons followed by Sanger sequencing of each of the seven exons and adjacent intron boundaries (52). Intronic mutation with a complex haplotype is also associated with Fabry disease (103). Other molecular methods that have been utilized for identification of gene mutations and carrier detection include fluorescence-assisted mismatch analysis and linkage analysis using intragenic and closely linked polymorphisms (57; 26). There are many variants of the GLA gene and many of them are mild or not associated with disease (122). Therefore, before concluding that a variant with relatively high α-galactosidase A activity is pathogenic, one must demonstrate evidence of altered sphingolipid homeostasis in a disease-relevant organ (122).

Neuroimaging. MRI studies have shown periventricular and other focal areas of signal intensity changes; these are thought to be clinically silent and associated with hyperperfusion (31; 90). Calcifications of the pulvinar (posterior thalamus) on T1-weighted images are virtually diagnostic of Fabry disease (94). Proton MRS of the brain demonstrates widespread reduction in N-acetylaspartate, suggesting diffuse neuronal involvement in Fabry disease (140).

Neurophysiology. Although motor and sensory nerve conduction velocities are typically normal, the elevated thresholds demonstrated in a study for cold stimuli, and warm stimuli to a lesser extent, in several patients with Fabry disease suggest a small fiber neuropathy (83).

Other studies. Some cardiac abnormalities suggest Fabry disease: these include a short PR interval on EKG as well as low native T1 times and prolonged T2 relaxation times with multimodality cardiac imaging (141).

Increased carotid intima media thickness and decreased brachial flow-mediated dilation occur in classic Fabry disease, but the significance and usefulness of these findings have not been established (115).

Management

Symptomatic management

Symptomatic management was a constant in Fabry disease before the availability of enzyme replacement therapies. This was mostly directed toward the most distressing symptom for patients with Fabry disease, which is the painful peripheral neuropathy; carbamazepine, diphenylhydantoin, gabapentin, and lamotrigine alone or in combination frequently provide relief of this symptom (70; 129). Gabapentin may be preferred over carbamazepine because gabapentin has fewer side effects (113).

Despite the benefits of enzyme replacement therapy, particularly on the renal complications of the disease, it does not prevent vascular events such as stroke (04).

“Nonspecific” standard medical care is important and effective in Fabry disease. Ischemic stroke in Fabry disease should be prevented and treated in the same standard way as in the general population, including the use of effective antiplatelet agents such as clopidogrel, anticoagulants when atrial fibrillation is present, and intravenous thrombolysis (87; 72). For the prevention of ischemic strokes, aspirin/dipyridamole (Aggrenox^®) or a platelet adenosine diphosphate chemoreceptor blocker (eg, clopidogrel) appear to be effective, whereas aspirin alone is not. These antiplatelet agents may be effective for both secondary and primary stroke prevention. Primary prevention should be initiated in the third decade of life in patients with Fabry disease with a family history of strokes, whether the strokes were clearly related or unrelated to Fabry disease. Other effective medical therapies include angiotensin receptor blockers and angiotensin II-converting enzyme inhibitors for proteinuria in renal disease, renal transplantation, and a variety of treatments for arrhythmia, cardiac insufficiency, and valve replacement (124).

Depression is a common problem in patients with Fabry disease, and it may be treated effectively with nonpharmacological interventions such as psychotherapy (02).

Renal transplantation corrects the renal failure in Fabry disease but does not provide enzymes to the rest of the body (131). An analysis of a case series of 197 kidney transplant recipients with Fabry disease found a superior graft survival and similar patient survival compared with patients with other causes of end-stage renal disease (132). However, patients with Fabry disease had a higher risk of death compared with a matched cohort of patients with other causes of end-stage renal disease. Caution should be used when considering a related donor transplant from a heterozygous female because many of these women also have asymptomatic but pathologically significant storage of glycolipids within the kidneys.

Cardiac transplantation alone or in conjunction with renal transplantation has been successfully performed in patients with Fabry disease (107).

Specific therapy

Currently, the only available primary specific therapies for Fabry disease are enzyme replacement therapy and pharmacological chaperone therapy.

Other treatment modalities under study include gene therapy, administration of exogenous mRNA via lipid nanoparticles, and substrate reduction therapy (55; 50).

It is likely that the efficacy of all specific therapies is significantly enhanced if treatment is initiated early in life, prior to the presence of irreversible changes in the kidney, heart, cerebral vasculature, and peripheral nerves (19; 108).

Enzyme replacement therapy. Enzyme replacement therapy must be used in conjunction with this nonspecific care (119). Because the accumulation of glycosphingolipid is the primary pathological feature seen in Fabry disease, several treatment approaches have been attempted either to provide the alpha-galactosidase A enzyme or secondarily to reduce the amount of accumulating glycosphingolipids.

Results of the initial treatment trials provided evidence of substrate clearance in the endothelial cells of the kidneys, and from the vascular endothelium of the skin associated with clinical and quality of life improvements in the patients (47; 125) with an excellent safety profile. This led to regulatory approval in 2002 in Europe and in 2003 in the United States.

A phase IV randomized controlled trial that, although inconclusive, suggested a slowing of the disease process in the kidney (10).

Studies using agalsidase alfa and agalsidase beta suggest that enzyme replacement therapy slows the progression of kidney disease (119; 148). This therapy has only a small effect on cardiac disease (96).

Other pathologic aspects in Fabry disease, such as left ventricular hypertrophy, auditory impairment, and impaired cerebral blood flow, improve with enzyme replacement therapy (91). Improvements in peripheral nerve and sweat function, as well as cardiac improvement have been noted in treated patients (120; 147). However, strokes continue to occur on enzyme replacement therapy (151; 110; 126).

Enzyme replacement therapy can also be used in heterozygous females (carriers) with Fabry disease (150).

Thus far, all studies that showed clinical improvements were open-label studies. Two meta-analyses showed little if any effect of enzyme replacement therapy in Fabry disease (44). A Kidney Disease: Improving Global Outcomes (KDIGO) controversies conference concluded that enzyme replacement therapy is the first specific therapy that has been developed that can slow kidney disease and alleviate symptoms but confers little benefit to cardiovascular and cerebrovascular outcomes (124).

Currently, approved enzyme replacement therapy has a short half-life. As a result, there is no residual therapeutic enzyme in the second week of the 2-week interval, thus, allowing progression of the disease (124). Another problem is the development of anti-alpha-galactosidase A antibodies, which reduce the activity and effectiveness of the infused enzyme (136). To mitigate these problems, a novel modified enzyme is being developed for Fabry disease (123). This product has at least a 60-fold longer circulation half-life and seems to be significantly less immunogenic.

Pharmacological chaperones. These are small molecules that, in high doses, are competitive inhibitors, but in lower concentrations promote the correct folding and intracellular transport of the enzyme. Migalastat (1-deoxygalactonojirmycin) has shown clinical efficacy in two studies and was approved by the Food and Drug Administration and the European Medicine Agency (58; 66). It is an oral drug with the advantage that, unlike enzyme replacement therapy, it is widely distributed throughout the body, it leads to a stable increase of the endogenous enzyme level, and it has an excellent safety record with no immune concerns. Long-term clinical effects need to be obtained to assess its full efficacy.

Substrate synthesis reduction. Reduction of substrate load was tested as an alternative therapeutic approach using N-butyldeoxynojirimycin, known to inhibit the first step in globotriaosylceramide synthesis (104). Novel inhibitors of ceramide glycosyltransferase show promise at least in a Fabry disease mouse model (86), and studies in patients are currently in progress. Although it is too early to tell how effective this approach will be in Fabry disease, based on its effectiveness in Gaucher disease, substrate synthesis reduction may work in Fabry disease, particularly in patients with residual enzyme activity.

Special considerations

Pregnancy

In pregnancies at risk for an affected fetus, enzyme analysis can be performed on chorionic villus tissue obtained at 8 weeks to 12 weeks gestation, or on cultured amniocytes obtained by amniocentesis later in the second trimester. Molecular diagnostic studies can identify a fetus at risk in families with a known mutation, but also in families whose specific GLA gene mutations have yet to be determined (26).

Anesthesia

The risk associated with the use of anesthesia is increased because of the medical problems associated with Fabry disease. Specifically, cardiac disease, hypertension, and autonomic nervous system dysfunction may complicate anesthesia (146).