Department of Pharmacology, B.V.V Sangha’s Hanagal Shri Kumareshwar College of Pharmacy Bagalkote 587101, Karnataka, India.
Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by deficient ?-galactosidase A activity, leading to the accumulation of globotriaosylceramide (Gb3) in various tissues. This results in progressive, multisystem involvement, including renal, cardiac, and neurological complications. Symptoms often begin in childhood and worsen with age, significantly impacting quality of life. Diagnosis relies on enzyme assays, biomarker analysis, and genetic testing, though early recognition remains challenging. Enzyme replacement therapy (ERT) has been the foundation of treatment, although it has disadvantages such as insufficient efficacy and infusion burden. Recent advances have brought promising options, including as gene therapy, pharmacological chaperones, substrate reduction treatment, and CRISPR/Cas-based gene editing. These approaches seek to improve long-term outcomes by offering more targeted, long-lasting therapy alternatives. This review outlines our current understanding of FD, focusing on its pathogenesis, clinical symptoms, diagnostic techniques, and novel medicines that are altering its care.
FD is a progressive, X-linked inherited disorder of glycosphingolipid metabolism due to deficient or absent lysosomal α-galactosidase A activity. FD is pan-ethnic and the reported annual incidence of 1 in 100,000 may underestimate the true prevalence of the disease [1]. FD results in accumulation of Gb3 and related neutral glycosphingolipids. Manifestations of FD include serious and progressive impairment of renal and cardiac function. In addition, patients experience pain, gastrointestinal disturbance, transient ischaemic attacks and strokes. Additional effects on the skin, eyes, ears, lungs and bones are often seen. The first symptoms of classic FD usually appear in childhood. Despite being X-linked, females can suffer the same severity of symptoms as males, and life expectancy is reduced in both females and males [2]. Lysosomal storage and cellular dysfunction are thought to set off a chain reaction that includes cellular death, impaired energy metabolism [3], small vessel injury [4], K(Ca)3.1 channel dysfunction in endothelial cells [5], oxidative stress [6], impaired autophagosome maturation [7], tissue ischemia, and, most importantly, the development of irreversible cardiac [8] and renal [9] tissue fibrosis. Classical FD symptoms include angiokeratomas, cornea verticillata, and heat and exercise-induced neuropathic pain (acroparesthesia). These symptoms usually appear in childhood. At an older age, proteinuria, renal function loss, white matter lesions in the brain, electrocardiographic abnormalities, and left ventricular hypertrophy may occur [10]. During their teenage years, patients develop angiokeratomas in the “bathing trunk” region. Proteinuria, a sign of kidney disease, may be detected at this time. Additionally, gastrointestinal distress, such as frequent and painful bowel movements, begins to affect patients. In adulthood, patients are at significant risk of end-stage renal disease, heart dysfunction (e.g. hypertrophic cardiomyopathy, cardiac arrhythmias, valvular disease), and cerebrovascular events (e.g., ransient ischemic attacks, ischemic strokes). Patients may also develop osteopenia or osteoporosis [11, 12]. With nephropathy being a major complication of FD, frequent dialysis treatments become a necessity. Neuropathic pain subsides in some adult patients, but many adults continue to live with debilitating pain [13]. Some adult patients display a unique neuropsychiatric phenotype, characterized by subtle movement impairment and depression [14]. Together, these numerous signs and symptoms significantly reduce quality of life [15].
Pathophysiology:
The accumulation of Gb3 during α-GalA deficiency takes place in lysosomes, but the subsequent mechanisms causing cellular dysfunction, and ultimately symptoms, are still poorly understood [16]. As with other inherited glycosphingolipidoses, lipid-laden lysosomes can be envisioned to cause impaired autophagic flux, including mitophagy, contributing to the observed mitochondrial dysfunction in fibroblasts of FD patients [17]. In patients with FD, coronary flow reserve is severely reduced. These findings correspond to the extensive remodeling of the intramural arterioles [18] Glycosphingolipid deposition in the endothelium has been classically considered the cause of the vascular abnormalities in FD; however, there is no directly proportional relationship between vascular damage and the amount of Gb3 deposition [19]. In FD, not only are the arteries altered due to endothelial degradation, but there is also accelerated hypertrophy in the medium-caliber arteries, with increased intima-media thickness, which affects the arteries' distensibility due to smooth muscle cell hypertrophy [20]. Renal impairment in FD is primarily defined by early damage to podocytes and fibrosis of epithelial cells [21]. Podocytes cover and contribute to the integrity of the glomerular basement membrane. Podocyte damage can be seen in patients with AFD during childhood and adolescence even when proteinuria is not present [23]. In podocytes, Gb3 deposition increases the expression of the fibrogenic cytokine TGF-1, which increases extracellular matrix synthesis of fibronectin and type IV collagen [22]. Gb3 promotes an inflammatory condition similar to that of hyperglycemia. Gb3 promotes the release of inflammatory cytokines through the CD74 receptor pathway, thereby modulating the function of podocytes [ 23]. The damage to podocytes is the event that triggers chronic kidney disease with proteinuria, and the loss of podocytes leads to glomerulosclerosis [22].The pathophysiological basis of neuronal damage is not well known. It has been proposed that the peripheral nervous system accumulates Gb3 in both the Schwann cells and in the dorsal spinal lymph nodes, affecting the small fibers Adelta and C, resulting not only in neuropathic pain but also autonomic abnormalities [24]. With regard to central nervous system involvement, the presence of ‘‘cerebral angiopathy’’ has been postulated, in which the intimately involved elements are endothelial dysfunction, brain hyperperfusion and a ROS-dependent prothrombotic state [25].
Clinical Manifestations:
Table 1: Signs, Symptoms, Concomitant Medications and Strategies In FD
|
Organ system |
Sign/symptoms |
Therapeutic strategy |
|
Nervous system |
Neuropathic pain |
Avoidance of pain triggers such as heat, cold, physical strain, stress, overtiredness medication: Pregabalin, in case of resistance to therapy possibly in combination with a dual serotonin and noradrenalin reuptake inhibitor (e.g. duloxetine) |
|
Stroke |
Platelet-aggregation inhibition |
|
|
Depression |
Psychiatric/psychological care; serotonin reuptake inhibitors |
|
|
Kidney |
Renal insufficiency (eGFR reduction albuminuria/proteinuria) terminal renal insufficiency |
RAS blocker (ACE inhibitor, ARB), anemia therapy Dialysis, kidney transplantation (first choice therapy) |
|
Heart |
Hypertension |
Antihypertensives, e.g., ACE inhibitors or ARBs (no beta blockers in patients with sinus bradycardia) |
|
|
Ventricular tachycardia |
Antiarrhythmics, implantable cardioverter defibrillator (ICD) |
|
|
Bradycardia |
Pacemaker implantation |
|
|
Heart failure |
Diuretics, ACE inhibitor (ARB for patients with ACE inhibitor intolerance), pacemaker or ICD implanta tion, heart transplantation |
|
|
Coronary stenosis |
PTCA, ACVB |
|
|
Dyslipidemia |
Statins |
|
Lungs |
Airway obstruction |
Abstention from nicotine, possibly bronchodilators |
|
Gastrointestinal tract |
Delayed gastric emptying, dyspepsia |
Small and frequent meals; metoclopramide, H2 blocker |
|
Ear |
Pronounced hearing loss |
Hearing aids, cochlear implant |
Table 2: Typical Signs and Symptoms of Fabry Disease According To Age
|
Typical time at onset |
Signs and symptoms |
|
Childhood and adolescence (16 years) |
Neuropathic pain, Ophthalmological abnormalities (cornea verticillata and tortuous retinal blood vessels), Hearing impairment, Dyshidrosis (hypohidrosis and hyperhidrosis), Hypersensitivity to heat and cold, Gastrointestinal disturbances and abdominal pain, Lethargy and tiredness, Angiokeratomas, Onset of renal and cardiac signs, e.g. microalbuminuria, proteinuria, abnormal heart rate variability. |
|
Early adulthood (17–30 years) |
Extension of any of the above, Proteinuria and progressive renal failure, Cardiomyopathy, Transient ischaemic attacks, strokes, Facial dysmorphism. |
|
Later adulthood (age >30 years) |
Worsening of any of the above, Heart disease (e.g. left ventricular hypertrophy, angina, arrhythmia and dyspnoea), Stroke and transient ischaemic attacks, Osteopenia and osteoporosis. |
Diagnostic procedure:
Enzyme Analysis:
Lysosomal α-Gal A activity was measured from DBS filter paper according to published methods. This assay measures the α-galactosidase catalyzed cleavage of an artificial fluorogenic substrate, 4- methylumbelliferyl-α-D-galactopyranoside (4-MUGal), by detecting the product 4-methylumbelliferone (4-MU) in a fluorometer. Two enzymes in human blood catalyze this reaction at acidic pH: The first is α-galactosidase A (EC 3.2.1.22), which is defective in FD; the second is α-N-acetylgalactosaminidase (EC 3.2.1.49), α-galactosidase B, which has secondary activity towards certain small galactoside substrates, such as 4-MUGal. For this study N-acetylgalactosamine was added to the assay reaction to selectively inhibit α-N-acetylgalactosaminidase, as this enzyme could obscure the deficiency of αGal A in some Fabry patients. Briefly, two 3mm punches were extracted in 500 μL of 1.0% sodium taurocholate and incubated with substrate for 20 h at 37 °C. 4-MU was quantified by measuring the fluorescence intensity with 355 nm excitation and 460 emission wavelengths. α-Gal A activity was reported as pmol/punch/h [26].
Biomarkers:
No surrogate biomarker has yet been shown to reflect the global burden of FD activity, or to reflect the global response to ERT [27]. The potential use of Gb3 as a marker of Fabry disease has been extensively evaluated by assaying its concentration in plasma and urinary sediment by different methods [28] [29]. Gb3 from urinary sediment comes from desquamated tubular cells and may reflect renal storage. The pattern of urinary sediment glycolipids from Fabry male patients revealed increased amounts of Gb3 [30], and the values from heterozygotes are between the ones from normal controls and hemizygotes. Moreover, urinary Gb3 excretion was found to correlate with type of mutation, sex, and treatment status [31]. Recently, high concentrations of globotriaosylsphingosine in plasma were found in male Fabry patients. Although no correlation with age or disease severity was found, plasma levels were reduced in patients receiving ERT [32].
Treatment Strategy:
Gene Therapies:
Gene therapies are being researched as a long-term therapeutic option. The concept is that targeted cells will overexpress α-GAL, secrete it, and then other cells will ingest it via mannose-6-phosphate receptors and transport it to the lysosomes. Effective gene therapy necessitates a transcription promoter that is active in afflicted tissues and tailored for high gene expression, mRNA stability, and virus replication inhibition [33]. The transduced bone marrow cells overexpressed and released α-GAL, which remained stable over time [34]. Transduced cells had more than 16-fold higher enzyme activity than unmodified FD cells. The duration of cross-correction depends on the type of the targeted cells; hematopoietic stem cells [35] or liver hepatocytes with prolonged lifespans can lead to prolonged enzyme expression. A possible disadvantage of currently investigated gene therapy approaches for FD is that they lack target specific vectors or mRNA/cDNA for cardiac, renal, and cardiovascular tissues. Current methods are similar to ERT in that they need systemic administration or to be targeted to liver or HSPCs, thus their effectiveness relies on the overexpression of-GAL into circulation for other tissues to uptake. However, if gene therapy does become available, it has the advantage of long-term supraphysiologic enzyme expression and a lack of anti--GAL antibodies. Figure 3 gives an overview of various gene therapy techniques.
CRISPR (clustered regularly interspaced palindromic repeats)/Cas (CRISPR-associated genes)
CRISPR/Cas can perform targeted DNA breaks for editing [36]. DNA breaks trigger DNA repair pathways through homology-directedrepair (HDR) gene or non-homologous end joining (NHEJ) [37, 38]. This strategy can be applied in treating FD by targeting dividing cells with HDR, or non-dividing cells, such as HSPCs, with NHEJ-based insertion or HDR followed by enrichment. The main hurdle will be low transgene insertion rates. CRISPR/Cas relies on programmable guide RNAs (gRNA) to target effector Cas proteins and cause double-stranded breaks in the genome for gene insertion or silencing. Current CRISPR-based gene-editing tools include gene insertion with HDR, base editing, CRISPR/Cas fused transposase and prime editing [39] used CRISPR/cas9 with dual gRNAs to delete the mutation (GLA IVS4 + 919 G > A) related to aberrant GLA splicing in the cardiac FD phenotype. It significantly increased-GAL enzyme activity and cleared GL3 in FD fibroblasts, thus proving a feasible approach for treating cardiac variant FD.
Chaperon therapy:
Chemical chaperones are tiny compounds that aid in the folding, maturation, binding, and trafficking of enzymes that are defective but partially present. They have already been employed in numerous lysosome storage disorders [40, 41]. Migalactat, a reversible, competitive inhibitor of α-Gal A, may stabilize and enhance the endogenous enzyme in FD patients by facilitating its trafficking from the endoplasmic reticulum to the lysosomes [42-44]. Treatment with migalastat is indicated in patients with FD attributed to amenable mutations, aged ≥12 years [45]. The safety and efficacy of migalastat in children younger than 12 years old have not yet been established. It is an oral treatment, administered every other day at a dose of 123 mg.
Substrate Reduction Therapies:
Substrate reduction therapies (SRT) act by restricting the biosynthesis of the substrate that is accumulated due to the deficient α-Gal A. The main advantage of these therapies is that they are active irrespective of the genetic mutation leading to the enzyme deficiency. Importantly, they may be administered as a monotherapy but also as a complementary therapy to ERT [46]. GLA hydrolyzes the terminal alpha-galactosyl moieties from glycosphingolipids. A deficiency in GLA causes the accumulation of the glycosphingolipid, globotriaosylceramide, in lysosomes. SRT circumvents enzyme replacement/modification by inhibiting synthesis of globotriaosylceramide. This approach involves the use of a glucosylceramide synthase inhibitor, which would slow the rate of Gb3 synthesis, and thus decrease lysosomal storage. Even if GLA activity is low or undetectable, SRT may convert a severe disease phenotype to a milder one. N-butyldeoxynojirimycin (NB-DNJ), an iminosugar analog, has been used as a glucosylceramide synthase inhibitor [47]. However, the inhibitory effect of NB-DNJ is not very specific for glucosylceramide synthase and side effects are observed, including gastrointestinal complaints [48, 49]. Since ERT for FD only shows modest efficacy, combinatorial therapy using ERT and SRT is being considered as a treatment strategy.
CONCLUSION:
FD is a rare X-linked lysosomal storage illness triggered by α-galactosidase. A deficiency that results in the buildup of globotriaosylceramide in organs. This results in progressive damage to the kidneys, heart, neurological system, and other organs, drastically lowering patients' quality of life. Early identification is critical, because prompt treatment can slow disease development. Enzyme replacement therapy has been the major treatment, but its limitations have motivated the development of other approaches such as gene therapy, pharmacological chaperones, and substrate reduction therapy. These developing approaches promise to provide more effective and tailored care for FD in the future.
REFERENCES
Vani Chatter*, Gayatri Sirimani, Sunilkumar Meti, Fabry Disease: Revisiting a Rare Disorder with Modern Therapies, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 4, 3136-3144 https://doi.org/10.5281/zenodo.15285449
10.5281/zenodo.15285449
