| Abstract|| |
Fabry disease (FD), the second most common type of lysosomal storage disease (LSD), is one of 41 disorders characterized by accumulation of substances normally degraded within lysosomes. It is an X-linked recessive disorder characterized by a deficiency of lysosomal alpha-galactosidase A (α-Gal A). The locus for human α-Gal A is located on the Xq22 chromosome. Most FD mutations are confined to a single family. Although FD is an X-linked disorder, up to one third of female carriers develop clinical manifestations of the disease. It typically presents during infancy or adolescence with crisis of neuropathic pain (acroparesthesia), angiokeratomas, and asymptomatic corneal lesions. As Gb3 deposition progresses, clinical manifestations occur in other organs. Patients typically die in the fourth or fifth decade of life due to cardiac, renal or cerebrovascular complications. Usually, there is diffuse deposition of glycosphingolipid in the renal glomeruli, tubules, interstitium, and vasculature. Clinically, the renal disease manifests with hypertension, microscopic hematuria (rare), moderate proteinuria, which can be in the nephrotic range, and lipiduria. End-stage renal disease can be treated with either dialysis or transplantation. Thegene for (x-Gal A was cloned and sequenced, which eventually led to production of enzyme for therapeutic use by either recombinant DNA technology or gene activation
Keywords: Fabry, Renal, Genes, Transplantation, Hemodialysis.
|How to cite this article:|
Moran V, Obrador GT, Thadhani R. Fabry Kidney Disease. Saudi J Kidney Dis Transpl 2003;14:367-77
| Introduction|| |
In recent decades, the genetic basis and the molecular pathology of many diseases have been characterized. Moreover, new therapeutic approaches, such as enzyme replacement and gene therapy, have been developed. Fabry disease (FD), the second most common type of lysosomal storage disease (LSD), is one of 41 disorders characterized by accumulation of substances normally degraded within lysosomes and is a good example of these advances. 
FD was first described in patients with characteristic skin lesions and albuminuria by Johannes Fabry in Germany and William Andersen in the UK in 1898. , It is an Xlinked recessive disorder characterized by a deficiency of lysosomal alpha-galactosidase A (α-Gal A). The deficient activity of α-Gal A leads to progressive accumulation of glycosphingolipids; mainly galabiosylceramide, globotriaosylceramide or ceramidetrihexoside (Gb3), in the lysosomes of vascular endothelial, smooth muscle, epithelial, and ganglion cells. ,, The lipid deposition results in cell dysfunction and death, and eventually in organ damage, which explains the variety of renal and extrarenal manifestations commonly seen in these patients.
FD is an uncommon disorder. Its incidence varies from 1 in 117,000 live births in Australia to 1 in 476,000 live births in the Netherlands.  In the UK, the incidence and prevalence of FD has been estimated at 1 in 100,000 and 1 in 366,000 male live births, respectively, and the prevalence of carriers at 1 in 339,000 female live births. [7,
However, these figures probably under represent the true incidence and prevalence of FD because it is often under-diagnosed and under-reported due to its rarity and nonspecific symptomatology. Although FD predominantly occurs in Caucasians, it is a panethnic disorder that has been reported in African American, Hispanic, Asian, Middle Eastern and Native American populations. 
In this review, we examine the genetics, clinical manifestations, diagnosis, and treatment of FD, with particular emphasis on the renal complications.
| Biochemistry and Genetics|| |
α-Gal A, a glycoprotein of 101 KDa with a homodimeric structure, contains 5 to 15 percent of asparagine-linked complexes and abundant mannose oligosaccharide chains.  Many lysosomal hydrolases have mannose 6-phosphate residues that bind to specific receptors in the Golgi apparatus, from where they are directed to pre-lysosomal compartments. Enzymes that escape this routing system exit the cell via the constitutive secretary pathway and are often recaptured by cell surface mannose-6-phophate receptors, which return the enzyme to the lysosome via the endocytic pathway. This characteristic of GAL has important implications for enzyme replacement therapy (see below). 
The locus for human α-Gal A is located in the Xq22 chromosome and spans 12 megabases. It has 7 exons ranging from 92 to 291 base pairs (bp) and several introns ranging from 200 bp to 3.7 kilobases (kb). Both exons and introns follow the GT/AG rule.  More than 266 mutations of the aGal A locus have been recorded in the Human Genome Mutations Database, and include missense and nonsense mutations, insertions, duplications, deletions, and splicing defects. Ishii et al has recently reported a G to A transversion at nucleotide 9331, which leads to alternative splicing and the resultant introduction of a 57 nucleotide intronic sequence at intron 4 of the a-Gal A transcript.  This mutation has been associated with the cardiac phenotype of FD (see below). Of note, patients with conservative missense mutations have delayed appearance of kidney disease when compared to patients with non-conservative missense mutations or other mutations. 
Most FD mutations are private; that is to say, they are confined to a single family.  Phenotype-genotype correlations are important because some mutations with residual α-Gal A activity may benefit from the administration of reversible competitive inhibitors of the enzyme, which may act as "chemical chaperones" that enhance its stability and promote adequate folding, dimerization, and processing of the enzyme. 
Although FD is an X-linked disorder, up to one third of female carriers develop clinical manifestations of the disease. , Thadhani and Obrador recently reported that among 42 patients with FD who began renal replacement therapy (RRT) in the United States between 1995 and 1998, 12% of them were women.  An identical figure was also reported in a study of 83 patients who began RRT in Europe between 1987 and 1993.  Likewise, in a survey of 60 female carriers from the United Kingdom (UK), 70% of them reported having neuropathic pain, 66% fatigue, and 58% gastrointestinal symptoms. Median survival in these patients was 70 years, which represents a 15 year reduction in life span compared to the UK general population.  The development of clinical manifestations in female carriers is probably related to random inactivation of the X chromosome, which is a mechanism for equalizing the sex chromosome gene dosage in males and females (Lyon phenomenon). Normally, there is an equal probability that either X chromosome will be inactivated in a given cell. ,,
Although the genetic defect of FD involves all cell types, the degree of damage varies in different organs, which suggests variable rates of sphingolipid metabolism. For example, axons from patients with FD are swollen and have dense lipid inclusions, whereas Schwann cells of the same patients have no lipid inclusions whatsoever. These findings suggest that axons and Schwann cells follow different metabolic pathways, and/or that Schwann cells are impervious to Gb3. ,
| Clinical Manifestations|| |
[Table - 1] lists the most frequent clinical manifestations of FD. It typically presents during infancy or adolescence with crisis of neuropathic pain (acroparesthesia), angioke ratomas, and asymptomatic corneal lesions. As Gb3 deposition progresses, clinical manifestations occur in other organs. Patients typically die in the fourth or fifth decade of life due to cardiac, renal or cerebrovascular complications. Significant intra-familial variation in clinical manifestations is not uncommon, particularly among female carriers. 
The clinical hallmark of FD is crises of neuropathic pain that occur in 80 to 90% of affected males. The crises typically involve palms and soles (acroparesthesia), may radiate to proximal extremities and other locations, and last from minutes to days. They are thought to be due to degeneration of nerve fibers in the dorsal root ganglion cells and axonal degeneration of small fibers due to the lipid deposition.  Since neuropathic pain is not specific for FD, the diagnosis is often delayed. The average time between onset of neuropathic pain and diagnosis of FD is 8.2  years.
Angiokeratomas are reddish-purple maculopapular skin lesions that typically appear between the ages of 5 and 10 years. Their size may vary from barely visible to a few millimeters in diameter and increase in number and size with age. The lesions may be generalized (angiokeratomas corporis diffusum), but more often are localized to the thighs, buttocks, umbilicus, lower abdomen, scrotum, and penis, and tend to be symmetric bilaterally ("bathing trunk" pattern).  As in the case of neuropathic pain, angiokeratomas are not specific for FD, and the average time between onset of angiokeratomas and diagnosis of FD is 10.7 years. 
Other abnormalities include decreased production of saliva and tears, hypohydrosis or anhydrosis, fever, and heat and exercise intolerance.  Ocular manifestations include tortuosity of conjuntival and retinal vessels even in the absence of hypertension, anterior and posterior lenticular deposits (cataracts), and a typical corneal dystrophy characterized by whorl-like feathery opacities (cornea verticillata). The latter two abnormalities may be detected by slit lamp examination in 100% of homozygous males and in 70% of heterozygous females. , Cardiac abnormalities are common and include left ventricular enlargement, valvular defects such as mitral insufficiency, and conduction defects such as various degrees of atrioventricular block, tachyarrhythmias, and ST-segment and T-wave abnormalities.  They are due to structural and functional changes related to glycosphingolipids deposition in the myocardium, valves, and conduction system. Left ventricular enlargement occurs in all older male homozygote patients and may lead to cardiomyopathy and congestive heart failure.  In a recent screening study of patients with left ventricular hypertrophy of unknown cause, 3% of them had low levels of a-Gal A. 12 A cardiac variant of FD, which is associated with reduced residual a-Gal A activity of 510% of normal, has recently been reported. 
Cerebrovascular abnormalities include early stroke, transient ischemic attacks, basilar artery ischemia and aneurysm, hemiplegia, hemianesthesia, and occasional seizures.  Increased endothelium-mediated vascular reactivity may lead to an excessive vascular response to normal hemodynamic stress and result in vessel wall remodeling with development of vessel tortuosity. Occlusive disease may also occur and appears to be related to glycosphingolipid deposition in the vessel wall.  Furthermore, increased levels of endothelial pro-thrombotic factors and leukocyte adhesion-molecule expression may play a significant role in the occurrence of vascular events and represent added risk factors for stroke in patients with FD. 
Gastrointestinal symptoms have been reported in both affected male homozygotes and carrier females. , Fifty percent of carriers complained of bloating, indigestion, and abdominal cramps. Diarrhea and constipation were present in over 40% and vomiting in 14%. In affected males, symptoms such as abdominal pain, nausea, vomiting, and abdominal distention are common. Gastrointestinal manifestations appear to be due to lipid deposition in autonomic ganglia and mesenteric blood vessels. The median survival age for affected males with gastrointestinal manifestations was 50 years, which represents an approximately 20-year reduction in life span.
Other extrarenal manifestations of FD include hearing loss, especially among patients with kidney failure or cerebrovascular lesions, airway obstructive disease, and psychiatric disorders including depression and suicidal ideation.  As stated earlier, heterozygous female carriers may be asymptomatic or severely affected due to random inactivation of chromosome X. The development of clinical manifestations, including skin, ocular and renal complications usually occurs later in life when compared to affected homozygous males.
Kidney involvement among patients with FD is notable for diffuse deposition of glycosphingolipid in the renal glomeruli, tubules, interstitium, and vasculature. , Under the light microscope the kidney has a "foamy" appearance with swelling and vacuolization of visceral podocytes, capillary endothelial and distal tubular cells, mesangial widening, and varying degrees of glomerular sclerosis, tubular atrophy and interstitial fibrosis.  Electron microscopy studies have shown that mesangial cells are filled with lysosomal electron dense granules arranged in lamellar, myelin-like patterns. Progressive lipid deposition may lead to irreversible tissue damage, which is an important consideration for enzyme replacement therapy.
Clinically, kidney disease manifests with hypertension, microscopic hematuria (rare), moderate proteinuria, which can be in the nephrotic range, and lipiduria.  The finding of lipiduria, demonstrated by birefringent oval fat bodies and Maltese crosses seen under polarized light; in association with only modest proteinuria can be a clue to the diagnosis of FD. ,,, Additionally, concentrating defects and nephrogenic diabetes insipidus, , distal renal tubular acidosis,  and impaired ammoniagenesis  have been reported. Decreased urinary concentrating capacity may be the earliest apparent renal abnormality, with onset of proteinuria in early adulthood and of uremia in the third to fifth decades of life. ,, Before the advent of dialysis and kidney transplant, uremia was the most common cause of death, at a mean age of 41 years. 
Branton has recently reported the clinical course of kidney disease in 105 male patients with FD who attended the National Institutes of Health (NIH) between 1970 and 2000.  Proteinuria was present in 66 of 78 patients with chronic kidney disease (CKD). The age of onset of non-nephrotic proteinuria was 34±10 years (range, 14-55 years). Fifty percent of all patients developed proteinuria by age 35, and 100% of surviving patients developed proteinuria by age 52. Nephrotic proteinuria was found in 19 of 78 (18%). Daily protein excretion was 5.6±3.6 g/day (range, 3-8 g/day) in these 19 patients, but the full presentation of nephrotic syndrome was uncommon. The age at onset of nephrotic proteinuria was 40±7 years (range, 26-55 years). Interestingly, "nephrotic proteinuria appeared before the onset of CKD in 18%, after the onset of CKD in 18%, and was never present in 23%; adequate data for magnitude of proteinuria in later stages of disease were lacking in 40%. Thirty-nine (37%) patients developed CKD and 24 (23%) end-stage renal disease (ESRD). The median age at onset of CKD and ESRD among patients for whom data were available was 42 and 47 years, respectively. Among 14 patients for whom data were available, estimated GFR declined at a rate of -12.2±8.1 ml/min per year and the time of progression from onset of CKD to ESRD was 4±3 years (range, 1-13 years). All patients who survived to the age of 55 years developed ESRD. Lastly, hypertension was present in 31 (30%) of patients with onset at age 38±11 years (range, 14-54 years). It is important to note that hypertension often did not appear until patients had declining kidney function.
Another interesting finding of the NIH report was that kidney Gb3 content, kidney pathology, and kidney function correlate with residual α-Gal A activity in peripheral leukocytes, suggesting the possibility that residual α-Gal A in kidney tissue retards the progression of Fabry kidney disease. However, it remains to be determined whether aGal A activity in peripheral leukocytes correlates with a-Gal A in kidney or other tissues, and whether it correlates with other clinical syndromes such as cerebrovascular and cardiovascular disease. Moreover, the NIH data suggest that all male Fabry patients who live long enough will eventually develop CKD or ESRD. 
The prevalence and characteristics of ESRD due to FD has been recently described. ,, Due to its low prevalence, FD is a rare cause of ESRD. Among 250,352 patients who began renal replacement therapy (RRT) in the United States (US) between April, 1995 and July, 1998, only 42 patients were identified as having ESRD due to FD, which corresponds to 0.0167% of all causes of treated ESRD.  Likewise, among 440,665 patients who began RRT in Europe between 1987 and 1993, only 83 patients were identified as having ESRD due to FD, which corresponds to 0.0188 % of all causes of treated ESRD.  The number of Fabry patients that began RRT in the US in 1996, 1997, and 1998 was 12, 11, and 14, respectively.  Patients with ESRD due to FD are younger and more likely to be male and Caucasian when compared to the overall US ESRD incident population. The mean age was 42 years and the majority of patients began RRT between the ages of 35 and 44 years. Despite the X-linked inheritance of FD, 12% of patients were female and their ages ranged from 20 to 68 years. Although FD has been described mostly in Caucasians, 10% of patients were African American and 7% of other races.  Interestingly, the demographic characteristics of Fabry patients with ESRD from the US and Europe were remarkably similar, despite the geographic and potentially genetic differences between them. 
| Diagnosis|| |
The typical Fabry patient is evaluated by an average of 10 specialists and spends an average of about 10 years before a correct diagnosis is made.  FD should be suspected on clinical grounds and confirmed with biochemical, histological and/or molecular genetics tests. A known family history of FD or its complications is an important clue for an early diagnosis. In the NIH series of 105 patients with FD, a family history was present in 44, absent in 50, and non-contributory in 11 patients. The age of diagnosis was 16±13 years among those with a family history and 28±12 years among those without a family history. Patients without a family history recalled experiencing clinical symptoms for 15±13 years before diagnosis (range, birth to 40 years), which was ultimately made by dermatologists (28%), ophthalmologists (26%), neurologists (23%), nephrologists (19%), rheumatologists (2%), and cardiologists (2%) . Ophthalmologic evaluation of typical asymptomatic lesions may be the first clue to the diagnosis of FD.
Histologic diagnosis can be made by demonstration of lipid occlusions and capillary dilatations on skin biopsy, birefringent oval fat bodies or Maltese crosses in the urine sediment, and the typical findings previously described on the kidney biopsy. 
Biochemical diagnosis can be made in homozygous males by demonstration of deficient α-Gal A activity in plasma, serum, leukocytes, or cultured fibroblasts. In heterozygous females, α-Gal A activity may not be noticeably low, and thus, diagnosis in these patients requires other confirmatory methods. , Antenatal diagnosis can be made by measurement of α-Gal A activity on skin fibroblasts obtained by amniocentesis or chorionic villous sampling. 
Molecular genetics techniques include PCR amplification and DNA sequence analysis. The former can be used when a restriction enzyme site is informative for a given family and consists of PCR gene amplification followed by Southern blot analysis. The latter is necessary for the majority of cases with grossly normal gene structure and is more reliable for identifycation of heterozygotes. A novel technique of chemical cleavage of mismatches is useful for identification of point mutations and of females carriers when biochemical testing is non-diagnostic. ,
| Treatment|| |
Nonsteroidal anti-inflammatory drugs are used to relieve pain crisis, as well as phenytoin, carbamazepine, and gabapentin. To prevent heat intolerance it is recommended to avoid exposure to heat, minimize physical activity, drink plenty of water, and in some cases, aspirin. The angiokeratomas may be removed for cosmetic reasons. Angiotensin converting enzyme inhibitors (or angiotensinreceptor antagonists) may be used to treat hypertension. There may also be a good option for delaying progression of CKD, as in other causes of chronic proteinuric diseases. In some patients, prophylactic anticoagulants may be indicated. A multidisciplinary approach with a geneticist, nephrologist, cardiologist, and neurologist is recommended. 
Renal Replacement Therapy
ESRD can be treated with either dialysis or transplantation. In a study of 42 patients who began chronic dialysis in the US between 1995 and 1998, hemodialysis was the initial modality in 64%, continuous ambulatory peritoneal dialysis in 22%, and continuous cycling peritoneal dialysis in 12%. Only one patient (2%) received a preemptive transplant, and two additional patients received a transplant one and two months after an initial course of Hemodialysis.  In another study of 83 patients who began chronic dialysis in Europe between 1985 and 1993, hemodialysis was the initial modality in 78%, peritoneal dialysis in 18%, and preemptive transplantation in 1%. 
Regarding outcomes of dialysis therapy, in a recent study 95 Fabry patients who began dialysis between 1985 and 1993 in the US were compared to 256 non-diabetic and 240 diabetic controls matched by age, gender, race, year, initial ESRD treatment modality, and ESRD network. The 3-year survival for Fabry patients in this study was 63% (95% CI, 50-75%), compared with 74% (95% CI, 67-80%) for non-diabetic controls (p=0.03), and 53% (95% CI, 46-61%) for diabetic controls (p=0.01). The survival curves for Fabry patients and non-diabetic controls began to diverge after approximately 1.5 years. Among the Fabry patients, 42% had undergone renal transplantation by three years, compared to 29% of non-diabetic and 13% of diabetic controls.  In a similar analysis that used data from the European registry, the 3-year survival was similar to that reported for US Fabry patients (60% versus 63%).  The survival data of the US and the European cohorts are in contrast to that reported by Nissenson and Port of 17 U.S. Fabry patients who began RRT (dialysis or transplantation) between 1983 and 1985 and found a survival of 83% at 3 years.  The primary difference between the USRDS and the European data and that from Nissenson was that in the first study, patients were censored at the time of transplantation, which was specifically not done by Nissenson. In the NIH series of 105 Fabry patients mentioned above, 14 began hemodialysis and 6 peritoneal dialysis (in 4 the initial modality could not be determined). Six patients have been treated with hemodialysis for 5.8±6.4 years (range, <1-17 years). Among these, one patient died after 17 years of hemodialysis and another after 10 years of hemodialysis, which demonstrates that prolonged survival on hemodialysis is possible in these patients.  Eventually, 14 patients received a kidney transplant.
Regarding outcomes of kidney transplantation, contrary to initial reports of 60% mortality at 1 year,  a recent study has shown that kidney and patient survival are comparable to that of patients with other causes of kidney disease.  Although Fabry lesions have been rarely reported in biopsies of transplanted kidneys, recurrent Fabry disease does not appear to compromise graft survival. ,,,
Enzyme Replacement Therapy
Several therapeutic approaches have been attempted among patients with FD, including kidney transplantation and exogenous enzyme replacement therapy. Kidney transplantation seemed to be an ideal treatment because it could replace abnormal kidney function and provide α-Gal A for all organs. Unfortunately, it was soon recognized that aGal A increased in urine but not in plasma, and thus, no detectable effects were observed on the progression of involvement in non-renal tissues.  Exogenous administration of purified α-Gal derived from human placental tissue or from plasma and spleen resulted in reduction of plasma Gb3 levels, but the effect only lasted 48 to 72 hours. , Although these studies demonstrated absence of any side effects or immune response to multiple doses of these unentrapped and partially purified isozymes over a period of almost 4 months, the problem was that significant amounts of enzyme were needed for repeat infusions.
In 1986, the gene for α-Gal A was cloned and sequenced, which eventually led to production of enzyme for therapeutic use by either recombinant DNA technology in Chinese hamster ovary cells or gene activation in cultured human skin fibroblasts. After demonstrating the safety and efficacy of α Gal A, two placebo controlled trials were conducted and reported in 2001. In one trial, biweekly infusions of recombinant α-Gal A were given to 29 patients for 20 weeks.  Although a significant reduction in endothelial and plasma Gb3 was observed, there were no significant differences in pain between the experimental and the placebo group (N=29). Rigors and fever occurred in 48% and 24% of patients who received α-Gal A, respectively. In the second trial, biweekly infusions of α-Gal A produced by gene activation were given to 14 patients for 24 weeks.  Compared to patients who received placebo (N=12), those who received a-Gal A appeared to have an improvement in pain and quality of life, and in kidney function and histology. Plasma Gb3 levels decreased, but Gb3 content in kidney and urine did not significantly change. Eight patients who received α-Gal A had rigors and 3 patients developed anti-α-Gal A antibodies, although their titers decreased over time. Despite that both trials differed in the enzyme preparation used, the dose per infusion, and patient characteristics and pain medications at entry, they showed that therapy with α-Gal A reduced glycolipid deposits in the kidney.  At present, both preparations of α-Gal A have been approved by the European Medical Evaluation Agency, and approval by the Food and Drug Administration in the US is still being reviewed. , Further studies are needed to determine the right timing for initiation of enzyme therapy in different subsets of patients with FD and its long term effects.  In addition, dosing and frequency of administration are still being sorted out. Given the high cost of enzyme replacement therapy, other alternatives such as galactose infusion, gene therapy, and substrate synthesis inhibitors are being explored. 
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[Table - 1]