Natural History of Fabry Renal Disease

Introduction Fabry disease is an X-linked sphingolipidosis caused by complete or partial deficiency of the glycohydrolase α-galactosidase A (α-gal A) (4). The enzyme deficiency results in accumulation of globotriaosylceramide (Gb3, also known as ceramide trihexoside), as well as digalactosyl ceramide and blood group B, B1, and P1 glycolipids in the lysosomes of vascular endothelial, smooth muscle, epithelial, and ganglion cells. The metabolic defect causes a painful neuropathy, angiokeratomas, cardiac and cerebrovascular injury, and renal failure. Hemizygous males usually experience multisystem involvement with symptoms beginning in childhood or infancy, although oligosymptomatic (usually cardiac) variants are reported (25,37,40,60). Heterozygous females have more variable expression due to random X chromosome inactivation, with some patients experiencing few or mild symptoms, and others developing skin, ocular, and renal manifestations, premature strokes, and myocardial infarctions, although usually later in life than affected males. Renal involvement has been recognized as a cardinal feature of Fabry disease since patients with characteristic skin lesions and albuminuria were first described in 1898 (2,17). The kidney pathology of renal involvement has been described as vacuolated epithelial cells and podocytes in the glomerulus and distal tubules (6,10). Lipid inclusions appear as clusters of intracellular vacuoles by conventional light microscopy, but exhibit dense osmiophilic staining in epon-embedded material stained with toluidine blue in epithelial cells. Electron microscopy shows intracytoplasmic irregular lamellar bodies that are lysosomes containing Gb3. With time, the glomeruli develop mesangial widening and progressive sclerosis, tubular atrophy, and interstitial fibrosis. Decreased urinary concentrating ability may be the earliest apparent renal abnormality, with onset of proteinuria in early adulthood and onset of renal failure in the fourth to fifth decades of life. Before the advent of dialysis and renal transplant, the most common cause of death was uremia, at a mean age of 41 years (11). Although there are accounts of individual patient presentations and follow-up of small kindreds, the rarity of Fabry disease has made evaluation of large groups of patients difficult to achieve. We reviewed the medical records of 105 male patients with Fabry disease. We describe the clinical course and histology of their renal disease and correlate them with residual α-gal A activity and with mutations in the α-gal A gene. Diagnosis of Fabry disease occurred later in patients without a known family history. Fifty percent of patients developed proteinuria by age 35 years and chronic renal insufficiency (CRI) by age 42 years. We found that detectable residual α-gal A activity was associated with a slower progression of Fabry renal disease, and with lower scores for renal histologic damage and renal Gb3 content. Conservative mutations in the α-gal A gene were also associated with slower progression of Fabry renal disease. Patients and Methods Definitions ( Table 1)TABLE 1: DefinitionsConditions are defined in Table 1. Hypertension was classified according to the sixth report of the Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure (53). For patients on antihypertensive therapy, control was considered to be a systolic blood pressure ≤130 mmHg and diastolic blood pressure ≤90 mmHg. Data collection We reviewed the clinical records of 105 male Fabry patients who were evaluated at the Warren Grant Magnuson Clinical Center of the National Institutes of Health, Bethesda, Maryland, (NIH) from 1970 to 2000. All patients were enrolled in clinical protocols approved by the appropriate Institutional Review Board. The diagnosis of Fabry disease was made by the presence of the typical symptoms and signs of neuropathic pain, angiokeratoma, diarrhea and abdominal pain, proteinuria and renal failure, ocular abnormalities, or early stroke. In all patients, the clinical diagnosis was confirmed by demonstration of leukocyte α-gal A activity <15% of the value in healthy In patients, of leukocyte α-gal A activity was at the and in the of the patients was at Clinical the onset of clinical of Fabry disease, earliest symptoms and diagnosis of Fabry disease, blood age and cause of and and the of and urinary in a or was was usually at Data on renal and urinary from were usually to the at the of In some to of symptoms, and that were and the diagnosis of Fabry disease. Data renal tubular as urinary concentrating ability and the presence of urinary cells containing Fabry were and were in the were for of the patients who A of patients in a of α-gal A that in Patients were the for were or the on to of enzyme in the of patients who in the α-gal A the age of onset of and and of progression to proteinuria and to renal disease We the of patients a age who an was as the the of patients who the by a age or and as the the of patients who the or or who were without the Fabry patient age years in We patients for to a and to an age of onset for the We for patients for 105 patients for patients for patients for and death for 105 We in the and groups patients for the age of onset of and be of 105 patients developed in the patients were in the as developing was the and and to the of progression in the patients for were by years of patients developed patients developed patients developed patients developed and patients of progression from to The mean from onset of to was for patients for the of onset of and the of onset of were was by the developed from as of the of in Renal as by Table The for or were to at of of renal were defined as were from onset of and mean of of were from the Renal pathology Renal were in of male patients with Fabry disease who were enrolled in a of α-gal A patient have a due to the presence of renal All were the of Patients were for the on the presence of neuropathic pain, was the Patients with were from but there was for renal was with a of patients patients and patients Renal were in a by renal who a histology for were in and The of glomeruli was The mesangial of glomerulus was classified as mesangial widening the or or classified as of mesangial widening or sclerosis, but The of glomeruli in was The pathology was by the individual scores and by the a of all glomeruli and a of all glomeruli The pathology was as a of the on a of tubular atrophy, interstitial interstitial vascular and vascular The pathology was by the of the pathology scores by for inclusions were by of toluidine blue stained The was as a of scores for the on a of epithelial tubular epithelial distal tubular epithelial vascular and vascular cells. The was by to the patient for Gb3 Gb3 was in and renal by in the patients enrolled in the α-gal A as described Gb3 was as of Gb3 was as of and renal Gb3 was as of kidney α-gal A of residual α-gal A activity was as described blood were in an and at for α-gal A activity was by of the at with in the without and with is a for α-gal A and α-gal α-gal activity is in the presence of the and in the of residual α-gal A α-gal A activity was as a patient α-gal A and healthy α-gal A on the was the mean of α-gal A activity were considered was from or All of the α-gal A gene were by from and the was in patients α-gal A activity and onset of renal insufficiency were in patients with and Data are as mean Data that were were the or the were Data that were were in were to the For in groups α-gal A activity or of α-gal A a was in the age of onset of renal were evaluated by the A value of was as and and 105 male patients, patients were patients were patient was patient was and patient was group were for patients, of were blood group were blood group B, and were blood group was from the of blood groups in the of patients have the mean age at death was years. were for patients and the causes of cerebrovascular cardiac failure, myocardial failure, and 1. Diagnosis of Fabry disease ( 1: at onset of clinical and diagnosis of Fabry disease. The of patients in of life is for earliest onset of Fabry symptoms and for age at Fabry diagnosis the clinical that to the diagnosis of Fabry disease in all 105 patients were with Fabry disease of known family or early childhood or family evaluation at the as the patient was In patients, the age of diagnosis was years to Fifty patients a family of Fabry disease. For patients the age of diagnosis was years was than that patients with a family of Fabry disease. patients experiencing clinical symptoms for years diagnosis For patients, was family to In patients without a family of Fabry disease, the diagnosis was first made by and considered of Fabry disease of disease, The presence of chronic in some patients considered or ( of patients developing renal and death with The of patients by age who developed the is The of patients in the the described in for 105 for for chronic renal insufficiency for renal disease and 105 for patients to age patients to age and patients age Renal pathology in disease bodies of in podocytes and mild mesangial widening in of in podocytes toluidine blue renal bodies in distal tubules with of and interstitial blue of in cells of is in of toluidine blue inclusions in cells and smooth cells toluidine vacuolated urinary epithelial cells in a Fabry patient from a Fabry patient shows the typical of and the lamellar of Fabry of 105 patients proteinuria or clinical of renal disease. was at some in the clinical course of of patients with renal disease. The age of onset of proteinuria was years Fifty percent of all Fabry patients developed proteinuria by age 35 and of patients developed proteinuria by age proteinuria was found in of patients with renal disease. was in The age at onset of proteinuria was years In patients who developed proteinuria the onset of in the onset of in and was in for of proteinuria in later of disease were in of patients with proteinuria at and of the of was in patients who In some patients, the presence of bodies in with a and lamellar may the diagnosis of Fabry disease of the of in of patients for was the proteinuria was of patient tubular proteinuria renal insufficiency and renal disease ( of of in The of of in is for patients for the of onset of chronic renal insufficiency and renal disease are The mean of was to by the of 105 patients developed The age of onset was 42 years the patients for for age of onset were patients developed at a age of years of progression from onset of to was years in patients for of onset of and were of patient age at onset of or of proteinuria the of were on residual enzyme activity and few of blood pressure to for In of are for patients with Fabry disease who progressive renal failure and for at of were All of patients have of patient who to of follow-up a to patients, the value at is patients, the patient who to a mild or of renal Renal as the of is time, as years from onset of chronic renal defined as a Data patients for at were a from the onset of chronic renal insufficiency to the onset of renal of 105 patients developed All patients in who to the age of years developed patients at the onset of and patients For patients the of dialysis be from the patients who renal were with and the of dialysis was for patients have been with for years of patients years on and was to follow-up years on that on dialysis is in Fabry disease. patients dialysis for and years and patient has been with dialysis for years the Hypertension 105 Fabry patients, was in with onset at age years onset of of patients and of patients patients for the be We the the onset of and the onset of since due to cause is associated with of 105 patients developed and of patients developed the onset of of patients a diagnosis of and and of patients developed years the onset of We the of enzyme or as a in the course of renal disease. of was of 105 patients an at for without renal with proteinuria with was for proteinuria without in patients, and for failure in For patients, the for be Renal patients kidney patient a renal from a and the renal The age at first renal was years. patients renal on and patients renal on patient was with and dialysis for renal patients renal or an of patients for years patients with at and years kidney transplant, the causes of death were and cardiac failure. of patients a first renal at age years with and at age a renal transplant, well for years. patient developed chronic and to dialysis years. patient with chronic renal failure at years and of years The kidney was to patients renal years renal transplant, and vascular that to of Fabry inclusions was found by light microscopy, and microscopy was on The years chronic and of Fabry inclusions by light or patients reported an in renal patient reported an and reported a in neuropathic renal transplant, but there was of renal on symptoms of Fabry disease. Renal with residual α-gal A activity ( and of residual α-galactosidase A (α-gal A) α-gal A activity was in from male Fabry patients, and is as of α-gal A activity in healthy α-gal A activity was in patients and was of control activity in the of chronic renal of of α-galactosidase A (α-gal A) The of is as a of age in Fabry patients with of α-gal A activity and in Fabry patients with α-gal A activity The of patients with follow-up at age is of onset of chronic renal insufficiency was later in patients with detectable α-gal A activity α-gal A activity was at the in at were in patients α-gal A activity and patients residual α-gal A activity and of control We the age of onset of in patients with α-gal A activity and the age of onset of in with residual α-gal A activity and found them to be In the the earliest onset was in the the earliest onset was years. the age of all patients with residual α-gal A activity developed patients with residual α-gal A activity renal The age of onset of proteinuria was the groups of the patients who of residual α-gal A activity all of α-gal A the groups Renal with residual α-gal A activity ( Table Renal renal and Electron lamellar osmiophilic inclusions in epithelial The is in the of a was on renal from light microscopy, the of of the epithelial cells and distal tubular epithelial cells with Fabry of the In some patients and to an were With more disease, distal and tubules inclusions and the fibrosis. and were by inclusions in and vascular smooth more in than in and inclusions in cells. of pathology scores with patient age of age pathology scores in the or inclusions but age correlate with pathology scores of α-gal A activity was for of patients who of renal Renal pathology scores were patients who α-gal A activity and patients who residual α-gal A activity was the groups pathology scores were in patients with α-gal A activity to patients with α-gal A activity pathology scores were also in patients with α-gal A activity to patients with residual α-gal A activity scores were in patients with α-gal A and in patients with α-gal A activity evaluation of renal typical osmiophilic lamellar inclusions in epithelial cells and vascular were to of Gb3 in and ( Table and urinary Gb3 were in patients with detectable residual α-gal A activity and patients with α-gal A activity Table Gb3 were in patients with detectable α-gal A activity with in patients with α-gal A was α-gal A with enzyme activity and onset of ( and of chronic renal of α-galactosidase A (α-gal A) gene The of patients with is as a of age in Fabry patients with mutations in the α-gal A gene and in patients with mutations in the α-gal A gene Patients with mutations a later onset of chronic renal insufficiency of chronic renal insufficiency by of with renal by the of Patients with are of the of the α-gal A gene was in was in there were and patients have been reported and were The clinical course of renal disease was defined for all patients, and of residual α-gal A activity were for of the patients who mutations were as in and is patients from who have known common but a α-gal A activity was of in patients with mutations and was in patients with mutations Table All patients with a have a although some have developed has developed in of patients with a first at age years We also residual α-gal A activity and clinical course in patients with mutations and patients with all mutations premature and α-gal A activity was in patients with to with all mutations Patients with mutations onset of to patients with all mutations We the of the of mutations on residual α-gal A activity and age of Conservative mutations were to and that the mutations were associated with α-gal A activity and later patients from mutations were found in patients, as and patient a in patients who more than were in in mutations in and were associated with progression to the of patient with mutations in or developed the of patients is small to that mutations in and may progression of renal disease. α-gal A activity was in patients with mutations in or with patients who mutations in or In describe the clinical of renal involvement in 105 patients with Fabry disease evaluated at the the years. We have the of residual α-gal A activity and α-gal A mutations on the course of renal disease. α-gal A may be for Fabry patients and may have a on the course of renal disease a of the of renal involvement in Fabry disease be to the typical course and of Fabry renal disease. and renal failure have been considered cardinal of Fabry disease for years. have been patients and Fabry renal disease. are are but due to random of the X may in some renal disease. The in Fabry disease may are renal tubular epithelial cells or with microscopy bodies a typical but the bodies in of have a lamellar In of the from Fabry patients with renal involvement characteristic lamellar osmiophilic inclusions in urinary cells. has been as a in the evaluation of family Renal tubular is in Fabry tubular is in urinary has been reported more with tubular for the of and and an renal tubular the first of renal in Fabry disease, in patients at a mean age of years. to with time, and in of patients with of renal disease. In of Fabry patients, proteinuria the onset of or may be the course of renal disease. In all of the and was of and were be that in the of there is for but the of in patients is of have been reported in proteinuria associated with is typical of lesions due to Hypertension in Fabry patients have at may be a of renal a of vascular disease, or may be a to the Fabry disease, as the presence of in a patient with Fabry disease. We found that was a in and appear patients renal Hypertension was found in of patients, of also developed In of Fabry patients, the appear the onset or well the onset of or with the mean age of onset in the fourth that the is more or to renal disease. In some Fabry patients, disease cause The age of the onset of clinical in male Fabry patients has been reported to be years the of clinical was the of proteinuria or renal In the mean age of onset was with of all patients developing by age is with an report by that the mean age of death in Fabry patients in the was 41 years. The age at onset was reported as 35 years years and years A of Renal Data for the that the mean age at Fabry patients developed was 42 years We found that at the of in renal for patients with in the from to A more that with control the of enzyme the of progression in patients may be to The in Fabry patients was than that in patients with or renal disease and was with a patient at a than the is in to the in renal is to progression that to the in renal in Fabry patients have and proteinuria are all associated with more progression of renal failure in and renal were in few patients with in that of the renal may be a of the metabolic defect and of be the metabolic defect is life is although is is that the renal is to disease with and that renal a for disease is may the is and renal has been to the of in renal in chronic renal of few of patients and their in the progression of Fabry renal disease. developed in of the patients in the a of in Fabry patients, as some patients in the may develop in the well for with The Renal Data patients with Fabry disease who the to a of patients has been found that of Fabry disease in the of is males of is although the is that in the have Fabry disease. from the in that at Fabry patients who are develop a life that Fabry patients well with the The renal pathology of Fabry disease has been described by the glomeruli on light microscopy have epithelial cells with mesangial and of may be in and distal renal tubular cells. that the vacuoles microscopy, osmiophilic inclusions are in the of epithelial and cells of the distal and In the renal described in patients, male patients and patients of the males and of the females developed but all inclusions in distal and cells. All males the developed some tubular and interstitial but the and fibrosis. The that renal Gb3 renal and renal correlate with residual α-gal A activity in the that residual α-gal A activity in kidney the progression of Fabry renal disease. to be α-gal A activity in kidney or with residual α-gal A activity in blood be to residual α-gal A in also with clinical cerebrovascular and disease. The of renal in patients with Fabry disease has been the of groups described patients renal α-gal A and that were that renal α-gal A activity is urinary of α-gal A to Renal has detectable on the progression of involvement in was Fabry disease Renal and years renal Fabry inclusions in the vascular by microscopy may of the by cells of osmiophilic inclusions in podocytes or tubular cells of renal has been reported the Fabry patients renal were reported to have a at has been reported that renal and patient are to that of patients with renal The clinical course of the patients in that renal of in Fabry patients, and that is to that of patients with of The of renal on symptoms of Fabry disease is in with the is that renal be considered an for in Fabry patients who are renal of Fabry renal disease was but have an of renal to the of histologic found that α-gal A activity was lower in Fabry patients with neuropathic to who neuropathic have of α-gal A activity in individual patients, or of a or have the presence or of renal with enzyme but has been to correlate enzyme with the clinical course of Fabry renal disease or with renal on a We report a of residual α-gal A activity in the onset of by years. a small of residual α-gal A activity is to an in renal that all male Fabry patients who develop and The results of the of renal from patients in a of enzyme with α-gal A that enzyme activity the of renal histologic damage in patients of the histologic of Gb3 inclusions in was patients with and detectable residual α-gal A of Gb3 to kidney Gb3 in renal of patients with residual α-gal A as Gb3 correlate with residual α-gal A The for but that in the enzyme activity that is to and that with may more α-gal of α-gal A mutations in Fabry disease have that most mutations are mutations have been patients who mutations in the have α-gal A in the of in the control patients mutations and mutations that in or premature The presence of a a residual α-gal A and a later onset of renal insufficiency to A in or in the in α-gal A with or and a renal disease We found mutations in all of the α-gal A gene In patients, mutations in and to be associated with progression to although the small of patients there was an in of and premature mutations to as the be to have a more on enzyme is to the of a for α-gal Although are that and may that have at the of the enzyme or in The of in Fabry disease has been the may cause In patients, α-gal A activity was in patients with mutations to with has been reported that the of neuropathic was in patients with mutations and mutations In the found that renal was in patients with mutations to and there was a in patients with mutations to all have a for renal the from of and may be the of patients in group and the The has all patients were at the from were first as of were by and all of were for all medical records on patients, to the onset of medical in the patients were as patients in clinical from or as a of the of Fabry disease were to renal the that the onset of renal disease have for patients to to the that the and course of Fabry renal disease reported are to be to found in patients were Fabry disease has been reported in all has been most reported in patients of or In the of Fabry disease has been reported to be in patients of with the of a a mild to cardiac pathology most in the patients with residual α-gal A of the was is in the of renal disease in patients with of α-gal A in the report has male The clinical course of Fabry patients is known to be due to random X chromosome in that of residual α-gal A activity are associated with renal may to the for with α-gal A has clinical or for gene in enzyme activity may be in the progression of renal disease. are to have to be that of α-gal A renal as a of enzyme by renal cells. have been cerebrovascular and disease, are causes of and death in patients, are in patients with of residual α-gal A In the some patients with onset of or disease at an early and most neuropathic for years. the that or gene therapy, at an early accumulation and renal be of appropriate but may be from a that the course of renal disease is to the described We reviewed the medical records of 105 male patients with Fabry disease. We describe the clinical course and histology of their renal disease and correlate them with residual α-galactosidase A (α-gal A) activity and with mutations in the α-gal A gene. Hemizygous male patients with Fabry disease may develop proteinuria and chronic renal insufficiency in or early age 35 of patients proteinuria and early renal Fifty percent of patients renal insufficiency by age 42 and to renal disease by age years. percent of all patients developed renal disease. age of the patients and all by age years. proteinuria was in of patients and was in of may appear or the onset of chronic renal the onset of chronic renal the mean of in was with patients renal disease years. The presence of detectable residual α-gal A activity in was associated with a later onset of chronic renal lower renal globotriaosylceramide and lower scores for renal histologic Conservative mutations were associated with renal with or The for with for for death for with the renal pathology and for and for