Seymour Packman

Fabry Disease, an Under-Recognized Multisystemic Disorder: Expert Recommendations for Diagnosis, Management, and Enzyme Replacement Therapy

Fabry disease is an X-linked recessive lysosomal storage disorder that is caused by the deficient activity of -galactosidase A (-Gal A, also termed ceramide trihexosidase) (1, 2) and the resultant accumulation of globotriaosylceramide (also termed ceramide trihexoside) and related glycosphingolipids (3-5). In patients with the classic phenotype, levels of -Gal A activity are very low or undetectable. Patients with detectable -Gal A activity have a milder, variant phenotype (6-8). In classically affected males, the progressive glycosphingolipid accumulation, particularly in the vascular endothelium (Figure 1), leads to renal, cardiac, and cerebrovascular manifestations and early death. The disease is panethnic, and estimates of incidence range from about 1 in 40 000 to 60 000 males (5, 9). Fabry disease predominantly affects males, although carrier (heterozygous) females also can be affected to a mild or severe degree because of random X-chromosomal inactivation (5). Figure 1. Distinctive laboratory findings in Fabry disease. A B In the absence of a family member who has already received a diagnosis of the disorder, many cases are not diagnosed until adulthood (average age, 29 years) (9, 10), when the pathology of the disorder may already be advanced. Although clinical onset occurs in childhood, disease presentation may be subtle, and its signs and symptoms are often discounted as malingering or are mistakenly attributed to other disorders, such as rheumatic fever, erythromelalgia, neurosis, the Raynaud syndrome, multiple sclerosis, chronic intermittent demyelinating polyneuropathy, lupus, acute appendicitis, growing pains, or petechiae (5, 11). Fabry disease was first identified a century ago, but until now, no disease-specific treatment has been available. Patients have been managed with supportive, nonspecific treatment for pain management, cardiac and cerebrovascular complications, and end-stage renal disease. These interventions may prolong life, but their utility is limited because they do not address the underlying cause of the disease, that is, the lack of -Gal A and the progressive accumulation of globotriaosylceramide. Recently, enzyme replacement with human -Gal A has been shown to safely reverse the pathogenesis of the major clinical manifestations, to decrease pain, and to stabilize renal function in patients with Fabry disease (12, 13). The European Agency for the Evaluation of Medicinal Products has approved the treatment, and the U.S. Food and Drug Administration is currently reviewing it. Thus, recommendations for the diagnosis and treatment of Fabry disease are timely. Formation of Expert Panel and Basis of Recommendations In June and July of 2001, two groups of investigators published randomized, placebo-controlled trials that demonstrated that enzyme replacement therapy in Fabry disease can reverse the major pathologic consequences and improve outcomes (12, 13). With a disease-specific therapy finally available, the need for prompt and accurate diagnosis of this devastating, progressive disease became paramount so that patients could be identified and treated before incurring irreversible organ damage. Recognizing the need for initial guidelines for diagnosis, management, and the use of enzyme replacement therapy, Dr. Robert Desnick and Dr. Roscoe Brady (senior authors of the enzyme replacement trials) assembled an international panel of experts with extensive clinical experience and diverse subspecialty expertise in Fabry disease and lysosomal storage disorders. Panelists met face-to-face to identify and discuss salient issues. An independent coordinator conducted numerous global and specific searches of the MEDLINE database (19912001), including a global search of the recent literature on Fabry disease. The coordinator then interviewed each panelist in detail and, with the first author, prepared a draft statement. In a second face-to-face session, the draft was reviewed, revised, and finalized by the panel. A teleconference was convened to revise the manuscript after journal review. Support for the expert panel process was obtained from the Genzyme Corporation (Cambridge, Massachusetts), which had no formative role in the literature review, the formulation of recommendations, or the drafting and revising of the manuscript. As would be expected for a rare, under-recognized disease, the literature on Fabry disease mostly consists of single or small case studies and reviews in addition to book chapters written by Fabry experts. The few larger studies focus on disease manifestations and mechanisms of disease rather than the effectiveness of interventions or disease management. The literature on enzyme replacement therapy is limited to the clinical trials published in the last 2 years. Thus, clinical experience and expertise played an important role in the formulation of these recommendations. Disease Pathophysiology and Clinical Manifestations The major debilitating manifestations of Fabry disease result from the progressive accumulation of globotriaosylceramide in the vascular endothelium (Figure 1), leading to ischemia and infarction, especially in the kidney, heart, and brain. The ischemia and infarction of small vessels are primarily due to vascular occlusion (5); however, evidence for a prothrombotic state has recently been published (14). In addition, early and substantial deposition of globotriaosylceramide occurs in podocytes, leading to proteinuria and, with age, in cardiomyocytes, causing cardiac hypertrophy and conduction abnormalities (Figure 1). Patients are generally divided into two major groups on the basis of the absence or presence of residual -Gal A activity: classic disease and milder, later-onset, atypical variants (5). Presentation and clinical course can vary within these phenotypes, and an intermediate phenotype has also been described (15-17). The Classic Phenotype Males with classic disease have no or very low -Gal A activity, resulting in severe renal, cardiac, and cerebrovascular disease manifestations. Before treatment of uremia became available, the average lifespan of affected males was about 40 years (18). With the advent of renal dialysis or transplantation, the median survival was about 50 years (19). Clinical manifestations (Figures 1 and 2), which usually begin in childhood or adolescence, include intermittent pain in the extremities (acroparesthesias); episodic Fabry crises of acute pain lasting hours to days; characteristic skin lesions (angiokeratomas); a corneal opacity that does not affect vision; hypohidrosis; heat, cold, and exercise intolerance; mild proteinuria; and gastrointestinal problems. By adulthood, the renal involvement inevitably results in end-stage renal disease, which requires dialysis or transplantation (20, 21). Cardiac manifestations include left ventricular hypertrophy, valvular disease (especially mitral insufficiency), ascending aortic dilatation, coronary artery disease, and conduction abnormalities (Figure 1), leading to congestive heart failure, arrhythmias, and myocardial infarction (5, 22-24). Cerebrovascular manifestations include early stroke, transient ischemic attacks, white matter lesions, hemiparesis, vertigo or dizziness, and complications of vascular disease (such as diplopia, dysarthria, nystagmus, tinnitus, hemiataxia, memory loss, and hearing loss) (5, 25). Figure 2. Distinctive clinical features of Fabry disease. A B C Clinical manifestations in carrier females range from asymptomatic to full-blown disease as severe as that in affected males (5, 26-28). Although many carriers will be relatively asymptomatic and have a normal lifespan, carriers may experience symptoms in childhood and adolescence (such as pain and proteinuria) and adulthood (such as cardiac or, more rarely, renal manifestations). In late adulthood, some carriers develop left ventricular hypertrophy and substantial cardiomyopathy. Data on carriers are limited. A recent study of obligate carrier females found significant disease manifestations in 20 of 60 women, including 17 of whom who had experienced transient ischemic attacks or cerebrovascular accidents (28). Atypical Variants Atypical male variants have a milder, later-onset phenotype (5-7, 17, 29). Because of low residual -Gal A levels, these patients do not have the early major clinical manifestations of classic Fabry disease. For example, cardiac variants present with cardiomegaly and mild proteinuria usually after 40 years of age, when patients with classic Fabry disease would be severely affected or would have died (6, 7, 29). Two recent studies have suggested that the cardiac variant of Fabry disease may be an important cause of idiopathic left ventricular hypertrophy (7) or late-onset hypertrophic cardiomyopathy (30). Tissue biopsies or autopsy studies of cardiac variants reveal globotriaosylceramide accumulation in the myocardium and not in the vascular endothelium throughout the body (5, 6, 29). These findings suggest that even low levels of -Gal A can prevent globotriaosylceramide accumulation in the microvasculature and that this lack of accumulation is associated with the absence or attenuation of disease manifestations. Thus, reversal of the underlying vascular endothelial pathology by enzyme replacement therapy will probably be clinically therapeutic in patients with classic Fabry disease. Enzymatic and Molecular Diagnosis In affected males with the classic or variant phenotype, the disease is readily diagnosed by determining the -Gal A activity in plasma or peripheral leukocytes. In contrast, female carriers can have normal to very low -Gal A activity; therefore, their specific family mutation in the -Gal A gene must be demonstrated. Most kindreds have family-specific or private mutations; to date, more than 300 mutations have been identified, of which most are missense (amino acid substitutions) or nonsense (causing premature truncation of the amino acid sequence) mutations. Spli

MULTIPLE BIOTIN-DEPENDENT CARBOXYLASE DEFICIENCIES ASSOCIATED WITH DEFECTS IN T-CELL AND B-CELL IMMUNITY

Three siblings presented in early childhood with central-nervous-system (CNS) dysfunction, candida dermatitis, keratoconjunctivitis, and alopecia. Two were studied immunologically and had absent delayed-hypersensitivity skin-test responses and absent in-vitro lymphocyte responses to candida antigen. One of them had selective IgA deficiency and no antibody response to pneumococcal polysaccharide immunisation, and the other had a subnormal percentage of T lymphocytes in peripheral blood. The first two siblings died with progressive CNS deterioration and overwhelming infection. The third child, who presented with a periorificial candida dermatitis, alopecia, keratoconjunctivitis, and intermittent ataxia at eighteen months of age, had intermittent lactic acidosis and raised excretion of beta-hydroxyproprionate, methylcitrate, beta-methylcrotonylglycine, and beta-hydroxyisovalerate in urine. After four days of oral biotin, 10 mg/per day, the metabolites in her urine were significantly reduced, suggesting a biotin-responsive multiple carboxylase deficiency. These findings, taken with previous reports of immune defects in patients with disorders of branched-chain aminoacid catabolism, suggest a new biochemical basis for primary immunodeficiency disease.

Musculoskeletal manifestations of Hurler syndrome: long-term follow-up after bone marrow transplantation.

Bone marrow transplantation (BMT) is effective in ameliorating many of the clinical manifestations of Hurler syndrome. However, long-term data on the natural history of the musculoskeletal disorders of Hurler syndrome after BMT are limited. The authors report the orthopaedic outcomes in seven patients with Hurler syndrome who were successfully engrafted between 1990 and 1999, and have been followed for a mean of 7.6 years since transplantation. Medical records, clinical examinations, and imaging studies were reviewed to assess the development and management of hip dysplasia, genu valgum, spine abnormalities, hand abnormalities, and joint range of motion. BMT does not appear to alter the natural history of the musculoskeletal disorders in Hurler syndrome, although there may be a beneficial effect on upper extremity joint mobility.

Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease

Background Fabry disease results from deficient α-galactosidase A activity and globotriaosylceramide accumulation causing renal insufficiency, strokes, hypertrophic cardiomyopathy and early demise. We assessed the 10-year outcome of recombinant α-galactosidase A therapy. Methods The outcomes (severe clinical events, renal function, cardiac structure) of 52/58 patients with classic Fabry disease from the phase 3 clinical trial and extension study, and the Fabry Registry were evaluated. Disease progression rates for patients with low renal involvement (LRI, n=32) or high renal involvement (HRI, n=20) at baseline were assessed. Results 81% of patients (42/52) did not experience any severe clinical event during the treatment interval and 94% (49/52) were alive at the end of the study period. Ten patients reported a total of 16 events. Patients classified as LRI started therapy 13 years younger than HRI (mean 25 years vs 38 years). Mean slopes for estimated glomerular filtration rate for LRI and HRI were −1.89 mL/min/1.73 m2/year and −6.82 mL/min/1.73 m2/year, respectively. Overall, the mean left ventricular posterior wall thickness and interventricular septum thickness remained unchanged and normal. Patients who initiated treatment at age ≥40 years exhibited significant increase in left ventricular posterior wall thickness and interventricular septum thickness. Mean plasma globotriaosylceramide normalised within 6 months. Conclusions This 10-year study documents the effectiveness of agalsidase beta (1 mg/kg/2 weeks) in patients with Fabry disease. Most patients remained alive and event-free. Patients who initiated treatment at a younger age and with less kidney involvement benefited the most from therapy. Patients who initiated treatment at older ages and/or had advanced renal disease experienced disease progression.

Improvement of bone disease by imiglucerase (Cerezyme) therapy in patients with skeletal manifestations of type 1 Gaucher disease: results of a 48-month longitudinal cohort study.

Progressive skeletal disease accounts for some of the most debilitating complications of type 1 Gaucher disease. In this 48‐month, prospective, non‐randomized, open‐label study of the effect of enzyme replacement therapy on bone response, 33 imiglucerase‐naïve patients (median age 43 years with one or more skeletal manifestations such as osteopenia, history of bone crisis, or other documented bone pathology) received imiglucerase 60 U/kg/2 weeks. Substantial improvements were observed in bone pain (BP), bone crises (BC), and bone mineral density (BMD). Improvements in BP were observed at 3 months (p < 0.001 vs baseline) and continued progressively throughout the study, with 39% of patients reporting pain at 48 months vs 73% at baseline. Eleven of the 13 patients with a pre‐treatment history of BC had no recurrences. Biochemical markers for bone formation increased; markers for bone resorption decreased. Steady improvement of spine and femoral neck BMD, measured using dual‐energy X‐ray absorptiometry was noted. Mean Z score for spine increased from −0.72 ± 1.302 at baseline to near‐normal levels (−0.09 ± 1.503) by month 48 (p = 0.042) and for femoral neck from −0.59 ± 1.352 to −0.17 ± 1.206 (p = 0.035) at month 36. This increase was sustained at 48 months. With imiglucerase treatment, patients should anticipate resolution of BC, rapid improvement in BP, increases in BMD, and decreased skeletal complications.

Periventricular heterotopia associated with chromosome 5p anomalies

Periventricular heterotopia (PH) is characterized by neuronal nodules along the lateral ventricles. Whereas mutations in X-linked FLNA cause such cortical malformations, the authors report two cases of PH localizing to chromosome 5p. Both subjects have complex partial seizures. MRI demonstrated bilateral nodular PH, with subcortical heterotopia or focal gliosis. FISH identified a duplication of 5p15.1 [46,XX,dup(5)(p15.1p15.1)] and a trisomy of 5p15.33 [46,XY,der(14)t(5;14)(p15.33;p11.2) mat]. These findings suggest a new PH locus along the telomeric end of chromosome 5p.

Imiglucerase (Cerezyme) improves quality of life in patients with skeletal manifestations of Gaucher disease.

Health‐related quality of life (HRQOL) can be diminished in patients with type 1 Gaucher disease (GD) owing to the debilitating clinical manifestations of this chronic disease. This study investigates the impact of imiglucerase treatment on HRQOL of patients with type 1 GD and bone involvement. Thirty‐two previously untreated type 1 GD patients with skeletal manifestations including bone pain, medullary infarctions, avascular necrosis, and lytic lesions received biweekly imiglucerase (at 60 U/kg). The Short Form‐36 Health Survey (SF‐36) was administered at regular intervals to assess HRQOL. Mean baseline SF‐36 physical component summary (PCS) scores were diminished relative to US general population norms. Low PCS scores were more common in patients with medullary infarction, lytic lesions, and higher bone pain severity scores. Statistically significant improvements were observed for all eight SF‐36 subscales after 2 years of treatment. Mean PCS and mental component summary (MCS) scores increased to within the normal range after 2 years of treatment and were maintained through year 4. Large HRQOL gains were observed even in patients with the most advanced disease and lowest baseline PCS scores. Imiglucerase treatment has a significant positive impact on HRQOL of type 1 GD patients with skeletal disease, including those with bone infarctions, lytic lesions, and avascular necrosis.

Treatment of Fabry’s Disease with the Pharmacologic Chaperone Migalastat

BACKGROUND Fabrys disease, an X-linked disorder of lysosomal α-galactosidase deficiency, leads to substrate accumulation in multiple organs. Migalastat, an oral pharmacologic chaperone, stabilizes specific mutant forms of α-galactosidase, increasing enzyme trafficking to lysosomes. METHODS The initial assay of mutant α-galactosidase forms that we used to categorize 67 patients with Fabrys disease for randomization to 6 months of double-blind migalastat or placebo (stage 1), followed by open-label migalastat from 6 to 12 months (stage 2) plus an additional year, had certain limitations. Before unblinding, a new, validated assay showed that 50 of the 67 participants had mutant α-galactosidase forms suitable for targeting by migalastat. The primary end point was the percentage of patients who had a response (≥50% reduction in the number of globotriaosylceramide inclusions per kidney interstitial capillary) at 6 months. We assessed safety along with disease substrates and renal, cardiovascular, and patient-reported outcomes. RESULTS The primary end-point analysis, involving patients with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy, did not show a significant treatment effect: 13 of 32 patients (41%) who received migalastat and 9 of 32 patients (28%) who received placebo had a response at 6 months (P=0.30). Among patients with suitable mutant α-galactosidase who received migalastat for up to 24 months, the annualized changes from baseline in the estimated glomerular filtration rate (GFR) and measured GFR were -0.30±0.66 and -1.51±1.33 ml per minute per 1.73 m(2) of body-surface area, respectively. The left-ventricular-mass index decreased significantly from baseline (-7.7 g per square meter; 95% confidence interval [CI], -15.4 to -0.01), particularly when left ventricular hypertrophy was present (-18.6 g per square meter; 95% CI, -38.2 to 1.0). The severity of diarrhea, reflux, and indigestion decreased. CONCLUSIONS Among all randomly assigned patients (with mutant α-galactosidase forms that were suitable or not suitable for migalastat therapy), the percentage of patients who had a response at 6 months did not differ significantly between the migalastat group and the placebo group. (Funded by Amicus Therapeutics; ClinicalTrials.gov numbers, NCT00925301 [study AT1001-011] and NCT01458119 [study AT1001-041].).

Mutation analysis and expression of the mottled gene in the macular mouse model of Menkes disease

The gene for Menkes disease, an X-linked disorder of copper transport, has recently been identified and shown to encode a copper-transporting P-type ATPase. The macular mutant mouse has been proposed as an animal model for Menkes disease. In the present study, we report the finding of a missense mutation in the mottled gene of the macular mouse. A single base change, T to C, at nucleotide position 4223, is predicted to result in an amino acid change from serine to proline at residue 1382 in the eighth transmembrane domain. This mutation differs from the 6-bp deletion we find in brindled cDNA. With validation of macular as an animal model of Menkes disease, we compared mottled gene expression in the intestine, kidney, and brain of macular and normal mice. In Northern analyses an 8.3-kb transcript was detected in the intestine, kidney, and brain of both normal and macular mice, with the level of transcript in macular approximately 80% that of normal. In situ hybridization studies revealed that the mottled gene was clearly expressed in intestinal epithelial cells, Paneth cells, and renal proximal tubular cells of both normal and macular mice. In normal brain, mottled gene expression was most intensely observed in the choroid plexus, in Ammons horn and the dentate gyrus in the hippocampus, in Purkinje cells, and the granular layer of the cerebellum. The intensity and localization of the signals in the brain of macular mice were similar to those of the controls. The distribution of expression of mottled is correlated with cells and tissues showing histopathology or abnormal copper sequestration in macular and other mutants.

Hyperammonemia in urea cycle disorders: Role of the nephrologist

Hyperammonemia associated with inherited disorders of amino acid and organic acid metabolism is usually manifested by irritability, somnolence, vomiting, seizures, and coma. Although the majority of these patients present in the newborn period, they may also present in childhood, adolescence, and adulthood with failure to thrive, persistent vomiting, developmental delay, or behavioral changes. Persistent hyperammonemia, if not treated rapidly, may cause irreversible neuronal damage. After the diagnosis of hyperammonemia is established in an acutely ill patient, certain diagnostic tests should be performed to differentiate between urea cycle defects and other causes of hyperammonemic encephalopathy. In a patient with a presumed inherited metabolic disorder, the aim of therapy should be to normalize blood ammonia levels. Recent experience has provided treatment guidelines that include minimizing endogenous ammonia production and protein catabolism, restricting nitrogen intake, administering substrates of the urea cycle, administering compounds that facilitate the removal of ammonia through alternative pathways, and, in severe cases, dialysis therapy. Initiation of dialysis in the encephalopathic patient with hyperammonemia is indicated if the ammonia blood level is greater than three to four times the upper limit of normal. Hemodialysis is the most effective treatment for rapidly reducing blood ammonia levels. Continuous hemofiltration and peritoneal dialysis are also effective modalities for reducing blood ammonia levels. An improved understanding of the metabolism of ammonia and neurological consequences of hyperammonemia will assist the nephrologist in providing optimal care for this high-risk patient population.