Involvement In Fabry Disease Research Articles

Diagnosis and Management of Kidney Involvement in Fabry Disease

Interest in the diagnosis and treatment of Fabry disease has been greatly stimulated by the availability of Food and Drug Administration-approved, effective enzyme replacement therapy. This review will update the progress in this area since enzyme replacement therapy has become available. Fabry disease is often associated with proteinuric chronic kidney disease (CKD), and it appears that the treatment paradigms that have proven to be so effective in diabetes mellitus and other forms of proteinuric kidney disease are also effective in conjunction with enzyme replacement therapy for treating the kidney manifestations of Fabry disease. As such, Fabry disease represents an interesting example of progressive proteinuric kidney disease in which the usual blood pressure is lower than in other forms of CKD. This makes the use of effective antiproteinuric therapy challenging, especially considering the autonomic dysfunction that appears to be part of the disease. Comprehensive therapy for Fabry disease includes enzyme replacement therapy and all of the adjunctive therapies that are currently used to treat all forms of proteinuric CKD. It is anticipated that this approach will preserve kidney function and also benefit the cardiac and cerebrovascular systems in patients with Fabry disease.

Tissue Doppler imaging in Fabry disease.

The development of effective enzyme replacement/enhancement therapy makes of clinical relevance considering Fabry disease in the differential diagnosis of patients with hypertrophic cardiomyopathy. In particular the opportunity to significantly modify the clinical progression of the disease has reinforced the need for early diagnosis of Fabry cardiomyopathy. The study with tissue Doppler of Fabry patients with endomyocardial biopsy-proven cardiac involvement showed a reduction of both diastolic and systolic myocardial velocities recorded at septal and lateral corners of mitral annulus. Tissue Doppler abnormalities were present not only in patients with left ventricular hypertrophy but also in younger patients with normal cardiac wall thickness and represent the first sign of myocardial damage. Furthermore tissue Doppler studies have been shown useful in detecting cardiac involvement in female carriers with no systemic manifestations of Fabry disease. In patients already submitted to enzyme-replacement therapy tissue Doppler and strain rate imaging represent useful noninvasive tools in assessing treatment efficacy. Tissue Doppler imaging can provide early detection of cardiac involvement in Fabry disease and represents the most accurate and sensitive noninvasive tool for the diagnosis of myocardial dysfunction and for the assessment of cardiac improvement during enzyme replacement therapy. The detection of tissue Doppler abnormalities in female carriers may represent a hint for an invasive assessment of cardiac involvement.

Fabry disease: Kidney involvement and enzyme replacement therapy

when he was 38 years old. At the time of onset of renal insufficiency, proteinuria was approximately 2500 mg/ 24 hours and continued at this level during all the years of follow-up until the patient reached ESRD, when a reduction to 300 mg/24 hours was noted. The patient’s mild to moderate hypertension was well controlled at a level of 130/84 mm Hg with an angiotensin-converting enzyme (ACE) inhibitor until 1 year before the onset of ESRD, when a calcium channel blocker was added. During the 10-year follow-up, the patient’s creatinine clearance (CCr) declined at a rate of 7.9 mL/min/year (Fig. 1). The CAPD program is 4 × 1 L dialysis fluid with 1.5% glucose concentration. The small size of the patient (54 kg body weight and 156 cm height) led to an intolerance of larger intraperitoneal volumes. Before he commenced CAPD, echocardiography revealed a left ventricular mass (LVM) of 430 g and an ejection fraction (EF) of 47%. In view of the renal findings and cardiac dysfunction, enzyme replacement treatment (ERT) with intravenous agalsidase beta (Fabrazyme), 1 mg/kg/body weight initially every other week, was initiated 1 month after he began CAPD. Before the commencement of treatment and after 1.5, 3, 6, 12, and 15 months, weekly residual renal creatinine clearance (wCrCr) and renal Kt/V urea (wKrt/Vurea) were determined according to standard equations. Peritoneal dialysis adequacy was also estimated by weekly peritoneal Kt/V urea (wKpt/Vurea) and creatinine clearance (wCpCr). The latter was adjusted for the patient’s size using a nomogram for body surface area. Table 1 displays routine laboratory investigation before and after ERT. The wCrCr rose after 1.5 months of therapy from 29 to 82 L/week/1.73 m 2 . It remained at approximately 80 L/week/1.73 m 2 after 3 and 6 months of therapy; a decrease to 60 L/week/1.73 m 2 was noticed at month 12 and continued until month 15 of therapy [these values are represented in the figure as Ccr (mL/min)]. Also, the wKrt/Vurea rose strikingly, from 0.8 to 2.3 after 1.5 months, remained around 2.0 after 3 and 6 months, dropped to 1.5 after 12 months, and remained stable after 15 months of treatment. The wCpCr, on the other hand, did not change significantly during the same period. Similarly,

Auditory and vestibular findings in Fabry disease: a study of hemizygous males and heterozygous females.

This study aimed to evaluate audiological and vestibular involvement in Fabry disease and the early effects of enzyme replacement therapy with human alpha-galactosidase A. Fourteen patients (10 males, 4 females) aged 14-57 years were studied. Each patient underwent a clinical (history of otological and vestibular aspects, otoscopy) and instrumental (pure tone and speech audiometry, impedance, auditory brainstem response and oto-acoustic emission recordings, vestibular caloric tests, electronystagmography during acceleratory stimulation, dynamic posturography) evaluation before starting enzyme replacement therapy. Fifty per cent of patients complained of hearing symptoms (hearing loss, tinnitus, ear fullness). Subjective hearing loss was present in six cases and in three cases it was the first reported symptom of Fabry disease. In six of the seven cases the onset and/or progression of hearing symptoms were sudden. Vertigo or dizziness was reported by four patients and in two cases was associated with hearing symptoms. Audiological evaluation showed sensorineural hearing loss in eight patients (5 males, 3 females). Hearing loss was unilateral in six cases and bilateral in the remaining two cases. The hearing loss (HL) ranged from 30 to 80 dB HL (mean, 43 dB HL) and the lesion was always cochlear. Vestibular examination showed abnormalities in four patients (bilateral weak/abolished response in three cases, side prevalence in one case), which were not related to either the audiological results or the history of vertigo/dizziness. Involvement of the inner ear is common in men and women with Fabry disease. We found a high incidence of cochlear hearing loss, which was typically unilateral and showed onset and/or progression by sudden episodes. Vascular or hydropic mechanisms could be hypothesized to explain audiological findings. Vestibular involvement had a lower incidence and showed a different pattern, thus suggesting that several pathophysiological mechanisms could play a role in determining inner ear damage in Fabry disease. Our preliminary results show that enzyme replacement therapy may stabilize hearing function; however, further follow-up is required.

Cardiac involvement in Fabry disease

Cardiac involvement in Fabry disease

Electrocardiographic signs of hypertrophy in Fabry disease‐associated hypertrophic cardiomyopathy

Fabry disease results from deficient activity of the lysosomal enzyme alpha-galactosidase A. Progressive accumulation of the major substrates leads, in both men and women, to progressive hypertrophic cardiomyopathy. We aimed to evaluate the utility of different electrocardiographic (ECG) parameters for assessing the degree and severity of hypertrophic cardiomyopathy in patients with Fabry disease. A total of 166 ECGs of 94 hemi- and heterozygous patients with Fabry disease were analysed and compared with echocardiographic-estimated left ventricular mass (LVM). There was a significant (p < 0.0001) correlation between QRS duration (R2 = 0.59), 12-lead amplitude/duration product (R2 = 0.61), Sokolow-Lyon voltage/duration product (R2 = 0.52) and LVM. Analysis of receiver operating characteristics revealed that the 12-lead amplitude/duration product had the highest sensitivity-specificity relationship (p < 0.01 compared with the Cornell index). In general, ECG signs of left ventricular hypertrophy correlated well with LVM as revealed by echocardiography. Of the parameters studied, the 12-lead amplitude/duration product was the most successful at describing the severity of cardiac involvement in Fabry disease. These data suggest that ECG parameters have potential for use as a simple and cost-effective means of screening for hypertrophic cardiomyopathy in patients with Fabry disease.

Severity of macrovascular involvement in Fabry disease: is there a correlation with interventricular septum thickness?

Severity of macrovascular involvement in Fabry disease: is there a correlation with interventricular septum thickness?

Pulmonary involvement in Fabry disease

Pulmonary involvement in Fabry disease

Cardiac involvement in Fabry disease

Fabry disease is a rare X-linked defect of the lysosomal enzyme alpha-galactosidase A. The disease is characterized by progressive intracellular accumulation of neutral glycosphingolipids. The storage occurs within various tissues and cells, including cardiocytes, the cardiac conduction system, and valvular fibrocytes. Cardiac involvement may be the sole manifestation of the disease, particularly in individuals with residual enzyme activity. In general, hemizygous men are more seriously affected than heterozygous women. The main cardiac manifestations include myocardial hypertrophy, which, in some patients, mimics hypertrophic cardiomyopathy. Conduction system involvement leads to PR shortening or, in later stages, to AV blocks. Arrhythmias presenting with variable severity also appear to be common. Valvular involvement is frequently noted but generally mild and clinically non-significant. Newly available enzyme replacement therapy has produced promising results in preventing further functional deterioration of affected organs and possibly also in reversing impaired function. With the advent of effective enzyme replacement therapy, early diagnosis of Fabry disease may be crucial for patient prognosis.

Natural History and Treatment of Renal Involvement in Fabry Disease

Renal involvement has been recognized as a complication of Fabry disease since the original reports by Anderson and Fabry in the late nineteenth century. Clinical involvement of the kidney typically begins before age 30 in male patients, although exceptions occur. In female carriers, the variability

Long-term enzyme correction and lipid reduction in multiple organs of primary and secondary transplanted Fabry mice receiving transduced bone marrow cells

Fabry disease is a compelling target for gene therapy as a treatment strategy. A deficiency in the lysosomal hydrolase alpha-galactosidase A (alpha-gal A; EC ) leads to impaired catabolism of alpha-galactosyl-terminal lipids such as globotriaosylceramide (Gb3). Patients develop vascular occlusions that cause cardiovascular, cerebrovascular, and renal disease. Unlike for some lysosomal storage disorders, there is limited primary nervous system involvement in Fabry disease. The enzyme defect can be corrected by gene transfer. Overexpression of alpha-gal A by transduced cells results in secretion of this enzyme. Secreted enzyme is available for uptake by nontransduced cells presumably by receptor-mediated endocytosis. Correction of bystander cells may occur locally or systemically after circulation of the enzyme in the blood. In this paper we report studies on long-term genetic correction in an alpha-gal A-deficient mouse model of Fabry disease. alpha-gal A-deficient bone marrow mononuclear cells (BMMCs) were transduced with a retrovirus encoding alpha-gal A and transplanted into sublethally and lethally irradiated alpha-gal A-deficient mice. alpha-gal A activity and Gb3 levels were analyzed in plasma, peripheral blood mononuclear cells, BMMCs, liver, spleen, heart, lung, kidney, and brain. Primary recipient animals were followed for up to 26 weeks. BMMCs were then transplanted into secondary recipients. Increased alpha-gal A activity and decreased Gb3 storage were observed in all recipient groups in all organs and tissues except the brain. These effects occurred even with a low percentage of transduced cells. The findings indicate that genetic correction of bone marrow cells derived from patients with Fabry disease may have utility for phenotypic correction of patients with this disorder.

Effect of Migalastat on Cardiac Involvement in Fabry Disease

Effect of Migalastat on Cardiac Involvement in Fabry Disease

Diffuse central neuronal involvement in Fabry disease: a proton MRS imaging study.

The in vivo determination of parenchymal involvement is important to evaluate disease burden. Proton MRS imaging (1H-MRSI) permits simultaneous measurement of N-acetylaspartate (NA), a putative neuron-specific molecule, choline-containing compounds, creatine-phosphocreatine, and lactate from four 15-mm slices divided into 0.84-mL single-volume elements. To assess the cortical and subcortical neuropathology in Fabry disease (FD). Regions of interest (ROIs) were selected from several cortical and subcortical locations in nine FD patients. Mean ROI metabolite ratios were compared with control values. FD patients showed a widespread pattern of cortical and subcortical NA reduction. Seven patients showed discrete MRI abnormalities consisting of white matter hyperintensities or basal ganglia infarcts. We found diffuse neuronal involvement in FD extending beyond the areas of MRI-visible cerebrovascular abnormalities. 1H-MRSI may become useful in therapeutic trials.

Abstracts of Literature

Abstracts of Literature

Quantitative analysis of cerebral vasculopathy in patients with Fabry disease

This study's purpose was to obtain a quantitative natural history of the cerebrovascular involvement in Fabry disease. Fabry disease is an X-linked recessive disorder due to alpha-galactosidase A deficiency. Progressive accumulation of ceramidetrihexoside within the intima and media of cerebral blood vessels causes ischemic lesions in the majority of affected patients. Determination of the natural history of the cerebral vasculopathy in Fabry disease is important to assess the effects of therapeutic intervention in this disorder. A longitudinal MRI study of 50 patients who had a total of 129 MRI scans was performed. The burden of cerebrovascular disease was determined using direct linear measurement. On T2-weighted MRI scans, 32% of the patients had no lesions (mean age, 33 years), 16% had gray matter lesions only (mean age, 36 years), 26% had lesions in white matter only (mean age, 43 years), and 26% had lesions in white and gray matter (mean age, 47 years). Disease burden increased with age, but no patient younger than 26 had lesions on MRI. All patients older than 54 had cerebrovascular involvement. The distribution of MRI-detectable lesions was typical of a small-vessel disease. Only 37.5% of patients with cerebral lesions had neurologic symptoms. These findings provide a predictable outcome measure to assess the effect of molecular interventions on the cerebrovascular circulation in Fabry disease.

Pulmonary involvement in Fabry disease.

Fabry disease is an X-linked inborn error of metabolism resulting from deficient activity of alpha-galactosidase A. Although several case reports have suggested an association between Fabry disease and airway obstruction, this has not been investigated in a large series of patients. We studied 25 unselected, consecutive, enzymatically diagnosed men referred to a General Clinical Research Center for evaluation. Thirty-six percent complained of dyspnea, and 24% had cough and/or wheezing. Symptoms were similar in smokers and nonsmokers. Nine (36%) had airway obstruction on spirometry; this finding was associated with age > or = 26 yr (p < 0.05) and dyspnea or wheezing (p < 0.005), but only weakly with smoking (p = 0.062). Five of eight patients responded to bronchodilators, but all 10 methacholine challenges were negative. Chest radiographs revealed normal lung fields in 24 patients and streaky bibasilar densities in one. No pulmonary uptake occurred on 67Ga citrate scans (18 patients) and 111In-tagged leukocyte scans (16 patients). Specific alpha-galactosidase A mutations were identified in 17 patients; all three patients with frameshift mutations and both subjects with the D264V missense mutation had obstructive impairment. We conclude that airway obstruction commonly occurs in patients with Fabry disease regardless of smoking history, and it increases with age. The presence of obstruction may be associated with certain mutations and most likely results from fixed narrowing of the airways by accumulated glycosphingolipid.