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At least 19 recordsLinked to original sources
PubMed1976

Fabry disease: ocular manifestations.

Fabry disease involves the different eye structures with variable frequencies. Typical alterations are the vascular lesions of the conjunctiva, the whirl-like opacities of the cornea, the wedge-shaped anterior opacities and the branching spokes of the lens, as well as the vascular lesions of the retina. Histopathologic examination correlates well with the observed symptoms. Several drugs may induce whirl-like opacities. The importance of the slit-lamp examination in Fabry disease has been further stressed by the discovery of angiokeratoma corporis diffusum in fucosidosis.

Adult↗
PubMed1978

Use of microtechniques for the detection of lysosomal enzyme disorders: Tay-Sachs disease, Gm1-gangliosidosis and Fabry disease.

A preliminary report on the use of microtechniques for the detection of three lysosomal storage diseases (Tay-Sachs, GM1-gangliosidosis and Fabry disease) is presented. This microassay method uses from 100 to 300 cultured amniotic fluid cells or skin fibroblasts. A comparison between values for total activity and heat inactivated forms of hexosaminidase (in Tay-Sachs disease) is presented. The feasibility of the use of this microtechnique in prenatal diagnosis is discussed.

Amniotic Fluid↗
PubMed1976

Angiokeratoma corporis diffusum (Fabry disease). A lysosomal disease.

Angiokeratoma corporis diffusum (Fabry disease) is an X-linked recessive disease. We had an opportunity to examine a heterozygous female patient with angiokeratoma and cornea verticillata. The patient's serum alpha-galactosidase activity was reported to be about 50% of normal. Skin lesion biopsy specimens were stained with electron microscopic acid phsophatase (ACP), with proper controls. Acid phosphatase activity was demonstrable within membrane-bound inclusions of cutaneous vascular endothelial cells. This suggested that the accumulation of abnormal glycolipids in the vascular cells occurs in the lysosomes.

Acid Phosphatase↗
PubMed2026

Epigenetic aging and autosomal methylation remodeling in Anderson-Fabry disease.

Anderson-Fabry disease (AFD) is a rare X-linked lysosomal storage disorder characterized by marked clinical heterogeneity and incompletely understood genotype-phenotype correlations. While X-chromosome inactivation has been extensively investigated, the contribution of autosomal epigenetic mechanisms to phenotypic variability remains poorly defined. Here, we performed an exploratory genome-wide DNA methylation analysis in 32 AFD patients (22 females and 10 males; mean age 51.7 years) recruited within a multicenter regional research project in Calabria (Italy). DNA methylation profiling was conducted using the Infinium MethylationEPIC v2.0 array. The analysis integrated two complementary approaches: differential methylation analysis and evaluation of biological aging through multiple epigenetic clocks, including Horvath, Hannum, PhenoAge, Skin & Blood, GrimAge, and DunedinPACE. Exploratory methylome-wide analysis identified a limited set of CpG loci showing nominal evidence of methylation differences between carriers of pathogenic and non-pathogenic variants; however, none remained statistically significant after correction for multiple testing. Annotation of the top-ranking nominal CpG associations highlighted genes involved in biological processes including vascular regulation, intracellular trafficking, cytoskeletal organization, immune signaling, and lipid metabolism. No significant differences between groups were observed for the conventional epigenetic age-acceleration measures examined. In contrast, carriers of pathogenic variants showed significantly higher DunedinPACE values (p = 0.0328), indicating a faster estimated pace of biological aging. This finding suggests that DunedinPACE may capture aspects of the cumulative systemic burden associated with pathogenic GLA variants, although confirmation in larger independent cohorts is required. Overall, this pilot epigenomic study provides preliminary evidence that autosomal epigenetic remodeling and biological aging acceleration may contribute to phenotypic heterogeneity in AFD.

Anderson-Fabry disease↗
PubMed2024

Fabry disease in female monozygotic twins with complex intronic haplotype variants: a case report.

BACKGROUND: Fabry disease is an X-linked lysosomal storage disease caused by the impairment of α-galactosidase A. The complex intronic haplotype (CIH) variants, located in promoter and intronic regulatory lesions, has been found in patients with classical forms of Fabry disease. We present a case of Fabry disease in female monozygotic twins exhibiting the CIH mutation and classical manifestations. CASE PRESENTATION: A 61-year-old woman with a history of stroke, carotid artery occlusion, hypertrophic cardiomyopathy, and chronic kidney disease was referred to the nephrology clinic for management of her chronic kidney disease. Her monozygotic twin sister also presented with hypertrophic cardiomyopathy, atrial flutter, carotid stenosis, and proteinuria. Clinical symptoms and a comprehensive family history strongly suggested the presence of Fabry disease. Genetic analysis revealed the presence of 5 variants within a complex intronic haplotype (CIH): c.-10 C > T, c.369 + 990 C > A, c.370 - 81_370-77delCAGCC, c.640-16 A > G, and c.1000-22 C > T. We conducted a review of the patient's previous kidney biopsy findings, which demonstrated the presence of lamellated inclusion bodies in electron microscopy. Remarkably, both the monozygotic twin sister and her son exhibited the same genetic mutation. Enzyme replacement therapy was initiated for the patient. Her kidney function decreased throughout a thorough 2-year follow-up period, while there was a slight decrease in the left ventricular mass index. CONCLUSIONS: This is the first reported case of female monozygotic twins with the CIH variants representing cardiac, cerebrovascular, and renal manifestations suggestive of Fabry disease.

Humans↗
PubMed1977

Evidence for preferential X-chromosome inactivation in a family with Fabry disease.

Severe clinical signs of Fabry disease were observed in four of eight heterozygous daughters of a male patient. Activities of alpha-galactosidase A in serum, white blood cells, and hair roots of the manifesting carriers were markedly lower than 50% of normal. These findings are not easy to interpret in terms of random X inactivation alone; several alternative models including nonrandom (preferential) X inactivation are discussed.

Blood Group Antigens↗
PubMed2026

Sex-Based Disparities in Fabry Disease Cause Challenges in Newborn Screening.

INTRODUCTION: Fabry disease (FD) is a multi-systemic, X-linked lysosomal storage disorder caused by decreased &#x3b1;-galactosidase activity. Early diagnosis enables timely treatment, but enzyme-based newborn screening (NBS) may not detect affected females. We hypothesized that enzyme-based NBS limitations contribute to sex-based diagnostic disparities in FD and investigated these differences. METHODS: Retrospective cohort analyses used data from the Fabry Registry (FR: 2001-2023) and Tennessee NBS (2017-2024). Sex differences in diagnosis via NBS, biochemical phenotype, symptom onset, and treatment initiation were analyzed using Wilcoxon and chi-square tests. RESULTS: Among 8,657 FR individuals, 73 (67 males, 6 females) were identified via NBS. FR data show that affected females had significantly higher residual &#x3b1;-galactosidase activity than affected males (leukocyte median: 45.9% vs. 3.9%, plasma median: 32.5% vs. 3.9%; p < 0.0001 for both). FR females had delayed symptom onset (18.1 vs. 11.1 years), later diagnosis (35.5 vs. 30.8 years), and lower treatment rates (51.1% vs. 80.8%) compared to males (all %, p < 0.0001). Tennessee NBS detected 25 males but no females. CONCLUSION: Females with FD have delays in symptom onset, diagnosis, and treatment compared to males. Furthermore, higher residual enzyme activity causes current enzyme-based NBS to miss most females. Incorporating sex-specific cutoffs and/or molecular sequencing into NBS could improve early detection and reduce sex-based disparities.

Humans↗
PubMed1975

Fabry disease: diagnosis by alpha-galactosidase activities in tears.

The enzymatic diagnosis of hemizygotes with Fabry disease and heterozygous carriers was accomplished by the fluorometric determination of alpha-galactosidase activities in tears. Two components of total alpha-galactosidase activity were differentiated by their relative thermostabilities and by chromatography on DEAE-cellulose. The major component, alpha-galactosidase A, was thermolabile and represented approximately 90% of total activity; the remaining activity was thermostable, eluted at a slightly higher salt concentration and was designated alpha-galactosidase B. A single, symmetric pH optimum was observed for total alpha-galactosidase activities from heterozygotes and normal individuals, whereas the total activity from hemizgotes, which was about 10% of that in normal controls, had a broad pH profile, identical to those for alpha-galactosidase B activities from all individuals studied. The apparent Km values for total activities were 3.2, 4.0, and greater than 13 mM for normal individuals, heterozygotes, and hemizygotes, respectively. In contrast, apparent Km values for alpha-galactosidase B activities were greater than 13 mM for all individuals, further suggesteng that the residual activity in hemizygotes with Fabry disease represented the alpha-galactosidase B component. of the potential inhibitors studied, alpha-D-melibiose was found to competitively inhibit total alpha-galactosidase activity (Ki approximately 10 mM). These studies demonstrate that tears provide an easily obtainable source of freshly secreted enzyme for the diagnosis of hemizygotes and heterozygotes with Fabry disease and suggest that tears may be useful for the diagnosis of other inborn errors of metabolism.

Drug Stability↗
PubMed1979

Fabry disease: cellular expression of enzyme deficiency in nerve xenografts.

Human sural nerve fascicles from a patient with Fabry disease were transplanted into nude-mouse sciatic nerves to determine whether transplanted perineurial cells and smooth-muscle cells of an epineurial artery would express the genetic abnormality of the disease. Four months after grafting, both perineurial cells and smooth-muscle cells contained the cytoplasmic lamellated inclusion bodies characteristic of Fabry disease. This provided evidence of human perineurial cells and smooth-muscle cells in the regenerated xenografts.

Adult↗
PubMed1976

Cardiac valvular anomalies in Fabry disease. Clinical, morphologic, and biochemical studies.

The cardiovascular abnormalities were investigated in two unrelated hemizygous males with Fabry disease who had clinical mitral insufficiency. Postmortem examination of their hearts revelaed anatomic, ultrastructural and biochemical abnormalities resulting from defective activity of the lysosomal enzyme, alpha-galactosidase A. The ultrastructural and biochemical studies demonstrated the marked accumulation of the major glycosphingolipd substrate, trihexosyl ceramide, in the lyosomes of all the cardiac tissues examined; the greatest concentrations were found in the mitral valve and elft ventricular myocardium. Intriguingly, digalactosyl ceramide, a glycosphingolipid substrate not detectable in normal lung, vessel or cardiac tissues, was found increased only in the lung and right heart tissues. Morphologic and chemical examination of cardiac and systemic vessels demonstrated accumulation of trihexosyl ceramide in lysosomes of the vascular endothelium. These studies demonstrate that the progressive accumulation of trihexosyl ceramide in the lysosomes of the cardiac structures and vascular system leads to the multiple cardiovascular manfiestation of Fabry disease.

Ceramides↗
PubMed2026

Sex-Specific Diagnostic Inequality in Fabry Disease: Lessons Learned from Analysis of Newborn Screening and Cascade Testing in Tennessee from 2017 to 2024.

INTRODUCTION: Fabry disease (FD) is an X-linked lysosomal storage disease caused by alpha-galactosidase A (aGAL) deficiency. Newborn screening (NBS) programs for FD have been implemented in several US states; however, its effectiveness in identifying affected females remains uncertain. We hypothesized that sex-specific inequality of NBS-based detection of FD results in different diagnostic pathways for males and females with FD. METHODS: We compared diagnostic approaches for males and females with FD using Tennessee NBS results and Vanderbilt Lysosomal Storage Disorders Database (VLSDD). Sex-specific detection differences were assessed using Fisher's exact test (&#x3b1; = 0.05). RESULTS: Tennessee NBS identified 25 males but no females with FD from 2017 to 2024. In VLSDD, among 81 individuals with FD, sex distribution was nearly equal (42 males, 39 females). Among males, 26/42 (62%) were diagnosed via NBS, 7/42 (17%) through known family history, and 9/42 (21%) based on clinical symptoms. All 16 males diagnosed through non-NBS were born before its implementation. In contrast, none of the 39 females were diagnosed through NBS (p value <0.05). Of these, 13/39 (33%) were diagnosed through cascade testing following their sons' detection by NBS, with a median age at diagnosis of 28 years (25th-75th percentile: 24.5-34.0). Of the remaining 26 females, 12/26 (46%) were diagnosed after a family member was diagnosed through clinical symptoms and 14/26 (54%) were diagnosed through clinical symptoms. CONCLUSIONS: NBS effectively identifies affected males but fails to detect females with FD, though it can indirectly facilitate diagnosis of older female relatives.

Humans↗
PubMed1975

Ultrastructural observations of the oral mucosa in Anderson-Fabry disease.

Electron microscopic study of oral mucosa from a patient with Anderson-Fabry disease (glycosphingolipid lipidosis) revealed lamellar and membranous osmiophilic intracytoplasmic inclusions having a periodicity of 4.5 nanometers. These were observed chiefly in reticulo-endothelial cells as membrane bound and occasionally unbound bodies. They could also be observed within the cytoplasm of squamous epithelial cells, particularly of the stratum germinativum. Morphologic features in endothelial and epithelial cells are described.

Cell Membrane↗
PubMed1975

On the diagnosis of Fabry's disease.

Fabry's disease is a recessive X-linked inborn error of metabolism due to deficiency of the lysosomal enzyme alpha-galactosidase. The large variety of symptoms may make the diagnosis difficult. A severely afflicted female patient is presented. For several years she had been treated under the diagnosis polyarteritis nodosa until the characteristic cutaneous lesions of Fabry's disease were recognized. Enzymatic studies and electronmicroscopic examinations confirmed the diagnosis. A symptomatic effect of corticosteroid treatment was proven. The grave prognosis, the recent attempts at enzyme substitution therapy and the possibility of preventing new cases by prenatal diagnosis should stimulate the efforts of the clinician to diagnose the disease.

Adult↗
PubMed1977

Electrocardiographic and vectorcardiographic abnormalities in Fabry's disease.

Fabry's disease has been reported to be associated with ECG abnormalities. Thirty-two patients with this disease followed in the University of Minnesota had ECG's and 15 had VCG's. An abonrmal rhythm was observed in two patients on initial examination and four more developed abnormal rhythm on follow-up examinations. A short PR interval (120 msec. or less) was seen in five patients. Thirteen others had a PR interval that was less than 140 msec. Conduction abnormalities involving the A-V node or His bundle or its branches were present in 22 per cent of the patients, most frequently the intraventricular conduction defects progressing to the right bundle branch block. Atrial or ventricular enlargement was seen in 60 per cent of the patients, left ventricular hypertrophy being the most common. ST-T changes with or without chamber enlargement were seen in 10 patients. One patient had an anterior myocardial infarction pattern on his ECG. Hemizygosity was found to be associated with significantly more abnormalities than heterozygosity. The severity of conduction defects also increased with the duration of the disease process. Vectorcardiography in this study did not provide significant additional information other than that observed on the ECG alone. Since the pathology usually reveals myocardial fibers, conduction system, and blood vessels infiltrated with glycosphingolipid, it is believed that lipid infiltration is responsible for conduction defects, chanber enlargement, and other abnormalities. Although Fabry's disease is rate, it may be amenable to therapy; therefore, recognition of cardiac involvement is important.

Adolescent↗
PubMed2026

[Analysis of clinical spectrum and genotype characteristics of 9 cases of Fabry disease].

Objective: To investigate the genetic characteristics and clinical phenotypes across different genotypes in patients with Fabry disease. Methods: Clinical data of 9 confirmed FD patients treated from June 2019 to December 2025 at the Affiliated Huai'an No.1 people's Hospital of Nanjing Medical University were retrospectively analyzed. The diagnostic criteria for FD included &#x3b1;-galactosidase A (&#x3b1;-GalA) activity, GLA gene sequencing, globotriaosylsphingosine levels, and renal biopsy findings, supplemented by clinical symptoms and signs. Genetic testing was performed on both the proband and their family members. Proband underwent next-generation sequencing of the GLA gene using the long-range PCR. Family members were verified by conventional PCR combined with Sanger sequencing. Variants were classified according to the 2015 American College of Medical Genetics and Genomics guidelines for sequence variation interpretation. Results: Of the 9 patients, 4 were males and 5 were females. The mean &#x3b1;-Gal A activity was (0.47&#xb1;0.13) &#x3bc;mol&#xb7;L-1&#xb7;h-1 in males and (2.38&#xb1;0.91) &#x3bc;mol&#xb7;L-1&#xb7;h-1 in females. The mean age at diagnosis was (43.0&#xb1;16.7) years. The main clinical manifestations included renal impairment in 7 cases (proteinuria, chronic kidney disease, or end-stage renal disease), cardiac involvement in 8 cases (myocardial hypertrophy, arrhythmia, etc.), and autonomic nervous system symptoms in 6 cases (hypohidrosis). Pathogenic or likely pathogenic GLA variants were identified in all 9 patients, of which 8 were classified as pathogenic and 1 as a variant of uncertain significance. Three patients underwent family screening: in one case, the variant was possibly inherited from the maternal grandmother; one case was confirmed as a de novo mutation; and in one case, paternal inheritance could not be excluded. Renal biopsy in one patient revealed characteristic myeloid bodies and zebra bodies. Among the 9 patients, 1 received agalsidase &#x3b1; and 8 received agalsidase &#x3b2;, with one case developing infusion-associated reactions after 12 infusions. During the follow-up period, one patient died due to cardiac complications. Conclusions: FD patients exhibit a broad clinical spectrum and diverse genotypes. Atypical presentations should be closely monitored to enable early diagnosis and treatment, thereby improving prognosis.

Humans↗
PubMed1977

Heterozygote detection in angiokeratoma corporis diffusum (Anderson-Fabry disease). Studies on plasma, leucocytes, and hair follicles.

Heterozygote detection for angiokeratoma corporis diffusum (Anderson-Fabry disease, ACD), an X-linked disorder of glycosphingolipid metabolism was examined using alpha-galactosidase activity, an alpha-galactosidase/beta-galactosidase activity ratios (alpha/beta ratio) in leucocytes, plasma, and hair follicles; For leucocytes, 22 obligate heterozygotes, 25 suspected heterozygotes, and 47 control subjects were studied, while for plasma, the groups were 17 obligate heterozygotes and 35 controls. The alpha/beta ratio in plasma and leucocytes was clearly a better discriminator between obligate heterozygotes and controls than alpha-galactosidase activity alone, but still failed to detect 3 obligates with leucocytes and 2 with plasma. Discrimination was not improved by joint use of plasma and leucocyte alpha/beta ratios, but was improved by measurement of hair-follicle alpha/beta ratios. The interdecile range of log (alpha-galactosidase/beta-galactosidase activity) in 20 hair follicles from each of 4 obligate and 7 suspected heterozygotes was clearly different from 11 control subjects. Accordingly, for rapid screening for carriers of ACD, we recommend use of leucocyte or plasma alpha/beta ratios which should detect greater than 85% of heterozygotes. When results are equivocal, and ancillary information suggests heterozygous status, the more time-consuming measurement of hair-follicle alpha/beta ratios is a useful additional test.

Fabry Disease↗
PubMed1978

Neurological manifestations of Fabry disease in female carriers.

A family is described in which a 33-year-old man has classic X-linked recessive Fabry disease. His 2 sisters were discovered to be heterozygous carriers of the Fabry gene and to have both episodic and permanent neurological deficits including vertigo, tinnitus, long tract motor signs, and bladder incontinence. The most concise explanation for these findings is that the sisters manifest central nervous system complications of the Fabry carrier state. This family provides additional evidence that female carriers of rare X-linked recessive disorders may exhibit serious consequences of the disease, presumably related to tissue variability in expression of mutant enzyme activity.

Adult↗