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Cardiac Hypertrophy, Heart Failure and Cardiomyopathy
Published in Mary N. Sheppard, Practical Cardiovascular Pathology, 2022
Fabry disease is the most common glycogen storage disorder, affecting approximately 1 in 50 000 individuals. It is an X-linked recessive disorder due to reduced or absent activity of α-galactosidase A caused by mutations in the GLA gene. More than 200 mutations have been identified. The disease is X-linked dominant and hemizygous male patients have no detectable serum Gal A activity in blood leucocytes. This deficiency results in progressive accumulation of globotriaosylceramide in the heart, kidneys and nerves. The disease generally presents with varying degrees of unexplained LVH. Cardiac manifestations often present in the third decade in males and later in heterozygous females. An atypical disease variant is occasionally encountered with unexplained LVH in adults in their sixth to eighth decade. LV wall thickness and mass increases as age and disease severity progress. Demonstration of decreased or absent serum or leukocyte α galactosidase A activity or sequencing the GLA gene for likely pathogenic or pathogenic variants usually establishes the diagnosis. Endomyocardial biopsy, which is occasionally necessary when genetic testing or α galactosidase A activity results are equivocal, reveals hypertrophy and vacuolization of myocytes with concentric lamellar bodies in the sarcoplasm of myocardial cells (Figs. 5.76, 5.77).
Stroke and Transient Ischemic Attacks of the Brain and Eye
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Fabry's disease (FD) is an X-linked lysosomal storage disorder caused by GLA gene mutations that result in α-galactosidase deficiency and subsequent accumulation of globotriaosylceramide in various organs (Table 12.23). Progressive accumulation of globotriaosylceramide in endothelial and vascular smooth muscle cells causes progressive stenosis and occlusion of small arterial vessels. Furthermore, the large vessels dilate, resulting in dolichoectatic changes and flow stagnation, particularly in the posterior circulation (e.g. basilar artery), increasing the risk of artery-to-artery embolism and vessel thrombosis. Hence, FD is associated with both cerebral macroangiopathy and microangiopathy, which leads to an increased incidence of stroke and first stroke at a younger age than the general population. Preliminary studies suggest that enzyme replacement therapy (e.g. agalsidase alfa or agalsidase beta) may reduce the risk of stroke.8
Fabry disease
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
The defective activity of α-galactosidase leads to the accumulation of glycosphingolipids that have a terminal α-galactosyl moiety [8, 46]. The most prominent is ceramide trihexoside (Figure 87.1), which is also known as globotriasylceramide [Gal(αl→4)Gal(β1→4)Glc(β1-1’)ceramide]. Galabiosylceramide, a compound in which ceramide is linked to two galactose moieties, is also found in large quantities in tissues such as kidney [23]. The blood group B antigenic glycosphingolipid also contains a terminal galactose and, hence, it accumulates in Fabry patients with B or AB blood types [47]. Changes in concentration of globotriaosylceramide did not appear to be useful biomarkers for progression disease manifestations [48].
Visual outcome, ocular findings, and visual quality of life in patients with Fabry disease
Published in Ophthalmic Genetics, 2022
Mattias Nilsson, Hani Tavakoli Kolagari, David Epstein, Branka Samolov, Monica Olsson, Karin Naess, Mikael Oscarson, Kristina Teaer Fahnehjelm
Fabry disease (FD) is a rare lysosomal storage disorder with an estimated prevalence of 1:40,000 to 1:117,000 world-wide (1). It is caused by pathogenic variants in the X-chromosomal (×q22.1) GLA gene encoding α-galactosidase A, necessary for metabolism of globotriaosylceramide (Gb3). Deficiency results in the progressive accumulation of Gb3 and related compounds in cells throughout the body. Many patients develop pain crisis (acroparasthesias), hypohidrosis, and skin lesions (angiokeratomas) during childhood, and later in life, gradual accumulation can result in end-stage renal disease, hypertrophic cardiomyopathy, and cerebrovascular disease (2). However, there is a wide spectrum of disease manifestations, ranging from the classical severe phenotype to atypical late-onset forms.
Myeloid bodies is not an uncommon ultrastructural finding
Published in Ultrastructural Pathology, 2022
Hae Yoon Grace Choung, Jerome Jean-Gilles, Bruce Goldman
Because the pathologic features of FD are not specific, it is almost impossible to make the diagnosis of FD on pathology alone and is rather dependent on clinical history, presentation, and genetics. Renal manifestations in FD most frequently present as subnephrotic-range proteinuria and renal insufficiency is likely related to the accumulation of undigested phospholipids leading to injury to podocytes and tubular epithelium. Patients with FD develop symptoms correlating with damage to the organ system affected by the accumulation of globotriaosylceramide such as those involving nerves (e.g. neuropathies or acroparasthesias), central nervous system (e.g. transient ischemic attacks and strokes), skin (e.g. angiokeratomas, hyperhidrosis), eyes (e.g. ocular opacities), heart, and kidneys. However, an increasing number of reports of atypical FD limited to the heart or kidney have been described 47–50 including female carriers who have a heterogeneous presentation due to lionization ranging from asymptomatic or minimal to severe disease.51 To that point, all the biopsies from the FG cohort were middle-aged women and likely reflects the challenges that arise with diagnosing female carriers who typically have an atypical presentation of the disease and are therefore often diagnosed later than males.
Recurrent acute coronary syndrome, polymorphic premature ventricular complexes and a son with a (mis)diagnosis of multiple sclerosis
Published in Acta Cardiologica, 2020
Jeremy Nestele, Carst van den Hoven, Emeline M. Van Craenenbroeck, Francois Eyskens, Bernard P. Paelinck, Amélie Dendooven, Steven E. Haine
Fabry disease is a X-linked lysosomal storage disorder that causes excessive accumulation of globotriaosylceramide (GB-3) in various organs. Male patients exhibit classical type Fabry disease, characterised by systemic organ damage. Female subjects can show variable organ involvement. This can be attributed to X-chromosome inactivation. The exact prevalence of Fabry disease is unknown, mainly due to underdiagnosis. As illustrated in our case, even at autopsy the correct diagnosis can be missed. Several family members suffering from undiagnosed Fabry disease, were identified subsequently. In patients with cardiac hypertrophy and multiple organ involvement, Fabry disease should be kept in mind and therefore, alfa galactosidase activity in men and GLA mutation analysis in men and women should be assessed.