Renal, cardiac, and neurologic disease in a patient with Fabry disease, hemizygous for the c.639+5G>C intronic variant in the galactosidase alpha (GLA) gene

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Fabry disease is a rare lysosomal storage disorder caused by pathogenic variants of the gene encoding the lysosomal enzyme alpha-galactosidase (GLA),1 responsible for catalyzing the hydrolysis of terminal, nonreducing α-D-galactose residues in α-D-galactosides. Impaired α-galactosidase activity leads to accumulation of undegraded neutral glycosphingolipids, particularly globotriaosylceramide (Gb3), in the lysosomes of numerous cell types across various organs. The most significant pathophysiological impact of Gb3 storage is on the vascular endothelial and arterial smooth muscle cells, cardiomyocytes, glomerular podocytes, and tubular cells in the kidney, as well as neurons in both the central and somatic and autonomic peripheral nervous systems. There is also substantial evidence that the deacylated metabolite of Gb-3, globotriaosylsphingosine (lysoGb3), plays a major role in the pathogenesis of Fabry disease. The GLA gene is located on the X-chromosome (Xq22.1), and the underlying X-linked inheritance explains why Fabry disease is usually more severe with earlier clinical onset and broader organ involvement in male as compared with their affected female relatives. Based on the age of onset, severity of symptoms, and extension of organ involvement, the clinical phenotypes resulting from impaired α-galactosidase activity may be classified into type 1 or “classic” Fabry disease, associated with GLA variants with little or no functional enzymatic activity, with the first signs and symptoms appearing in childhood or adolescence, and type 2 or α-galactosidase insufficiency (also commonly designated as “later-onset,” “nonclassic,” or “atypical”), associated with GLA variants retaining some residual enzymatic activity, enough to prevent Gb3 accumulation in capillaries and small blood vessels, where symptoms usually appear in the fourth to sixth decades of life.2 The most characteristic early-onset manifestations of classic Fabry disease include angiokeratomas, which are small, dark red to purple papules or nodules on the skin, usually clustering on the buttocks, groin, umbilicus, and upper thighs (“bathing trunk distribution”); reduced or absent sweating (i.e., hypohidrosis or anhidrosis), which impairs the regulation of body temperature during warm weather or physical exertion, leading to heat intolerance and dry skin; “cornea verticillata,” which is a distinct type of corneal dystrophy that does not affect vision and requires slit-lamp ophthalmologic examination for diagnosis; gastrointestinal symptoms such as abdominal pain and cramping, which typically worsen after meals, along with frequent bowel movements and diarrhea; and neuropathic pain and dysesthesias in the distal upper and lower limbs. The neuropathic pain can be chronic, typically described as burning, tingling, or nagging, affecting symmetrically the palms of the hands and soles of the feet (“acroparesthesias”), and/or occur as attacks of excruciating pain (“pain crises”) elicited by fever, physical activity, stress, fatigue, and other triggers. With increasing age, complications of disease progression involving the heart (left ventricular hypertrophy, conduction disturbances, arrhythmias, and valvular disease), cerebral vasculature (transient ischemic attacks and strokes), and kidneys (proteinuric chronic kidney disease and kidney failure) become the major causes of morbidity and mortality.1 As clinically judged from correlations between residual enzyme activity and clinical phenotypes, the heart is the most vulnerable organ to α-galactosidase insufficiency, with cardiac disease being its most common presentation. A 41-year-old man, long-time smoker with a medical history of paranoid schizophrenia treated with monthly injections of haloperidol, arterial hypertension, hemodialysis-dependent kidney failure, and cerebral small vessel disease, was referred to the cardiology outpatient clinic at a university hospital for etiological investigation of infiltrative biventricular hypertrophy, which had been recently detected by echocardiography in the setting of an acute ischemic midbrain stroke. High blood pressure and chronic kidney disease had been first documented at age 30, during hospitalization for the patient's presenting psychotic episode. Electrocardiographic left ventricular hypertrophy was detected on the baseline assessment of hypertension; however, the echocardiographic findings were unremarkable, with the end-diastolic left ventricular wall thickness at the upper limit of normal. The estimated glomerular filtration rate, calculated using the Chronic Kidney Disease Epidemiology Collaboration 2009 equation, was 49 ml/min/1.73 m2; urinalysis revealed moderate proteinuria (protein-to-creatinine ratio = 1095 mg/g); and microscopic examination of the urine sediment did not show any abnormalities. Results of brain computed tomography scan were normal. The patient's kidney function declined rapidly over the next few years, eventually requiring initiation of maintenance hemodialysis at age 36. At age 37, as part of prekidney transplant protocol assessment, the patient underwent myocardial scintigraphy that did not reveal any perfusion defects; the left ventricle was dilated, with motility and thickening changes at the septal, apical, and lower levels after stress, partially reversing at rest; moderate impairment of global systolic function was observed after stress, with recovery to normal values at rest. A chest computed tomography additionally showed upper lobe predominant linear densities, multiple centrilobular micronodules, and ground glass opacities, compatible with smoking-related lung disease. Finally, 3 months before his cardiology consultation, the patient had been hospitalized for a midbrain ischemic stroke presenting with gait instability, numbness of the right limbs, dysarthria, and blurred vision, with the brain magnetic resonance imaging showing a recent ischemic lesion in the right paramedian topography of the lower midbrain, reaching the transition to the pons. Additional relevant findings on the brain magnetic resonance imaging were decreased brain volume, multiple nonspecific gliotic foci in the parasagittal deep white matter of the frontal lobe, several old lacunar infarcts in the thalami and the left paramedian aspect of the pons, and slight elongations of intracranial arteries. At the cardiology outpatient clinic, electrocardiographic examination revealed sinus rhythm and left ventricular hypertrophy (Fig. 1). Echocardiography showed significant hypertrophy of both the left and right ventricles, with an infiltrative pattern, and maximal left ventricular wall thickness of 16 mm, at the interventricular septum; the estimated left ventricular ejection fraction was 40%, with hypokinesia of the anterior septum and akinesia of the basal and middle segments of the inferior septum and the basal segment of the inferior wall. Magnetic resonance imaging demonstrated cardiomyopathy with a hypertrophic phenotype and biventricular involvement (Fig. 2), the left ventricular systolic function was moderately impaired (ejection fraction of 35%), there were no areas of delayed myocardial enhancement suggestive of focal fibrosis, and right ventricular systolic function was preserved.Figure 1.: 12-Lead electrocardiogram, presented in tracings obtained at 10 mm/mV (top), 5 mm/mV (middle), and 2.5 mm/mV (bottom); the 2 upper tracings are incomplete in lead V4 (all in 25 mm/second).Figure 2.: Cardiovascular magnetic resonance (CMR) assessment: Steady-state free precession (SSFP) CINE long-axis view in diastole (A1) and systole (A2) showing increased biventricular wall thickness and left ventricle systolic dysfunction (ejection fraction of 35%). (B) Native T1 mapping showing “pseudonormal” myocardial T1 value in the septum (1181 ms; normal reference value 1144–1290 ms for this 3-T scanner). (C) Late gadolinium enhancement (LGE) imaging showing no focal myocardial fibrosis.The coexistence of kidn

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