Fabry Disease—A Diagnostic and Therapeutic Problem

Abstract

The authors present a patient with Fabry syndrome that remained undiagnosed for several years. Fabry syndrome is a genetic disease related to changes on the X chromosome. Its complex clinical presentation and diverse symptomatology is caused by deficient activity of lysosomal hydrolase alpha-galactosidase enzyme. Defect in the basic alpha-galactosidase molecule implies genetic change, which can be a predisposing factor for the development of atypical and typical forms of this genetic disease. In the presented case, clinical manifestation and hemizygous symptomatology were the evidence of metabolic and genetic irregularity, typical clinical presentation of Fabry disease. Many authors report generalized vasculopathy as a basic characteristic of Fabry disease and a causative factor of multiorgan changes. Some authors indicate that persons with diagnosed asymmetric hypertrophy of the left ventricle have decreased alpha-galactosidase. Cardiac complications, coronary disease, and acute myocardial ischemia are often present in cases of Fabry disease, frequently causing death in such patients. Characteristic central nervous system symptoms with skin-burning sensation and paresthesia were also present in our case. Cerebrovascular complications were caused by changes on small blood vessels. Clinical signs of renal failure were nonspecific, and the diagnosis was based on extrarenal symptoms. Initial renal manifestations were insignificant as asymptomatic proteinuria and microhematuria, due to which our patient was referred to further examination. The level of alpha-galactosidase was significantly decreased. The severity and progression of this disease depends on the level of alpha-galactosidase enzyme in serum and its catabolic effect. More recent studies have showed that deficient enzyme can be synthetic zed and, accordingly, our patient has been successfully enrolled in the replacement therapy program.

• Fabry disease
• diagnosis
• replacement therapy
• synthetic enzyme

Introduction

Pathologic metabolism of lipids has been observed and described in numerous genetic diseases, such as Alport, Gaucher, Niemann-Pick, and Fabry disease.[1-3] Fabry disease is an X-chromosome recessive disease related to deficient activity of lysosomal hydrolase alpha-galactosidase enzyme (ceramide trihexosidase). Alpha-galactosidase is an essential enzyme for ceramide trihexosidase catabolism. Enzyme deficiency leads to accumulation of glycosphingolipids with laminar deposits in vascular endothelium and tissue of kidneys, myocardium, liver, brain, skin, eyes, peripheral nervous system, and other organs.[4-7]

The most characteristic sign of glycosphingolipid accumulation is the production of fat foamy cells, which often contain “myelin” and “zebra bodies,” and deposits of ceramide trihexosidase.[8-11] Glycosphingolipid accumulation results in disturbed angioarchitecture leading to the development of dilatations, angiectasia, and dolichoectasia.[12] The diagnosis of Fabry disease is based on determination of alpha-galactosidase enzyme activity in leukocytes, urine, nails, amniotic fluid, which enables prenatal diagnosis of this metabolic disease.[13] Clinical manifestations vary from typical hemizygous formations to atypical hemizygous forms. Heterozygous women are less frequently affected, and the disease occurs later than in hemizygous men.[14] Cardiac complications are very frequent, often causing death in such patients.[15] Changes in the small blood vessels cause cerebrovascular disease, equally in vertebrobasilar and carotid artery.[16&17] At first, renal manifestations are insignificant and related to hematuria and proteinuria. However, further development of the disease leads to renal insufficiency.[17&18] Cutaneous changes are related to the development of angiokeratomas, whereas corneal opacities and central retinal artery occlusions can also be frequently found.[14]

Complex clinical manifestation and symptomatology observed in our patient raised our suspicion about an X-chromosome-related genetic disease.

Case Report

Patient A.B., born in 1971, chemistry student, was admitted for clinical examination due to proteinuria and hematuria. At the age of 12, petechiae were noticed on the gluteal regions and upper arms, suspected to be the result of an allergic reaction.

In 1989, at 18 years of age, the patient underwent hydrocele surgery. Skin changes persisted in the area of groins, gluteus, and medial upper extremities. For the first time, the patient felt pain in the lumbar region. Erythrocytes were noticed in urine sediment. Echosonography revealed a cyst in the right kidney.

In 1995, the patient felt paresthesia on upper extremities.

Cardiopulmonary status was normal (RR 130/70 mmHg). Papules and petechial hemorrhage were visible on body and upper extremities.

Laboratory Results

Erythrocyte sedimentation rate 15; urine, in several instances, 10 to 15 erythrocytes in sediment; albumin positive; creatinine clearance 75.6 mL/min; 24-h proteins 1.02 g/L; urine volume 2000 mL; red blood cells, white blood cells, PTL, coagulation factors, electrolytes, proteins, aminotransferases, Fe, transferrins, acidum uricum, urea, creatinine, lipids, bilirubin, glucose, catecholamines, immunoglobulins, and complements were all within normal ranges. All TRH and LH stimulation tests showed normal values, as well as gonadotrophins, which excluded the presence of hypogonadism. Cortisol findings were within normal ranges 332 nmol/L, 207 nmol/L. Growth hormone < 0.25 µG/L. IGF 1021 J/L. Insulin and C-peptide values were normal. Testosterone 16.8 nmol/L. Alpha-galactosidase activity (nmol of substrate hydrolyzed hourly by serum mL) 0.5 ± 0.2 (control 10.3 ± 2).

• Normal value of enzyme in serum 8.5 to 18.9 µn/min. Heart and chest x-ray—hyperemic hiluses; other results normal.

• Electrocardiogram (ECG)—sinus bradycardia, right branch block.

• Ergometry—6 min of Bruce test showed further horizontal ST-segment depression inferolaterally for 1.5 mm.

• Echocardiography—incipient asymmetric hypertrophy of the left ventricle. Fibrous borderline thickening of the left coronary cuspis. Mild mitral regurgitation from 1 to 2 +. Right and left heart cavities within normal ranges.

• Holter—significant 2 mm ST-segment depression, Q-T prolongation.

• Myocardial scintigraphy performed with 201 Tl under exertion—suspected inferior ischemia and anteroseptal myocardial fibrosis of the left ventricle.

• IV urography within normal ranges.

• Kidney echosonography: left kidney—numerous parapyelic cysts up to 3.5 cm; right kidney—less parapyelic cysts up to 1 cm in size; normal parenchyma noted.

• Kidney computed tomography (CT)—kidneys of normal position, somewhat more voluminous. Postcontrast delayed CT showed slower contrast excretion with homogenous opacification of kidney parenchyma. Bilaterally visible parapyelic cysts (indicating fatty infiltration of kidney cells).

• Brain CT—normal. Gastroscopy—normal. Electroencephalogram—slight dysrhythmic changes.

• Electromyelogram—mild lesions of motoneuron with mildly expressed polyphase action potentials in the right upper leg and feet muscles. Motor conduction in the right n. peroneus profundus slightly decreased. Other studied nerves were normal. Fundus—numerous tortuous retinal vessels and opacities.

• Skin—numerous angiokeratomas on body and upper extremities. Pathohistologic finding—angiokeratoma.

Discussion

Fabry syndrome is an X-linked genetic disease. Its complex clinical presentation and diverse symptomatology is caused by deficient activity of lysosomal hydrolase alpha-galactosidase, which occurs in 1:40,000 hemizygous men.[11] The frequency of atypical heterozygous variants is not known because they often remain unrecognized due to less severe symptomatology and minimal pathologic changes or later onset of disease.[14], [19] Defect in the basic alpha-galactosidase molecule implies genetic change, which can be a predisposing factor for the development of atypical and typical forms of this genetic disease.[20] The patient's family history indicated no genetic metabolic abnormality. The first symptom that demanded further examination was hematuria and persistent skin changes in the shape of papules and petechial hemorrhage. Diffuse skin lesions were localized on typical positions—groins, gluteus, and upper extremities, dermatologically presenting as angiokeratomas or vascular changes. Biopsy finding indicated the presence of numerous vacuoles in endothelial cells and pericytes.

Many authors describe generalized vasculopathy as a basic characteristic of Fabry disease and a causative factor of multiorgan changes.[21] Cardiac changes in the presented case were observed on the ECG finding, incomplete right side block with significantly expressed myocardial ischemia after exertion (ergometry finding), and myocardial scintigram. Echosonographic finding confirmed the presence of asymmetric hypertrophy of the left ventricle, often described in cases of Fabry disease. Some authors stress the need for further investigations of Fabry disease in younger patients with echosonographic finding showing asymmetric hypertrophy of the left ventricle because such persons have decreased alpha-galactosidase.[22] Cardiac complications, coronary disease, and acute myocardial ischemia are often present in cases of Fabry disease, frequently causing death in such patients.[23]

Autopsy findings often reveal glycosphingolipid deposits in myocardial muscle and coronary blood vessels.[24] Characteristic central nervous system (CNS) symptoms with skin-burning sensation and paresthesia were also present in our case. Lesion of the autonomous nervous system can result in hypotension and hypohidrosis. Cerebrovascular complications are caused by changes on small blood vessels.[17] Apart from anamnestic data, clinical presentation of CNS lesion was not noticed in our patient, nor did ECG, brain CT, or magnetic resonance imaging, confirm it.

Changes in the retinal blood vessels presenting as tortuotic corneal opacities were also observed. Many authors describe frequent occlusions of the central retinal artery.[19], [25] Clinical signs of renal failure are nonspecific, and the diagnosis is based on extrarenal symptoms.[26] Initial renal manifestations are insignificant as asymptomatic proteinuria and microhematuria, due to which our patient was referred to further examination. We noticed neither renal dysfunction nor morphologic changes, and the patient did not agree to percutaneous kidney biopsy. According to some studies, tubular apparatus also becomes damaged in the course of the disease, with the development of renal acidosis and renal diabetes insipidus.[26&27] Renal insufficiency usually develops in the third decade of life with the development of glomerular sclerosis and tubular atrophy with interstitial fibrosis, whereas artery hypertension is very rare.[28] Biochemical parameters were within normal ranges and the level of alpha-galactosidase was significantly decreased. Diagnostic tests were performed at the Ruðer Bošković Institute, Biochemistry Department (Boris Lenhard, molecular biologist) 0.5 ± 0.2 (control: 10.3 ± 2).

Normal value of enzyme in serum was 8.5 to 18.9 µn/min.[9], [29]

Several years later, decreased activity of alpha-galactosidase was confirmed at the Genzyme laboratory.

The severity and progression of Fabry disease depends on the level of alpha-galactosidase enzyme in serum and its catabolic effect. The therapy is aimed at treating individual symptoms relieving the effects of pathologic metabolic mechanism. Our patient has been enrolled in the replacement therapy program, where synthetic enzyme, made from recombinant DNA, has been shown to reverse many pathologic abnormalities in kidneys, heart and skin.