Fabry disease: what the cardiologist should consider in non-cardiac screening, diagnosis, and management—narrative review

Introduction

Fabry’s disease (FD) was independently described by Johannes Fabry and William Anderson in 1898 (1). FD is a chronically progressive disease that reduces life expectancy and restricts quality of life.

The underlying cause of FD is a lysosomal storage defect. FD is a rare disease with reported prevalence ranging from 1/40,000 to 1/117,000 (2-4). However, higher prevalence have been described in newborn screening (1/3,100 to 1/8,454) suggesting an overall higher prevalence (5). In the newborn screening, all types of variants on the GLA gene were included in the analysis, including variants of uncertain significance. This is most likely the reason for the high prevalence (6).

FD is x-chromosomal transmitted and can affect all organ systems of the body. The defect encoding the enzyme galactosidase A (GLA) is located in the region q21, 22 in the long arm of the X chromosome. To date, more than 900 mutations of the GLA gen have been detected (7), among them many of unclear significance (GUVS) (8).

The mutations in the GLA gene reduce or deteriorate the function of alpha-GLA. This results in an accumulation of globotriaosylceramide (Gb3) in the lysosomes of the organs, including the endothelial cells of the vessel walls (9).

The differentiation into a classic phenotype and a late phenotype is used to differentiate the course of the disease and the prognosis (10). The heterozygous classic phenotype is characterised by an undetectable or significantly reduced GLA (<3%) as well as an early occurrence of symptoms of several organs. In the classic phenotype, organ damage can be detected at an age of 20 to 30 years.

The hemizygous late phenotype differs from the classic type as GLA is only slightly reduced and organ damage occurs much later (around the age of 50), whereby usually only one organ is affected (10).

Particularly affected by the accumulation of Gb3 are kidneys, heart, vessels and the nervous system (11). Depending on the course of the disease, the accumulation of Gb3 can induce organ damage of varying degrees. Due to the extremely varying symptoms, the diagnosis is very often seriously delayed.

Recent publications have shown that the time to diagnosis has not shortened over the years. This is despite better knowledge of the pathology of the disease and early detection programmes (12). The average time until a diagnosis is confirmed is 10.5 years for adults.

In childhood, acroparaesthesia (13), hypo-, anhidrosis (14,15) and gastrointestinal complaints are particularly prominent (16). Angiokeratomas can also occur (14).

With increasing age, damage to the myocardial cells, the glomerula and the peripheral neurons and glia cells develops.

The consequences are progressive left ventricular hypertrophy (LVH), high-grade cardiac dysrhythmia, renal insufficiency, apoplexy, polyneuropathy, arthralgia, sensorineural hearing loss and unspecific gastro-intestinal complaints.

Until 2001 the disease could only be treated symptomatically. With the development of enzyme replacement therapy (ERT), a causal therapy became possible (17). Here, a biotechnologically produced alpha-galactosidase is infused intravenously at two-week intervals. Two preparations are available, agalsidase alfa, produced from human cells and agalsidase beta, produced from the ovarian cells of the Chinese hamster.

Chaperone therapy is also available, which induces a correct folding of alpha-galactosidase. The preparation Migalastat (18) has been authorised in the European Union since 2016.

Lucerastat is a new drug that directly inhibits glucosylceramide synthase. The mechanism of action corresponds to a substrate reduction therapy. The drug is currently in phase III trials.

The ultimate cure, gene therapy, of FD is currently subject of many studies. This involves the use of DNA or RNA in a vector—usually a virus vector—with the code for the GLA gene (alpha-galactosidase gene). With viral vectors, however, there is a risk of side effects such as cancer through inactivation of tumour suppressor genes. It is also important to mention that the germ cells are not affected by gene therapy, thus, continue to carry the defective GLA gene, so that the inheritance of the disease is still not broken. Germ line therapies are prohibited in most countries on humans.

As early diagnosis is of the highest importance in FD, it is important to screen and diagnose the disease as early as possible. Once the diagnosis is made, the patient has to be closely monitored and treated bearing in mind the multitude of different organ involvements. This necessitates a multidisciplinary approach.

Treatment options and algorhythms are reviewed in the article of Oder et al. As the specificities of the heart are reviewed in dept by Linhart et al. in this issue, we focus on all organs other than the heart.

In this article we focus on the following questions:

• Who should we screen?
• How to prove the diagnosis?
• How to manage the patient?

We present the following article in accordance with the Narrative Review reporting checklist (available at http://dx.doi.org/10.21037/cdt-20-845).

Methods

We searched for references relevant to the topic in Medline, personal libraries, discussion with experts in the field of reviews of the literature and personal experience participating in and writing several reviews of the literature.

Screening

Early diagnosis is prerequisite for the reduction of morbidity and mortality. Causes of death in Fabry patients are primarily cardiovascular events as renal function can be substituted by dialysis (19,20).

As FD is a genetic disease, pedigree analysis and genetic counselling are an essential part of diagnostics. In families with index patients and/or high risk populations, a screening should be carried out early on (21,22).

Although genome analysis is the gold standard, it is not necessary to perform in all patients.

In men, due to the x-linked chromosomal inheritance, a missing/significantly reduced alpha-galactosidase from leukocytes or plasma can be diagnosed in an enzyme assay. However, for completion, a mutation analysis should be performed.

In women, a molecular genetic examination in dry blood is necessary to ensure a reliable diagnosis.

While under therapy, the effects of treatment should be monitored.

The biomarker lyso-Gb3, the deacetylated form of Gb3 (plasma globotriaosylsphingosine) in EDTA or dry blood is available for the assessment of the course of the disease. Lyso-Gb3 correlates with the stage of the disease, the detected mutation and can be used to monitor ERT (23). In patients with lyso-Gb3 <1.3 nmol/l (standard value <0.8 nmol/L) without typical symptoms, a Fabry can be excluded. Furthermore, the measurement of Gb3 in urine and plasma is available. However, it should be noted that in the case of non-classical mutations, Gb3 concentrations in urine may be normal (24). Gb3 can also be detected in biopsies of the kidney, myocardium and skin.

Lyso-Gb3 levels are significantly higher in male patients with classic FD than in late-onset FD (25). In female FD patients, the lyso-Gb3 level is often within the normal range or slightly elevated (26). Elevated lyso-Gb3 levels are found in 40% to 60% of female FD patients (27).

A polymorphism in the GLA gene always shows normal lyso-Gb3 levels (11). However, lyso-Gb3 levels do not correlate with disease severity (28). Therefore, further biomarkers are needed. Furthermore, lyso-Gb3 is not a prognostic biomarker under ERT (29) or chaperone therapy with migalastat.

Although FD is a multifaceted disease, some patient group should specifically be addressed and screened for FD. These are patients with unclear LVH >12 mm, who may also have higher-grade dysrhythmia (30,31), patients with renal insufficiency of unknown etiology associated with microalbuminuria (32) and younger patients (15–55 years) with stroke of unclear cause (33). Table 1 summarizes organ manifestations of unclear etiology. An algorithm by Vardarli (34) clearly shows the way of screening (Figure 1).

Table 1 Fabry diagnosis with the following organ manifestation of unclear etiology
Full table

Figure 1 Updated diagnostic algorithm for FD. Adapted with permission from Vardarli I, Rischpler C, Herrmann K, et al. Diagnosis and Screening of Patients with Fabry Disease. Ther Clin Risk Manag 2020;16:551-8.

Diagnosis

FD is more than the disease of one organ. The disease affects almost all human organs albeit to varying degrees (Table 2). Thus, patients diagnosed with FD should be transferred to a centre. Cooperation between the various disciplines is essential to ensure optimal and individualized diagnosis and treatment.

Table 2 Organ manifestations and symptoms
Full table

Diagnostics in the centre include anamnesis with pedigree preparation, clinical examination, laboratory testing, genetic testing, and various imaging procedures (34-36).

Kidney

In up to 50% of male and 20% of female patients kidney function is impaired (4).

Thus, kidney evaluation is essential. Before the introduction of ERT, renal failure occurred in 42% of male patients (19).

The earliest diagnostic parameter is proteinuria, which is already detectable in adolescence (2).

If the proximal tubules damaged, isothenuria and polyuria may result (37).

In the kidney Gb3, the bioactive molecule accumulates in tubules, mesangium cells, podocytes, interstitium, vascular endothelium, and smooth muscle cells. Furthermore, in podocytes CD74 and TGF-1 expression is induced. CD74, a macrophage migration inhibitory factor (MIF) receptor involved in signal transduction, stimulates cytokines expression resulting in apoptosis and inflammation. TGF-1 stimulates the production of extracellular matrix proteins such as fibronectin and collagen type IV particularly in the glomeruli but also in the interstitium (38). These processes result in the development of focal and global glomerulosclerosis with tubular atrophy, interstitial fibrosis and inflammation in the second decade of life (39) (Figure 2).

Figure 2 Scoring system for renal pathology in Fabry disease: report of the international study group of Fabry nephropathy (ISGFN). Vacuolization and glycosphingolipid deposits in Fabry nephropathy. (A) The glomerulus shows vacuolization of podocytes (arrowheads), and mild corrugation of glomerular basement membranes, with periglomerular and interstitial fibrosis (periodic acid-Schiff, ×400). (B) The glomerulus shows massive expanded deposits in most podocytes (arrowheads) and also in mesangial and endothelial cells and parietal epithelial cells in this male Fabry patient (toluidine blue, ×400). (C) The glomerulus shows occasional small deposits in podocytes (arrowheads) and rare deposits in mesangial areas in this female patient (toluidine blue, ×400). (D) There are prominent deposits in some proximal tubular cells and peritubular capillary endothelium (toluidine blue, ×1,000). (E) Numerous deposits in distal tubules and very rare deposits in proximal tubules. The vascular smooth muscle of a large artery (top left corner) also shows deposits, as do parietal epithelial cells lining the Bowman’s capsule (bottom) (toluidine blue, ×1,000). (F) Numerous deposits in distal tubules with rare deposits in proximal tubules and frequent deposits in peritubular capillaries and interstitium (toluidine blue, ×200). Adapted with permission from Fogo AB, Bostad L, Svarstad E, et al. Scoring system for renal pathology in Fabry disease: report of the International Study Group of Fabry Nephropathy (ISGFN). Nephrol Dial Transplant 2010;25:2168-77.

As a consequence eGFR annually decreases at a rate of ‒2.93 to ‒6.8 mL/min/1.73 m² in male, and ‒1.02 to 2.1 mL/min/1.73m² female patients. The prognosis is worse in the presence of proteinuria exceeding >1 g/day (40).

To verify the diagnosis of FD in kidneys, a biopsy with electron microscopic detection of zebra bodies, an onion-shell-like wound myelin in the cytoplasm of the podocytes, is the gold standard (41). A detection of Maltese crosses in the urine sediment is an indication of an FD, but also occurs with other glomerulonephritides. Another rather new option is the detection of CD77-positive epithelial cells in the urine with a sensitivity of 97.1% and a specificity of 100% for FD (42). However, this has not been validated in larger studies so far.

Cardiac

Cardiac involvement is also very important, accounting for 40% to 60% of FD patients (43). The deposition of Gb3 in myocytes, vascular endothelial cells and valvular fibroblasts promotes LVH and consequential heart insufficiency. An electrocardiogram (ECG) is essential for the detection of arrhythmias as well as for initial diagnosis and follow-up of the LVH. Short PR interval, sinus bradycardia and atrioventricular conduction disturbances are possible (44,45). Long-duration ECG is recommended to rule out higher grade arrhythmias (46). Echocardiography, and MRI are becoming increasingly important to specifically characterize LVH (22). Particularly during follow-up, high-sensitive Troponin T (hs-TNT) may be useful as a biomarker (47).

Neurology

The accumulation of Gb3 in the nerves induces a rather typical small-fibre neuropathy. Common signs are acroparaesthesia of the palms of hands feet (48). Triggers of possible pain crises are stress, fever, heat amongst other factors (49,50).

The accumulation of Gb3 in the vasculature of the brain induces vasculopathy and dilated arteriopathy. These cerebrovascular complications can become apparent in the form of transient ischemic attacks (TIA) or strokes (51). The underlying accumulation of Gb3 can be detected as white matter lesions in the fluid-attenuated inversion recovery (FLAIR) sequence of magnetic resonance imaging (MRI). Furthermore, MRI can also be used to visualize other signs common in FD patients such as vascular abnormalities or a symmetrically high signal in the thalamus (pulvinar sign) in T1-weight (52).

ENT (ear, nose, throat)

The accumulation of glycosphingolipids causes a direct damage in the stria vascularis and ganglion cells as well as to the vasculature of the ear. The resulting vestibulo-chochlear disorder may lead to dizziness, tinnitus and sudden deafness, or an inner ear hearing loss with impaired sound sensation and disturbance in the high-frequency range (53). Cochlear damage frequently impairs sensorineural hearing of the inner ear (54,55).

Gastro-intestinal tract

The cause of gastro-intestinal symptoms is probably a deposition of Gb3 in the ganglia autonomica of intestine and mesenteric blood vessels (16). The consequential abdominal pain, nausea, vomiting and diarrhea can already occur in childhood (16,56). About one third of FD patients describes abdominal complaints (57). The diagnosis is based on the patient's symptoms. One possibility to clarify the significance of such complaints is the Rome III questionnaire, which has been validated for the differential diagnosis of functional gastrointestinal disorders (FGID). Alternatively, a biopsy can also be performed (58). However, while most biopsies react positive in the anti-Gb3 immunostaining, some mutation variants are not detectable (59).

Lung

In the lungs, glycosphingolipids are deposited in pneumocytes, muciparous goblet cells, bronchial ciliate epithelium, bronchial smooth muscle cells and pulmonary vessels (60). A narrowing of the bronchial system develops as a result of the deposit. The lung function test with measurement of the forced expiratory volume in the first second (FEV1) and the forced (expiratory) vital capacity (FEC) shows a deterioration in the course of the disease. This is aggravated by male patients, smoking, cardiac involvement due to FD and age at onset of ERT (61). Symptoms of pulmonary involvement are dyspnoea, dry cough and bronchospasm. they may also be present in cardiac involvement of FD and are therefore non-specific (62).

The prevalence of obstructive lung disease is higher in Fabry patients than in the general population (18% and 33%) (63). The diagnosis of obstructive lung disease is defined as FEV1/FEC <70% (64).

Skin

Damage based on the accumulation of Gb3 to the endothelium peri-vascular myocytes results in a dysregulation of the vasotonus of peripheral capillaries. The structural changes as well as inadequate vasodilatation lead to the appearance of reddish-livid, raised, punctiform, 1–5 mm in diameter efflorescences. Angiokeratomas (Figure 3), which can already appear in childhood, develop in 66% of male and 36% of female patients with FD (65).

Figure 3 Picture of one of our patients with umbilical angiokeratomas.

Eye

Corneal opacity is an early symptom of FD and is known as cornea verticillata (66). It can be verified by Corneal opacity does not affect visual acuity. These changes have to be differentiated from other reasons for vortex keratopathy such as amiodarone or chloroquine (67).

Management

Multidisciplinarity is a prerequisite to ensure optimal care of patients with FD. FD patients should be cared for in a centre where the professional competence of the individual areas is reflected.

The reduction in life expectancy is determined by the degree of manifestation in kidneys, heart and central nervous system (68). Quality of life is also severely impaired by small-fibre polyneuropathy and hearing disorders. Regular follow-up examinations are therefore of great importance. Even in childhood, the quality of life can be reduced by chronic pain (69). Thus, regular evaluations via questionnaires is mandatory. The questionnaires available include SF-36, BPI (pain questionnaire), WHO5 (depression questionnaire) and MDI10. Table 3 summarizes recommended monitoring by organ system.

Table 3 Organ systems and monitoring
Full table

Kidney

Kidney parameters should be determined every 6 months. These include creatinine, at early stages cystatin C, urea, albuminuria (g per g creatinine) and proteinuria (g per g creatinine). Albuminuria and proteinuria should be measured in the morning spot urine, but can also be determined in 24-hour urine collections. Vitamin D levels should be measured during the winter months.

An ultrasound should be performed at least once at the initial examination. As a consequence of kidney deterioration, hypertension develop over time. Thus, a long-term blood pressure measurement is recommended annually (2).

Cardiac

ECG and echocardiography should be performed annually to assess arrhythmias and LVH.

A 48-h Holter monitoring is also recommended annually for the detection of intermittent arrhythmias. Cardiac magnetic resonance imaging with gadolinium should be performed if progression is suspected or in intervals of >2 years (70).

Neurology

Initially doppler/duplex ultrasound to assess intima media thickening and ectasia of the basilar artery should be performed. An MRI of the brain should be performed approximately every 3 years in the case of central nervous involvement or in case of a stroke.

As pain is affecting many patients with FD, questionnaires for pain, depression, and over-all life quality (SF-36) should be performed on a yearly basis.

Gastro-intestinal tract

Abdominal sonography should be performed routinely at the initial presentation and at the time of the examination. Gastroscopy with biopsies and colonoscopy with biopsies should be performed only in case of unclear symptoms or as recommended for the standard population (71).

Lung

If there are no other causes such as asthma, smoking, cardiac involvement by FD, a lung function and radiograph are indicated (60). Deposition of Gb3 in bronchial, arteriolar and endothelial smooth muscle cells results in different imaging modalities (72).

ENT

At the initial examination, an ENT examination with hearing and possibly tinnitus diagnosis and examination of the vestibular apparatus is recommended (70,71).

As a follow-up, a sound threshold audiometry and, if necessary, tinnitus diagnostics and examination of the vestibular apparatus should be regularly carried out.

Therapy

ERT

Two preparations are currently available for causal therapy, ERT. Agalsidase alfa (Replagal^®) (73) and Agalsidase beta (Fabrazyme^®). ERT is infused regularly at two-week intervals. Agalsidase alfa is given at 0.2 mg/kg body weight, agalsidase beta is given at 1.0 mg/kg body weight once every 2 weeks as an IV infusion (70). According to the consensus of the European Fabry working group, ERT should be started before the age of 18 in asymptomatic male patients with classic FD (30).

A new preparation, the pegunigalsidase alfa, a pegylated dimerized version of agalsidase alfa has an 80-fold increase in half-life (74). Pegunigalsidase alfa has a reduced immunity, so it is assumed that a small amount of anti drug antibodies (ADA) are formed.

Chaperon: Migalastat

In addition, chaperone therapy with Migalastat has been available since 2016. This can only be instilled if the mutation is predicted as “amenable”. Migalastat induced a correct folding of alpha-galactosidase to increase enzyme activity (75). It is an oral therapy, the patient takes one tablet every 2 days.

Substrate reduction therapy under investigation

Lucerastat and Venglustat: It is an iminosugar. It inhibits the glucosylceramide synthase so that reduced glucosylceramides can be formed which are a precursor of the Gb3 (76,77).

Gene therapy under investigation:

In ex vivo gene therapy, hematopoietic stem cells are collected from the patient and subjected to gene editing. the stem cells are then transfused back to the patient (78).

In the in vivo gene therapy, an infusion of adeno-associated virus (AAV) mediated gene transfer is carried out, resulting in increased enzyme activity levels (79).

Conclusions

FD is a rare X-linked lysosomal storage disease. The deposition of Gb3 leads to multiple organ damage. Care in specialised centres with a multidisciplinary approach is therefore of great importance for the management of the disease.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Yskert von Kodolitsch, Harald Kaemmerer, Koichiro Niwa) for the series “Current Management Aspects in Adult Congenital Heart Disease (ACHD): Part III” published in Cardiovascular Diagnosis and Therapy. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at http://dx.doi.org/10.21037/cdt-20-845

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/cdt-20-845). The series “Current Management Aspects in Adult Congenital Heart Disease (ACHD): Part III” was commissioned by the editorial office without any funding or sponsorship. MB reports personal fees from Vifor Pharma, outside the submitted work. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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