How to Diagnose Fabry Disease

Clinical trial summary

Fabry disease and the heart: A comprehensive review
AZEVEDO O, CORDEIRO F, GAGO MF, ET AL. INT J MOLECULAR SCIENCES 2021;22:4434

Non-specific gastrointestinal features: Could it be fabry disease?
HILZ MJ, ARBUSTINI E, DAGNA L, ET AL. DIGESTIVE AND LIVER DISEASE 2018;50:429–437

Fabry disease: A disorder of childhood onset¹
SCHIFFMANN R, RIES M. PEDIATRIC NEUROLOGY 2016;64:10-20.

Fabry for Nephrologists - Fabry and Renal

Fabry Disease is a genetic condition that may account for a prevalence of 0.7% of unexplained end-stage renal disease (ESRD) cases.¹
People with Fabry disease are at risk of developing ESRD between the third and fifth decades of life.^2-5 Signs indicative of early, progressing renal damage which include microalbuminuria and proteinuria developing are seen as early as in the second decade of life.⁴

Fabry disease results from deficient ɑ-galactosidase A (ɑ-Gal A) activity which causes progressive accumulation of globotriaosylceramide (GL-3) in various cells.^4,7,8

• A biopsy may demonstrate GL-3 storage in various cell types and signs of injury, including glomerular sclerosis which may be present as early as childhood⁹

The European Renal Association-European Dialysis and Transplant Association recommends screening for Fabry disease in:

• male patients with chronic kidney disease (CKD) below 50 years of age in whom a reliable renal diagnosis is absent,
• female patients with unexplained CKD, irrespective of age, and other unexplained symptoms potentially associated with Fabry disease ⁶
   

Consider Fabry disease in the differential diagnosis of patients with unexplained renal disease or chronic kidney disease (CKD)

Agalsidase ß therapy reduced GL-3 accumulation to zero at 54 months in various types of kidney cells. For distal convoluted tubule (DCT)/collecting duct cells, baseline scores were obtained at the beginning of the double-blind trial and at month 54 on a 0 to 3 scale. For all other cell types, pretreatment scores were obtained before agalsidase ß treatment as defined in Materials and Methods. Mesangial cells were scored on a scale of 0 to 2, and other cell types were scored on a scale of 0 to 3.¹⁰
 

Study Design: A randomised, 1:1, double-blind, placebo-controlled study was conducted in 58 patients with Fabry disease, Patients were randomised 1;1 to receive either 1 mg/kg of FABRAZYME^® EOW or placebo for 5 months (20 weeks). Inclusion severity at baseline ranged from 0 (normal or near normal) to 3 (severe inclusions).¹⁰

Open-label extension of the study: All 58 patients enrolled in the open-label extension study of 54 months in which they received biweekly 1.0 mg/kg FABRAZYME^® infusions for up to an additional 54 months.¹⁰

Long-term agalsidase β therapy decreases GL-3 accumulation in podocytes. (A) Kidney biopsy that was obtained before agalsidase β therapy exhibits darkstaining granules in podocytes. (B) By month 54, fewer GL-3 inclusions are evident from a specimen that was obtained from the same patient.¹⁰
Methylene blue/azure II stain. Magnification, x 400.¹⁰

Continued improvement in podocyte clearance was seen at month 54. By month 54, 67% of patients demonstrated a one-point reduction in podocyte GL-3 inclusions from baseline. Although podocytes were not completely cleared of GL-3 deposits, serum creatinine levels remained stable in all but one patient.¹⁰

Fabry Disease
A Multisystemic Condition¹¹

Fabry for Cardiologists - Fabry and Heart

The main manifestation of cardiac involvement in Fabry disease is the progressive thickening of the heart walls expressed as a hypertrophic cardiomyopathy (HCM).^1,4

Fabry Disease – A Multisystemic Condition¹
Common signs and symptoms of Fabry disease¹

In Fabry patients, cardiac involvement may predominate commonly mimicking sarcomeric HCM.²

HCM – Hypertrophic cardiomyopathy

• Registries data suggest that at least 10% of patients may first present with a cardiac event.³
• Cardiac disease is 1 of the 3 major causes of morbidity and mortality in affected males and females.³

The main manifestation of cardiac involvement in Fabry disease is the progressive thickening of the heart walls expressed as a HCM.^1,4

Fabry prevalence in patients with unexplained HCM/LVH⁵

The intracellular accumulation of Gb3 also occurs within myocytes, valves and vascular endothelium of the heart.⁴

HCM: Hypertrophic cardiomyopathy; LVH: Left ventricular hypertrophy; Gb3: Globotriaosylceramide

Should you wish to test for Fabry, kindly use the contact details below for any DBS kit requests, sample collections or diagnostics related queries:

Email: Ansie.Mienie@nwu.ac.za / pliem@nwu.ac.za

Contact Numbers: 018 299 2312 / 018 285 2544

WhatsApp Number: 082 393 8505

Fabry for Neurologists - Fabry and CNS

The Central Nervous System (CNS) Manifestations and Fabry Disease

include strokes, transient ischaemic attacks (TIAs) and white matter involvement.^1,4
Stroke/TIA is often the first serious clinical event in patients with Fabry Disease.^2,3

Stroke is a common and serious clinical manifestation of Fabry Disease and can occur in the absence of other key signs of the disease.²

First stroke before diagnosis²

Stroke and Transient Ischaemic Attacks:

Fabry disease puts individuals at increased risk for early TIA and stroke: according to natural history data, 6.9% of males and 4.3% of females experienced strokes with a median age at first stroke being <30 years in males and <45 years in females.³

Progressive accumulation of globotriaosylceramide (GL-3) in the endothelium of intracranial blood vessels is thought to play an important role in the increased risk of ischaemic stroke and TIAs.²

Stroke before any renal or cardiac events²

White Matter Lesions:

A characteristic sign, found in up to 80% of individuals with Fabry disease. These patients show a variable degree of periventricular, deep and/or subcortical white matter involvement. They usually have non-specific distribution and is the most common neuroradiological finding in Fabry Disease.⁴

The cause of chronic white matter lesions in Fabry disease remains controversial. It is believed that GL-3 related endothelial damage may appear as abnormal hyperintensities in the white matter.³

In patients with Fabry disease, aged 35-45 years, risk of stroke vs the general population is:³

White matter involvement in Fabry disease could range from small, scattered and punctuate T2- weighted hyperintense foci to bilateral diffuse, patchy and partly confluent white matter hyperintensities as seen in the images of a 40-year-old woman (below). Although being the most common neuroimaging finding in Fabry disease, white matter hyperintensities appearance and distribution are not specific in this condition.⁴

Fabry Disease
A Multisystemic Condition¹¹

Fabry for Neurologists and Physicians

Peripheral Nervous System manifestations include pain and auditory abnormalities.¹

Extremity pain is one of the earliest and most common clinical symptoms of Fabry disease.^2,3

It typically manifests as episodes of burning, stabbing, tingling or shooting pain and has a significant impact on a patient’s quality of life.^2,3

Pain:

Pain in Fabry disease is multimodal, driven by multiple diverse pathophysiological mechanisms.²

Globotriaosylceramide (GL-3) accumulation in the dorsal root ganglia and microvascular endothelium results in small fiber neuropathy, ischaemia and axonal degeneration.^1,2

Pain may also be due to ectopic discharges, altered pain modulation and central nervous system sensitisation.^1,2

• One of the earliest and most common clinical symptoms of Fabry disease.²
• Typically manifests as episodes of burning, stabbing, tingling or shooting pain.2
• Begins in the distal extremities and radiates proximally.²
• May manifest as ‘pain crises’, which are attacks of excruciating pain that may spread over the entire body.²
• Most important triggers of pain are physical exercise, thermal stimuli, and fever.²
• Has a significant physical and social impact on a patient’s quality of life and may contribute to depression, anxiety and illicit drug use to manage the pain.^2,3

Auditory and vestibular abnormalities:

Hearing loss, tinnitus and vertigo occurs in Fabry disease, potentially due to narrowing of cochlear and vestibular vessels, globotriaosylceramide (GL-3) deposition in spiral ganglia and vestibular structures and ischaemic auditory neuropathy.¹

• Frequently observed symptoms which include hearing loss, tinnitus and vertigo.¹
• High incidence of both progressive hearing Loss and sudden deafness has been demonstrated in males with classic Fabry disease.

• Pain
• Auditory abnormalities
• Headaches
• Depression
• Fatigue

• Stroke
• Transient ischaemic attacks
• White matter lesions
• Abnormalities of intercranial vessels

• Premature death

Fabry Disease
A Multisystemic Condition¹¹