INTRODUCING

CLINICAL INDICATORS

Fabry disease is a multisystemic disorder with a range of signs and symptoms, and should be considered in the differential diagnosis of many systemic diseases.

In patients with lysosomal storage disorders, biomarkers can be used to support a diagnosis.¹ In Fabry disease, deficient enzymatic activity of alpha-galactosidase A, due to variants in the GLA gene, leads to an accumulation of the glycosphingolipids globotriaosylceramide (Gb₃) and globotriaosylsphingosine (lyso-Gb₃) within almost all cell types and various organs.^2-5 One diagnostic biomarker is lyso-Gb₃, as levels are markedly elevated in some patients with Fabry disease.^5-7To assess the extent of organ involvement in Fabry disease, numerous clinical indicators can be used.⁸

The international PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease (PREDICT-FD) modified Delphi initiative (funded by Shire, now part of Takeda) aimed to determine early clinical indicators that may lead to the initiation of Fabry disease-specific treatment in treatment-naïve patients. Early indicators of Fabry disease, on which consensus was reached, are presented in Figure 1.⁸

Kidney

Elevated urine albumin: creatinine ratio*
Histological damage using kidney biopsy*
Microalbuminuria*^†
Abnormal glomerular filtration rate
Decline in iohexol glomerular filtration rate
Podocyte inclusions.

^*The prognostic significance of this indicator is different between male and female patients
^†A causal relationship between this indicator and Fabry disease is required to justify treatment initiation

Cardiac

Markers of early systolic or diastolic dysfunction*^†
Elevated serum cardiac troponin*
Early indicators of left ventricular hypertrophy
Early indicators of histological damage using heart biopsy^‡§
Late gadolinium enhancement on cardiac magnetic resonance imaging (MRI)
Elevated serum N-terminal probrain natriuretic peptide*
Reduced myocardial T1 relaxation time on cardiac MRI
Abnormal electrocardiogram^†‡
Abnormal echocardiogram*^†
Abnormal wall motion on echocardiogram.

*A causal relationship between this indicator and Fabry disease is required to justify treatment initiation
^†Including decreased myocardial strain and strain rate, tissue Doppler abnormalities, enlarged left atrium or pulmonary venous flow abnormalities on echocardiogram
^‡Including shortened PR interval, non-sustained ventricular tachycardia and symptomatic bradycardia
^§Cardiac histological changes have been reported in Fabry disease; however, cardiac biopsy is too invasive to be recommended

Peripheral nervous system

Neuropathic pain^*
Painful gastrointestinal symptoms suggestive of gastrointestinal neuropathy related to Fabry disease.^*

^*A causal relationship between this indicator and Fabry disease is required to justify treatment initiation

Other

Pain in extremities or neuropathy
Stroke or transient ischaemic attack
Angiokeratoma
Organ biopsy*
Non-pain gastrointestinal symptoms, including diarrhoea or frequent diarrhoea, related to Fabry disease
Sweating abnormalities or heat or exercise intolerance.

^*Including skin biopsy for small-fibre neuropathy, and kidney and heart biopsy

Patient-reported

Febrile crises
Patient-reported progression of symptoms or signs
Angiokeratoma.

Figure 1.
Early clinical indicators of Fabry disease based on the PREDICT-FD initiative. Reproduced and adapted with permission from Hughes DA et al. BMJ Open 2020; 10: e035182.

C-ANPROM/INT/FAB/0016; Date of preparation: March 2021

Simonetta I, Tuttolomondo A, Daidone M, et al. Biomarkers in Anderson-Fabry Disease. Int J Mol Sci 2020; 21.
Felis A, Whitlow M, Kraus A, et al. Current and investigational therapeutics for Fabry disease. Kidney Int Rep 2019; 5: 407-413.
Schiffmann R, Hughes DA, Linthorst GE, et al. Screening, diagnosis, and management of patients with Fabry disease: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference. Kidney Int 2017; 91: 284-293.
Brady RO, Gal AE, Bradley RM, et al. Enzymatic defect in Fabry's disease. Ceramidetrihexosidase deficiency. N Engl J Med 1967; 276: 1163-1167.
Vardarli I, Rischpler C, Herrmann K, et al. Diagnosis and screening of patients with Fabry disease. Ther Clin Risk Manag 2020; 16: 551-558.
Aerts JM, Groener JE, Kuiper S, et al. Elevated globotriaosylsphingosine is a hallmark of Fabry disease. Proc Natl Acad Sci U S A 2008; 105: 2812-2817.
Rombach SM, Dekker N, Bouwman MG, et al. Plasma globotriaosylsphingosine: diagnostic value and relation to clinical manifestations of Fabry disease. Biochim Biophys Acta 2010; 1802: 741-748.
Hughes DA, Aguiar P, Deegan PB, et al. Early indicators of disease progression in Fabry disease that may indicate the need for disease-specific treatment initiation: findings from the opinion-based PREDICT-FD modified Delphi consensus initiative. BMJ Open 2020; 10: e035182.

Brochure

STRIVING FOR ORGAN PROTECTION
Fabry Disease: Cardiac considerations for diagnosis

Due to the high prevalence of cardiac involvement in patients with Fabry disease, cardiologists are vital in the screening and diagnosis of the disease. Cardiologists are recommended to maintain an awareness of Fabry disease.

Brochure

STRIVING FOR ORGAN PROTECTION
Fabry Disease: Neurological considerations for diagnosis

Neurologists can aid an early diagnosis of Fabry disease and document neurological involvement associated with the disease.

DIFFERENTIAL DIAGNOSIS

Signs and symptoms of Fabry disease

What are the signs and symptoms of Fabry disease?

The prevalence and age at onset of Fabry disease manifestations can vary between males and females but the severe multisystemic involvement of the disease may ultimately lead to major organ failure.

DIFFERENTIAL DIAGNOSIS

Globotriaosylsphingosine (lyso-Gb₃)

How can globotriaosylsphingosine (lyso-Gb₃) levels be assessed in patients with Fabry disease?

Levels of lyso-Gb₃ can be assessed in the plasma, urine or dried blood spots of patients with Fabry disease.

CLINICAL INDICATORS

STRIVING FOR ORGAN PROTECTION Fabry Disease: Cardiac considerations for diagnosis

STRIVING FOR ORGAN PROTECTION Fabry Disease: Neurological considerations for diagnosis

Signs and symptoms of Fabry disease

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STRIVING FOR ORGAN PROTECTION
Fabry Disease: Cardiac considerations for diagnosis

STRIVING FOR ORGAN PROTECTION
Fabry Disease: Neurological considerations for diagnosis