Table 2.

Cardiac signs: guideline stipulations and PREDICT-FD consensus [11]

	Early indicators of histological damage (heart biopsy)	Markers of early systolic/diastolic dysfunction	Elevated serum cardiac troponin	Early indicators of LVH	Late Gd+ on cMRI	Elevated serum NT-proBNP	Reduced myocardial T1 relaxation time on cMRI	Abnormal ECG	Abnormal echocardiogram	Abnormal wall motion on echocardiogram	Symptomatic cardiac disease
PREDICT-FDa [11]	+ (NR)	+	+	+	+	+	+	+	+	+	–
EFWGb [1]	–	–	–	Wall thickness > 12 mm with minimal/no fibrosis All, I	–	–	–	Rhythm disturbances All, I	–	–	–
Australia [24]	All	Allc	–	Alld	Alld	–	Allc	Allc	Alld	–	–
Canadae [21]	Confirmatory diagnosis	Grade 2 or 3 diastolic dysfunctionf	> 2 × ULN	Wall thickness: M, > 12 mm F, > 11 mm LVH Romhilt–Estes score > 5g	Left ventricular wall	> ULN	1.5 T magnet M, < 901 ms F, 916 ms	Conduction/rhythm abnormalh	Diastolic filling abnormal Left atrium > 34 mL/m2 Moderate-to-severe mitral or aortic insufficiency Abnormal longitudinal strain gradient left ventricle		–
Catalonia (Spain)	–	Alli	–	Alli,j	Allk	–	Allj	Allj	Alli	Alli	–
Francel [23, 25]	Fm	–	–	–	–	Fm	–	Fm	Fm	–	–
Portugal [22]	–		–	LVH in adults Cardiomyopathy in children	Myocardial fibrosis	–	–	All, arrhythmia Adults, conduction disturbance	–	–	Dyspnea, palpitations, syncope, thoracic pain
Slovenia (FCGHSG)	Confirmatory biopsy if needed in cF and in late-onset adultsn	Diastolic dysfunction	–	Hypertrophic cardiomyopathy	Signs of fibrosis	–	–		Signs of fibrosis by speckle tracing
Switzerlando	Fp	Fq	–	Fq	–	–	Fq	Fq	–	–	–
UKr [26]	–	–	–	Wall thickness: M, > 13 mm F, > 12 mm	All	–	–	–	Alls	–	–

Unpublished guidelines are summarized in Additional file 1: Table S1

^aConsensus was reached that FD-specific treatment should be initiated at diagnosis in male patients aged 16 years or older who are asymptomatic for organ involvement, in boys younger than 16 years old with early indicators of organ involvement, and in all patients with guideline indicators of organ involvement

^bRecommendations are based on class of evidence assigned: class I, treatment recommended or indicated; class IIA, treatment should be considered; class IIB, treatment may be considered; class III, treatment not recommended

^cSignificant life-threatening arrhythmia or conduction defect

^dLVH as evidenced by cMRI or echocardiogram data, in the absence of hypertension

^eTreatment initiated based two criteria. Many cardiac manifestations may be attributable to hypertension, so this must be ruled out or treated for 12 months. One additional criterion not shown in the table: abnormal base–apex circumferential strain gradient on cMRI

^fAmerican Society of Echocardiography and/or the presence of speckle tracking abnormalities

^gAdditional criteria: LVM increase of 5 g/m²/y based on three measurements over at least 12 months; LVMI ≥ 20% above normal

^hAtrioventricular block, short PR interval, left bundle branch block, ventricular or atrial tachyarrhythmias, sinus bradycardia in the absence of negative chronotropic drugs or other causes

ⁱEchocardiographic changes: increased LVM, systolic or diastolic dysfunction, echocardiogram with persistently altered Doppler tissue

^jElectrocardiographic changes; LVH; arrhythmia

^kAlteration in cMRI suggestive of deposit

^lAll male patients with a confirmed FD diagnosis should be offered ERT from age 18 years; ERT may be considered in children (6–18 years) with cardiac involvement

^mTreatment should be offered to women who develop cardiomyopathy; guideline does not specify how cardiomyopathy should be diagnosed, so various methods of diagnosis have been included except cMRI

ⁿAlso if necessary in asymptomatic boys with a classical mutation

^oERT is practically always indicated in men, even those with mild symptoms and low organ involvement, and in patients undergoing hemodialysis or with a kidney transplant

^pRelevant, histologically proven Gb3 deposits in kidney or heart biopsies

^qManifest diastolic dysfunction, LVH, arrhythmias, attributable to cardiac involvement in FD

^rFD-specific therapy should be considered in male patients with classical mutations at diagnosis; tabulated additional considerations apply to male and female patients with later-onset disease

^sLVMI above normal for age and sex by 2D echocardiogram/cMRI

 + , achieved consensus in PREDICT-FD; 2D, two-dimensional; cF, female patient(s) with classical disease; cMRI, cardiac magnetic resonance imaging; ECG, electrocardiogram; EFWG, European Fabry Working Group; F, female patient(s); FCGHSG, Fabry Center, General Hospital Slovenj Gradec; FD, Fabry disease; Gb3, globotriaosylceramide; Gd+ , gadolinium enhancement; LVH, left ventricular hypertrophy; LVM, left ventricular mass; LVMI, LVM index; M, male patient(s); NR, achieved consensus but not recommended for safety reasons; NT-proBNP, N-terminal pro-natriuretic brain peptide; ULN, upper limit of normal; y, year