Table 3.

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

	White matter lesions	Neuropathic pain	Painful GI symptoms suggestive of neuropathy	Stroke/TIA	Sudden onset unilateral hearing loss	Acute ischemic optic neuropathy	Silent cerebral infarct on MRI
PREDICT-FDa [11]	–	+	+	+b	No consensus	–	–
EFWGc [1]	All, IIB	All, IIAd	–	All, IIA	All, IIBe	–	–
Australia [24]	–	Allf	–	Allg	–	–	–
Canadah [21]	–i	–j	–	All	All	All	–
Catalonia (Spain)	–	Allk	–	Alll	–	–	–
Francem [23, 25]	–	Childrenn		F, children	F,o childrenp	–	–
Portugal [22]	All adults	All	Abdominal pain in children	All adults	All adults	–	All adults
Slovenia (FCGHSG)	Allq	All	Allr	Allq	–	–	–
Switzerlands	–	Ft	F	Fu	–	–	–
UKv [26]	–	Allw	Allw	–	–	–	–

Unpublished guidelines are summarized in Additional file 1: Table S1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

^bOriginally classified under “Other” [11]

^cRecommendations 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

^dIf neuropathic pain is controlled and does not interfere with activities of daily living, all classified as IIB

^eAge-adjusted hearing loss

^fUncontrolled chronic pain despite the use of maximum doses of appropriate analgesia and antiepileptic medications for peripheral neuropathy

^gIschemic vascular disease

^hTreatment initiated based on one criterion

ⁱClinical significance of imaging abnormalities (white matter lesions, vessel dolichoectasia, cerebral microbleeds) alone is unclear and not an indication for ERT

^jPain in isolation does not warrant ERT. A 12-month trial of ERT may be considered based on agreed outcomes (e.g. reduced need for analgesics, reduced school/work time lost, reduced hospital admission for pain crises)

^kChronic pain, uncontrolled with drugs, that alters quality of life

^lIschemic cardiopathy; imaged vascular ischemic lesions attributable to FD

^mAll male patients with a confirmed FD diagnosis should be offered ERT from age 18 years

ⁿMajor painful crises refractory to analgesic treatment with carbamazepine, diphenylhydantoin, gabapentin, amitryptiline in children aged 6–18 years

^oSevere cochlear damage

^pCochleo-vestibular involvement (hearing loss assessed by audiogram; vertigo of vestibular origin) in children aged 6–18 years

^qCentral and/or autonomic nervous system involvement consistent with FD

^rTreatment initiation in classical male patients and girls with abdominal pain and postprandial diarrhea; additional confirmation of disease progression required in adult cF and in both sexes with the late-onset phenotype

^sERT is practically always indicated in men, even those with mild symptoms and low organ involvement, and in patients undergoing hemodialysis or after kidney transplantation

^tTherapy-resistant pain

^uCerebrovascular manifestations (insult, transient ischemic attack); dizziness

^vFD-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

^wUncontrolled pain or GI symptoms requiring altered lifestyle or interfering with quality of life

 + , achieved consensus in PREDICT-FD; cF, female patient(s) with classical disease; EFWG, European Fabry Working Group; ERT, enzyme replacement therapy; F, female patient(s); FCGHSG, Fabry Center, General Hospital Slovenj Gradec; FD, Fabry disease; GI, gastrointestinal; MRI, magnetic resonance imaging; TIA, transient ischemic attack