As reported to us by affected acquaintances, most German centres for Fabry disease now consider the GLA-variants D313Y und A143T to be benign polymorphisms that do not necessitate treatment. This appears to be in accordance with international practice.
We have studied publications in peer-reviewed journals to verify if this consensus is backed up by available scientific data.
Several clinical studies report a highly significant statistical correlation between the occurrence of these variants and mainly neurological symptoms and structural changes of the nervous system. The following symptoms were reported for carriers of the D313Y-variant in at least two independent publications:
- Paresthesia (Lenders et al. 2013, Koulousios et al. 2017, Godel et al. 2019, Zompola et al. 2020)
- Pain (Lenders et al. 2013, du Moulin et al. 2017, Reková et al. 2021)
- White matter lesions = WML (Lenders et al. 2013, du Moulin et al. 2017, Koulousios et al. 2017, Reková et al. 2021)
- Stroke (Ferreira et al. 2015, du Moulin et al. 2017, Zompola et al. 2020, Reková et al. 2021)
- Cornea verticillata (du Moulin et al. 2017, Koulousios et al. 2017, Zompola et al. 2020, Reková et al. 2021)
- Gastrointestinal disturbances (du Moulin et al. 2017, Koulousios et al. 2017)
Note: Du Moulin et al. (2017) and Godel et al. (2019) most likely reviewed overlapping groups of patients; theresults obtained by these publications are not considered independent for the above list.
Despite the fact that these publications mention symptomless carriers, the GLA-variant D313Y appears to be generally associated with a number of clinical symptoms (mainly pain, paresthesia, stroke, reduction of health-related quality of life) and structural changes (white matter lesions, small fibre neuropathy, increased dorsal root ganglia volume).
Apparently, these variants can, in rare cases, lead to an increased (lyso-)Gb3-concentration in blood plasma or urine or a decreased α-galactosidase A activity in leukocytes. Several patients report a reduction in renal function or cardiomyopathy, though these symptoms are obviously atypical for carriers of the D313Y variant.
With this in mind, it’s surprising that a number of publications explicitly try to establish the
apathogenic nature of the GLA variants D313Y and A143T and present the supposed proof as a highly relevant and innovative conclusion.
Apparently, these publications equate the absence of specific symptoms associated with varying definitions of a “classical” manifestation of Fabry disease with the complete lack of a pathogenic potential, which in our view is an invalid conclusion. Several indexes have been developed to quantify disease severity in a patient, each with marginally different criteria (https://fabry-institute.com/differential-diagnosis/diagnosis-of-fabry-disease/disease-severity-indexes; retrieved May 8, 2022).
In summary, the following diagnostic criteria appear to be broadly accepted for classical Fabry disease:
- reduced α-galactosidase A activity; the exact cut-off value differs
between 5% and 30%
- increased concentration of (lyso-)Gb3 in blood plasm and/or urine
- renal or cardiac pathology (chronic kidney disease or cardiac hypertrophy)
- specific afflictions of other organs like cornea verticillata, angiokeratomas, acroparesthesia or neuropathy
This combination of symptoms is rare amongst carriers of the D313Y variant, as severe renal and cardiac pathology are atypical and the aforementioned biomarkers are often in a normal range. But even though this variant might not usually lead to a full manifestation of Fabry disease as defined by the above criteria, its apathogenicity is far from proven.
Almost all of the original publications we have reviewed avoid a definitive conclusion, mentioning the possibility that certain groups of patients with as yet unknown risk factors might still develop symptoms. The only publications missing such a caveat are Yasuda (2003) and Froissart (2003). However, despite the fact that the authors explicitly negate this, the data presented in these publications regarding the abnormal physicochemical characteristics of the mutated α-galactosidase A enzyme as compared to the wild-type does suggest a possible pathogenic potential to readers with the necessary scientific background. Review papers citing these publications often ignore such details, suggesting an implicit intention to prove the harmlessness of the D313Y variant, regardless of the data.
Nevertheless, a systematic review and meta-analysis of the studies published before January 30, 2022 reporting D313Y as single GLA gene variant was performed by Palaiodimou et al. (2022).
The authors state in their discussion “Our findings underscore that D313Y is probably
causally related to FD, but its clinical relevance still remains insufficiently characterized” and finally conclude “the finding of the present meta-analysis indicate that D313Y variation
correlates with an atypical, mild, and late-onset FD phenotype with predominantly