Fabry disease (FD) is an X-linked multisystem lysosomal storage disorder caused by mutations in the GLA gene. These mutations result in a deficient or absent activity of the lysosomal enzyme alpha-galactosidase A (αGal-A). This leads to a systemic accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids in the plasma and cellular lysosomes of a wide range of organs and tissues, as podocytes and other cells in the kidneys, cardiomyocytes, vascular endothelial cells, cells of the nervous system and others.1

Gb3 deposition, however, may not be the only responsible for the organ manifestations, since it might exist other unexplained factors that could cause some features of FD, considering that disease manifestations may be present in the absence of severe deposits.2

The FD diagnosis is usually difficult since there are numerous possible manifestations and several different pathogenic variants with variable organ involvement. The mean delay to accurate diagnosis was estimated to be 13.7 years for males and 16.3 for females on the Fabry Outcome Survey.3

In the classic phenotype the first symptoms initiate during childhood such as neuropathic pain, renal manifestations (kidney injury and proteinuria), cutaneous lesions (angiokeratomas and telangiectasias), cornea verticillata and other unspecific symptoms (gastrointestinal disturbances, hypohidrosis, exercise intolerance). These symptoms are followed by transient ischaemic attacks and strokes, progressive renal insufficiency, concentric left ventricular hypertrophy, heart failure and typically premature death in the fourth or fifth decade of life.4

Heterozygous female patients have a vast range of possible manifestations and severity which are dependent on the X chromosome inactivation and the type of variant. Nevertheless, a large proportion of patients present with later-onset phenotypes with a great variety of age of onset, organ involvement and αGal-A levels.5

More than 900 variants in the GLA gene have been identified in the Human Gene Mutation Database.

There is still much debate about the pathogenicity of the D313Y variant, although in recent years it has been considered to be a benign variant or a variant of unknown significance (VUS), especially after the concept of LysoGb3 levels as the biomarker of FD. They are normally not increased in patients with D313Y variant. Nonetheless, there are several reports of patients with this variant that have important manifestations of FD with no other clinical or laboratory explanation. This will be covered in more detail in the discussion.

In this article we present 2 cases within the same family (mother and son) that carry the D313Y variant.

There are contradicting findings about the clinical importance of the D313Y variant in the literature. Yasuda et al.6 reported that in patients with this variant the expressed α-Gal A transported to the lysosomes had about 60% of the wild-type activity but resulted in a pseudodeficiency in plasma, due to its instability at neutral pH. This implies a lower D313Y mutant enzyme's activity in plasma than in leukocytes. They also suggest that the presence of the D313Y variant should prompt further investigation to detect a second causative mutation, since this can further impair the α-Gal A activity and/or stability and explain the disease manifestation in those patients. Oder et al.7 also corroborate that D313Y variant by itself does not lead to severe organ manifestations. They assessed 6 patients with that variant at baseline and during a 4-year follow-up. No significant manifestations were identified. Only one patient showed white matter lesions in the MRI but without neurological manifestations. Niemann et al.8 present 2 patients of the same family (father and daughter) with D313Y variant with reduced levels of α-Gal A activity, without relevant clinical manifestations of FD (the daughter had only unspecific pain in her arms) and LysoGb3 was found below the average in the daughter and undetectable in the father. This strengthens their assumption that this variant is not associated with FD with the current concept of lyso-Gb3 accumulation as a hallmark of the disease.9 Since there is significant activity of α-Gal A with the D313Y variant it only leads to a small amount of lyso-Gb3. Nevertheless, the pathogenic role of lyso-Gb3 is not well established since the mechanisms apart from lyso-Gb3 accumulation, that lead to organ manifestations, are still unknown.10,11

On the other hand, there is some clinical evidence in the literature that this variant may present with clinical features of FD. In some studies, it was identified a leading feature, more frequently cerebrovascular involvement followed by renal manifestations. Some cases presented with a later-onset phenotype. Yenicerioglu et al.12 tried to estimate the prevalence of FD in CKD patients not on dialysis and without a known cause (1453 CKD patients, with disclosure of 3 variants in mutation analysis) and found 2 D313Y carriers with moderate renal insufficiency (CKD stage G3b) and mild proteinuria. Data from another study13 that included 14 patients carrying the D313Y variant provided more evidence that this mutation might lead to organ manifestations compatible with FD: 4 patients had cerebrovascular involvement (stroke at a young age); 7 with acroparaesthesias/polyneuropathy; 2 presented cardiac hypertrophy but suffered from arterial hypertension; 1 had impaired renal function of unknown aetiology but without proteinuria; 1 with cornea verticillata. Another example of central nervous system involvement is in Lenders et al.14 also reported neurological involvement. They presented a family of 8 carriers of GLA D313Y and demonstrated the existence of multifocal WML in 7 carriers, without any other possible cause in the extensive investigation. None of those patients had other symptoms of FD. In another study,15 where they include 62 subjects demonstrating phenotypic traits suggestive of FD or belonging to families with a FD diagnosis, the authors identified 17 individuals with the D313Y variant. LysoGb3 was found normal in all patients. In the male subjects, except for one, had α-galA activity decreased in a range 56.2–87.5% compared to normal. In the group of D313Y variant, 4 were healthy but the rest presented characteristic manifestations of FD. Notably, 4 had end-stage renal disease (ESRD) on dialysis, 6 had WML, and also with other typical traits (acroparesthesias – 5, CKD not on dialysis – 2, LVH – 1, strokes of unknow origin – 1, cornea venticillata – 1, hearing loss – 1, GI symptoms – 1). Like in our case, one patient reported, in this article, initiated dialysis at a young age (25).

The manifestations of FD are nonspecific. Both our patients had unexplained renal insufficiency with mild or absent proteinuria, which is very atypical for the usual progression of the renal manifestations of FD. Normally, proteinuria is one of the initial kidney manifestations and it may initiate in the early teen years and more frequently during early adulthood. CKD progressively develops over time. The time of the presentation of end-stage renal failure in patient 1 is also highly unusual. Although, in an English cohort study of 98 hemizygous males, the mean age of ESRF was 37 years, the youngest ESFR patient presented at 18 years of age.16 One important limitation in our article was the unavailability of kidney biopsy, which we abdicated due to unacceptable risks without significant benefit. Patient 1 had only another trait of FD, LVH, but it may have other explanations like hypertension. As for patient 2, she has cerebral involvement with WML patent in the MRI and neurologic symptoms (paresis in the right lower limb and neuropathic pain in both lower limbs). Although these manifestations have some factors that do not fully fit in FD, no other explanation for them was identified despite thorough investigation.

Even if D313Y variant is currently not considered to be pathogenic for presenting normal lyso-Gb3 values and for the majority of cases having a benign course, there is a considerable number of patients that presented with signs/symptoms consistent with FD without any other explanation. Although, at the same time, it is difficult to attribute them to FD as it has a great range of different presentations and there are important FD traits missing. Based in our findings in these particular patients, we cannot claim that their definite diagnosis is FD but this VUS should not be undervalued, and identified D313Y carriers may benefit of a consistent follow-up/assessment, expecting and monitoring possible manifestations of FD.

The authors received no financial support for the research, authorship, and/or publication of this article.

All the authors declared no competing interests.