The widespread availability of MRI has resulted in an increased recognition that WML are common incidental findings in elderly individuals >65 years of age (up to 97%), but have rarely be seen as early as in the third and fourth life decades 
. Although the clinical relevance of such MRI findings primarily depends on the respective etiology, even incidentally discovered WML are frequently reported to be associated with various neurological symptoms, e.g. progressive cognitive and neurobehavioral deficits, gait and balance disturbances, epileptic seizures, or depression 
. In general, WML show a strong correlation with a wide range of neurodegenerative and neuropsychiatric disorders, independent of other risk factors 
. Specific treatment is available for some of the underlying causes, which effectively could modify symptoms and prognosis, e.g. some metabolic and inflammatory disorders. Furthermore, the cerebral lesions are often irreversible, and thus the underlying etiology is particularly important to consider. However, in clinical practice, uncovering the underlying etiology of WML in adults without cardiovascular risk factors remains dissatisfying in most of the cases. There are many different causes of WML, which can occur at all ages, be progressive or static, and be genetically determined or acquired. The diagnostic workup is complicated as many different analyses have to be performed, at high financial costs as well as emotional stress and often with disappointing results 
With more widespread use of neuroimaging, neurologists will increasingly be confronted with WML in younger adults. In recent years, a considerable number of new sporadic or hereditary small artery diseases of the brain have been detected which preferably occur <45 years of age 
. FD is one of those hereditary diseases that can cause cerebral vasculopathy. Apart from macroangiopathic changes, FD is frequently associated with early microangiopathic brain alterations with progressive WML 
. However, the typical FD symptom complex includes further manifestations such as cornea verticillata or angiokeratoma, renal or cardiac manifestations, strokes and peripheral neuropathy 
. Of note, strokes are highly important for Fabry diagnosis, because they often occur before FD is readily diagnosed and in absence of other clinical events 
. Although most patients present with the classical phenotype, “variant” forms with prominent cardiac or renal manifestations have been described 
. Whether these mono- or oligo-organic phenotypes are associated with specific mutations remains unclear. In fact, efforts to associate genotype with clinical phenotype have been largely unsuccessful 
In the current study, we report on a family carrying the GLA D313Y mutation and being affected by a potentially exclusive neurologic manifestation of the CNS with multifocal WML, in the absence of other FD-specific symptoms. The diagnosis was further supported by the reduced intraepidermal nerve fiber density in the index patient (small-fiber neuropathy), which is also known as a frequent and early manifestation of FD. D313Y resulted in normal GLA enzyme activities in leukocytes and severely decreased activities in plasma. There is still an ongoing discussion whether D313Y is a causal GLA mutation of FD or just leading to a “pseudo-deficiency”. Recent case series or studies reported an association of D313Y with other typical FD manifestations, e.g. peripheral neuropathy, hypertrophic cardiomyopathy, renal failure, or stroke 
. However, most authors considered the D313Y mutation as non-causal. Thus, as a consequence, to date almost all D313Y-carriers are not treated with ERT 
. Other studies support our results and found also primarily neurological organ manifestations in patients carrying GLA D313Y. In this respect, a recent prospective study including 625 patients with cerebral ischemia aged between 18 and 55 reported that GLA D313Y was associated with cryptogenic stroke 
. Recent reports point to an association of particular mutations with a” late-onset” or “intermediate” type of FD, e.g. N215S, A143T or F113C 
. In this regard, the authors concluded that mutations that were formerly assumed as non-causal but nonetheless showed variable FD symptoms might be considered as “predisposing polymorphisms” (e.g. R118C or E66Q). In view of the above mentioned studies, this could particularly be the case with the D313Y mutation causing a CNS involvement. It should, however, be noted that our findings could still represent a clinical coincidence. Thus, further studies are necessary to confirm a causal relationship between the D313Y mutation and cerebral manifestations.
The significant difference of enzymatic activity in leukocytes and plasma caused by the change of aspartic acid to threonine at position 313 is most likely due to a functional intolerance to blood plasma neutral pH conditions. This obviously results in a profound decrease of enzymatic GLA activity in plasma 
. Additionally, this effect seems to be irreversible. Once in contact with a neutral or basic pH environment D313Y remains inactive, even if transferred to optimal pH (unpublished data). The GLA substrate Gb3, also known as CD77, has been shown to act as a cell surface receptor in apoptotic signaling triggered not only by Shiga toxin and Shiga-like toxins (vero toxin), but also by Gb3/CD77 antibodies 
If extracellular GLA activity is involved in inactivation of CD77 or its removal from the cellular surface, then a decrease of extracellular GLA activity could lead to an increased initiation of apoptosis. If so, the occurrence of abundant WML and the mild FD symptoms in D313Y carriers points to a higher susceptibility of neural tissues to this possible pathomechanism. To strengthen the hypothesis, GLA should be further analyzed in appropriate studies as a potential extracellular regulator of CD77.
From the clinical point of view, the most appropriate time to start evaluating and follow-up the neurological manifestations of D313Y carriers, or whether and when starting treatment with ERT, remains to be investigated and should be based on more clinical data. We, therefore, decided to perform a follow-up MRI within 6 months and started a symptomatic treatment of the neuropathic pain of the index patient with pregabaline. If the neuropathic pain does not respond to appropriate medication, ERT should be suggested, in particular with regard to the excellent ERT response on neuropathic pain in appropriate studies 
. In case of a significant increase of WML an effective anti-platelet agent such as clopidogrel should be considered as an appropriate therapeutic option.
In conclusion, our results provide evidence that GLA D313Y could be involved in neural damage with consecutive WML, demonstrating the necessity of evaluating patients carrying D313Y more thoroughly. D313Y might broaden the spectrum of hereditary small artery diseases of the brain which preferably occur in young adults. In view of the existing causal therapy regime (ERT), D313Y should be more specifically taken into account in patients with multifocal WML in the absence of classical risk factors.