Introduction

Fabry disease (FD) is a rare, X-linked disorder characterized by a progressive accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids in different cells 1, 2. In contrast to many other lysosomal storage disorders (LSD) 3, 4, FD is regarded as a clinical adult-onset multisystemic condition2. Despite the frequency of brain involvement in FD, the physiopathology of CNS alterations in this condition has not yet been completely understood. Along with vascular and neurodegenerative mechanisms, both due to glycosphingolipid accumulation, the possibility that in FD an abnormal development of CNS could occur has never been fully investigated. The aim of our study was to perform a volumetric analysis of intracranial tissues in FD, investigating eventual differences in terms of total intracranial volume (ICV) between FD patients and a group of healthy controls (HC) as a possible expression of abnormal brain development in this condition.

Methods

Forty-two patients with genetically proven FD were recruited, along with thirty-eight HC of comparable age and sex. All MRI exams have been carried out on the same 3 Tesla MR scanner and included an isotropic T1w acquisition for the volumetric analysis5, which was conducted using the Statistical Parametric Mapping (SPM12) software package (http://www.fil.ion.ucl.ac.uk/spm). For ICV and global GM, WM and cerebrospinal fluid (CSF) volumes estimation, structural data were processed using the unified segmentation tool 6; then, ICV was computed with the “tissue volumes” utility by adding up the segmented GM, WM and CSF volumes 7. To investigate possible changes in brain or GM volumes independent from ICV, brain parenchymal volume was defined as the sum of GM and WM, and normalized volumes were calculated as the ratio to ICV, thus obtaining brain parenchymal fraction (BPF) and gray matter fraction (GMF), respectively 8, 9. Finally, as a post-hoc evaluation, a voxel based morphometry (VBM) analysis was carried out to investigate possible regional GM differences between the two groups, as described in previous works10, 11.

Results

FD patients showed significantly smaller intracranial volumes compared to HC, with a mean ICV that was 8.1% lower compared to the control group (1267.8 ± 121.5 ml vs 1379.8 ± 137.2 ml in FD and HC, respectively; p < 5·10-5). No significant differences emerged between the two groups when comparing both the BPF (81.2 ± 4.4% vs 81.5 ± 4.0% in FD and HC, respectively; p = 0.86) and the GMF (50.5 ± 3.6% vs 50.1 ± 3.9% in FD and HC, respectively; p = 0.21), while the post-hoc VBM analysis revealed a cluster of reduced GM density in FD patients compared to HC at the level of the thalami, bilaterally, extending towards the left hippocampus (p = 0.001) (Figure 1). No significant clusters of increased GM density were found in FD patients compared to HC.

Discussion

ICV is defined as the sum of GM, WM and CSF, and it is a representation of the maximal brain growth obtained during development and maturation 12, 13. Indeed, ICV peaks early in life and once the skull sutures are completely fused, there is no further change in this measure, regardless of changes that may occur in brain tissue 14. In our study, we found significantly smaller ICV in FD patients, suggesting that in this condition a neurodevelopmental abnormality may be also present. It may be hypothesized that α-galactosidase A could play a role in the normal development of the CNS and its deficiency could lead to detectable neurodevelopmental abnormalities. These findings indicate that FD, once considered as an adult-onset condition, is a more complex phenomenon that encompass all ages, stressing the importance of a timely diagnosis and the importance of an early initiation of the enzyme-replacement therapy (ERT). Furthermore, we found no difference between FD and HC in terms of BPF and GMF, thus suggesting a harmonious volumetric reduction of all intracranial structures in FD patients, rather than a pure neurodegenerative phenomenon. Interestingly, in the post-hoc VBM analysis we found two clusters of reduced GM density involving both thalami with extension to the left hippocampus, in line with previous studies that demonstrated hippocampal atrophy in FD patients as a possible surrogate of primitive neuronal involvement, independent from brain vasculopathy 15, 16.

Conclusion

In conclusion, we demonstrated that FD patients show an almost 10% reduction of the ICV compared to HC, with a preservation of BPF and GMF. Our results suggest that in FD patients an abnormality of brain development could be also present, thus emphasizing the importance of an early diagnosis of FD, and probably of an early ERT initiation.

Acknowledgements

No acknowledgement found.

References

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