TY  - JOUR
A1  - Lau, Kolja
A1  - Üçeyler, Nurcan
A1  - Cairns, Tereza
A1  - Lorenz, Lora
A1  - Sommer, Claudia
A1  - Schindehütte, Magnus
A1  - Amann, Kerstin
A1  - Wanner, Christoph
A1  - Nordbeck, Peter
T1  - Gene variants of unknown significance in Fabry disease: Clinical characteristics of c.376AG (p.Ser126Gly)
JF  - Molecular Genetics & Genomic Medicine
N2  - Background
Anderson–Fabry disease (FD) is an X-linked lysosomal storage disorder with varying organ involvement and symptoms, depending on the underlying mutation in the alpha-galactosidase A gene (HGNC: GLA). With genetic testing becoming more readily available, it is crucial to precisely evaluate pathogenicity of each genetic variant, in order to determine whether there is or might be not a need for FD-specific therapy in affected patients and relatives at the time point of presentation or in the future.

Methods
This case series investigates the clinical impact of the specific GLA gene variant c.376A>G (p.Ser126Gly) in five (one heterozygous and one homozygous female, three males) individuals from different families, who visited our center between 2009 and 2021. Comprehensive neurological, nephrological and cardiac examinations were performed in all cases. One patient received a follow-up examination after 12 years.

Results
Index events leading to suspicion of FD were mainly unspecific neurological symptoms. However, FD-specific biomarkers, imaging examinations (i.e., brain MRI, heart MRI), and tissue-specific diagnostics, including kidney and skin biopsies, did not reveal evidence for FD-specific symptoms or organ involvement but showed normal results in all cases. This includes findings from 12-year follow-up in one patient with renal biopsy.

Conclusion
These findings suggest that p.Ser126Gly represents a benign GLA gene variant which per se does not cause FD. Precise clinical evaluation in individuals diagnosed with genetic variations of unknown significance should be performed to distinguish common symptoms broadly prevalent in the general population from those secondary to FD.
KW  - diagnosis in Fabry disease
KW  - Fabry disease
KW  - gene variant
KW  - genotype/phenotype correlation
KW  - lysosomal storage disease
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312817
VL  - 10
IS  - 5
ER  - 
TY  - JOUR
A1  - Petritsch, B.
A1  - Köstler, H.
A1  - Weng, A. M.
A1  - Horn, M.
A1  - Gassenmaier, T.
A1  - Kunz, A. S.
A1  - Weidemann, F.
A1  - Wanner, C.
A1  - Bley, T. A.
A1  - Beer, M.
T1  - Myocardial lipid content in Fabry disease: a combined \(^1\)H-MR spectroscopy and MR imaging study at 3 Tesla
JF  - BMC Cardiovascular Disorders
N2  - Background

Fabry disease is characterized by a progressive deposition of sphingolipids in different organ systems, whereby cardiac involvement leads to death. We hypothesize that lysosomal storage of sphingolipids in the heart as occurring in Fabry disease does not reflect in higher cardiac lipid concentrations detectable by \(^1\)H magnetic resonance spectroscopy (MRS) at 3 Tesla.

Methods

Myocardial lipid content was quantified in vivo by \(^1\)H-MRS in 30 patients (12 male, 18 female; 18 patients treated with enzyme replacement therapy) with genetically proven Fabry disease and in 30 healthy controls. The study protocol combined \(^1\)H-MRS with cardiac cine imaging and LGE MRI in a single examination.

Results

Myocardial lipid content was not significantly elevated in Fabry disease (p = 0.225). Left ventricular (LV) mass was significantly higher in patients suffering from Fabry disease compared to controls (p = 0.019). Comparison of patients without signs of myocardial fibrosis in MRI (LGE negative; n = 12) to patients with signs of fibrosis (LGE positive; n = 18) revealed similar myocardial lipid content in both groups (p > 0.05), while the latter showed a trend towards elevated LV mass (p = 0.076).

Conclusions

This study demonstrates the potential of lipid metabolic investigation embedded in a comprehensive examination of cardiac morphology and function in Fabry disease. There was no evidence that lysosomal storage of sphingolipids influences cardiac lipid content as measured by \(^1\)H-MRS. Finally, the authors share the opinion that a comprehensive cardiac examination including three subsections (LGE; \(^1\)H-MRS; T\(_1\) mapping), could hold the highest potential for the final assessment of early and late myocardial changes in Fabry disease.
KW  - late gadolinium enhancement
KW  - myocardial lipid content
KW  - magnetic resonance spectroscopy
KW  - Morbus Fabry
KW  - rare diseases
KW  - lysosomal storage disease
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146693
VL  - 16
IS  - 205
ER  -