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Case Reports
. 2019 May 7;55(5):122.
doi: 10.3390/medicina55050122.

Genotype⁻Phenotype Correlation in a New Fabry-Disease-Causing Mutation

Agnė Čerkauskaitė  1 , Rimantė Čerkauskienė  2 , Marius Miglinas  3 , Arvydas Laurinavičius  4 , Can Ding  5 , Arndt Rolfs  6   7 , Lina Vencevičienė  8 , Jūratė Barysienė  9 , Edita Kazėnaitė  10 , Eglė Sadauskienė  11
Affiliations
Case Reports

Genotype⁻Phenotype Correlation in a New Fabry-Disease-Causing Mutation

Agnė Čerkauskaitė et al. Medicina (Kaunas). .

Abstract

Background: Fabry disease (FD) is a rare X-linked inherited lysosomal storage disorder caused by α-galactosidase A deficiency leading to intracellular glycosphingolipid accumulation. FD manifestation is multisystem, and can differ depending on disease-related genetic variants. Currently, more than 700 different FD-causing mutations have been identified in the human GLA gene. We identified a novel mutation in a Lithuanian family with classical manifestations of Fabry disease, revealing severe effects to the cardiovascular systems of heterozygous women. Case presentation: A 49-year-old woman underwent echocardiography due to progressive dyspnea that lasted seven years, reduced physical activity, and periodic cardiac arrhythmia. Echocardiography revealed left ventricular hypertrophy with normal diastolic function. The patient had experienced acroparesthesia in her upper limbs and abdominal pain since childhood, and in the last decade had experienced mild proteinuria without renal failure. Her renal biopsy was typical for Fabry disease. The patient's brain magnetic resonance imaging (MRI) (T2 flair) showed white matter hyperintensities lesions. DNA sequencing of the proband, her mother and one of her sons showed a novel GLA gene exon 2 mutation, c.270C>G (p.Cys90Trp). All three patients had decreased α-galactosidase A activity and specific FD manifestations. Conclusion: A novel GLA mutation, c.270C>G (p.Cys90Trp), was found in a Lithuanian family with a classical form of Fabry disease in heterozygous women with predominant cardiac involvement. However, the exact manifestation of this mutation is still unclear as it is newly reported and further research must be done.

Keywords: Fabry disease; GLA gene; classical manifestation; novel mutation; α-galactosidase A.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Alignment of gene sequences. Portion of the sequence of exon 2 of the GLA gene in the patient. The blue arrow indicates the position of the mutation c.270C>G (p.Cys90Trp).
Figure 2
Figure 2
Light and electron microscopic findings of renal biopsy from the patient. (A) Microscopic examination revealed minimal mesangial proliferative changes; (B,C) Typical findings of Fabry disease-multilamellated myelin figures (yellow arrowhead) are seen in the cytoplasm of podocytes on electron microscopy; (D) Light microscopy showed the vacuolization of podocytes (blue arrowhead), although the patient had normal renal function and nonsignificant proteinuria (Haemotoxylin and Eosin stain, ×400).
Figure 3
Figure 3
Pedigree of the family of the patient. The proband is a heterozygous carrier for her mutation, inherited from her mother. One of the patient’s sons is affected by Fabry disease, while the other son is healthy. The brother of the proband should also be screened.
See this image and copyright information in PMC

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