{
  "abstract": "Background Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by pathogenic variants in the GLA gene and commonly involves the heart. This study aimed to investigate the pathogenicity of a novel missense variant and its amenability to migalastat.Methods A retrospective analysis was conducted on 28 patients with FD collected over the past 10 years. Pathogenicity was assessed within a family carrying a de novo GLA missense variant through myocardial histopathology, bioinformatic predictions, protein structural modelling and in vitro cellular assays.Results In a cohort of 28 patients (15 males, 13 females), cardiac involvement was prevalent. We further reported a family with GLA c.227T>A (p.Met76Lys) variant. Myocardial biopsy showed cardiomyocyte hypertrophy with diffuse vacuolisation, interstitial fibrosis and microvascular dysfunction. Immunohistochemistry demonstrated markedly decreased expression of α-galactosidase A (α-Gal A) in vacuolated cardiomyocytes. Biochemical testing revealed low-to-normal α-Gal A enzymatic activity together with elevated plasma globotriaosylsphingosine (lyso-Gb3). Bioinformatic analyses suggested this variant was probably pathogenic by altering the three-dimensional structure of GLA protein. AC16 cardiomyocytes overexpressing wild-type and mutant GLA were constructed via lentiviral vectors. Immunofluorescence staining revealed that the intracellular localisation of the mutant protein remained unaltered, whereas α-Gal A enzyme activity was significantly reduced. Treatment with migalastat, a pharmacological chaperone for α-Gal A, partially restored the mutant α-Gal A enzymatic activity.Conclusions This study identified GLA c.227T>A (p.Met76Lys) as a novel pathogenic variant that primarily causes cardiac dysfunction. Migalastat may represent a therapeutic option for this variant.",
  "authors": [
    {
      "affiliations": [
        "Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China"
      ],
      "name": "Yingao Fan"
    },
    {
      "affiliations": [
        "Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China"
      ],
      "name": "Chenyu Cui"
    },
    {
      "affiliations": [
        "Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China"
      ],
      "name": "Xue Zhang"
    },
    {
      "affiliations": [
        "Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China"
      ],
      "name": "Chao Hu"
    },
    {
      "affiliations": [
        "Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China"
      ],
      "name": "Andi Xu"
    },
    {
      "affiliations": [
        "Department of Cardiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China"
      ],
      "name": "Lian Wang"
    },
    {
      "affiliations": [
        "Department of Radiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China"
      ],
      "name": "Hui Li"
    },
    {
      "affiliations": [
        "Department of Neurology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China"
      ],
      "name": "Xiaolei Zhu"
    },
    {
      "affiliations": [
        "Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China"
      ],
      "name": "Fengnan Niu"
    }
  ],
  "title": "Novel GLA variant in Fabry cardiomyopathy: evidence of pathogenicity and amenability to migalastat",
  "uid": "8a806bc4-b75e-5f8c-8e7e-fa44cd99b7ba"
}