Brain MR Imaging Findings of Cardiac-Type Fabry Disease with an IVS4+919G>A Mutation

BACKGROUND AND PURPOSE:A high incidence of cardiac-type Fabry disease with an α-galactosidase A mutation, IVS4 + 919 G>A, has been identified in the Taiwanese population. The neurologic manifestation has not been understood in this specific cardiac variant. This study aimed to investigate the typical imaging features of classic Fabry disease in patients with IVS4 Fabry disease.MATERIALS AND METHODS:Twenty-six patients with IVS4-type Fabry disease (20 men and 6 women; age range, 43–71 years; median age, 61 years) and 26 age- and sex-matched healthy controls (age range, 44–68 years; median age, 60 years) were analyzed for white matter hyperintensities, the pulvinar sign, and basilar artery diameter. The volumes of white matter hyperintensities were calculated by comparison with an in-house data base of 276 controls.RESULTS:Infarctions were found in 9 patients with IVS4 Fabry disease (35%) and in none of the healthy controls (P = .001). A pulvinar sign was found in 8 patients with IVS4 Fabry disease (30%) and in none of the healthy controls (P = .002). No significant difference was found in Fazekas scale scores for white matter hyperintensities; however, white matter hyperintensity volume in the deep white matter was higher in patients with IVS4 Fabry disease than in those from the healthy control data base (P = .004).CONCLUSIONS:Along with its involvement of the cardiac system, IVS4-type Fabry disease has features similar to those of classic Fabry disease and a higher frequency of deep white matter hyperintensities and a higher incidence of infarctions and pulvinar signs than in healthy controls.

Classic Fabry disease is a multisystem X-linked lysosomal disorder due to lysosomal α-galactosidase A (GLA) deficiency, which subsequently leads to accumulation of glycosphingolipids, primarily globotriaosylceramide, throughout the body.¹ The disease results in severe renal, cardiac, and central nervous system complications in adulthood. On brain MR imaging, classic Fabry disease is characterized by white matter hyperintensities, infarcts, and dolichoectasia.²In the general population, the incidence of Fabry disease has been reported as 1 in 40,000–117,000 live births. However, our previous studies by using neonate screening had identified a high incidence (approximately 1 in 1600 males) of a cardiac variant resulting from a GLA mutation, IVS4 + 919G>A (IVS4-type).^3,4 Another study revealed that 12 of 10,499 males (1/875) and 24 of the 9564 females (1/399) had the IVS4 + 919G>A mutation in neonate screening.⁵ The natural course of the IVS4-type Fabry disease is still largely unknown. The intronic mutation (IVS4 + 919G>A) was reported to be a “cardiac-type” Fabry mutation,⁶ which may present with asymptomatic, mild symptomatic as microalbuminuria and retinal vessel tortuosity, to severe cardiac symptoms causing significant morbidity after the fifth decade of life. However, the neurologic symptoms in the specific subtype have never been understood. Therefore, the current study aimed to analyze the degrees of CNS involvement in IVS4-type Fabry disease by retrospectively comparing brain imaging results of this patient population with images from a healthy control data base.