A classic variant of Fabry disease in a family with the M296I late-onset variant

Abstract

Fabry disease is an X-linked recessive disease of glycosphingolipid metabolism caused by deficiency or reduced activity of α-galactosidase A. Fabry disease phenotypes are known to consist of a classic variant and a late-onset variant. In patients with Fabry disease, the phenotype is generally considered to be defined (at least partially) by the genotype. However, patients with the classic variant have been encountered in families with mutations that are expected to produce the late-onset variant. Here, we describe a 4-year-old boy with a classic variant of Fabry disease in a family with the M296I late-onset variant. The patient's grandfather, mother, and aunt experienced late-onset disease, characteristic of the M296I variant. Conversely, the patient experienced typical disease symptoms in childhood. He had symptoms of hypohidrosis and associated heat accumulation. He cried at night due to the occurrence of severe acroparaesthesia. This symptom became more pronounced in warmer climates. Although the patient's family had a late-onset variant mutation of Fabry disease, we determined that the patient's symptoms were similar to those of classic Fabry disease. Therefore, the patient began enzyme replacement therapy, which alleviated his symptoms. Notably, enzyme replacement therapy led to rapid improvement of the patient's subjective symptoms. Thus, we presumed that the patient's symptoms supported a diagnosis of classic Fabry disease. These findings suggest that childhood symptoms may occur in patients with Fabry disease, even in families with late-onset variant mutations. The genotype-phenotype correlation in Fabry disease remains controversial.

Keywords: Classic variant; Fabry disease; Genotype; Late-onset variant; M296I mutation; Phenotype.

Fig. 1

Findings of renal biopsy in the patient’s grandfather. a, b First renal biopsy (47 years of age). There is no evidence to suggest hardening of the glomeruli. There are no findings of vacuolation or foamy appearance in glomeruli. Tubulointerstitial fibrosis is also inconspicuous. There are few signs of arteriosclerosis. Scale bars indicate 50 and 20 µm, respectively. (Masson’s trichrome stain). c, d Second renal biopsy (53 years of age). Segmental nephrosclerosis and hypertrophy of glomeruli are noticeable. The presence of vacuolation or foamy appearance in glomeruli remains unclear. Tubulointerstitial fibrosis is present. These findings are similar to ischaemic changes due to nephrosclerosis. Scale bars indicate 50 and 20 µm, respectively. (Periodic acid-methenamine-silver stain). e,f. Third renal biopsy (55 years of age). Many glomeruli have collapsed. Remaining glomeruli clearly exhibit vacuolation and foamy appearance (panel f, red arrows). Electron microscopy findings confirm the presence of Zebra bodies (panel f, small window, scale bars indicate 5 µm). Significant arteriosclerosis is present. Tubulointerstitial lesions show minimal progression. Scale bars indicate 50 and 20 µm, respectively. (Periodic acid–Schiff stain)

Fig. 2

Pedigree of the patient’s family. Blue arrow indicates proband. The enzyme activities of the proband, his mother, his aunt, and his grandfather are shown below their locations in the pedigree. Some of the proband’s relatives died suddenly of an unknown cause between 30 and 40 years of age, while another relative died of end-stage renal disease between 50 and 60 years of age. Abbreviation: ESKD, end-stage kidney disease