Fabry’s Disease: Heterozygous Form of Different Expression in Two Monozygous Twin Sisters

Abstract

A 26-year-old woman presented widespread angiokeratomas predominantly in a swimsuit distribution pattern associated with acroparesthesia in all four limbs. The tentative diagnosis of Fabry’s disease (FD) was confirmed by optical and electron-microscopic findings and by appropriate biochemical testing. The work-up showed ocular and renal manifestations of the disease. The monozygous twin sister of the patient was asymptomatic although she was shown to be heterozygous for the enzymatic defect. These 2 cases illustrate the concept of extreme lyonization which can explain observed phenotypic differences in heterozygous females with X-linked hereditary diseases. The father and mother of the patient were shown to be noncarriers of the trait, suggesting de novo mutation in the twin pregnancy. However, biochemical testing for the detection of FD heterozygous females cannot rule out the possibility of the mother being heterozygous with normal enzyme activity.

X chromosome inactivation in clinical practice

“…Several MZ twin pairs have been reported where one twin is healthy and the co-twin severely aVected with an X-linked disorder. This discordance has been attributed to skewed XCI in the aVected twin in several cases, such as Duchenne muscular dystrophy (Burn et al 1986;Richards et al 1990;Lupski et al 1991;Tiberio 1994), Hunter disease (Winchester et al 1992), Fabry disease (Marguery et al 1993;Redonnet-Vernhet et al 1996) and hemophilia A (Bennett et al 2008). It has been speculated that skewed X inactivation of the inner cell mass may lead to MZ twinning (Nance 1990;Lubinsky and Hall 1991).…”

Naked Plasmid DNA-Based α-Galactosidase A Gene Transfer Partially Reduces Systemic Accumulation of Globotriaosylceramide in Fabry Mice

“…With advancing age there is increased morbidity and mortality due to renal failure, cardiac disease, and early stroke. Heterozygous female Fabry patients manifest a wide spectrum of disease severity, ranging from a virtually symptom-free course [3] to a course comparable to that in males [4].…”

Novel mutations of the GLA gene in Japanese patients with Fabry disease and their functional characterization by active site specific chaperone

“…Hemizygous male patients with no or very low α-galactosidase A activity usually have severe clinical symptoms and die as young adults. Heterozygous female Fabry patients exhibit a wide range of severity, from a virtually symptom-free course (Marguery et al, 1993) to one comparable to that of their male counterparts (Whybra et al, 2001), although they usually have no symptoms or very mild manifestations.We examined Fabry patients in Japan and sequenced the patients' α-galactosidase A gene (GLA) (MIM# 300644). To analyze the mutant α-galactosidase A activities, we transfected COS-7 cells with the mutant GLAs.…”