Clinical manifestations and natural history of Japanese heterozygous females with Fabry disease

Abstract

Fabry disease is an X linked lysosomal storage disorder resulting from deficiency of α-galactosidase A activity. Although disease manifestations in heterozygous females with Fabry disease have been considered to be rare and mild, heterozygous patients with severe symptoms have recently been reported. In this study we focused on the clinical characteristics of Japanese females patients with Fabry disease and analysed data from 36 women. Data on clinical manifestations such as acroparaesthesia, hypohidrosis, angiokeratoma, corneal opacities, proteinuria, end-stage renal disease (ESRD), left ventricular hypertrophy (LVH) and cerebral infarction were obtained by questionnaire; these analysed by the Kaplan-Meier method and compared with the data from Japanese male patients. Eighty-six per cent of female patients had at least one clinical sign of Fabry disease. Their most common symptoms were acroparaesthesia and corneal opacities, and diagnosis was most commonly based on family history. The cumulative incidences of angiokeratoma, corneal opacities, proteinuria, ESRD, LVH and cerebral infarction were significantly lower in female than in male patients. However, corneal opacities, proteinuria and LVH developed progressively in female patients as well as in male patients. The incidence of LVH was especially high in older female patients and the cumulative incidence of LVH in women over 68 years of age was 100%. We consider that the term X-linked 'recessive' is inappropriate for Fabry disease because of the high prevalence of its pathognomonic signs in heterozygous female patients. Careful and long-term evaluation of clinical signs is important in heterozygous females patients with Fabry disease.

A 4-year study of the efficacy and tolerability of enzyme replacement therapy with agalsidase alfa in 36 women with Fabry disease

“…In several cross-sectional studies, the percentage of women with ESRD is reported to be about one third that of men. 21,25 The difference is even greater in the Fabry Outcome Survey, where ESRD was reported in 17% of men and only 1% of women with Fabry disease. 27 Similar findings have emerged from the Fabry Registry, where ESRD was reported in 13-17% of men and only 2.2-4.4% of women.…”

“…Like in some X-linked conditions, 14 heterozygous women may be symptomatic 15,16 but with an onset and rate of progression that is more variable than that observed in men. [15][16][17][18][19][20][21][22] The onset of signs and symptoms of Fabry disease occurs during childhood and adolescence in girls, just as it does in boys. 4,23,24 However, the onset of major organ involvement (kidney, heart, brain) occurs about 6 -10 years later in women than in men.…”

A Sporadic Case of Fabry Disease Involving Repeated Fever, Psychiatric Symptoms, Headache, and Ischemic Stroke in an Adult Japanese Woman

“…However, cases of Fabry disease involving de novo mutations have been reported in various countries (21,(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). In an analysis of Japanese pedigrees associated with reduced α-GAL activity, 5 out of 93 pedigrees (5.6%) were found to possess de novo mutations (33). In addition to the present study, there have been two detailed case reports on sporadic Fabry disease in Japanese patients.…”

“…However, the patient's CNS symptoms were more marked than the symptoms associated with other organs. Heterozygous female patients with Fabry disease can present with various clinical manifesta- tions (36), and it is important to keep in mind that atypical clinical manifestations can be observed in such patients. The pathogenic mechanism of the CNS symptoms seen in Fabry disease might be elucidated by examining the relationship between α-GAL gene mutations and CNS symptoms.…”

X Inactivation, Female Mosaicism, and Sex Differences in Renal Diseases

“…Generally benign, their presence suggests that having 50% normal cells is not enough to prevent all manifestations of this disease. 14 Approximately 10% of Fabry carriers eventually undergo dialysis or kidney transplants, usually because such "manifesting" heterozygotes have significantly more mutant than wild-type cells, reflecting skewed rather than random patterns of X inactivation. In this case, the skewing is not the result of a growth advantage of the mutant cells but reflects instead stochastic events, or skewing for reasons unrelated to the mutant gene, such as chromosome abnormalities and twinning.…”