Fabry disease is an X-linked condition that affects both men and women. The manifestations of this complex disease are progressive and multisystemic. The classic form is seen in both males and females, although the manifestations are often less severe in females and disease progression is generally delayed compared with males. This chapter describes the natural history of the classic form of the disease, as well as the different signs and symptoms in females, and atypical late-onset disease in males.

Classic Fabry disease

Although clinically heterogeneous, classic Fabry disease is usually a slowly progressive disease in which signs and symptoms change as the patient ages [1]. The clinical manifestations usually first become apparent in childhood or adolescence (Table 1). Lifespan is typically reduced in both males and females, and the main causes of death are renal failure, heart disease or stroke [2, 3].

Table 1

Disease progression in patients with Fabry disease.

Pain

Neuropathic pain typically appears during childhood [4, 5], and has been reported to affect 77% of men and 70% of women in adulthood [2, 3]. Data from FOS – the Fabry Outcome Survey – show that 64% of males and 83% of females experience neuropathic pain (defined as chronic pain, pain attacks, abdominal pain or joint pain). Pain may be chronic or experienced as episodic Fabry 'crises' or acroparaesthesiae. In FOS, pain attacks are reported by 72% of males and 52% of females (67% of boys; 45% of girls) (Table 2). Patients describe the pain as an excruciating burning sensation in the palms of the hands and soles of the feet, often radiating to the proximal extremities and occasionally to the abdomen. Pain may occur spontaneously but is exacerbated by temperature changes, fever, stress, physical exercise and alcohol [2].

Table 2

Frequency and age at onset of specific signs and symptoms of Fabry disease in male (n = 318) and female (n = 337) patients enrolled in FOS – the Fabry Outcome Survey.

Appearance

Hemizygous males often have a characteristic facial appearance – with prominent supraorbital ridges, frontal bossing and thickening of the lips – which is recognizable from approximately 12–14 years of age [2] (Figure 1).

Figure 1

Characteristic facial appearance.

Fabry disease in women and children

Although Fabry disease is an X-linked disorder, females are symptomatic in a high proportion of cases (see Chapter 30) (Table 2). Disease manifestations in females tend to occur at a later age than in males and are often less severe (see Chapter 32). Symptoms typically start in childhood, but the diagnosis is often difficult to establish in the index case and there is frequently a delay between the onset of signs and symptoms and diagnosis (see Chapter 16). FOS data on females [18] and children [5] with Fabry disease have recently been published.

Atypical variants of Fabry disease

There have been numerous reports in the literature regarding late-onset Fabry disease in males, generally presenting with features involving only a single organ system. It has been proposed that these so-called cardiac [6] and renal [19] variants arise as a result of missense mutations that are associated with sufficient residual enzyme activity to prevent symptoms in childhood and early adult life.

Within the FOS database, there are no clear data supporting the concept of single organ variants of Fabry disease. There are 18 individuals who currently report no signs and symptoms of Fabry disease, and there are three females (aged 19, 21 and 47 years) and one male (aged 19 years) who have reported only renal signs and/or symptoms to date. These data must be interpreted with care, as such reports of single organ involvement might be due to missing data in the FOS database. Overall, FOS data suggest wide clinical heterogeneity.

Close scrutiny of the published literature on renal and cardiac variants shows that many of the patients do, in fact, have changes in other organ systems [17, 19]. Increasing numbers of patients with Fabry disease are being diagnosed following investigations of specific medical conditions such as hypertrophic cardiomyopathy, cerebrovascular disease and renal failure [16, 20, 21] (see Chapter 17). It may well be that many of these patients have mutations associated with residual enzyme activity (see Chapter 34), which could, in turn, be associated with a milder disease phenotype.

Cause of death in Fabry disease

Life expectancy is reduced for both males and females with Fabry disease. The surveys by MacDermott et al. [2, 3] indicate that life expectancy is decreased by approximately 20 years in males and 10–15 years in females.

To date, FOS has collected data on the cause and age of death for 107 affected relatives of patients (68 presumed hemizygous males and 39 presumed heterozygous females) (Figure 2). The peak decade of death among presumed hemizygous males is the fifth decade, and there are approximately equal numbers of males dying in their fourth and sixth decades. As shown in Table 3, the principal cause of death in these males was renal failure (n = 33), followed by cardiac (n = 11) and cerebrovascular causes (n = 5); however, some deaths were also attributed to a combination of these causes (cardiac/renal, n = 4; renal/cerebrovascular, n = 3). The peak decade of death among presumed heterozygous females is the seventh decade, but there also appears to be an excess number of deaths in the fifth and sixth decades. The principal causes of death reported in females were cardiac in origin (n = 8) and cancer (n = 8). There also appears to be a significant number of premature deaths among females as a result of cerebrovascular disease (n = 5).

Figure 2

Age at death in male (n = 68) and female (n = 39) relatives of patients in FOS – the Fabry Outcome Survey – who are presumed to have had Fabry disease.

Table 3

Causes of death reported in male (n = 66) and female (n = 38) relatives of patients in FOS – the Fabry Outcome Survey – who are presumed to have had Fabry disease.

Conclusions

Fabry disease is a clinically heterogeneous, progressive X-linked disorder which results in a range of manifestations. Females tend to develop symptoms at a later age and of a lesser severity than males. Symptoms and signs typically begin in childhood and include pain, angiokeratomas, oedema, abnormalities of hearing, eye changes, dyshidrosis and gastrointestinal disturbances. Renal, cardiac and cerebrovascular complications cause premature death in both males and females.

It remains to be seen if enzyme replacement therapy can alter the natural history of Fabry disease. Data from FOS – the most comprehensive database on patients with Fabry disease – will help to answer this question.

References

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2.

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6.

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14.

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16.

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17.

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19.

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21.

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