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Mehta A, Beck M, Sunder-Plassmann G, editors. Fabry Disease: Perspectives from 5 Years of FOS. Oxford: Oxford PharmaGenesis; 2006.

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Fabry Disease: Perspectives from 5 Years of FOS.

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Chapter 19Natural history of Fabry disease

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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.

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.

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.

Figure 1

Characteristic facial appearance.

Angiokeratomas

Angiokeratomas are small, raised, dark red spots; they may be absent in patients with atypical Fabry disease [6]. Lesions typically develop slowly and are predominantly found in the 'bathing trunk' area (genitalia, scrotum, buttocks and inner thighs), and on the back and around the mouth. Data from FOS show that approximately 70% of males and 35% of females have angiokeratomas (Table 2) and that these may first be observed during childhood. Angiokeratomas were reported in 39% of boys and 23% of girls in FOS (age at onset, 9.4 ± 3.3 years in boys and 13.7 ± 3.5 years in girls).

Dyshidrosis

Male patients commonly suffer from hypohidrosis or anhidrosis, which results in heat intolerance. Hypohidrosis may begin at a very early age [4]. In FOS, the mean age at onset of this symptom in children is before 10 years (9.3 ± 5.1 years in boys and 9.7 ± 6.3 years in girls). Patients do not tolerate exercise well and may suffer nausea, dyspnoea, light-headedness and headache, or complete collapse with loss of consciousness [7]. There may also be reduced production of tears and saliva [8]. Rarely, cases of hyperhidrosis are reported.

Sensory organs

The eyes are affected in most patients with Fabry disease [9], and cornea verticillata (a whorl-shaped opacity) strongly suggests a diagnosis of Fabry disease, although it does not usually affect vision. Posterior subcapsular cataracts also occur, as do tortuous vascular lesions in the retina and conjunctiva, which sometimes cause severe visual loss.

FOS data suggest that tinnitus may also be an early sign of Fabry disease. This manifestation is reported in 27% of boys (age at onset, 12.3 ± 4.0 years) and 27% of girls (age at onset, 11.5 ± 4.1 years). Vertigo may also be reported. High-frequency sensorineural hearing loss is common [10].

Gastrointestinal symptoms

Gastrointestinal symptoms of Fabry disease tend to occur after meals and comprise recurrent bouts of abdominal pain in the mid and lower abdomen. Nausea, vomiting, abdominal distension, episodic diarrhoea and constipation may all occur. In many patients, gastrointestinal symptoms are similar to those associated with irritable bowel syndrome. Data from FOS suggest that gastrointestinal symptoms are one of the most common early manifestations of Fabry disease [5]. Diarrhoea was reported by 35% of boys and 24% of girls in FOS. Abdominal pain was experienced by 41% of boys and 38% of girls. This was the earliest symptom reported in girls (8.2 ± 4.8 years), and the second earliest in boys (7.0 ± 4.4 years) after diarrhoea (5.6 ± 4.3 years).

Renal function

Kidney involvement is common in classic Fabry disease and is an important cause of death. Abnormalities include proteinuria, haematuria, nephrotic syndrome and chronic renal failure requiring dialysis and/or renal transplantation [11, 12]. Proteinuria may be apparent during childhood. Data from FOS show that proteinuria occurs in 10% of boys and 17% of girls with Fabry disease. Onset of end-stage renal failure usually occurs in male patients when they are in their 30s and is not seen in childhood. Abnormalities of renal function are frequently seen in females, but end-stage renal failure is uncommon.

Cardiac function

Cardiac disease is one of the most frequent causes of death in patients with Fabry disease. Common cardiac defects include left and right ventricular hypertrophy, enlarged left atrium, heart valve abnormalities and conduction disturbances. Cardiac involvement may be the only symptom in some hemizygous males [6], and up to 5% of males with hypertrophic cardiomyopathy may have a 'cardiac' variant of Fabry disease [13] (see section below on 'Atypical variants of Fabry disease').

Nervous system

Cerebrovascular manifestations such as transient ischaemic attacks or stroke have been reported to affect 15–20% of patients with Fabry disease, and such attacks frequently recur and indicate a poor prognosis [14, 15]. Data from FOS show that some 6–9% of patients have experienced stroke; however, this value may be an underestimate of the true prevalence due to the high number of patients in the early stages of the disease who are included in this database. A recent study has indicated a prevalence of Fabry disease as high as 5% in males and 2.5% in females under the age of 55 years presenting with 'cryptogenic' stroke – that is, stroke occurring in the absence of other obvious risk factors [16]. Disturbed concentration, dizziness, dementia, headaches and learning difficulties also occur [2]. In addition, fatigue and depression have been reported in young patients.

The peripheral nervous system may also be affected, with disturbances of touch, pain and sensitivity to temperature.

Respiratory function

Significant airflow obstruction is common in patients with Fabry disease. Hence, smoking is particularly inadvisable as it seriously exacerbates pulmonary impairment [17]. Shortness of breath, tiredness and fatigue are common symptoms in early adulthood, and these symptoms arise as a result of cardiac, renal and pulmonary insufficiency. Asthma and reversible airways obstruction also occur [17].

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.

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.

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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Copyright © 2006, Oxford PharmaGenesis™.
Bookshelf ID: NBK11572PMID: 21290671

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