Many of the signs and symptoms of Fabry disease occur frequently in early childhood. These include acute and chronic neuropathic pain, acroparaesthesiae, hypohidrosis, angiokeratoma and gastrointestinal symptoms. Such manifestations occur in both boys and girls and may impair quality of life (QoL) and affect daily activities at home and school. Cornea verticillata is also commonly seen in affected children. In addition, although stroke, end-stage renal failure and heart failure are not found in children with Fabry disease, early signs of cerebrovascular, renal and cardiac involvement are encountered. Despite early manifestations of Fabry disease occurring in childhood, correct diagnosis is frequently delayed. Data from FOS – the Fabry Outcome Survey –and from clinical trials on the effects of enzyme replacement therapy (ERT) in children with Fabry disease have demonstrated that ERT with agalsidase alfa is well tolerated and has beneficial clinical effects on pain, QoL and gastrointestinal symptoms, at least in the short term. Early diagnosis is therefore important, because early initiation of ERT could potentially prevent or at least delay progression to end-stage organ failure.

Introduction

It has recently been recognized that the effects of Fabry disease are evident during childhood [1–3]. As in adults [4], manifestations of Fabry disease in children, including acute and chronic neuropathic pain, hypohidrosis, angiokeratoma and gastrointestinal symptoms, reduce quality of life (QoL) [1–3, 5]. Few data, however, are available on the efficacy of enzyme replacement therapy (ERT) in children with Fabry disease. This chapter discusses the natural course of Fabry disease in children and presents demographic data from FOS – the Fabry Outcome Survey. The efficacy and safety of ERT in preventing or delaying the onset of clinical manifestations of Fabry disease in children are also reviewed, with specific reference to FOS data.

Natural course of Fabry disease in children

Most patients with Fabry disease present with symptoms in early childhood, but these symptoms are not necessarily specific to the disease. As a result, there may be a significant delay in diagnosis. Fabry disease is progressive, and its characteristic life-threatening complications, including stroke, end-stage renal disease (ESRD) and cardiac failure, are not seen in childhood. The early clinical features of Fabry disease in children include poorly understood gastrointestinal manifestations, with alternating diarrhoea, constipation and abdominal bloating. In adults, a history of malabsorption, steatorrhoea and weight loss, with normal pancreatic enzymes, has been reported, but such symptoms are uncommon in children.

The burning and tingling sensation, and debilitating pain described in Fabry disease, known as acroparaesthesiae, is often the first presenting symptom in children. There has been anecdotal evidence of unexplained crying during infancy in children with Fabry disease, which is often diagnosed as colic. During childhood, they suffer from an acute onset of intense pain, predominantly in their hands and feet, and some children develop sudden abdominal pain, which may be mistaken for acute abdominal problems, such as appendicitis. These episodes are called Fabry crises and are usually precipitated by infections, fever, a change in temperature, or stress. Simple analgesics, opiates and gabapentin have been used with variable success. Fabry pain is debilitating, and often misdiagnosed in childhood. As in adults, it affects quality of life and normal childhood activities, such as participation in sport.

The characteristic skin rash with non-blanching small red lesions, known as angiokeratomas, seen in the groin, buttocks, abdomen and mucosal membrane of the mouth and lips, can appear in late childhood.

Cornea verticillata is common and can be seen by slit-lamp examination, performed by an experienced ophthalmologist, even in children under the age of 5 years. Tortuous retinal vessels and subcapsular cataracts are uncommon in children, but preliminary FOS data suggest that vessel tortuosity correlates with rates of progression of the systemic disease (see Chapter 26). The presence of subcapsular cataracts and retinal vessel tortuosity may also reflect disease severity, but there are currently too few data to be able to confirm this.

Hearing impairment, as a result of glue ear or due to sensorineural hearing loss at high and low frequencies, has been documented in children with Fabry disease. These symptoms, however, rarely occur in isolation and are usually accompanied by acroparaesthesiae and gastrointestinal manifestations.

Non-specific lethargy and myalgia are not uncommon in children with Fabry disease, but may be mistaken for rheumatological problems. In the author's experience, children with Fabry disease have difficulty in keeping up with their peers during sporting activities, because of excessive tiredness and decreased sweating.

Although cardiomyopathy and arrhythmias are uncommon in children with Fabry disease, mild valvular dysfunction is often revealed by echocardiography. Evidence of cardiomyopathy may be present in late childhood.

Proteinuria is documented mostly in late childhood, and ESRD has not been documented in patients below 18 years of age. Although most boys with classic Fabry disease who develop proteinuria will progress to ESRD, girls who present with proteinuria in their teenage years seldom progress to ESRD.

The burden of Fabry disease in young children is mainly due to debilitating pain, fever and pain crises, tiredness and lethargy, decreased sweating, impaired ability to participate in sports compared with peers, and gastrointestinal manifestations. It is therefore essential to have questionnaires that address these issues specifically, and which children themselves can complete. These questionnaires also aim to monitor functioning at school, relationships with peers and physical activity. Such a questionnaire is currently being evaluated in FOS.

FOS data

In March 2005, there were 119 patients in the FOS database who were under the age of 18 years (50 boys and 69 girls). The median age of these children at baseline evaluation was 12.7 years (range, 0.7–17.9 years), with a median age for boys of 11.1 years (0.7–17.8 years) and a median age for girls of 13.2 years (2.4–17.9 years) [5].

The children were reported to come from 86 families. In 44% of patients, the diagnosis was suspected from their family history. In the remaining patients, the diagnosis was suspected and confirmed by clinicians, including paediatricians, geneticists, dermatologists, general physicians, ophthalmologists, neurologists and nephrologists. Data for both the age at onset of symptoms and the age at diagnosis were available for 76 of the 119 patients (Table 1). For these 76 children, the mean age at diagnosis was approximately 10 years, and the delay between the onset of symptoms and diagnosis of Fabry disease was 2.8 ± 3.5 years (mean ± SD). The age at onset of symptoms was reported in only six of the remaining 43 patients. In many of the children detected by pedigree analysis, symptoms of Fabry disease had not yet developed.

Table 1

Delay in diagnosis after onset of symptoms in patients below 18 years of age enrolled in FOS – the Fabry Outcome Survey. Values are means ± SD, with 95% confidence intervals and numbers of patients in parentheses.

The common signs and symptoms, including acroparaesthesiae, pain crises, angiokeratoma and gastrointestinal manifestations, were present in both male and female patients and were seen even in children below 10 years of age (Figure 1). Girls presented later than boys, with similar clinical manifestations [5].

Figure 1

Age at onset of symptoms in boys and girls with Fabry disease in FOS – the Fabry Outcome Survey. Bars represent the 95% confidence interval.

Table 2 shows the frequency of different signs and symptoms of Fabry disease and age at onset in children in FOS, as of March 2005. The most frequently reported early clinical manifestations were gastrointestinal problems, pain attacks, hypohidrosis and cornea verticillata, all of which were reported in 30–50% of patients.

Table 2

Frequency and age at onset of specific signs and symptoms of Fabry disease in boys (n = 49) and girls (n = 66) enrolled in FOS – the Fabry Outcome Survey.

Other less frequent clinical features reported in children in FOS included claudication, Raynaud's syndrome, peripheral oedema, lymphoedema, headache, behavioural problems and anxiety, arrhythmias, chest pain, dyspnoea, left ventricular hypertrophy, palpitations, syncope and frequent infections.

Stroke, chronic kidney disease and heart failure, which together mainly account for the reduced lifespan of adults with Fabry disease, are not found in children. However, other cerebrovascular, renal and cardiac manifestations, as shown in Table 2, do occur in childhood, reflecting early onset of major organ involvement.

The symptoms of Fabry disease in children are likely to have an impact on QoL. Although detailed analyses of QoL data in children with Fabry disease are currently unavailable, limited data from Ries et al. [2] suggest that there is a decreased QoL.

Benefits of ERT

Data available in large outcomes databases such as FOS are important, not only for early diagnosis of Fabry disease in children but also for understanding the natural history of the disease and predicting the rate of disease progression. This is particularly relevant in view of the recent introduction of ERT. The beneficial effects and safety of ERT have been demonstrated in adults with Fabry disease [6–10]. It is possible that ERT should be initiated early, as it offers the potential to change the natural course of this progressive disease.

In March 2005, there were 55 children (31 boys, 24 girls) from nine European countries receiving ERT in FOS (Table 3). Diagnosis of Fabry disease was confirmed in all patients by enzyme and/or DNA analysis.

Table 3

Demographic data from 55 children receiving enzyme replacement therapy (ERT) in FOS – the Fabry Outcome Survey. Data are presented as means ± SD.

At the start of therapy, 20 of the 55 children (13 boys, 7 girls) who were receiving ERT in FOS were younger than 12 years of age, and 35 (18 boys, 17 girls) were aged between 12 and 18 years. The median dose of agalsidase alfa was 0.2 mg (range, 0.17–0.23 mg), infused over 40 minutes every 2 weeks. It should be noted that all of the children and adolescents treated in two European trials of paediatric patients have been entered into FOS and account for a third of this population (11 boys, 8 girls).

Data on the safety of ERT – as well as the effects of ERT on pain, QoL, hearing and gastrointestinal, cardiac and renal symptoms, have been analysed after 12 months of therapy.

Pain and QoL

The European QoL (EQ-5D) questionnaire was used to measure QoL (see Chapter 40). EQ-5D scores at the start of therapy (baseline) and after 12 months of therapy are shown in Figure 2 for the ten patients (6 boys, 4 girls) for whom paired QoL data were available in FOS. An improvement or no change in EQ-5D scores was observed in all ten patients (baseline scores were normal in those patients with no change in scores between baseline and 12 months).

Figure 2

Effect of 1 year of enzyme replacement therapy (ERT) on quality of life (QoL), as assessed using the European QoL (EQ-5D) questionnaire, in six boys and four girls in FOS – the Fabry Outcome Survey.

The Brief Pain Inventory (BPI) (see Chapter 40 was completed by 11 patients (6 boys, 5 girls). The median age of these patients was 14.7 years (range, 6.3–16.9 years). The median score at baseline for pain on average was 3 (range, 0–8) and the median change in score after 12 months of ERT was −1 (range, −6 to 4) (Figure 3). The median score at baseline for pain at its worse was 7 (range, 2–10) and the median change in score after 12 months of ERT was 0 (range, −7 to 7). Although only a small number of patients was studied, these results reveal an overall improvement in pain, with either improvement or no change from baseline in most patients.

Figure 3

Effect of 1 year of enzyme replacement therapy (ERT) on pain experienced on average, as assessed using the Brief Pain Inventory (BPI), in six boys and five girls in FOS – the Fabry Outcome Survey.

Hearing

Hearing was assessed using pure-tone audiometry in patients older than 5 years. Audiometry data were available from ten patients at baseline and after 1 year of therapy. In nine of these patients, there was either no change or an improvement in hearing at high, medium and low frequencies.

Gastrointestinal symptoms

Eleven patients (4 boys, 7 girls) suffered from diarrhoea at baseline. After 12 months of therapy, there was a reduction in symptom frequency in ten of these patients from every day or more than once a week to once or twice or month or almost never. In one female, aged 18.3 years, the frequency of diarrhoea was documented as being the same after 9 months of ERT.

Renal features

Serial measurements of urine protein concentrations and glomerular filtration rate (GFR) were available at baseline and 1 year of therapy in only ten patients (4 boys, 6 girls). The mean age of these children at baseline was 14.5 years (range, 12.7–15.7 years in males; 9.1–17.3 years in females). Mean 24-hour urinary protein excretion was 229 mg/l (range, 77–615 mg/l) at baseline and 241 mg/l (range, 96–491 mg/l) after 1 year of therapy. Mean GFR, assessed using plasma ⁵¹Cr-EDTA clearance, was 119 ml/min/1.73 m² (range, 72–221 ml/min/1.73 m²) at baseline and 117 ml/min/1.73 m² (range, 84–143 ml/min/1.73 m²) after 1 year of ERT. No patient showed deterioration in renal function after 1 year of therapy.

Cardiac features

Paired data for left ventricular (LV) mass at baseline and after 1 year of treatment were available in ten patients (4 boys, 6 girls). LV mass was within the normal range at baseline and after 1 year of ERT.

Discussion

Fabry disease is a progressive disorder, with life-threatening complications by the time patients reach early adulthood. Early studies of ERT in Fabry disease focused on adult males only. More recently, studies have clearly demonstrated that heterozygous women with Fabry disease should no longer be considered as asymptomatic carriers [11–16]. The burden of disease in children has also been documented [1, 17].

Clinical manifestations of Fabry disease are common in girls as well as boys, although they may be of later onset in girls. Healthcare workers therefore need to remain alert to signs and symptoms of Fabry disease in girls and boys. Given the non-specific nature of the clinical presentation of Fabry disease, the diagnosis in children should be suspected on the basis of a cluster of symptoms, including generalized pain, acroparaesthesiae, non-specific bowel disturbances, and hearing problems such as tinnitus and conductive or sensorineural hearing loss. When Fabry disease is a possible diagnosis, slit-lamp examination for cornea verticillata is useful, even in patients below 5 years of age, although its absence in early childhood does not exclude Fabry disease. In girls, it is essential to confirm the diagnosis by DNA analysis, as enzyme activity in heterozygous girls may be within the normal reference range. Family history, particularly concerning early deaths and renal, cardiac and neurological disease, is also important when Fabry disease is suspected.

Early treatment of Fabry disease, before irreversible organ damage occurs, is desirable. At the present time, however, there are no sensitive biomarkers to assess the efficacy of ERT when started before the onset of signs and symptoms. Until it is possible to show that the natural history of the disease is altered by starting therapy whilst the patient is asymptomatic, ERT will usually be indicated in children who are symptomatic. However, where there is a family history of severe disease, with very early onset of renal disease, cardiac disease or stroke, the clinician might consider treating asymptomatic children. As life-threatening complications of Fabry disease are very rare in children and not seen in individuals younger than 10 years of age, it is important that the indications for therapy in children are based on prevention of early complications of Fabry disease, such as pain crises, gastrointestinal and musculoskeletal problems and proteinuria, and on improving QoL.

The majority of boys in the FOS database were symptomatic at the start of ERT. However, the criteria for initiating ERT in females are less clear cut and, therefore, fewer girls within FOS are receiving treatment. The reasons for this inconsistency may be the cost implications in different countries and, more importantly, perhaps, the absence of specific guidelines for starting ERT in both males and females. In the UK, national guidelines have been developed for the management of all patients with Fabry disease (see Chapter 41). These will be reviewed annually but are an important milestone in the management of patients with Fabry disease.

In adult males who are not receiving ERT, the deterioration of renal function from early adulthood may reach 12 ml/min/year [18, 19]. Renal dysfunction is also common in females, although ESRD is infrequent. Beck et al. (2004) have shown that ERT with agalsidase alfa can stabilize or even improve renal function in patients in whom renal impairment is mild or moderate at baseline [10]. Significant improvements were not noted, however, in patients with ESRD. Early treatment therefore has the potential to reverse the underlying and otherwise inevitable renal failure in patients with Fabry disease.

Conclusions

The burden of Fabry disease in children is mainly due to neurological (e.g. pain crises) and gastrointestinal manifestations. Data from FOS are encouraging and indicate that ERT has beneficial effects on QoL, pain and gastrointestinal symptoms in children. Furthermore, agalsidase alfa has a good safety profile and is well tolerated in children with Fabry disease.

It is very rare for children to present with life-threatening complications, such as cardiac failure, ESRD and stroke. Therefore, it is important to note that the outcome measures used in adults are not necessarily the most appropriate for assessing the efficacy of ERT in children.

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