Pediatric Summary Report

Secondary Findings in Pediatric Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Pediatric): Passed (Consensus scoring is Complete)
• Curation Status (Pediatric): Released 1.0.0
• Status (Adult): Passed (Consensus scoring is Incomplete)
• GENE/GENE PANEL: GLA
• Condition: Fabry Disease
• Mode(s) of Inheritance: X-linked

Actionability Assertion

• GLA ⇔ 0010526 (fabry disease): Assertion Pending

Actionability Rationale

This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Final Consensus Scores

Gene Condition Pairs: GLA ⇔ 0010526 (OMIM:301500)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Cardiovascular disease (males) / Enzyme replacement therapy (ERT) with agalsidase alpha or beta	2	3C	2A	2	9CA
Cardiovascular disease (females) / Enzyme replacement therapy (ERT) with agalsidase alpha or beta	2	2C	2A	2	8CA
Cerebrovascular events (males) / Enzyme replacement therapy (ERT) with agalsidase alpha or beta	2	2C	2A	2	8CA
Cerebrovascular events (females) / Enzyme replacement therapy (ERT) with agalsidase alpha or beta	2	2C	2A	2	8CA
End-stage renal disease (males) / Enzyme replacement therapy (ERT) with agalsidase alpha or beta	2	2C	2A	2	8CA
End-stage renal disease (females) / Enzyme replacement therapy (ERT) with agalsidase alpha or beta	2	1C	2D	2	7CD

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

The incidence of Fabry disease (FD) has historically been estimated as 1:22,570 to 1:117,000 male births; however, more recent studies suggest the incidence may be as high as 1:1,250 to 1:3,100. This likely reflects a broader phenotypic spectrum identified in the last decade with a ratio of 11:1 of persons with the later-onset:classic phenotypes. [1, 2, 3, 4, 5, 6, 7, 8, 9]

Clinical Features

FD encompasses a spectrum of phenotypes resulting from deficient activity of the enzyme α-galactosidase (α-Gal A) and progressive lysosomal deposition of enzyme substrates in cells throughout the body. The classic form occurs in males with less than 1% α-Gal A enzyme activity with periodic crises of severe pain in the extremities, appearance of vascular cutaneous lesions, sweating abnormalities, microalbuminuria, proteinuria, and corneal and lenticular opacities. Disease progression can lead to cardiac and/or cerebrovascular disease. Progressive decline in renal function leads to end stage renal disease (ESRD). Patients may also have gastrointestinal, auditory, pulmonary, vascular, cranial nerve, and psychological manifestations. Cognitive function can be impaired. While general intellectual and global cognitive functioning appear unaffected, there is evidence for impairment in executive functioning, information processing speed, and attention. Psychological difficulties, in particular depression, are common in FD.
Heterozygous females typically have milder and more variable symptoms. In addition, males with a greater than 1% α-Gal A activity present later and may have either a cardiac variant phenotype, renal variant phenotype, or cerebrovascular disease presenting as stroke or transient ischemic attack (TIA). Males and females with the cardiac variant present with left ventricular hypertrophy (LVH), mitral insufficiency, cardiomyopathy and arrhythmia, with proteinuria but without ESRD. The renal variant phenotype is typically associated with ESRD without the skin or pain symptoms associated with classic FD. [1, 2, 10, 11, 3, 4, 12, 5, 6, 7, 8, 9, 13, 14, 15]

Natural History

In classic FD, the first symptoms, including chronic neuropathic pain and episodic severe pain crises, emerge during childhood (typically age 3-10 years). Heterozygous females typically have a later median age of onset than males (9-13 years versus 13-23 years). Rarely, females may be relatively asymptomatic and have a normal life span or may have symptoms as severe as males with the classic phenotype. Patients with FD overall have a lower quality of life (QoL) compared to the general population. Mitral valve insufficiency and precursors of renal failure may present in childhood or adolescence. Cardiac and/or cerebrovascular disease is present in most males by middle age while ESRD usually develops during the third to fifth decade. Renal and cardiac failure represent major sources of morbidity, and account for the reduced lifespan among affected males (50-58 years) and females (70-75 years) compared to the normal population. The most common cause of death among both sexes is cardiovascular disease as a result of heart failure and arrhythmia, with a significant proportion categorized as sudden. Most patients dying of cardiovascular disease have previously received renal replacement therapy. Patients with late-onset atypical variants of the disease are generally asymptomatic most of their lives. Those with the cardiac variant generally present in the sixth to eighth decade of life; many are diagnosed as the result of having hypertrophic cardiomyopathy. For those with the renal variant, age at onset is typically after 25 years. [1, 2, 10, 11, 4, 5, 6, 7, 9, 14, 15]

2. How effective are interventions for preventing harm?

Patient Management

The American College of Medical Genetics and Genomics (ACMG) has developed an ACT sheet to help clinical decision-making following newborn screening for Fabry disease: https://www.acmg.net/PDFLibrary/Fabry.pdf

Management of FD patients depends on the following:
- A personalized approach to care, reflecting the natural history of the specific disease phenotype and the individual’s clinical signs and symptoms
- Comprehensive baseline evaluation of disease involvement prior to enzyme replacement therapy (ERT) initiation
- Timely ERT initiation
- Thorough routine monitoring for evidence of organ involvement in non-classic asymptomatic patients
- Use of appropriate adjuvant treatments for specific disease manifestations
- Management by an experienced multidisciplinary team. (Tier 2) [4, 5, 6, 7, 9, 12, 15, 16]

Adult and pediatric patients should undergo baseline evaluation that should include a complete physical and psychological exam (including QoL, and work/academic attendance and performance), measurement of overall glycolipid burden, and examination of the following systems: renal, cardiovascular, neurologic, ear/nose/throat, ophthalmologic, pulmonary, gastrointestinal, and skeletal. (Tier 2) [7, 16]

Baseline data and all follow up data should be transferred to a central registry. (Tier 2) [4, 5]

In practice, there is wide variability in the use of ERT even for hemizygous individuals, with some starting therapy at a young age even without symptoms and others waiting until end organ damage is evident. The decision to initiate ERT should be made according to the clinical judgment of the managing metabolic physician in conjunction with the family of the patient. (Tier 2) [4, 6, 7, 9, 11, 12, 16]

A systematic review of RCTs of ERT reported on nine studies of 351 FD patients; however, many of these studies reported only on the effect of ERT on levels of enzyme substrate. Data from 2 trials (n=39 males) found no statistically significant differences in plasma enzyme substrate and one trial (n=24 males) found no statistical differences in renal function between individuals treated with agalsidase alfa and placebo (up to 6-month follow-up). Similar results were seen for agalsidase beta. One trial of 26 male patients found a statistically significant difference in pain, favoring agalsidase alfa compared to placebo at 5-6 months after treatment. No trial reported on the effect of agalsidase alfa on mortality or cardiac/cerebrovascular disease. One trial of agalsidase beta (n=82 males and females) found no difference in mortality, renal function, or symptoms or complications of cardiac or cerebrovascular disease over 18 months. The long-term influence of ERT on risk of morbidity and mortality related to FD remains to be established. (Tier 1) [1]

With ERT treatment, some patients have disease progression and elevated levels of plasma enzyme substrates, for reasons that are not clearly delineated. In addition, others develop antibodies to ERT over time, though the impact on clinical outcomes and disease progression is not understood. These results suggest long-term failure in some patients, but further study is needed. (Tier 2) [9, 15]

Currently, only algalsidase beta is approved for treatment of FD in the United States.

A meta-analysis of 7 cohort studies and 2 RCTs included 7513 participants with 1471 on ERT versus 6042 placebo controls, mean follow-up of 4 years, 52% male, and mean age of 41 years. Results showed that the stroke recurrence ratio in the ERT treatment group was 8.2% and 16% in the placebo group, favoring ERT treatment group over placebo (p = 0.03). (Tier 1) [13]

A systematic review and analysis of pooled proportions included 77 cohort studies comprising 15,305 participants followed over a mean of 3.8 years; however, only data from 39 of these studies could be pooled. Within these cohorts 66% of participants were male and had a mean age of 35 years. For 66% of the cohorts, the phenotype (classic/non-classic) was not reported. Although the rate of all-cause mortality in the primary analysis was higher in the untreated patients (10.8%), followed by agalsidase alfa (9%), and agalsidase beta (4.4%), there was no significant difference between the groups. Compared with untreated patients, treatment with agalsidase beta resulted in statistically significantly lower proportion of patients with renal complications (6% versus 21%), cardiovascular complications (7% versus 26%), and cerebrovascular complications (3.5% versus 17.8%). The differences between agalsidase alpha and untreated patients were not significantly different. (Tier 1) [17]

There is limited evidence for the impact of ERT on certain outcomes in FD. A systematic review of trials and observational studies was unable to draw any definitive conclusions about the effect of ERT on patient QoL. (Tier 1) [10]

Two prospective, randomized studies (97-100% male) using ERT to treat FD reported on cerebrovascular outcomes with short follow-up periods and found no reduction in stroke incidence, making the effectiveness of ERT in stroke prevention unknown. (Tier 2) [18]

Migalastat, an oral chaperone drug, is recommended as an option for treatment for some patients with FD who are over 16 years with an amenable genetic variant who would usually be offered ERT. For non-amenable genotypes, migalastat may result in a net loss of alpha-Gal A activity, potentially worsening the disease condition. (Tier 2) [19]

A systematic review evaluated 2 phase III RCTs that both included males and females. One RCT randomized patients to switch from ERT to migalastat (n = 36) or continue with ERT (n = 24) during an 18-month period with a 12-month extension in which all patients received migalastat. During the treatment period, the percentage of patients who had a renal, cardiac, or cerebrovascular event or died was 29% of patients on migalastat compared to 44% of patients on ERT. However, this difference was not statistically significant. A second RCT compared migalastat (n=34) with placebo (n=33) over a 6-month period, with an 18-month extension study. The primary outcome was change from baseline in interstitial capillary inclusions of the enzyme substrate globotriaosylceramide (GL-3), which was not significantly different between groups. Results from both trials indicate that migalastat does not have a significant beneficial effect on pain, health-related quality of life outcomes, or glomerular filtration rate (results were uncertain due to large confidence intervals, small sample sizes, and/or short follow-up time). Migalastat did not influence left ventricular ejection fraction but did improve left ventricular mass over 18 months. In the extension studies from both trials, efficacy outcomes were similar to the main trials; no clear conclusions can be made regarding the long-term efficacy of migalastat in patients with FD due to the absence of comparator groups and the short duration of treatment. (Tier 1) [20]

Due to an increased risk of vascular events, other vascular risk factors (hypertension, dyslipidemia, diabetes mellitus, increased weight) should be aggressively managed. (Tier 2) [4]

General anesthesia and regional anesthesia techniques might present potential problems for patients with FD due to organ and tissue involvement and physical features. Preoperative assessment needs to be thorough and organ dysfunction should be assessed carefully. Difficult airway management should be anticipated and extreme positioning for specific operations may be problematic. In patients with decreased renal function, doses of certain drugs that undergo renal clearance should be adapted. (Tier 4) [21]

Surveillance

Adult and pediatric patients should undergo regular surveillance including complete physical and psychological exams (including QoL and work/academic attendance and performance), measurement of overall glycolipid burden, and surveillance of the following systems: kidney, cardiac, cardiovascular, neurologic, ear/nose/throat, ophthalmologic, pulmonary, gastrointestinal, and skeletal. Comprehensive evaluation of renal function of all patients should be made; however, some measures may have limited utility in children. Type and frequency of surveillance vary across systems and with individual patient symptoms. (Tier 2) [4, 7, 9, 12, 16]

The assessment of concomitant prothrombotic factors and the monitoring of changes in cerebral blood flow velocities with Doppler sonography are relevant to determine the increased risk of stroke for patients with FD. (Tier 2) [15]

Adults and children should be monitored for vitamin D deficiency as it is common in patients with FD and is associated with adverse cardiovascular outcomes, worse renal outcomes, and increased risk of osteoporosis. It is reasonable to monitor vitamin D levels in patients with Fabry nephropathy and to correct any observed nutritional vitamin D deficiency as part of routine management. (Tier 2) [7, 9, 15]

Circumstances to Avoid

Due to the high risk of vascular events patients should be discouraged from smoking. (Tier 2) [4, 7]

Adult and pediatric patients should avoid pain triggers with lifestyle modifications: avoid temperature extremes, maintain proper hydration, avoid some types of strenuous activity (e.g., long distance running), and avoid overheating by using air conditioning, cooling vests, facial mist/spray, and rapid treatment of fever. (Tier 2) [2, 9, 16]

Antiarrhythmic treatment with amiodarone is not recommended because of a reported interference with ERT, though no clinical data is currently available to support this
statement. (Tier 3) [9, 15]

3. What is the chance that this threat will materialize?

Mode of Inheritance

X-linked

Prevalence of Genetic Variants

Based on 6 studies in newborn screening populations in Europe and Taiwan, the pooled prevalence of newborns with a variant in the GLA gene, which includes variants of undetermined significance, is about 0.04%. (Tier 1) [8]

Penetrance

Severe clinical manifestations have been reported in at least 43% of obligate carrier women. (Tier 3) [9]

A systematic review of 12 studies estimated that between 15-62.5% of patients have depression or some other psychopathology, with pain being the most common factor associated with depression. (Tier 1) [3]

A systematic review of 13 studies (N=4185 FD patients; 50% male with an average age of 37.6 years and 1.2-10 years of follow-up) reported that death from any cause was 8.3%. Of these, 75% was due to cardiovascular problems, with the majority being sudden cardiac death (SCD) events (62% of reported deaths). Ventricular tachycardia has an average prevalence of 15.3%. (Tier 1) [14]

The incidence of cardiac complications is similar in individuals with the atypical Fabry cardiac variant and individuals with classic FD. (Tier 3) [2]

The following baseline clinical manifestations were reported for individuals in the Fabry Registry and the Fabry Outcomes Study (FOS); however, a degree of ascertainment bias regarding disease severity is likely, particularly in female patients who may come to clinical attention due to the presence of symptoms:
Neurological symptoms
- Total (all ages): males: 67-84%, females: 47-79%
- Pain (all ages): males: 62-76%, females: 41-64%
- Chronic (not acute) pain (pediatric patients): males: 34-36%, females: 28-32%
- Acute pain crises (pediatric patients): males: 10-67 %, females: 6-59%
Renal symptoms
- Total (all ages): male: 17%, female: 11%
- Proteinuria: (all ages) males: 44%, females: 33%, (pediatric patients) males: 8%, females: 31%
- End-stage renal failure (all ages): males: 17% (10% with renal transplants, 7% on dialysis, females: 1%)
Cardiac symptoms
- Palpitations/arrhythmias, angina and exertional dyspnea (all ages): males: 22-69%, females: 23-65%
- Left ventricular hypertrophy (all ages): males: 46%, females: 28%
- Hypertension (adults only): males: 57%, females: 47%)
- Valvular dysfunction (pediatric patients): males: 6-23%, females: 14-24%
- Conduction abnormalities (pediatric patients): males: 8-10%, females: 4-7%
Cerebrovascular events (e.g., stroke, TIA) (all ages): males: 12-25%, females: 12-27%
Gastrointestinal symptoms (e.g., abdominal pain and diarrhea)
- All ages: males: 55%, females: 50%
- Pediatric patients: males: 23-44%, females: 11-52%
Heat/cold intolerance (pediatric patients)
- Heat (males: 39%, females: 38%)
- Cold (males: 17%, females: 17%) (Tier 3) [2, 7]

Relative Risk

An analysis of 2446 FD registry patients showed that stroke occurs in 6.9% of men and 4.3% of women, and that the incidence of stroke is markedly higher in FD patients than the general population, especially in men of 35–45 years’ age group whose relative risk of stroke is 12 times higher. (Tier 3) [13]

Expressivity

Fabry disease encompasses a spectrum of phenotypes ranging from the severe classic phenotype to atypical forms that often lack many of the classical characteristics of the disease (e.g., skin lesion, sweating abnormalities). (Tier 3) [2]

Substantial intrafamilial and interfamilial variability in age of disease onset and disease progression exists, even between males of the same family that have the same pathogenic variant. (Tier 3) [9, 11]

4. What is the Nature of the Intervention?

Nature of Intervention

Patient management involves non-invasive, multiple organ system medical screening and potentially the use of ERT (infused bi-weekly). ERT infusions tend to be reasonably well tolerated, with reported infusion reactions of about 10%, mostly consisting of fever and transient rigors of mild to moderate intensity. Within a pooled analysis of registry data, the rates of reported adverse events was 31% for agalsidase alfa and 34% for agalsidase beta. However, these rates were not significantly different from those reported by placebo-infused patients (37%). Because most infusion-associated reactions to ERT tend occur in the first few months, patients should start infusions in a clinical setting with direct physician supervision (e.g. hospital, outpatient clinic familiar with ERT) where reactions can be managed appropriately. If patients tolerate hospital infusions for the first few months of treatment, then home infusions may be an option. Treatment-emergent adverse events (TEAEs) for migalastat mostly consist of nasopharyngitis (18%) and headache (35%), which were significantly higher than the placebo group and similar to ERT-treated patients. Serious adverse events (SAEs) were less frequent in migalastat-treated patients compared to ERT-treated patients (19% versus 33%). The most commonly occurring SAEs reported for migalastat are chest pain and morbid obesity. [1, 7, 9, 17]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Misdiagnosis in individuals with FD is common (up to 25%) with some patients having a delay of >50 years before the correct diagnosis, and a delay of >20 years between the onset of symptoms and diagnosis being common. The diagnosis can be difficult, as patients commonly present with nonspecific complaints such as headaches, limb or abdominal pain plus diarrhea. Later disease manifestations are also nonspecific and common in other conditions including diabetes, hypertension, and atheromatosis, leading to FD being under-diagnosed. Delay in diagnosis in females arises partially from disease heterogeneity associated with an X-linked disease but also from the now-discredited assumption that females with pathogenic variants for FD are merely carriers. A definitive diagnosis is most commonly made following severe complications such as stroke, heart and kidney failure. Recent studies have found that 46% of FD patients experience their first stroke before being diagnosed. Atypical forms of FD with later onset may be more common than classic FD but are often underdiagnosed. [2, 4, 5, 7, 21, 22]

Date of Search: 12.11.2019

Reference List

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