Uncertain diagnosis of Fabry disease: Consensus recommendation on diagnosis in adults with left ventricular hypertrophy and genetic variants of unknown significance

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Abstract

Background

Screening in subjects with left ventricular hypertrophy (LVH) reveals a high prevalence of Fabry disease (FD). Often, a diagnosis is uncertain because characteristic clinical features are absent and genetic variants of unknown significance (GVUS) in the α-galactosidase A (GLA) gene are identified. This carries a risk of misdiagnosis, inappropriate counselling and extremely expensive treatment. We developed a diagnostic algorithm for adults with LVH (maximal wall thickness (MWT) of > 12 mm), GLA GVUS and an uncertain diagnosis of FD.

Methods

A Delphi method was used to reach a consensus between FD experts. We performed a systematic review selecting criteria on electrocardiogram, MRI and echocardiography to confirm or exclude FD. Criteria for a definite or uncertain diagnosis and a gold standard were defined.

Results

A definite diagnosis of FD was defined as follows: a GLA mutation with ≤ 5% GLA activity (leucocytes, mean of reference value, males only) with ≥ 1 characteristic FD symptom or sign (neuropathic pain, cornea verticillata, angiokeratoma) or increased plasma (lyso)Gb3 (classical male range) or family members with definite FD. Subjects with LVH failing these criteria have a GVUS and an uncertain diagnosis. The gold standard was defined as characteristic storage in an endomyocardial biopsy on electron microscopy. Abnormally low voltages on ECG and severe LVH (MWT > 15 mm) < 20 years exclude FD. Other criteria were rejected due to insufficient evidence.

Conclusions

In adults with unexplained LVH and a GLA GVUS, severe LVH at young age and low voltages on ECG exclude FD. If absent, an endomyocardial biopsy with electron microscopy should be performed.

Introduction

Fabry disease (FD; OMIM 301500 [2]) is an X-linked lysosomal storage disorder caused by a deficiency of α-galactosidase A (AGAL-A). Estimated birth prevalence range between 1:40.000 and 110.000 [3], [4], [5]. Over 670 mutations in the α-galactosidase A (GLA) gene have been described [6], mostly appearing in single families. Since the availability of enzyme replacement therapy (ERT) screening in newborns, high risk populations, as well as individual case finding is increasing [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]. These screening studies report a surprisingly high prevalence of FD in subjects with left ventricular hypertrophy (LVH) (range, 0–12%). However, while the pathogenicity of some GLA mutations is well described, the subjects identified through screening often have a GLA genetic variant/mutation of unknown significance (GVUS) [17], [18], [19].

Interestingly, most males with such GVUS demonstrate significant residual AGAL-A enzyme activity, in contrast to the absent or near absent enzyme activity in classically affected males [5]. Moreover, most subjects identified through screening are lacking characteristic classical Fabry signs or symptoms such as neuropathic pain, angiokeratoma or cornea verticillata, but present with a single, non-specific Fabry sign such as cryptogenic stroke, proteinuria or LVH, all associated with other more common diseases [20]. Because these subjects have symptoms restricted to single organs, they were coined as cardiac, renal or late onset variants of the disease [21], [22]. In addition, while classically affected males invariably have significant elevations in plasma globotriaosylsphingosine (lysoGb3), non-classical FD patients and subjects with a non-pathogenic GLA mutation, such as p.D313Y, have low or normal levels [23], [24], [25]. While some still consider the p.D313Y mutation pathogenic [26], [27], it has been shown that this mutation results in a pseudo-deficiency of AGAL-A in plasma, with only minimally reduced enzyme activity in cell expression models [28]. Another example of advancing insight concerns the p.A143T mutation, which is frequently identified through screening studies. However, in subjects with this variant presenting with LVH or kidney failure, no characteristic Gb3 deposits were found in biopsies [17]. These examples show that the lack of unequivocal definitions for a definite FD diagnosis leads to difficult clinical dilemmas with a risk of misdiagnosis. Early diagnosis of a true FD patient is of great importance to offer adequate support, but prompt identification of those without FD is of equal importance to avoid distress in families and inappropriate initiation of ERT, an invasive and extremely expensive treatment.

As part of the Hamlet study [1], designed to address the uncertainties related to diagnosing FD, we aimed to gain international consensus on a diagnostic algorithm for adult subjects presenting with LVH (maximal wall thickness in diastole (MWTd) of > 12 mm) with an uncertain diagnosis of FD, harbouring a GVUS in the GLA gene.

Section snippets

Delphi participants

We used a modified Delphi procedure [29] to gain a consensus. The voting panel consisted of internists with expertise in the diagnosis and general management of FD and cardiologists with expertise in FD cardiomyopathy.

Pre-selection of voting items

A proposal was made for definitions of a definite and uncertain diagnosis of FD, and the gold standard (by MB, CH, BS, and LT). A systematic review was performed to find criteria on electrocardiogram (ECG), cardiac magnetic resonance imaging (CMR) or echocardiography that could be

Delphi procedure and participants

Nine FD experts were invited to participate; seven FD experts (FC, PE, DH, JT, GL, FW and MW) completed all three rounds. At the face-to-face meeting, five experts were present and two were involved by telephone.

Pre-selection of voting items: systematic review

To preselect voting items proposed to the panel, a systematic review was performed. Our search retrieved 140 articles of which 88 were excluded (Supplementary Fig. 1). From the remaining 52 articles, 9 entry or exit criteria were pre-selected (Table 1). A summary of all articles

Discussion

Among an international group of experts a consensus was reached on a diagnostic algorithm for patients presenting with isolated LVH and an uncertain diagnosis of FD, harbouring a GVUS in the GLA gene. First of all, a consensus on definitions of a definite and an uncertain diagnosis was reached, emphasizing that in cases with an uncertain, non-classical phenotype, enzymatic or genetic tests cannot always confirm a definite diagnosis of FD. In these uncertain cases, additional studies are

Conclusions

This study presents a diagnostic algorithm for patients presenting with unexplained LVH (MWT > 12 mm) with an uncertain diagnosis of FD. Via a Delphi procedure a consensus was reached on general diagnostic criteria for a definite diagnosis of FD. The gold standard was defined as characteristic storage in an endomyocardial biopsy on electron microscopy. The presence of abnormally low voltages on ECG and severe LVH (MWT > 15 mm)< 20 years can exclude FD and should discourage physicians to screen for FD.

Funding

This study is part of the Hamlet trial [1] which is supported by TI Pharma, a nonprofit organization that catalyzes research by founding partnerships between academia and industry project number T6-504. Partners: Genzyme (a Sanofi company), Academic Medical Centre of the University of Amsterdam; subsidizing party: Shire. http://www.tipharma.com/pharmaceutical-research-projects/drug-discovery-development-and-utilisation/hamlet-study.html. The industry partners have no role in the development of

Contribution

BS: study design, systematic review, data acquisition and interpretation, preparation and analyses of Delphi voting rounds, drafting of the manuscript.

LT: study design, data acquisition and interpretation, preparation and analyses of Delphi voting rounds, revision of the manuscript.

MB: study design, preparation and analyses of Delphi voting rounds, revision of the manuscript.

CH: study design, data interpretation, preparation and analyses of Delphi voting rounds, group leader face-to-face

Conflict of interests

No honorarium was provided for participation in this consensus recommendation.

BS and LT received travel support and reimbursement of expenses from Genzyme, a Sanofi company, Shire HGT and Actelion.

MB, GL and CH have received honoraria for consultancies and speakers fees from Actelion, Genzyme, Shire HGT, Protalix or Amicus. All fees are donated to the Gaucher Stichting or the AMC Medical Research BV for research support.

FC has received reimbursement of expenses and honoraria for lectures from

Acknowledgements

We would like to acknowledge the following: B.J.H.M. Poorthuis, for his valuable advice on the biochemical analyses used in the disease criteria and for the revision of the manuscript, H.A.C.M. Bon and M. Groenink for echocardiography and CMR analyses in the Dutch FD patients.

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      Citation Excerpt :

      FD is unlikely in young patients with cardiac hypertrophy. According to the consensus recommendation on diagnosis in adults with LVH and genetic variants of unknown significance in uncertain diagnosis of FD, severe LVH (wall thickness > 15 mm) at a young age (<age 20 years) excludes FD [10]. In electrographic findings, short Pend-Q time (Pend-Q interval < 40 msec) and high voltage (SV1 + RV5 > 4.0 mV) were associated with FD in our study.

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    All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

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