Case report
Cardiac Anderson-Fabry disease: Lessons from a 25-year-follow up
Doença cardíaca de Anderson–Fabry: lições de um caso com 25 anos de seguimento
Dulce Britoa,e, Gabriel Miltenberger–Miltenyib,
, Oana Moldovanc, Carmen Navarrod, Hugo Costa Madeirae
Autor para correspondência
a Cardiology Department, Hospital Universitario de Santa Maria, Lisbon, Portugal
b Instituto de Medicina Molecular, Faculty of Medicine, Lisbon, Portugal
c Clinical Genetics Department, Hospital Universitario de Santa Maria, Lisbon, Portugal
d Department of Pathology & Neuropathology, Institute of Biomedical Research of Vigo (IBIV), University Hospital of Vigo (CHUVI), Spain
e Lisbon Academic Medical Centre/Cardiovascular Centre of the University of Lisbon, Portugal
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(A) PR interval 0.11 s; LVH/ST‐T pattern (1997, age 44 years); (B) marked LVH and ST‐T abnormalities (2007, age 54 years); (C) atrial fibrillation (2010, age 57 years); (D) recent ECG (2012, age 59 years).</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Dulce Brito, Gabriel Miltenberger–Miltenyi, Oana Moldovan, Carmen Navarro, Hugo Costa Madeira" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Dulce" "apellidos" => "Brito" ] 1 => array:2 [ "nombre" => "Gabriel" "apellidos" => "Miltenberger–Miltenyi" ] 2 => array:2 [ "nombre" => "Oana" "apellidos" => "Moldovan" ] 3 => array:2 [ "nombre" => "Carmen" "apellidos" => "Navarro" ] 4 => array:2 [ "nombre" => "Hugo Costa" "apellidos" => "Madeira" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S0870255114000808" "doi" => "10.1016/j.repc.2013.10.014" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true 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array:4 [ "nombre" => "Gabriel" "apellidos" => "Miltenberger–Miltenyi" "email" => array:1 [ 0 => "gmiltenyi@fm.ul.pt" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] 2 => array:3 [ "nombre" => "Oana" "apellidos" => "Moldovan" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "Carmen" "apellidos" => "Navarro" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] 4 => array:3 [ "nombre" => "Hugo Costa" "apellidos" => "Madeira" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "aff0025" ] ] ] ] "afiliaciones" => array:5 [ 0 => array:3 [ "entidad" => "Cardiology Department, Hospital Universitario de Santa Maria, Lisbon, Portugal" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Instituto de Medicina Molecular, Faculty of Medicine, Lisbon, Portugal" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Clinical Genetics Department, Hospital Universitario de Santa Maria, Lisbon, Portugal" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Department of Pathology & Neuropathology, Institute of Biomedical Research of Vigo (IBIV), University Hospital of Vigo (CHUVI), Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Lisbon Academic Medical Centre/Cardiovascular Centre of the University of Lisbon, Portugal" "etiqueta" => "e" "identificador" => "aff0025" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Doença cardíaca de Anderson–Fabry: lições de um caso com 25 anos de seguimento" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 4000 "Ancho" => 2949 "Tamanyo" => 975355 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Transthoracic echocardiogram/Doppler imaging. Top (1998, age 45 years): long-axis view showing mild septal thickening, non-dilated and normally contracting left ventricle, and normal left atrium (A, B, C); short-axis view at the level of the mitral leaflet tips (D) and mid-cavity (E); apical 4-chamber view showing slight thickening of the lateral-apical wall (F); middle (2007, age 54 years) – normal tissue Doppler imaging at the septal (G) and lateral (H) corners of the mitral annulus; bottom (2012, age 59-years) – thickened septum (I, J, M – 20 mm); thickened lateral-apical wall (J); non-dilated and normally contracting left ventricle (M); dilated left atrium, 51 mm (L); mild mitral regurgitation (K); diastolic dysfunction and affected longitudinal systolic LV function (N, O, P – see text for details).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Hypertrophic cardiomyopathy (HCM) is a common autosomal dominant disease<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> limited to the heart and associated with mutations in sarcomere-related genes. It is characterized by unexplained left ventricular hypertrophy (LVH). Its penetrance is variable and age-related; some mutations determine the phenotype well after middle age.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,3</span></a> In 30%–40% of patients no mutations are found.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Anderson-Fabry disease (AFD) is a rare X-linked lysosomal storage disease, caused by a deficiency in the enzyme alpha-galactosidase A (alpha-Gal A) due to mutations in the <span class="elsevierStyleItalic">GLA</span> gene. It leads to accumulation of globotriaosylceramide (Gb3) within lysosomes, resulting in multiorgan cell dysfunction. In its classical form it is a multisystemic disease, most frequently involving the kidneys, heart, nervous system and skin.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Males (hemizygous) are more severely affected and usually manifest earlier than females (heterozygous).<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,7</span></a> The predominant cardiac phenotype usually reflects late-onset AFD and may be associated with <span class="elsevierStyleItalic">GLA</span> mutations that maintain residual enzymatic activity. Thus the cardiac variant presents unexplained LVH diagnosed in middle-aged patients.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Differentiating AFD from sarcomeric HCM on a clinical basis can be very difficult, but the distinction is important since specific treatment is now available for AFD (enzyme replacement therapy). Alpha-Gal A activity in plasma or peripheral leukocytes is low in most affected men and confirms the diagnosis.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> However, in women differential diagnosis between the two conditions usually requires genetic testing.</p><p id="par0015" class="elsevierStylePara elsevierViewall">We report the identification of a novel mutation in the <span class="elsevierStyleItalic">GLA</span> gene by next-generation sequencing (NGS) analysis in a female patient followed for 25 years with a diagnosis of familial HCM.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Case report – part I</span><p id="par0020" class="elsevierStylePara elsevierViewall">In 1987, a 34-year-old woman sought cardiological advice because her father (who died at 61) had been diagnosed several years before as having HCM and heart failure (HF). The woman was apparently healthy and had normal physical examination. The ECG showed sinus rhythm (SR) with a heart rate of 50 bpm and short PR interval (0.11 s) but was otherwise normal. The echocardiogram (echo) was also normal.</p><p id="par0025" class="elsevierStylePara elsevierViewall">After ten years of annual follow-up, at 44 years of age a diagnosis of HCM was made on the basis of an LVH pattern on ECG with significant anterolateral ST-T strain changes (<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>A). One year later, an echo showed mild septal (13 mm) and lateral-distal (16 mm) hypertrophy (<a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>, top).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">Over the following eight years, septal thickness progressed to 17 mm, the left atrium (LA) enlarged to 44 mm and prolonged mitral inflow deceleration time (DT) of >300 ms was observed on Doppler echo, suggesting LV diastolic dysfunction. She complained of palpitations (short runs of supraventricular tachycardia were detected on Holter monitoring) but became asymptomatic after effective beta-blocking treatment. Periodic exercise tests were normal (including exercise tolerance and blood pressure response). She had no clinical evidence of other organ involvement.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Genetic testing became possible when she was 50 years old and the six most common HCM-associated sarcomeric genes (<span class="elsevierStyleItalic">MYBPC3</span>, <span class="elsevierStyleItalic">MYH7</span>, <span class="elsevierStyleItalic">TNNT2</span>, <span class="elsevierStyleItalic">TNNI3</span>, <span class="elsevierStyleItalic">MYL2</span>, and <span class="elsevierStyleItalic">MYL3</span>) were screened for mutations by PCR and direct sequencing of all coding regions. The results were negative.</p><p id="par0040" class="elsevierStylePara elsevierViewall">At the age of 54 years the LVH pattern on the ECG was striking (<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>B), and while septal hypertrophy remained stable, apical LVH on echo was more pronounced. There was mild mitral regurgitation (MR) but mitral inflow parameters were similar. On tissue Doppler imaging (TDI), peak diastolic (E′) septal and lateral mitral annulus velocities were respectively 7.2 cm/s and 11.2 cm/s. The E/E′ ratio was <8 and systolic velocities were also normal (<a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>, middle).</p><p id="par0045" class="elsevierStylePara elsevierViewall">Three years later she had an episode of HF. Atrial fibrillation (AF) was diagnosed (<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>C) and successfully converted to SR by electrical cardioversion. Plasma NT-proBNP was 5816 pg/ml. Echocardiographic examination showed a dilated LA and mild MR persisted. Warfarin was added to the therapy. The plasma NT-proBNP value at discharge was 3555 pg/ml.</p><p id="par0050" class="elsevierStylePara elsevierViewall">During the following two years (2011–2012) she remained stable although with moderate intolerance to daily exertion. Several recurrences of AF worsened her fatigue severely but were always converted to SR. Thyroid function tests were normal.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Recent echocardiographic examination (<a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>, bottom) showed septal thickness of 20 mm, marked apical LVH, significant diastolic dysfunction (much lower E′ septal and lateral velocities, respectively 5.0 cm/s and 7.0 cm/s), higher LV filling pressures (septal E/E′ 14.5) and compromised longitudinal systolic function (septal and lateral systolic velocities of 5.0 cm/s and 8.0 cm/s) (<a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>, bottom). The mitral inflow Doppler pattern changed to almost restrictive filling (E/A 2.94; DT 189 ms). NT-proBNP levels remained high (1278 pg/ml), as frequently observed in HCM,<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> related to the presence of LVH and to ventricular dysfunction.</p><p id="par0060" class="elsevierStylePara elsevierViewall">A second genetic test was planned, covering a wider spectrum of genes associated with the HCM phenotype, given the need to clarify the genetic diagnosis.</p><p id="par0065" class="elsevierStylePara elsevierViewall">Since the diagnosis of familial HCM, her first-degree relatives have also been regularly followed. The daughter was apparently normal. The patient's only brother and her mother both had mild septal hypertrophy and a history of hypertension. Her nephew was normal.</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Mutation screening and results</span><p id="par0070" class="elsevierStylePara elsevierViewall">In addition to the six genes screened previously, further 13 genes associated with HCM phenotypes – <span class="elsevierStyleItalic">ACTC1</span>, <span class="elsevierStyleItalic">ACTN2</span>, <span class="elsevierStyleItalic">CSRP3</span>, <span class="elsevierStyleItalic">GLA</span>, <span class="elsevierStyleItalic">LAMP2</span>, <span class="elsevierStyleItalic">MYL3</span>, <span class="elsevierStyleItalic">MYOZ2</span>, <span class="elsevierStyleItalic">NEXN</span>, <span class="elsevierStyleItalic">PLN</span>, <span class="elsevierStyleItalic">PRKAG2</span>, <span class="elsevierStyleItalic">TNNC1</span>, <span class="elsevierStyleItalic">TPM1</span> and <span class="elsevierStyleItalic">TTR</span> – were analyzed in genomic DNA by oligonucleotide-based target capture (SureSelect, Agilent) followed by next-generation sequencing (Illumina HiSeq2000). Sanger sequencing was used to provide data for bases with insufficient coverage, and to confirm all novel variants.</p><p id="par0075" class="elsevierStylePara elsevierViewall">NGS detected a novel hemizygous single nucleotide exchange in the <span class="elsevierStyleItalic">GLA</span> gene (GenBank accession number <a id="intr0010" class="elsevierStyleInterRef" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=nucleotide&doptcmdl=genbank&term=NM_000169.2">NM_000169.2</a>): c.187T>A (p.Cys63Ser), affecting an amino acid that is highly conserved in various species (<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>B). A pathogenic mutation in the same codon but with a different amino acid change (p.Cys63Tyr) has been reported by Schäfer et al.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> The change of the amino acid cysteine to tyrosine or to serine disrupts a disulfide bond of the protein that is essential for maintaining the correct structure of the protein's active site.</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">To assess the pathogenic impact of the novel identified variant, in silico analyses was performed using the evolutionary model program SNPs&GO (<a id="intr0015" class="elsevierStyleInterRef" href="http://snps-and-go.biocomp.unibo.it/">http://snps-and-go.biocomp.unibo.it</a>)<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> and the pathogenicity prediction program PolyPhen-2 (<a id="intr0020" class="elsevierStyleInterRef" href="http://genetics.bwh.harvard.edu/pph/">http://genetics.bwh.harvard.edu/pph/</a>).<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Both attributed a high probability of pathogenicity to this novel mutation.</p></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Case report – part II</span><p id="par0085" class="elsevierStylePara elsevierViewall">After the genetic diagnosis of AFD, the index patient was re-evaluated and a full organ assessment was carried out. The concentration of alpha-Gal A in dried blood spots on filter-paper was low (0.28 nmol/h/spot: mean reference in 120 controls: 0.64) and urine analysis showed a significant increase in Gb3 (Gb3/sphingosine 1.97).</p><p id="par0090" class="elsevierStylePara elsevierViewall">The patient reported no neurological, cutaneous, gastrointestinal or pulmonary involvement, but the ophthalmologic examination showed cornea verticillata typical of the disease. Although the patient denied hearing loss, audiometric studies revealed cochlear involvement with sensory deficits on the right for all tested frequencies (125–8000 Hz).</p><p id="par0095" class="elsevierStylePara elsevierViewall">She had proteinuria (317.5 mg/24 hours) and although serum creatinine was within the normal range (0.7 mg/dl), she had a mildly impaired glomerular filtration rate of 52 ml/min/m<span class="elsevierStyleSup">2</span> by the Cockcroft-Gault equation.</p><p id="par0100" class="elsevierStylePara elsevierViewall">A biopsy of normal skin observed by electron microscopy revealed lysosomic inclusions (“zebra bodies”) typical of AFD (<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>C). Brain magnetic resonance imaging (MRI) (PD, T2 and FLAIR) revealed multiple white matter lesions in the frontal and parietal regions of both hemispheres compatible with microvasculopathy. Cardiac MRI showed no areas of late gadolinium enhancement, making cardiac fibrosis unlikely. Therapy with recombinant alpha-Gal A every two weeks was initiated.</p><p id="par0105" class="elsevierStylePara elsevierViewall">The patient's daughter, brother and mother were screened for the p.Cys63Ser mutation, which was found in the daughter and enzyme analysis revealed reduced alpha-Gal A activity (0.41 nmol/h/spot). The mutation was excluded in the patient's brother and mother (<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>A).</p><p id="par0110" class="elsevierStylePara elsevierViewall">Considering the possible diagnosis of AFD in the father, some retrospective investigation was carried out. The patient reported that her father had been a “very sick man since his youth”. He frequently had “pain in his hands and feet” that was never investigated. However, it was not possible to rely on these data to make any diagnosis. His main problem was “heart disease” with a diagnosis of HCM since his 40s, and had been regularly followed thereafter. Available exams from a hospital discharge (admitted for “HCM and HF” at age 61) revealed AF and LVH on the ECG, “severe and diffuse LVH, dilated LA and excellent systolic function” (echo) and “severe mitral regurgitation, preserved LV systolic function and normal coronary arteries” (hemodynamic study). He was referred for mitral prosthesis implantation but committed suicide while awaiting surgery. It is worth noting that according to the hospital discharge report all laboratory parameters were in the normal range.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Discussion</span><p id="par0115" class="elsevierStylePara elsevierViewall">AFD is rare, has a heterogeneous clinical course, especially in women,<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14,15</span></a> and is often not considered as a first diagnosis in the presence of cardiac isolated hypertrophy. In fact the diagnosis of AFD is particularly challenging in female patients when non-cardiac traits are absent. In these cases the presence of LVH is usually attributed to sarcomeric HCM.</p><p id="par0120" class="elsevierStylePara elsevierViewall">In our patient, low alpha-Gal A activity, high urinary levels of the biomarker Gb3 and the results of the skin biopsy filled the gap between the identified mutation and the cardiac phenotypic presentation and proved that the novel mutation was pathogenic.</p><p id="par0125" class="elsevierStylePara elsevierViewall">In retrospect, the first clue of cardiac AFD in our patient was at 34 years of age, when an ECG showed a short PR interval with no delta wave, a finding observed in up to 40% of adults with AFD.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> However, normalization of the PR interval can be expected as the patient gets older, as in our case. Only 10 years after the first observation, an LVH pattern appeared on the ECG – which is present in 18% of women carriers<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> – followed by mild LVH on echocardiographic examination. In women with AFD, the progression to LVH becomes manifest between the ages of 40 and 50,<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> as in this patient. Asymmetric LVH is in fact unusual in AFD, as is involvement of the apical lateral wall, as in the case presented.</p><p id="par0130" class="elsevierStylePara elsevierViewall">Mild to moderate diastolic dysfunction is frequently observed in AFD cardiomyopathy but a restrictive pattern is uncommon.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> In advanced disease systolic heart failure may also occur. Our patient showed progressive ventricular dysfunction with a pattern of mitral inflow and diastolic TDI almost meeting the criteria for restrictive pathophysiology. This explains her very poor tolerance to AF episodes. Longitudinal systolic function was also affected.</p><p id="par0135" class="elsevierStylePara elsevierViewall">Several studies have reported data on the prevalence of AFD in cohorts of patients with HCM, with different results.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8,19–22</span></a> A screening study among 508 HCM patients found that around 1% in fact had AFD on further evaluation.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> In the ACES study,<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> which included 1386 patients with unexplained LVH, the prevalence of <span class="elsevierStyleItalic">GLA</span> mutations was only 0.5%. Higher prevalences were found in previous smaller studies,<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8,21,22</span></a> while Havndrup et al.,<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> in a cohort of 59 probands with HCM and no identified sarcomere gene mutations (nine genes screened), found a mutation in the <span class="elsevierStyleItalic">GLA</span> gene in 5%. However, in women with HCM and with no identified sarcomere mutations, the prevalence of AFD was 10% and in those older than 45 it reached 13%.</p><p id="par0140" class="elsevierStylePara elsevierViewall">AFD is nowadays a potentially treatable cause of LVH, in contrast to sarcomeric HCM, for which no specific treatment exists. As cardiac disease is the most frequent cause of death in AFD in both genders,<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">24,25</span></a> and as women with AFD are more likely to develop a predominantly cardiac phenotype, the clinical diagnostic algorithm suggested by Havndrup et al.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> and recently supported by other authors<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> seems an appropriate approach when facing an unexplained diagnosis of HCM: when there is no clear documented family history of HCM and the proband is negative for sarcomere mutations, AFD should always be considered. Alpha-Gal A enzyme activity in plasma or peripheral leukocytes should be assessed in males but suspected female patients should undergo gene testing as a first-line approach.</p><p id="par0145" class="elsevierStylePara elsevierViewall">Our patient's final diagnosis was revealed by next-generation sequencing technologies and included a total of 19 HCM-associated genes. NGS methods have opened a new era in routine molecular genetic diagnosis, providing reliable (with practically 100% sensitivity), rapid and cost-effective analysis of several genes in parallel. As our case demonstrates, the application of NGS in unclear HCM cases can provide a positive result and thus reveal the exact cause of the disease. In the near future, NGS will probably become the method of choice in routine diagnosis world-wide. If so, correct interpretation of the various novel and sometimes multiple mutations detected in a patient will demand particularly close collaboration between physicians, geneticists and the testing laboratory.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Ethical disclosures</span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Protection of human and animal subjects</span><p id="par0150" class="elsevierStylePara elsevierViewall">The authors declare that the procedures followed were in accordance with the regulations of the relevant clinical research ethics committee and with those of the Code of Ethics of the World Medical Association (Declaration of Helsinki).</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Confidentiality of data</span><p id="par0155" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their work center on the publication of patient data and that all the patients included in the study received sufficient information and gave their written informed consent to participate in the study.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Right to privacy and informed consent</span><p id="par0160" class="elsevierStylePara elsevierViewall">The authors have obtained the written informed consent of the patients or subjects mentioned in the article. The corresponding author is in possession of this document.</p></span></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conflicts of interest</span><p id="par0165" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:2 [ "identificador" => "xres341193" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec322958" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres341192" "titulo" => "Resumo" ] 3 => array:2 [ "identificador" => "xpalclavsec322957" "titulo" => "Palavras-chave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Case report – part I" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Mutation screening and results" ] ] ] 6 => array:2 [ "identificador" => "sec0020" "titulo" => "Case report – part II" ] 7 => array:2 [ "identificador" => "sec0025" "titulo" => "Discussion" ] 8 => array:3 [ "identificador" => "sec0030" "titulo" => "Ethical disclosures" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Protection of human and animal subjects" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Confidentiality of data" ] 2 => array:2 [ "identificador" => "sec0045" "titulo" => "Right to privacy and informed consent" ] ] ] 9 => array:2 [ "identificador" => "sec0050" "titulo" => "Conflicts of interest" ] 10 => array:2 [ "identificador" => "xack83342" "titulo" => "Acknowledgments" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2013-07-22" "fechaAceptado" => "2013-10-29" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec322958" "palabras" => array:3 [ 0 => "Hypertrophic cardiomyopathy" 1 => "Anderson-Fabry disease" 2 => "Next-generation sequencing" ] ] ] "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras-chave" "identificador" => "xpalclavsec322957" "palabras" => array:3 [ 0 => "Miocardiopatia hipertrófica" 1 => "Doença de Anderson-Fabry" 2 => "Sequenciação de nova geração" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Sarcomeric hypertrophic cardiomyopathy (HCM) is the most common genetic cause of unexplained left ventricular hypertrophy and has no specific treatment. Anderson-Fabry disease (AFD) is rare and usually multisystemic, but occasionally expresses clinically as a predominantly cardiac phenotype mimicking HCM. We describe an illustrative case of a patient followed regularly for 25 years with a diagnosis of familial HCM and no identified sarcomeric mutations. Next-generation sequencing analysis identified a novel pathogenic mutation in the <span class="elsevierStyleItalic">GLA</span> gene, leading to a diagnosis of previously unknown multisystemic AFD, with consequent implications for the patient's treatment and prognosis and familial screening.</p>" ] "pt" => array:2 [ "titulo" => "Resumo" "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A miocardiopatia hipertrófica sarcomérica é a causa genética mais comum da hipertrofia ventricular esquerda inexplicada e não tem tratamento específico. A doença de Anderson-Fabry é rara, geralmente multissistémica mas, ocasionalmente, pode expressar-se clinicamente com um fenótipo predominantemente cardíaco, imitando miocardiopatia hipertrófica. Os autores descrevem o caso ilustrativo de uma doente seguida regularmente durante 25 anos com o diagnóstico de miocardiopatia hipertrófica familiar, sem mutação sarcomérica identificada. A utilização da análise de sequenciação de nova geração identificou uma mutação patogénica nova no gene <span class="elsevierStyleItalic">GLA</span>, aclarando o diagnóstico oculto de doença de Anderson-Fabry multissistémica, com as consequentes implicações terapêuticas, prognósticas e na investigação familiar.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Grant from the Fondo de Investigación Sanitaria, Spanish National Institute of Health Carlos III, Ref. PI10/02628, to CN.</p>" ] ] "multimedia" => array:3 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1503 "Ancho" => 2964 "Tamanyo" => 594995 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Electrocardiographic changes in the patient throughout life. (A) PR interval 0.11 s; LVH/ST-T pattern (1997, age 44 years); (B) marked LVH and ST-T abnormalities (2007, age 54 years); (C) atrial fibrillation (2010, age 57 years); (D) recent ECG (2012, age 59 years).</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 4000 "Ancho" => 2949 "Tamanyo" => 975355 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Transthoracic echocardiogram/Doppler imaging. Top (1998, age 45 years): long-axis view showing mild septal thickening, non-dilated and normally contracting left ventricle, and normal left atrium (A, B, C); short-axis view at the level of the mitral leaflet tips (D) and mid-cavity (E); apical 4-chamber view showing slight thickening of the lateral-apical wall (F); middle (2007, age 54 years) – normal tissue Doppler imaging at the septal (G) and lateral (H) corners of the mitral annulus; bottom (2012, age 59-years) – thickened septum (I, J, M – 20 mm); thickened lateral-apical wall (J); non-dilated and normally contracting left ventricle (M); dilated left atrium, 51 mm (L); mild mitral regurgitation (K); diastolic dysfunction and affected longitudinal systolic LV function (N, O, P – see text for details).</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 2424 "Ancho" => 3051 "Tamanyo" => 498490 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">(A) Pedigree and main clinical, enzymatic and genetic findings of the family. Circles indicate females; squares, males; filled symbols, affected individuals; open symbols, unaffected individuals; slash, deceased; AFD: Anderson-Fabry disease; AGA: alpha-Gal A; <span class="elsevierStyleItalic">GLA</span> pos, carrier of <span class="elsevierStyleItalic">GLA</span> mutation; HCM: hypertrophic cardiomyopathy; nd: no data. The index patient is marked with an arrow; (B, top) part of nucleotide sequence of exon 1 of the <span class="elsevierStyleItalic">GLA</span> gene, harboring the affected amino acid. Upper row: control individual, lower row: index patient. The mutation is marked with an arrow; (B, bottom) homology analysis of amino acid sequence of alpha-Gal in various species (<a class="elsevierStyleInterRef" id="intr0005" href="http://www.ncbi.nlm.nih.gov/homologene">http://www.ncbi.nlm.nih.gov/homologene</a>). Affected amino acid is marked with a rectangle; (C) electron micrograph of an intradermal vessel. Note the marked abnormal storage of an endothelial cell, with multilamellar and zebra bodies, characteristic of AFD. Scale bar is 5 μm.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:26 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "B.J. Maron" 1 => "J.A. Towbin" 2 => "G. 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The authors thank Shire and Merck Sharp & Dohme for their support in the study of this family.</p>" "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/08702551/0000003300000004/v1_201405230947/S0870255114000808/v1_201405230947/en/main.assets" "Apartado" => array:4 [ "identificador" => "362" "tipo" => "SECCION" "pt" => array:2 [ "titulo" => "Casos clínicos" "idiomaDefecto" => true ] "idiomaDefecto" => "pt" ] "PDF" => "https://static.elsevier.es/multimedia/08702551/0000003300000004/v1_201405230947/S0870255114000808/v1_201405230947/en/main.pdf?idApp=UINPBA00004E&text.app=https://revportcardiol.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0870255114000808?idApp=UINPBA00004E" ]
| Ano/Mês | Html | Total | |
|---|---|---|---|
| 2024 Novembro | 16 | 6 | 22 |
| 2024 Outubro | 52 | 30 | 82 |
| 2024 Setembro | 64 | 27 | 91 |
| 2024 Agosto | 69 | 36 | 105 |
| 2024 Julho | 60 | 31 | 91 |
| 2024 Junho | 44 | 27 | 71 |
| 2024 Maio | 60 | 37 | 97 |
| 2024 Abril | 51 | 42 | 93 |
| 2024 Maro | 46 | 29 | 75 |
| 2024 Fevereiro | 55 | 36 | 91 |
| 2024 Janeiro | 56 | 43 | 99 |
| 2023 Dezembro | 42 | 32 | 74 |
| 2023 Novembro | 54 | 26 | 80 |
| 2023 Outubro | 69 | 27 | 96 |
| 2023 Setembro | 48 | 19 | 67 |
| 2023 Agosto | 43 | 25 | 68 |
| 2023 Julho | 44 | 9 | 53 |
| 2023 Junho | 26 | 20 | 46 |
| 2023 Maio | 76 | 29 | 105 |
| 2023 Abril | 39 | 11 | 50 |
| 2023 Maro | 31 | 26 | 57 |
| 2023 Fevereiro | 34 | 20 | 54 |
| 2023 Janeiro | 37 | 18 | 55 |
| 2022 Dezembro | 38 | 23 | 61 |
| 2022 Novembro | 58 | 26 | 84 |
| 2022 Outubro | 39 | 17 | 56 |
| 2022 Setembro | 31 | 43 | 74 |
| 2022 Agosto | 48 | 44 | 92 |
| 2022 Julho | 50 | 47 | 97 |
| 2022 Junho | 35 | 22 | 57 |
| 2022 Maio | 37 | 38 | 75 |
| 2022 Abril | 35 | 22 | 57 |
| 2022 Maro | 41 | 41 | 82 |
| 2022 Fevereiro | 27 | 29 | 56 |
| 2022 Janeiro | 26 | 33 | 59 |
| 2021 Dezembro | 30 | 40 | 70 |
| 2021 Novembro | 35 | 37 | 72 |
| 2021 Outubro | 38 | 44 | 82 |
| 2021 Setembro | 27 | 31 | 58 |
| 2021 Agosto | 26 | 49 | 75 |
| 2021 Julho | 21 | 40 | 61 |
| 2021 Junho | 35 | 13 | 48 |
| 2021 Maio | 34 | 43 | 77 |
| 2021 Abril | 49 | 37 | 86 |
| 2021 Maro | 57 | 25 | 82 |
| 2021 Fevereiro | 71 | 13 | 84 |
| 2021 Janeiro | 35 | 17 | 52 |
| 2020 Dezembro | 37 | 9 | 46 |
| 2020 Novembro | 41 | 14 | 55 |
| 2020 Outubro | 25 | 10 | 35 |
| 2020 Setembro | 35 | 16 | 51 |
| 2020 Agosto | 20 | 7 | 27 |
| 2020 Julho | 36 | 19 | 55 |
| 2020 Junho | 26 | 10 | 36 |
| 2020 Maio | 35 | 8 | 43 |
| 2020 Abril | 32 | 20 | 52 |
| 2020 Maro | 24 | 12 | 36 |
| 2020 Fevereiro | 79 | 24 | 103 |
| 2020 Janeiro | 17 | 5 | 22 |
| 2019 Dezembro | 41 | 7 | 48 |
| 2019 Novembro | 25 | 5 | 30 |
| 2019 Outubro | 22 | 3 | 25 |
| 2019 Setembro | 44 | 14 | 58 |
| 2019 Agosto | 34 | 6 | 40 |
| 2019 Julho | 38 | 11 | 49 |
| 2019 Junho | 25 | 8 | 33 |
| 2019 Maio | 35 | 9 | 44 |
| 2019 Abril | 23 | 20 | 43 |
| 2019 Maro | 37 | 12 | 49 |
| 2019 Fevereiro | 53 | 10 | 63 |
| 2019 Janeiro | 70 | 10 | 80 |
| 2018 Dezembro | 108 | 14 | 122 |
| 2018 Novembro | 84 | 18 | 102 |
| 2018 Outubro | 328 | 16 | 344 |
| 2018 Setembro | 102 | 12 | 114 |
| 2018 Agosto | 105 | 18 | 123 |
| 2018 Julho | 58 | 14 | 72 |
| 2018 Junho | 68 | 8 | 76 |
| 2018 Maio | 85 | 12 | 97 |
| 2018 Abril | 80 | 4 | 84 |
| 2018 Maro | 120 | 9 | 129 |
| 2018 Fevereiro | 29 | 4 | 33 |
| 2018 Janeiro | 37 | 6 | 43 |
| 2017 Dezembro | 110 | 8 | 118 |
| 2017 Novembro | 42 | 11 | 53 |
| 2017 Outubro | 50 | 12 | 62 |
| 2017 Setembro | 47 | 10 | 57 |
| 2017 Agosto | 60 | 23 | 83 |
| 2017 Julho | 43 | 7 | 50 |
| 2017 Junho | 59 | 15 | 74 |
| 2017 Maio | 36 | 5 | 41 |
| 2017 Abril | 31 | 5 | 36 |
| 2017 Maro | 32 | 25 | 57 |
| 2017 Fevereiro | 35 | 10 | 45 |
| 2017 Janeiro | 31 | 4 | 35 |
| 2016 Dezembro | 37 | 4 | 41 |
| 2016 Novembro | 38 | 9 | 47 |
| 2016 Outubro | 52 | 10 | 62 |
| 2016 Setembro | 90 | 7 | 97 |
| 2016 Agosto | 24 | 0 | 24 |
| 2016 Julho | 10 | 2 | 12 |
| 2016 Junho | 6 | 3 | 9 |
| 2016 Maio | 21 | 4 | 25 |
| 2016 Abril | 30 | 1 | 31 |
| 2016 Maro | 38 | 14 | 52 |
| 2016 Fevereiro | 59 | 25 | 84 |
| 2016 Janeiro | 41 | 12 | 53 |
| 2015 Dezembro | 54 | 21 | 75 |
| 2015 Novembro | 32 | 11 | 43 |
| 2015 Outubro | 60 | 11 | 71 |
| 2015 Setembro | 46 | 18 | 64 |
| 2015 Agosto | 56 | 19 | 75 |
| 2015 Julho | 55 | 15 | 70 |
| 2015 Junho | 31 | 9 | 40 |
| 2015 Maio | 41 | 11 | 52 |
| 2015 Abril | 40 | 22 | 62 |
| 2015 Maro | 37 | 8 | 45 |
| 2015 Fevereiro | 25 | 10 | 35 |
| 2015 Janeiro | 20 | 18 | 38 |
| 2014 Dezembro | 38 | 15 | 53 |
| 2014 Novembro | 43 | 19 | 62 |
| 2014 Outubro | 59 | 17 | 76 |
| 2014 Setembro | 41 | 20 | 61 |
| 2014 Agosto | 35 | 18 | 53 |
| 2014 Julho | 60 | 31 | 91 |
| 2014 Junho | 62 | 78 | 140 |
| 2014 Maio | 34 | 33 | 67 |
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