Diagnosis Of Anderson-Fabry Disease Research Articles

P900Electrocardiographic findings in Anderson-Fabry disease versus sarcomeric hypertrophic cardiomyopathy

Abstract Background Cardiac involvement is one of the most frequent and disabling organ damage in Anderson-Fabry (AF) disease, causing hypertrophic cardiomyopathy (HCM), conduction disturbances, arrhythmias and coronary disease. Differential diagnosis from sarcomeric HCM is often very challenging, especially for patients with exclusive cardiac involvement. Purpose To gain new insights from standard electrocardiogram (ECG) in AF disease, and identify ECG differences from sarcomeric HCM. Methods Sixty-two consecutive patients (27 males, mean age: 62±16 years) with definite diagnosis of AF disease from 2 Italian centres were evaluated for ECG analysis and divided in 2 groups, according to the presence (Group A, N=39) or the absence (Group B, N=26) of cardiac involvement [hypertrophy detected at echocardiogram or cardiac magnetic resonance (CMR)]. All ECGs were analysed by 2 independent investigators. For Group A, when CMR was performed, a correlation between CMR and ECG was assessed. Patients with cardiac involvement were matched with 78 sarcomeric HCM patients according to sex, age and septal wall thickness on echocardiogram. Results Two AF patients out 39 with cardiac involvement (5%) had normal ECG. Short PR and I degree atrio-ventricular (AV) block were both reported in 6 (15%) cases. Twenty-six (67%) patients showed left ventricular hypertrophy and the majority (85%) had abnormal repolarization. CMR was performed in 22 patients (56%); the 11 (50%) patients with replacement fibrosis had a higher mean Sokolow-Lyon score (4.1±1.8 vs 2.9±1.0 mV; p=0.05), more frequent ST segment depression (82 vs 27%; p=0.03) and negative T waves (91 vs 36%; p=0.027; sensitivity: 90%; specificity: 63%), compared with the 11 without replacement fibrosis. When compared with sarcomeric HCM, AF patients with cardiac involvement had a significantly wider QRS (120±30 vs 100±16 msec; p<0.0001), a higher frequency of right bundle branch block (RBBB) (18 vs 3%; p=0.01), ST segment depression (54 vs 20%; p<0.0001) and negative T waves (72 vs 46%; p=0.01), typically in the inferior leads (44 vs 14%; p<0.0001). No significant differences in terms of pseudo-necrosis and QRS voltages were found. Among Group B AF patients (26, mean age: 36±12 years), 4 had short PR and 5 incomplete RBBB. Four had an abnormal ECG (1 left atrial enlargement, 2 unspecific repolarization abnormalities, 1 Sokolow score of 3.5 mV). Conclusions Standard ECG can detect cardiac involvement in AF disease. A good correlation was reported between repolarization abnormalities and replacement fibrosis on CMR. Wide QRS and RBBB were more frequent among AF patients compared to age-sex-matched sarcomeric HCM ones, probably due to the different aetiology of the diseases (infiltrative disease vs pure hypertrophy).

Nature’s Genetic Gradients and the Clinical Phenotype

When God created the earth, he placed (modern) mankind in East Africa ≈200 000 years ago, as suggested by the phylogenetic and archeological studies.1,2 These hunter-gatherers populated the land and started to migrate, first to the west and southern tip of Africa and then north toward North Africa. Mankind gradually crossed the Arabian Peninsula to the Middle East and Eurasia. Then, over thousands of years of northerly movement, man crossed the Bering land bridge that connected Siberia to Alaska and migrated down to the Americas. This out-of-Africa migration took thousands of generations. It was interrupted by the Ice Age, which led to depopulation and isolation of the surviving population followed by the new waves of migrations, resulting in multiple founding populations.3 Articles see pages 552 and 558 At the genetic level, the tree of life was produced through replication of the genome. For the genome to replicate, cells are equipped with DNA polymerases to copy the parental DNA, which they do at blazing speeds.4 However, “no protein is perfect,” and neither are the DNA polymerases. So, the DNA polymerases commit occasional errors in copying the template (parental) DNA and incorporate wrong nucleotides into the new DNA strands. To correct the errors, nature afforded the cells with DNA repair enzymes, which are assigned the task of maintaining the integrity of the nucleotide pools before replication.5 Nevertheless, the process of DNA replication and editing, although exceedingly precise, is imperfect. The error rate of the DNA replication and editing machinery is estimated to be at 10−6 to 10−10 nucleotides incorporated into the new strand of DNA.6,7 The inheritance is forward. Therefore, the misincorporated nucleotides are passed on to the next generation, and with each generation, new errors in DNA replication are introduced. The occasional “errors of …

Utility of Cardiovascular Magnetic Resonance in the Diagnosis of Anderson-Fabry Disease

A 54-year-old man was evaluated for a 6-month history of intermittent palpitations with associated shortness of breath, fatigue, and lightheadedness. The episodes would last several hours and were triggered by exertion, although he never experienced syncope. He had no prior medical problems, and he had no family history of heart disease or unexplained sudden death. He was normotensive and had no abnormalities on physical examination. A 12-lead electrocardiogram showed sinus arrhythmia, left bundle-branch block, and left ventricular (LV) hypertrophy with associated ST- and T-wave strain abnormalities (Figure A). A 2-dimensional echocardiogram demonstrated hyperdynamic LV systolic function with an ejection fraction of 65% (online-only Data Supplement Movie I). There was concentric LV hypertrophy, with the ventricular septum and free wall measuring 17 mm at end diastole. Biatrial enlargement was noted, …

Anderson-Fabry disease: diagnostic problems from gastrointestinal manifestations to the diagnosis of kidney disease

We report a case of a 52-year-old male who has been diagnosed for many years because of chronic diarrhea and proteinuria with concomitant gradually progressing chronic kidney disease. Diagnostic problems associated with the initial diagnosis of amyloidosis as a primary cause of the patient's complaints have been described. Anderson-Fabry disease (AFD) was suspected following comprehensive evaluation that resulted eventually in the exclusion of amyloidosis and the echocardiographic examination showing hypertrophic cardiomyopathy in the patient with no history of hypertension and aortic valve defects. The diagnosis of AFD was confirmed by results of enzymatic tests.

Anderson-Fabry disease: a case-finding study among male kidney transplant recipients in Austria

The diagnosis of Anderson-Fabry disease is often delayed or even missed. As severe renal manifestations are a hallmark of alfa-galactosidase A (AGAL) deficiency, we tested the hypothesis that Anderson-Fabry disease is under-recognized among male kidney transplant recipients. This nation-wide study in Austria enrolled 1306 patients (ca 65% of all kidney transplanted males) from 30 kidney centers. AGAL activity was determined from filter paper dried blood spots by a fluorescence assay. A positive screening test was defined by an AGAL activity below 1.5 nmol/h/ml. In patients with a positive blood spot-screening test, AGAL activity was re-examined in peripheral blood leukocytes. Genetic testing for mutations in the GLA gene was performed by sequencing to confirm the diagnosis of Anderson-Fabry disease. Two previously not recognized cases with Anderson-Fabry disease were identified. Our study is the first showing that a diagnosis of Anderson-Fabry disease can be missed even in patients who undergo kidney transplantation. Case-finding strategies may be considered a useful tool for diagnosis of this rare disease that may be somewhat more prevalent among kidney transplant recipients compared with dialysis populations.

Two unusual cases of Anderson-Fabry disease in a Japanese family

A 16-year-old Japanese girl was admitted to our hospital on February 27, 2001, for acute renal failure. She had not shown proteinuria or hematuria in any school examination through 2000. The first renal biopsy specimen showed focal segmental glomerulosclerosis and tubulointerstitial change. Electron microscopy showed numerous myeloid bodies in the glomerular epithelium suggesting the diagnosis of Anderson-Fabry disease. After electron microscopy, we measured WBC alpha-galactosidase A, which was slightly decreased to 36.1 nmol/mg P/h (normal: 49.8 - 116.4). WBC alpha-galactosidase A levels for other family members were 74.3 for the mother, 4.8 for the father, 45.6 for the elder sister, and 16.3 for the younger sister. During the follow-up, she had two episodes of nephrotic syndrome, which responded well to steroid therapy. Both second and third renal biopsy showed numerous myeloid bodies by electron microscopy. A 52-year-old man, the father of the case one patient, was admitted for renal biopsy because of proteinuria and low levels of WBC alpha-galactosidase. Biopsy specimen showed typical changes under light microscopy and typical myeloid bodies by electron microscopy. Our cases underscore the importance of electron microscopy when examining the biopsy specimen and suggest that undiagnosed Anderson-Fabry disease may be present, in particular on chronic dialysis.

Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males

OBJECTIVESTo determine the natural history of Anderson-Fabry disease (AFD) as a baseline for efficacy assessment of potentially therapeutic drugs.DESIGNThe first large cross sectional study of a patient cohort from the...