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Molecular diagnosis has undergone rapid and significant advancements in recent years. But because molecular diagnosis can be conducted independently of phenotype, it can engender ambiguity and potential misinterpretations in disease diagnosis. Fabry disease, an X-linked lysosomal storage disorder, arises from a deficiency in α-galactosidase A. In 2002, Ishii and colleagues uncovered a variant (IVS4+919G > A) deep within intron 4 of the GLA gene that could lead to aberrant splicing of the GLA mRNA. This variant is present in 1:875 males in Taiwan, and many patients with hypertrophic cardiomyopathy and the IVS4+919G > A variant are currently treated by enzyme replacement therapy, an expensive treatment. Unfortunately, till now only one article published in 2013 described the outcome of treatment. This review summarized the conflicting evidence about the clinical relevance of the IVS4+919G > A variant, and suggest a multifactorial model, rather than a monogenic model, for the involvement of the IVS4+919G > A variant in hypertrophic cardiomyopathy. The diagnostic dilemma for this Taiwanese cardiac variant in Fabry disease clearly emphasizes the need for precise interpretation and application of molecular diagnostic results.

Molecular diagnosis has undergone rapid and significant advancements in recent years. But because molecular diagnosis can be conducted independently of phenotype, it can engender ambiguity and potential misinterpretations in disease diagnosis. Fabry disease, an X-linked lysosomal storage disorder, arises from a deficiency in α-galactosidase A. In 2002, Ishii and colleagues uncovered a variant (IVS4+919G > A) deep within intron 4 of the GLA gene that could lead to aberrant splicing of the GLA mRNA. This variant is present in 1:875 males in Taiwan, and many patients with hypertrophic cardiomyopathy and the IVS4+919G > A variant are currently treated by enzyme replacement therapy, an expensive treatment. Unfortunately, till now only one article published in 2013 described the outcome of treatment. This review summarized the conflicting evidence about the clinical relevance of the IVS4+919G > A variant, and suggest a multifactorial model, rather than a monogenic model, for the involvement of the IVS4+919G > A variant in hypertrophic cardiomyopathy. The diagnostic dilemma for this Taiwanese cardiac variant in Fabry disease clearly emphasizes the need for precise interpretation and application of molecular diagnostic results. [ABSTRACT FROM AUTHOR]

The p.Asn215Ser or p.N215S GLA variant has been associated with late-onset cardiac variant of Fabry disease. To expand on the scarce phenotype data, we analyzed natural history data from 125 p.N215S patients (66 females, 59 males) enrolled in the Fabry Registry (NCT00196742) and compared it with data from 401 patients (237 females, 164 males) harboring mutations associated with classic Fabry disease. We evaluated interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT), estimated glomerular filtration rate and severe clinical events. In p.N215S males, mildly abnormal mean IVST and LVPWT values were observed in patients aged 25-34 years, and values gradually increased with advancing age. Mean values were similar to those of classic males. In p.N215S females, these abnormalities occurred primarily in patients aged 55-64 years. Severe clinical events in p.N215S patients were mainly cardiac (males 31%, females 8%) while renal and cerebrovascular events were rare. Renal impairment occurred in 17% of p.N215S males (mostly in patients aged 65-74 years), and rarely in females (3%). p.N215S is a disease-causing mutation with severe clinical manifestations found primarily in the heart. Cardiac involvement may become as severe as in classic Fabry patients, especially in males.

As an X-linked inherited lysosomal storage disease that is caused by α-galactosidase A gene variants resulting in progressive accumulation of pathogenic glycosphingolipid (Gb3) accumulation in multiple tissues and organs, Fabry disease (FD) can be classified into classic or late-onset phenotypes. In classic phenotype patients, α-galactosidase A activity is absent or severely reduced, resulting in a more progressive disease course with multi-systemic involvement. Conversely, late-onset phenotype, often with missense variants (e.g., IVS4+919G>A) in Taiwan, may present with a more chronic clinical course with predominant cardiac involvement (cardiac subtype), as they tend to have residual enzyme activity, remaining asymptomatic or clinically silent during childhood and adolescence. In either form, cardiac hypertrophy remains the most common feature of cardiac involvement, potentially leading to myocardial fibrosis, arrhythmias, and heart failure. Diagnosis is established through α-galactosidase enzyme activity assessment or biomarker analyisis (globotriaosylsphingosine, Lyso-Gb3), advanced imaging modalities (echocardiography and cardiac magnetic resonance imaging), and genotyping to differentiate FD from other cardiomyopathy. Successful therapeutic response relies on early recognition and by disease awareness from typical features in classic phenotype and cardiac red flags in cardiac variants for timely therapeutic interventions. Recent advances in pharmacological approach including enzyme replacement therapy (agalsidase alfa or beta), oral chaperone therapy (migalastat), and substrate reduction therapy (venglustat) aim to prevent from irreversible organ damage. Genotype- and gender-based monitoring of treatment effects through biomarker (Lyso-Gb3), renal assessment, and cardiac responses using advanced imaging modalities are key steps to optimizing patient care in FD., Competing Interests: All the authors declare no conflict of interest.

Background: Fabry disease (FD) is an X-linked lysosomal storage disorder engendered by a deficiency of the enzyme α- galactosidase A, leading to systemic accumulation of glycolipids. Studies have reported that the cardiac subtype of FD has a later onset and minimal extracardiac involvement. However, whether the severity of cardiac involvement differs between the classic and cardiac subtypes of FD remains unclear. Methods: We enrolled consecutive patients with classic FD (n = 22; median age [25th-75th percentile], 47.0 [32.75-56.25] years; men, 72.7%) as well as age- and sex-matched patients with a later-onset cardiac subtype of FD who were selected from our cohort of patients with IVS4 919G>A mutation. FD was diagnosed on the basis of clinical symptoms/signs and pedigree screening of index case, plasma α-galactosidase activity, and molecular analysis. Data on clinical manifestations, laboratory findings, and echocardiogram findings were collected before enzyme replacement treatment. Disease severity was evaluated using the Mainz Severity Score Index score. Results: All female patients demonstrated heterozygous mutations, with five, one, and four of them showing normal α- galactosidase activity, classic FD, and cardiac subtype of FD, respectively. The distributions of left ventricular performance indices and comorbidities, including hypertension, diabetes mellitus, and dyslipidemia, were similar between the two groups. Moreover, MSSI cardiovascular scores did not differ significantly between the groups (classic vs cardiac subtype, 10.0 [2.0-12.5] vs 10.5 [9.0-15.25]; p = 0.277). Conclusion: Cardiac manifestations are similar between patients with classic and cardiac subtype of FD. [ABSTRACT FROM AUTHOR]

Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to deficient α-galactosidase A activity and, consequently, to glycosphingolipid accumulation in a wide variety of cells. Fabry disease due to N215S (c.644A>G, p.Asn215Ser) missense mutation usually results in a late-onset phenotype presenting with isolated cardiac involvement. We herein present the case of a patient with N215S mutation with cardiac involvement, namely left ventricular hypertrophy and ventricular arrhythmias, and end-stage renal disease requiring kidney transplantation. To the best of our knowledge, this is the first report of a kidney-transplanted Fabry patient treated with oral pharmacologic chaperone migalastat.

Fabry disease' (FD) phenotype is heterogeneous: alpha-galactosidase A gene mutations (GLA) can lead to classical or non-classical FD, or no FD. The aim of this study is to describe pitfalls in diagnosing non-classical FD and assess the diagnostic value of plasma globotriaosylsphingosine. This is a case series study. Family 1 (p.A143T) presented with hypertrophic cardiomyopathy (HCM), absent classical FD signs, high residual alpha-galactosidase A activity (AGAL-A) and normal plasma globotriaosylsphingosine. Co-segregating sarcomeric mutations were found. Cardiac biopsy excluded FD. In family 2 (p.P60L), FD was suspected after kidney biopsy in a female with chloroquine use. Males had residual AGAL-A, no classical FD signs and minimally increased plasma globotriaosylsphingosine, indicating that p.P60L is most likely non-pathogenic. Non-specific complications and histology can be explained by chloroquine and alternative causes. Males of two unrelated families (p.R112H) show AGAL-A <5%, but slightly elevated plasma globotriaosylsphingosine (1.2-2.0 classical males >50 nmol/l). Histological evidence suggests a variable penetrance of this mutation. Patients with GLA mutations and non-specific findings such as HCM may have non-classical FD or no FD. Other (genetic) causes of FD-like findings should be excluded, including medication inducing FD-like storage. Plasma globotriaosylsphingosine may serve as a diagnostic tool, but histology of an affected organ is often mandatory. [ABSTRACT FROM AUTHOR]

Mucopolysaccharidosis type VI (MPS VI) is a rare lysosomal, autosomal recessive storage disorder caused by deficient activity of N-acetylgalactosamine-4-sulfatase (ARSB). Approximately, 140 ARSB gene mutations have been identified; however, most are private mutations making genotype-phenotype correlation for most MPS VI patients difficult. The aim of this study was to describe the natural clinical course in patients homozygous for the p.R152W mutation from eight unrelated families. From our database of 70 patients with MPS VI, we selected 10 patients homozygous for the p.R152W mutant allele (median age 27.5 years, range 18-38 years). We performed a cross-sectional observational study characterizing the onset and prevalence of clinical manifestations. First signs of the disease, such as cardiac valve disease, slightly decreased joint range of motion and mild growth retardation, were observed in mid-adolescent years (median 15 years). Within the disease course, the most common clinical feature in all the patients was progressive heart disease of predominantly valve origin leading to symptoms of heart failure. Other typical MPS VI features were subtle and not present in all the patients. Delays up to 23 years (median 8.5 years) intervened between symptom onset and disease diagnosis. Patients homozygous for the p.R152W mutation present a cardiac variant of MPS VI characterized by progressive cardiac valve disease leading to serious cardiac complications including abrupt death due to cardiac failure. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Fabry disease is an X-linked sphingolipidosis due to a deficiency of α-galactosidase A, which leads to the accumulation of globotriaosylceramide (GL-3) in several organs. When recombinant human α-galactosidase A is intravenously administered repeatedly before the patient develops permanent tissue damage, there is evidence that the accumulation of GL-3 is decreased in some organs and that the clinical symptoms are alleviated in some patients. However, Fabry disease is rare and many patients are not diagnosed until adulthood after irreversible tissue damage has occurred. Our group has developed a simple and non-invasive screening method for Fabry disease that measures total GL-3 in whole urine samples by tandem mass spectrometry. Using this method, we found that the concentration of GL-3 in whole urine sample from hemizygous patients, including pre-symptomatic young children with classic type Fabry disease, was significantly higher than that in controls. The mean concentration of GL-3 in urine from heterozygotes with symptoms was significantly higher than control concentrations, but GL-3 levels in the urine from 2 out of 8 heterozygotes of classic type Fabry disease were within control levels. An asymptomatic 14-year old hemizygote in the family of a cardiac variant did not have elevated urinary GL-3. Therefore, screening for the classic type and probably renal variant of Fabry disease is possible by measuring urinary GL-3, using our method. The early diagnosis of cardiac variant hemizygotes and some heterozygotes with all types of Fabry disease will not be possible using our method. We propose that this procedure can be used as a reliable, non-invasive, simple method for general and high-risk population screening for hemizygotic patients with the classic type and probably renal variant of Fabry disease. [Copyright &y& Elsevier]

Hauser AC, Lorenz M, Sunder-Plassmann G (University of Vienna, Vienna, Austria). The expanding clinical spectrum of Anderson–Fabry disease: a challenge to diagnosis in the novel era of enzyme replacement therapy (Review). J Intern Med 2004; 255: 629–636. Anderson–Fabry disease is an X-linked recessive lysosomal storage disease resulting from deficient α-galactosidase A activity. The conception of the disease has changed within the last decade. Studies of the last years have shown that the disease is not limited to the classical full-blown manifestation in affected males, which is well known since more than a century, but may also occur in carrier females. The phenomenology may differ in severity and kind of organ manifestation. Cardiac and renal variants with solely disease manifestation of these organs have also been described in an increasing number. It is likely that a spectrum exists regarding α-galactosidase A activity in both genders on the one hand, and an additional one regarding the severity and the number of organs affected on the other. The purpose of this review is to sharpen physicians’ perception of this disease. Early and accurate diagnosis is mandatory considering that this disorder is now, after introduction of the novel enzyme replacement therapy, a treatable disease. [ABSTRACT FROM AUTHOR]

Fabry disease is a rare X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to deficient α-galactosidase A activity and, consequently, to glycosphingolipid accumulation in a wide variety of cells. Fabry disease due to N215S (c.644A>G, p.Asn215Ser) missense mutation usually results in a late-onset phenotype presenting with isolated cardiac involvement. We herein present the case of a patient with N215S mutation with cardiac involvement, namely left ventricular hypertrophy and ventricular arrhythmias, and end-stage renal disease requiring kidney transplantation. To the best of our knowledge, this is the first report of a kidney-transplanted Fabry patient treated with oral pharmacologic chaperone migalastat. [ABSTRACT FROM AUTHOR]

Fabry disease (FD) is an X-linked, rare inherited lysosomal storage disease caused by α-galactosidase A gene variants resulting in deficient or undetectable α-galactosidase A enzyme activity. Progressive accumulation of pathogenic globotriaosylceramide and its deacylated form globotriaosylsphingosine in multiple cell types and organs is proposed as main pathophysiology of FD, with elicited pro-inflammatory cascade as alternative key pathological process. The clinical manifestations may present with either early onset and multisystemic involvement (cutaneous, neurological, nephrological and the cardiovascular system) with a progressive disease nature in classic phenotype, or present with a later-onset course with predominant cardiac involvement (non-classical or cardiac variant; e.g. IVS4+919G>A in Taiwan) from missense variants. In either form, cardiac involvement is featured by progressive cardiac hypertrophy, myocardial fibrosis, various arrhythmias, and heart failure known as Fabry cardiomyopathy with potential risk of sudden cardiac death. Several plasma biomarkers and advances in imaging modalities along with novel parameters, cardiac magnetic resonance (CMR: native T1/T2 mapping) for myocardial tissue characterization or echocardiographic deformations, have shown promising performance in differentiating from other etiologies of cardiomyopathy and are presumed to be helpful in assessing the extent of cardiac involvement of FD and in guiding or monitoring subsequent treatment. Early recognition from extra-cardiac red flag signs either in classic form or red flags from cardiac manifestations in cardiac variants, and awareness from multispecialty team work remains the cornerstone for timely managements and beneficial responses from therapeutic interventions (e.g. oral chaperone therapy or enzyme replacement therapy) prior to irreversible organ damage. We aim to summarize contemporary knowledge based on literature review and the gap or future perspectives in clinical practice of FD-related cardiomyopathy in an attempt to form a current expert consensus in Taiwan.

Type 3c Gaucher disease, an ultra-rare cardiac variant with progressive calcification of aortic and/or mitral heart valves, is generally fatal in teenage-hood. Vitamin D Receptors (VDR) are involved in calcium transport. The purpose of this pilot was to ascertain if VDR polymorphisms ( BsmI, TaqI, ApaI, and FokI) are associated with type 3c Gaucher disease. There was a higher incidence of wild type alleles of all polymorphisms. Although a very small series, results seem to confirm preponderance of the BsmI B allele in type 3c as in other aortic calcifications, but also implicate linkage between ApaI and BsmI genotypes. [ABSTRACT FROM AUTHOR]

Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of α-galactosidase A and is classified into two types: classical and variant. The classical type exhibits classic manifestations, but the variant type does not and is therefore difficult to identify sometimes. A 73-year-old woman with a first episode of heart failure was admitted to our hospital. Her left ventricular wall motion was mildly reduced without hypertrophy. Urine sediment revealed mulberry cells, leading to the diagnosis of Fabry disease. In cases without typical clinical findings, urinary mulberry cells may help diagnose Fabry disease.

Background Patients with Fabry disease (FD) show left ventricular hypertrophy (LVH) mimicking hypertrophic cardiomyopathy (HCM) of sarcomeric origin and might benefit, if detected early, from specific enzyme replacement therapy. The prevalence of FD in patients with LVH of 13⇔…mm or greater, screened using the leucocyte alpha-galactosidase A (α-gal A) activity test, a technique that is difficult to apply routinely, ranged from 0% to 6%. Objective To screen systematically for FD in patients with a diagnosis of HCM (LVH ≥15⇔…mm) in primary cardiology practice, a validated, physician-friendly α-gal A assay was used on dried blood spots using a filter paper test. Design and patients A cohort of 392 adults (278 men) followed for HCM were screened for FD. A standard blood test was used for confirmation in nine men in whom the α-gal A result was 40% or less. Results Four men (1.5%; 1.8% of men ≥40⇔…years vs 0% <40⇔…years; all with α-gal A <30%), but no women, were diagnosed with FD. Index cases presented with diffuse but asymmetric LVH, with severe obstruction in one case and frequent high-grade atrioventricular conduction block necessitating a pacemaker in three cases. Family screening identified eight additional cases. Genotyping was performed successfully on DNA extracted from the filter papers. Conclusion In male patients diagnosed as having HCM, pure FD cardiac variants are not exceptional and can be specifically identified using a simple filter-paper test. The sensitivity of this test is low in female patients. [ABSTRACT FROM AUTHOR]