Plasma Globotriaosylsphingosine Level as a Primary Screening Target for Fabry Disease in Patients With Left Ventricular Hypertrophy

Abstract

Background: Although previous studies have suggested a certain prevalence of Fabry disease (FD) in left ventricular hypertrophy (LVH) patients, the screening of FD is difficult because of its wide-ranging clinical phenotypes. We aimed to clarify the utility of combined measurement of plasma globotriaosylsphingosine (lyso-Gb3) concentration and α-galactosidase A activity (α-GAL) as a primary screening of FD in unexplained LVH patients. Methods and Results: Between 2014 and 2016, both lyso-Gb3 and α-GAL were measured in 277 consecutive patients (male 215, female 62, age 25-79 years) with left ventricular wall thickness >12 mm on echocardiogram: 5 patients (1.8%) screened positive (2 (0.7%) showed high lyso-Gb3 and 4 (1.4%) had low α-GAL levels). Finally, 2 patients (0.7%) were diagnosed with clinically significant FD. In 1 case, a female heterozygote with normal α-GAL levels had genetic variants of unknown significance and was diagnosed as FD by endomyocardial biopsy. The other case was a male chronic renal failure patient requiring hemodialysis, and he had a p.R112H mutation. In both cases there were high lyso-Gb3 levels. Conclusions: The serum lyso-Gb3 level can be relevant for clinically significant FD, and combined measurement of lyso-Gb3 and α-GAL can provide better screening of FD in unexplained LVH patients.

Clinical and diagnostic aspects of Fabry disease management: a narrative review with a particular focus on Brazilian experts’ perspectives

“…Concerning the specific cardiac phenotype, increased levels of lyso-Gb3 analogs at m/z 836 were found only in patients manifesting severe heart disease, suggesting that it might be an earlier biomarker of progressive heart disease but nonspecific to FD cardiomyopathy [49]. Plasma lyso-Gb3 and urine lyso-Gb3 in m/z (+16), (+34), and (+50) were positively associated with left ventricular hypertrophy (LHV) and the Mainz Severity Score Index in adults and children [50,51].…”

The 30-year Natural History of Non-classic Fabry Disease with an R112H Mutation

“…The follow-up duration was nine months ( 6 ). Yamashita et al reported a 61-year-old man diagnosed with Fabry disease with an R112H mutation who had undergone hemodialysis at 39 years old and also had cardiac manifestations, such as left ventricular hypertrophy ( 7 ). The details of his clinical course are unclear.…”

“…Our patient did not develop ESRD beyond 50 years old, which was consistent with the majority of non-classic Fabry disease patients with an R112H mutation who show relatively mild manifestations, such as proteinuria ( 6 ). However, some studies have reported severe manifestations, such as ESRD in one patient at 39 years old ( 7 ). Therefore, the R112H mutation may have a wide phenotypic spectrum, ranging from mild to severe manifestations.…”

Enfermedad de Fabry

“…Cabe destacar que la mayoría de los laboratorios de todo el mundo que realizan estudios genéticos para investigar las causas de la miocardiopatía hipertrófica incluyen actualmente el gen GLA en sus paneles mediante el método de secuenciación masiva en paralelo (NGS, next-generation sequencing), lo que posibilita que hoy haya un mayor diagnóstico de variantes con afectación predominantemente cardiaca, como la p.N215S o la IVS4+919G>A 8,9,14 . Si una variante genética no se encuentra reportada o se considera de significado incierto, la presencia de sintomatología asociada a EF, sumado a una actividad enzimática disminuida y a altos niveles de liso-GL3, son suficientes para confirmar el diagnóstico de EF 5,6,[15][16][17] .…”