Renal globotriaosylceramide deposits for Fabry disease linked to uncertain pathogenicity gene variant c.352C&gt;T/p.Arg118Cys: A family study

Cerón‐Rodríguez, Magdalena; Ramón-Garcı́a, Guillermo; Barajas-Colón, Edgar; Franco-Álvarez, Isidro; Salgado-Loza, Juan L.

doi:10.1002/mgg3.981

Cited by 3 publications

(2 citation statements)

References 23 publications

(45 reference statements)

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“…Recently, it has been emphasized the importance of a high level of LysoGb3 as a diagnostic marker of pathogenicity in VUS (Ortiz et al, 2018). However, there are several reports of affected patients with VUS, where LysoGb3 was within the normal range despite the presence of deposits observed in kidney biopsy (Cerón-Rodríguez et al, 2019). Alternatively, the identification of typical lysosomal inclusions in tissue biopsy specimens has been suggested as the gold standard of FD diagnosis (Schiffmann et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

No evidence of Fabry disease in a patient with the new p.Met70Val GLA gene variant

Capelli,

Di Costanzo,

Aiello

et al. 2024

Molec Gen & Gen Med

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BackgroundFabry disease (FD) is a rare X‐linked lysosomal storage disorder caused by variants in GLA gene leading to deficient α‐galactosidase A enzyme activity. This deficiency leads to the accumulation of glycosphingolipids, particularly globotriaosylceramide (Gb3), in various tissues and organs, which can result in life‐threatening complications. The clinical presentation of the disease can vary from the “classic” phenotype with pediatric onset and multi‐organ involvement to the “later‐onset” phenotype, which presents with predominantly cardiac symptoms. In recent years, advances in screening studies have led to the identification of an increasing number of variants of unknown significance that have not yet been described, and whose pathogenic role remains undetermined.MethodsIn this clinical report, we describe the case of an asymptomatic adult female who was found to have a new variant of unknown significance, p.Met70Val. Given the unknown pathogenic role of this variant, a thorough analysis of the potential organ involvement was conducted. The clinical data were analyzed retrospectively.ResultsThe analysis revealed that there were no signs of significant organ involvement, and the benignity of the variant was confirmed.ConclusionThis case underscores the importance of a comprehensive evaluation of new variants of unknown significance to establish their pathogenicity accurately.

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Section: Discussionmentioning

confidence: 99%

No evidence of Fabry disease in a patient with the new p.Met70Val GLA gene variant

Capelli,

Di Costanzo,

Aiello

et al. 2024

Molec Gen & Gen Med

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“…This assessment can be troublesome and may even be conflicting. For instance, variant c.352C>T ( R118C) was categorized 'apathogenic' [24] and 'possibly disease triggering' [25, 26]. The same applies to variant c .937G>T ( D313Y) [27‐29].…”

Section: Discussionmentioning

confidence: 99%

Stratification of Fabry mutations in clinical practice: a closer look at α‐galactosidase A‐3D structure

et al. 2020

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Background. Fabry disease (FD) is an X-linked lysosomal storage and multi-system disorder due to mutations in the a-galactosidase A (a-GalA) gene. We investigated the impact of individual amino acid exchanges in the a-GalA 3D-structure on the clinical phenotype of FD patients. Patients and methods. We enrolled 80 adult FD patients with a-GalA missense mutations and stratified them into three groups based on the amino acid exchange location in the a-GalA 3Dstructure: patients with active site mutations, buried mutations and other mutations. Patient subgroups were deep phenotyped for clinical and laboratory parameters and FD-specific treatment. Results. Patients with active site or buried mutations showed a severe phenotype with multi-organ involvement and early disease manifestation. Patients with other mutations had a milder phenotype with less organ impairment and later disease onset. a-GalA activity was lower in patients with active site or buried mutations than in those with other mutations (P < 0.01 in men; P < 0.05 in women) whilst lyso-Gb3 levels were higher (P < 0.01 in men; <0.05 in women). Conclusions. The type of amino acid exchange location in the a-GalA 3D-structure determines disease severity and temporal course of symptom onset. Patient stratification using this parameter may become a useful tool in the management of FD patients.

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Fabry nephropathy: a treatable cause of chronic kidney disease

West,

Geldenhuys,

Bichet

2024

Rare Dis Orphan Drugs J

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Fabry disease is a rare X-linked inborn error of metabolism that has a high prevalence of chronic kidney disease (CKD) and renal failure. It is due to the deficiency of the α-galactosidase A (α-Gal) lysosomal enzyme with subsequent accumulation of globotriaosylceramide (Gb3) in lysosomes. In the kidney, the podocyte is the main target of this disease, although all cell types are involved. The podocyte, being terminally differentiated, does not replicate and thus accumulates Gb3 throughout life. Podocytes are injured by Gb3, leading to their detachment from the glomerular basement membrane and subsequent loss in the urine. Albuminuria starts in childhood and progresses to overt proteinuria in the teens and 20 s. CKD ensues with adults starting dialysis at an average age of 42 years. Patients have a high prevalence of stroke and cardiomyopathy with hypertrophic change, heart failure, and dysrhythmias. Patient survival is limited in both genders. Diagnosis is based on the demonstration of a low α-Gal activity and a pathogenic GLA mutation. Clinical features are highly variable, which makes recognition of this condition difficult. Treatment with intravenous recombinant human enzyme replacement therapy (ERT) and oral pharmacologic chaperone are available. Control of proteinuria to 0.5 g/day or less is of critical importance to limit progression to end-stage renal disease. Early initiation of treatment gives the best results, but the optimal age to start is uncertain. Fabry nephropathy remains a challenge due to its multisystem nature, difficult diagnosis, and complicated management. It is important as a treatable cause of CKD.

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Renal globotriaosylceramide deposits for Fabry disease linked to uncertain pathogenicity gene variant c.352C>T/p.Arg118Cys: A family study

Cited by 3 publications

References 23 publications

No evidence of Fabry disease in a patient with the new p.Met70Val GLA gene variant

No evidence of Fabry disease in a patient with the new p.Met70Val GLA gene variant

Stratification of Fabry mutations in clinical practice: a closer look at α‐galactosidase A‐3D structure

Fabry nephropathy: a treatable cause of chronic kidney disease

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