Fabry disease and enzyme replacement therapy in classic patients with same mutation: different formulations – different outcome?

Abstract

We describe the results of the multidisciplinary evaluation in patients with Fabry disease and the same genetic mutation and their outcomes using different approved enzyme replacement therapy (ERT). We measured baseline data and serial results of neuropathic pain assessment and renal, cardiac and cerebrovascular functioning. Pain scale showed improvement in all male cases treated with agalsidasa beta. A mild improvement was detected in agalsidasa alfa-treated patients after 1 year with posterior increase. During the agalsidase beta shortage, two male patients were switched to agalsidasa alfa, after 1 year both cases presented an increase in scale values. Renal evolution showed a tendency toward a decrease in proteinuria in patients using agalsidase beta and worsening with agalsidase alfa. We found improvement in two females using agalsidase beta and no changes in the other cases regarding cardiac functioning. Brain magnetic resonance imaging (MRI) showed increase of white matter lesions in four patients. Improvement and stabilization in neuropathic pain, renal and cardiac functioning and brain MRI were found mainly in patients treated with agalsidase beta. Following the reported recommendations on reintroduction of agalsidase beta after the enzyme shortage, we decided to switch all patients to agalsidase beta.

Pain in Fabry Disease: Practical Recommendations for Diagnosis and Treatment

“…There is some indirect evidence from dose‐switching studies that suggests that ERT dose may be of relevance for pain outcomes, at least in the short term. At 1‐year follow‐up, there was improvement or stabilization of pain symptoms in patients who continued treatment with agalsidase beta, but an increase in pain when patients receiving agalsidase beta were transferred to treatment with agalsidase alfa . In a different study, patients who switched from agalsidase beta 1.0 mg/kg to a lower dose or to agalsidase alfa 0.2 mg/kg reported an increase in pain attacks, chronic pain, gastrointestinal pain, and diarrhea compared with those who continued receiving agalsidase beta 1.0 mg/kg after 1 year .…”

“…In terms of small nerve fiber sensory function, a study of 22 patients with FD revealed improved thermal perception and vibration detection thresholds with agalsidase beta . Although ERT reduces pain outcomes in a variety of Fabry‐related pain conditions, pain does not always completely resolve , explaining the need for adjunctive medications.…”

A case of rapid progression of Fabry nephropathy with remarkable glomerulomegaly: a case report and mini literature review of weak response to enzyme replacement therapy (ERT)

“…For example, cases of nephropathy only, classic type, and an atypical variant have been reported [8,25,26]. In addition, Politei et al revealed that patients with the same mutation as the current case (L415P) show different organ damage [27]. These findings suggest that gene mutation is not the only factor involved in organ damage.…”

Fabry Disease

“…Ambas están compuestas por la misma cadena de aminoácidos, es decir, son la misma proteína humana. La diferencia reside en la dosis aprobada (agalsidasa beta 1 mg/kg de peso y agalsidasa alfa 0,2mg/kg) y en la cantidad de residuos de manosa 6-fosfato (agalsidasa beta 3,6mol/mol de proteína y agalsidasa alfa 1,3mol/mol de proteína) 3,9,68 . Su principal mecanismo de acción es la sustitución de la enzima alfa-galactosidasa A, posibilitando la hidrólisis del Gb3 y liso-Gb3 al separar un residuo de galactosa terminal de la molécula, disminuyendo así su acumulación en los tejidos 2,9 .…”

“…La presencia de mayor cantidad de residuos de manosa 6 -fosfato produce un mejor reconocimiento por los receptores de manosa 6 -fosfato de la membrana celular y consecuentemente mayor internalización celular de la enzima 9,66 . De acuerdo con los estudios publicados, pareciera que el beneficio tisular y clínico tiene relación directa con la dosis de TRE utilizada 9,[67][68][69][70][71][72] . Distintos protocolos han demostrado que el uso de agalsidasa beta a dosis de 1mg/kg cada 14 días produce remoción total de Gb3 de los podocitos renales en comparación con la agalsidasa alfa a dosis de 0,2mg/kg9,70-72.…”