Abstract
Enzyme replacement therapy (ERT) has been shown to stabilize certain aspects of Fabry disease (FD). However, in some patients on ERT, high antibody titres have been documented, with limited clinical improvement in systemic manifestations and often with significant adverse drug reactions. We present two related adolescent males with a 4.5 kb GLA deletion, not amenable to chaperone therapy, leading to profound reduction in α-galactosidase A (α-gal A) enzyme activity. Over a 3-year period of ERT, increasing IgG antibody titres against α-gal A were noted. After starting ERT serial urine globotriaosylceramide (Gb3) measurements showed an upward trend from 333 to 2260 μg/mmol creatinine for patient 1 and 1165 to 2260 μg/mmol creatinine for patient 2. Markedly increased levels of urine and plasma globotriaosylsphingosine (Lyso-Gb3) analogues were also found. The patients experienced recurrent infusion-associated reactions necessitating premedication and prolonged infusion times. Over the 3-year period of ERT, the patients experienced continued malaise, gastrointestinal symptoms and neuropathic pain. In addition, they had increasing anxiety related to their disease and apparent lack of response to ERT which led to a decision to ultimately stop ERT. No other approved treatment options are currently available for these patients. It is possible that the rapid development of the high antidrug neutralizing antibody (ADA) titres is related to the large GLA deletion leading to virtually absent enzyme activity. It remains unclear if their symptomatology during the period of receiving ERT is related to lack of its efficacy, the rising ADA titres, or both. These two patients highlight the need for further research into the management of antidrug antibodies and additional therapeutic approaches for FD. SynopsisThe development of very high antidrug antibody titres in response to ERT in two related adolescent males with FD highlight the need for other therapeutic options for patients in whom ERT or other currently approved therapies does not meet their treatment needs.
Highlights
Fabry disease (FD) (OMIM #301500) is an X-linked multisystem lysosomal storage disorder (LSD) caused by a deficiency of α-galactosidase A enzyme (α-gal A, EC 3.2.1.22) known as
Seroconversion with antidrug neutralizing antibody (ADA) is reported in 73% males as opposed to 12% females treated with agalsidase beta
As identified by the method of Aerts, these antibodies cross react with both agalsidase products, tend to be persistent and have only been reported in males with FD [30]
Summary
Fabry disease (FD) (OMIM #301500) is an X-linked multisystem lysosomal storage disorder (LSD) caused by a deficiency of α-galactosidase A enzyme (α-gal A, EC 3.2.1.22) known as (ceramide trihexosidase). ELISA assays have been used by ERT manufacturers who have identified IgG antidrug antibodies in many patients [7,33,39]. These antibodies are more frequent in males than females and in more patients receiving agalsidase beta than agalsidase alfa and associated with higher urine Gb3 and plasma LysoGb3 levels suggesting reduced action of α-gal A as reviewed by [14]. Neutralizing antidrug antibodies to ERT in Fabry disease were first reported in 2004. Titration studies have shown a total absence of plasma α-gal A activity during agalsidase infusion suggesting that complete inactivation of the infused enzyme can occur in the presence of neutralizing antibody [26]. We report treatment challenges caused by the heightened immune response in two male adolescents who received ERT for up to three years
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