The youngest pair of siblings with Mucopolysaccharidosis type IVA to receive enzyme replacement therapy to date: A case report

Abstract

Mucopolysaccharidosis type IVA (OMIM 253000) is an autosomal recessive disorder caused by defective activity of the N‐acetylgalactosamine 6‐sulfatase (GALNS) enzyme. In 2014, enzyme replacement therapy (ERT) using recombinant human GALNS became available for affected patients. There is a limited number of studies to date that have explored the effect of ERT in infancy and there is also a lack of data assessing the effect of ERT in systems other than the skeletal. Here, we report on the effect of ERT in the youngest pair of siblings treated to date: Patient A, currently 4 years old, who started treatment at the age of 5 months; and Patient B, currently 3 years old, who started treatment at 58 days of life. Moreover, we investigate the effect of early ERT on the cardiovascular system. Our results show that, even when ERT is started before 2 months of age, it cannot fully prevent disease progression. As for the effect of ERT on the cardiovascular system, our preliminary results suggest that early treatment might play a role in preserving a normal left ventricular mass index in affected patients at least up to 1 year, but further observation over time will be required. Overall, this report shows that early diagnosis remains crucial and that prompt initiation of ERT has limited effect in slowing progression of the skeletal phenotype, thus confirming the need for new therapeutic approaches that target the skeletal system in affected patients.

Exome Sequencing Identifies a Biallelic GALNS Variant (p.Asp233Asn) Causing Mucopolysaccharidosis Type IVA in a Pakistani Consanguineous Family

“…Lysosomal storage diseases such as MPS IV can be treated with either enzyme replacement therapy (ERT), pharmaceutical chaperones, substrate reduction, or hematopoietic stem cell transplantation (HSCT) [ 25 , 26 , 27 ]. In ERT the patients are treated with recombinant enzymes approved by US Food and Drug Administration (FDA).…”

“…The FDA has approved recombinant GALNS enzymes include elosulfase alfa and recombinant GALNS enzyme (rhGALNS) for the treatment of MPSIV. ERT is generally considered safe to use [ 28 ], however there are studies, which show that the ERT may not be able to completely alter the skeletal phenotype seen in this condition [ 25 ]. As metabolic disorders are congenital and associated with irreversible damage to the cells and tissues such as the bones, such as the bones, the physical manifestations may be too advanced at the time of clinical diagnosis to be reversed by the treatment.…”

“…However, this procedure is highly risky having multiple complications and an increased mortality rate [ 27 , 29 , 30 ]. Pharmacological chaperones are also being used for MPSIVA treatment [ 25 ]. These small molecules bind to the protein target and stabilize the protein conformation or promote the correct folding and trafficking of the altered protein.…”

“…The pharmacological chaperones can be administered orally and can be used as a monotherapy. Molecular chaperons have been reported to enhance the enzyme activity of the mutated protein and when coupled with ERT can increase the recombinant lysosomal enzymes activity, which suggests that these chaperon along with recombinant enzyme when co-administered can increase ERT efficacy [ 25 ]. The combination of both treatments is reported to reduce the lysosomal mass in the patient cells by the administration of hrGALNS with pharmaceutical chaperone (pranlukask) in MPSIVA fibroblast has been reported to reduce patient cell lysosomal mass and normalised cell function [ 29 ].…”

MPSI Manifestations and Treatment Outcome: Skeletal Focus

“…Although there is a close genotype/phenotype correlation in MPSI, predicting the phenotype of patients with missense, splice site, and insertions, as well as small deletions and duplications, remains a challenge [ 4 ]. In addition, intrafamilial variability has been described in male siblings with MPSII and MPSIVA; thus, caution must be used when counseling families [ 19 , 20 ].…”