RhIGF-1 Therapy for Growth Failure and IGF-1 Deficiency in Congenital Disorder of Glycosylation Ia (PMM2 Deficiency).

Bradley S Miller,Meghann M Duffy,Kyriakie Sarafoglou,O Yaw Addo

doi:10.1177/2324709613503316

Abstract

Background. Congenital disorders of glycosylation (CDG) are a group of rare disorders in which glycosylation required for proper protein-protein interactions and protein stability is disrupted, manifesting clinically with multiple system involvement and growth failure. The insulin-like growth factor (IGF) system plays an important role in childhood growth and has been shown to be dysfunctional with low IGF-1 levels in children with CDG type Ia (PMM2 deficiency). Case report. A 3-year-old Caucasian male with failure to thrive was diagnosed with PMM2-CDG at 5 months of age. Initially, his length and weight were less than −2 standard deviation score, IGF-1 <25 ng/mL (normal 55-327 ng/mL), IGFBP-3 1.0 µg/mL (normal 0.7-3.6 ng/mL), and acid-labile subunit 1.3 mg/L (normal 0.7-7.9 mg/L). Despite aggressive feeding, he continued to show poor linear growth and weight gain. At 17 months, he underwent an IGF-1 generation test with growth hormone (0.1 mg/kg/d) for 7 days; baseline IGF-1of 27 ng/mL (normal 55-327 ng/mL) stimulated to only 33 ng/mL. Recombinant human IGF-1 (rhIGF-1) therapy (up to 130 µg/kg/dose twice daily) was initiated at 21 months of age resulting in an excellent linear growth response with height increasing from −2.73 to −1.39 standard deviation score over 22 months. IGF-1 and IGFBP-3 levels also increased. Conclusion. This is the first case report of rhIGF-1 therapy in a patient with PMM2-CDG. The child had an excellent linear growth response. These results provide additional in vivo evidence for IGF dysfunction in PMM2-CDG and suggest that rhIGF-1 may be a novel treatment for growth failure in PMM2-CDG.

Highlights

Congenital disorders of glycosylation (CDG) are rare disorders of carbohydrate metabolism in which N-linked glycosylation is defective
Not all processes in the growth hormone (GH)-insulin-like growth factor-1 (IGF-1) cascade are glycosylated, in vitro and in vivo evidence has demonstrated that defective glycosylation leads to lower levels of insulin-like growth factor (IGF)-1, IGF-2, acid-labile subunit (ALS), and IGF binding protein-3 (IGFBP-3) that may contribute to poor linear growth in these patients.[5]
The key role of GH-IGF system glycosylation in the impaired growth of children with CDG is demonstrated by the growth response of a child with PMI-CDG who received mannose therapy to bypass the enzymatic defect

Summary

Introduction

Congenital disorders of glycosylation (CDG) are rare disorders of carbohydrate metabolism in which N-linked glycosylation is defective These enzymatic defects lead to alterations in activity, structure, and stability of glycosylated glycoproteins. Not all processes in the GH-IGF-1 cascade are glycosylated, in vitro and in vivo evidence has demonstrated that defective glycosylation leads to lower levels of IGF-1, IGF-2, acid-labile subunit (ALS), and IGF binding protein-3 (IGFBP-3) that may contribute to poor linear growth in these patients.[5] Inadequate glycosylation of ALS and IGFBP-3 leads to a reduction in the formation of the ternary complex necessary to stabilize IGF-1 and transport it to the target tissues because of increasing susceptibility to proteolysis (IGFBP-3) and reduced binding affinity (ALS).[7,8].

Materials and Methods

Discussion

Declaration of Conflicting Interests