Abstract
Context: Acid labile subunit (ALS) deficiency, caused by IGFALS mutations, is a subtype of primary IGF-I deficiency (PIGFD) and has been associated with insulin resistance (IR) and osteopenia. Whether patients respond to recombinant human IGF-I (rhIGF-I) is unknown. Objective and Design: This study determined the 14-hour pharmacokinetic response of free and total IGF-I and IGF binding protein 3 (IGFBP-3) to a single sc dose of rhIGF-I (120g/kg) in four ALS-deficient patients, compared with severe PIGFD, moderate PIGFD, and controls. Intravenous glucose tolerance tests, fasting bloodlevels,dual-energyX ray absorptiometry, peripheralquantitativecomputedtomography,andmetacarpal
radiogrammetry were performed in the four patients and 12 heterozygous family members.
Results: IGF-I and IGFBP-3 increased above baseline (P .05) for 2.5 hours, returning to baseline
7 hours after rhIGF-I injection. Mean (SD) IGF-I Z-score increased by 2.49 (0.90), whereas IGFBP-3
Z-score increased by 0.57 (0.10) only. IGF-I elimination rates in ALS deficiency were similar, but the
IGF-I increment was lower than those for severe PIGFD. Significant gene dosage effects were found
for all IGF-I peptides, height, forearm muscle size,andmetacarpal width.Boneanalysisshowedthat
ALS deficiency creates a phenotype of slender bones with normal size-corrected density. Abnormal
glucose handling and IR was found in three of four patients and 6 of 12 carriers.
Conclusions: These gene dosage effects demonstrate that one functional IGFALS allele is insufficient
to maintain normal ALS levels, endocrine IGF-I action, full growth potential, muscle size, and periosteal
expansion. Similar gene dosage effects may exist for parameters of IR. Despite similar IGF-I elimination
comparedwith severe PIGFD, ALS-deficient patients cannotmountasimilar response. Alternativeways
of rhIGF-I administration should be sought.
radiogrammetry were performed in the four patients and 12 heterozygous family members.
Results: IGF-I and IGFBP-3 increased above baseline (P .05) for 2.5 hours, returning to baseline
7 hours after rhIGF-I injection. Mean (SD) IGF-I Z-score increased by 2.49 (0.90), whereas IGFBP-3
Z-score increased by 0.57 (0.10) only. IGF-I elimination rates in ALS deficiency were similar, but the
IGF-I increment was lower than those for severe PIGFD. Significant gene dosage effects were found
for all IGF-I peptides, height, forearm muscle size,andmetacarpal width.Boneanalysisshowedthat
ALS deficiency creates a phenotype of slender bones with normal size-corrected density. Abnormal
glucose handling and IR was found in three of four patients and 6 of 12 carriers.
Conclusions: These gene dosage effects demonstrate that one functional IGFALS allele is insufficient
to maintain normal ALS levels, endocrine IGF-I action, full growth potential, muscle size, and periosteal
expansion. Similar gene dosage effects may exist for parameters of IR. Despite similar IGF-I elimination
comparedwith severe PIGFD, ALS-deficient patients cannotmountasimilar response. Alternativeways
of rhIGF-I administration should be sought.
| Original language | English |
|---|---|
| Pages (from-to) | E703-E712 |
| Journal | Journal of Clinical Endocrinology and Metabolism |
| Volume | 99 |
| Issue number | 4 |
| Early online date | 13 Jan 2014 |
| DOIs | |
| Publication status | Published - Apr 2014 |