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In ALS deficiency, one IGFALS allele inadequate for sustaining levels
In patients with acid labile subunit deficiency, a single dosage of recombinant human insulin-like growth factor I is not adequate to sustain normal acid labile subunit levels, endocrine IGF-I action, aptitude for growth, muscle size and periosteal expansion, according to recent study findings.
In the open-label, pharmacodynamic, pharmacokinetic study, the researchers sought to evaluate the effects of a single injection of recombinant human IGF-I on the blood levels of IGF-1 on patients with acid labile subunit deficiency. A secondary aim of the study was to compare acid labile subunit–deficient patients with their heterozygous first-degree relatives in terms of IGF-I metabolism, insulin resistance, glucose handling, lipid profile, body composition, bone geometry and bone density.
The study researchers enrolled patients from families known to have children with acid labile subunit deficiency; four acid labile subunit–deficient patients and 12 heterozygous carriers agreed to participate. The researchers administered a single subcutaneous dose of recombinant human IGF-I and collected serial blood samples during a 14-hour period. They compared the serum levels of IGF-I and IGF binding protein-3 (IGFBP-3) in the acid labile subunit patients with those characteristic of severe primary IGF-I deficiency (PIGFD), moderate PIGFD and controls.
They gathered data for the secondary analysis through IV glucose tolerance tests, fasting blood work, DXA and metacarpal radiogrammetry conducted on the patients and their heterozygous first-degree relatives.
The study data indicated that IGF-I and IGFBP-3 concentrations rose above baseline (P<.05) for 2.5 hours, but they returned to baseline 7 hours after recombinant human IGF-I injection. There was a 2.49 increase in mean IGF-I z score, whereas IGFBP-3 z score increased by only 0.57.
The rates of IGF-I elimination were similar across acid labile subunit–deficient patients, but the IGF-I was lower for those seen in severe PIGFD. There were significant gene dosage effects observed in terms of IGF-I peptides, height, forearm muscle size and metacarpal width. An acid labile subunit deficiency-specific phenotype of slender bones with normal size-corrected density was revealed through bone analyses. Insulin resistance and abnormal glucose regulation were observed in three of the four patients and six of the 12 heterozygous carriers.
The researchers said, in light of these findings, alternative approaches to recombinant human IGF-I treatment should be explored.
“Despite similar elimination pharmacokinetics, subjects with [acid labile subunit] deficiency respond less to [recombinant human] IGF-I treatment compared to patients with severe PIGFD,” the researchers wrote.
Disclosure: The researchers report no relevant financial disclosures.