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Status of Growth Hormone/ Insulin-like Growth Factor-1 (GH/IGF-1) Axis and Growth Failure in Ataxia Telangiectasia (AT)

2014-08-27 03:16:32 | BioPortfolio

Summary

This study will evaluate the status of the growth hormone/ insulin-like growth factor-1 (GH/IGF-1) axis in relation to growth failure, body weight and composition and neuroprotection in children with Ataxia telangiectasia (AT).

Description

Growth failure and GH/IgF-1 deficiency has been described in patients diagnosed with Ataxia telangiectasia (AT) [Boder et al.,1958]. This condition is a fatal inherited disease caused by a mutation of the ATM gene on chromosome 11 leading to chromosomal instability, immunodeficiency, cancer susceptibility and and endocrinological abnormalities. In this regard, several groups demonstrated a cross-linking of ATM with growth factor pathways. Participation of the ATM protein in insulin signaling through phosphorylation of eIF-4E-binding protein 1 has been postulated [Yang et al.,2000]. Peretz et al.[2001] described that expression of the insulin-like growth factor-I receptor is (IGF-I R) ATM dependent in a pathway regulating radiation response. In addition, Shahrabani-Gargir et al.[2004] found that the ATM gene controls IGF-I R gene expression in a DNA damage response pathway. Suzuki et al.[2004] described that IGF-I phosphorylates AMPK-alpha, a key regulator of cholesterol and fatty acid synthesis, acts in an ATM-dependent manner . We have recently demonstrated reduced levels of circulating Insulin-like growth factor-I (IGF-I) and its main binding protein 3 (IGFBP-3) in AT patients accompanied with decreased body mass index [Schubert et al.,2005]. Furthermore, apart from regulating somatic growth and metabolism, evidence suggests that the GH/IGF-I axis is involved in the regulation of brain growth, development and myelination. Moreover, GH and particularly IGF-1 have potential neuroprotective effects in different in vitro and in vivo experimental models. In addition we have recently shown that extracerebellar MRI-lesions in AT go along with deficiency of the GH/IGF-1 Axis, markedly reduced body weight, high ataxia scores and advanced age [Kieslich et al.,2009]. Supplementation with these growth hormones might overcome the progressive dystrophy and may have clinical benefits against the progression of neurodegeneration and immunodeficiency.

We found that supplementation with GH significantly increased longevity of Atm-deficient mice and improve T-cell immunity and locomotor behaviour [Schubert et al.,2009]. Surprisingly IGF-1 was not generated in the ATM deficient mice, indicating that the GH/IGF-1 signalling is impaired. Taken this into account a accurate diagnostic approach of the GH/IGF-1 axis is mandatory including a IGF-1 generation test before long term treatment either with GH or IGF-1 is justified in humans.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Diagnostic

Conditions

Ataxia Telangiectasia

Intervention

Somatropin, Clonidine, L-Arginin-Hydrochloride, Estradiol valerate

Location

Children's Hospital, Goethe-University
Frankfurt am Main
Germany
60590

Status

Recruiting

Source

Johann Wolfgang Goethe University Hospitals

Results (where available)

View Results

Links

Published on BioPortfolio: 2014-08-27T03:16:32-0400

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An autosomal recessive inherited disorder characterized by choreoathetosis beginning in childhood, progressive CEREBELLAR ATAXIA; TELANGIECTASIS of CONJUNCTIVA and SKIN; DYSARTHRIA; B- and T-cell immunodeficiency, and RADIOSENSITIVITY to IONIZING RADIATION. Affected individuals are prone to recurrent sinobronchopulmonary infections, lymphoreticular neoplasms, and other malignancies. Serum ALPHA-FETOPROTEINS are usually elevated. (Menkes, Textbook of Child Neurology, 5th ed, p688) The gene for this disorder (ATM) encodes a cell cycle checkpoint protein kinase and has been mapped to chromosome 11 (11q22-q23).

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