Characterization of Four Latin-American Families Confirms Previous Findings and Reveals Novel Features of ALS Deficiency

BRASLAVSKY, DEBORA; SCAGLIA, PAULA; DOMENE SABINA; MARTUCCI, LUCIA; ROPELATO, MARIA GABRIELA; GUTIERREZ, MARIANA; SAITO TARTUCI, J; SPINOLA-CASTRO, ANGELA MARIA; JASPER, HECTOR; RODRIGUEZ AZRAK, SOL; BERGADA, IGNACIO; KESELMAN, ANA; KARABATAS, LILIANA; BALLERINI, MARIA GABRIELA; SIVIERO-MIACHON, A; REY, RODOLFO; DOMENE, HORACIO

Buenos Aires

Congreso; XXVI Congreso de la Sociedad Latinoamericana de Endocrinología Pediátrica; 2016

Sociedad Latinoamericana de Endocrinología Pediátrica

Introduction: ALS deficiency (ALS-D), caused by inactivating mutations in both IGFALS gene alleles, is characterized by diminished levels of IGF-I and IGFBP-3 associated to mild growth retardation. The aim of this study was to evaluate the impact on growth and on the IGF system of seven different IGFALS gene variants detected in four families. Functional in vitro characterization was also performed.Subjects and Methods: We have diagnosed complete ALS-D in 4 subjects from Latino America, (3 boys), aged 2.4 to 13.8 years, presenting either short (-2.65 and -3.01 SDS) or normal height (-1.28 and -1.67 SDS). Auxological data, biochemical and genetic studies were also extended to all available relatives. Measurements included: basal levels of IGF-I, IGFBP-3 and ALS, IGF generation test in the index cases, serum Western and ligand immunoblot and in vitro ternary complex formation (ivTCF). The IGFALS gene was completely sequenced and the variants found were functionally characterized in vitro.Results: Four index cases and four relatives were diagnosed as ALS-D (3 homozygous, 5 compound heterozygous), 14 relatives as heterozygous carriers and 3 as homozygous wild type. The following variants were found: p.E35Gfs*17, p.E35Kfs*87, p.L213F, p.N276S, p.L409F, p.A475V and p.S490W. Except one, ALS-D patients presented low IGF-I, undetectable levels of IGFBP-3 and ALS, and did not normalize IGF-I levels in the IGF generation test. Seven out of 8 patients did not form ivTCF. Functional studies revealed that variants p.E35Gfs*17, p.E35Kfs*87, p.N276S, p.L409F and p.S490W were not expressed, while p.L213F was synthetized but not secreted and p.A475V was normally synthetized and secreted, albeit at lower levels.Conclusion: This study confirms that despite the severe effect on the circulating IGF system, ALS-D has a mild effect on height. The diagnosis of 2 adults with ALS-D suggests that this condition is underdiagnosed in childhood. In addition, we have found a father and son affected with ALS-D, evidence of preserved fertility, a variable response of IGF-I to IGF generation test and, the first case of a compound heterozygous patient retaining some marginal expression of ALS. In vitro expression studies were useful to classify the IGFALS variants as pathogenic or benign.