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

SCAGLIA, P.A.; KESELMAN, A.; BRASLAVSKY, D.; MARTUCCI, L.; KARABATAS, L.; DOMENÉ, S.; GUTIÉRREZ, M.; BALLERINI, M.G.; ROPELATO, M.G.; SPINOLA-CASTRO, A.; SIVIERO-MIACHON, A.; SAITO TARTUCI, J.; RODRÍGUEZ AZRAK, S.; REY, R.A.; JASPER, H.; BERGADÁ, I.; DOMENÉ, H.

Buenos Aires

Congreso; XXVI Reunion Anual de la Sociedad Latinoamericana de Endocrinología Pediatrica; 2016

Introduction: ALS deficiency (ALS-D), caused by inactivatingmutations in both IGFALS gene alleles, is characterized by diminishedlevels of IGF-I and IGFBP-3 associated to mild growth retardation.The aim of this study was to evaluate the impact on growthand on the IGF system of seven different IGFALS gene variantsdetected in four families. Functional in vitro characterization wasalso performed.Subjects and Methods: We have diagnosed complete ALS-Din 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 geneticstudies were also extended to all available relatives. Measurementsincluded: basal levels of IGF-I, IGFBP-3 and ALS, IGF generationtest in the index cases, serum Western and ligand immunoblot andin vitro ternary complex formation (ivTCF). The IGFALS gene wascompletely sequenced and the variants found were functionallycharacterized in vitro.Results: Four index cases and four relatives were diagnosed asALS-D (3 homozygous, 5 compound heterozygous), 14 relatives asheterozygous carriers and 3 as homozygous wild type. The followingvariants were found: p.E35Gfs􀈗17, p.E35Kfs􀈗87, p.L213F,p.N276S, p.L409F, p.A475V and p.S490W. Except one, ALS-D patientspresented low IGF-I, undetectable levels of IGFBP-3 andALS, and did not normalize IGF-I levels in the IGF generation test.Seven out of 8 patients did not form ivTCF. Functional studies revealedthat variants p.E35Gfs􀈗17, p.E35Kfs􀈗87, p.N276S, p.L409Fand p.S490W were not expressed, while p.L213F was synthetizedbut not secreted and p.A475V was normally synthetized and secreted,albeit at lower levels.Conclusion: This study confirms that despite the severe effecton the circulating IGF system, ALS-D has a mild effect on height.The diagnosis of 2 adults with ALS-D suggests that this conditionis underdiagnosed in childhood. In addition, we have found a fatherand son affected with ALS-D, evidence of preserved fertility,a variable response of IGF-I to IGF generation test and, the firstcase of a compound heterozygous patient retaining some marginalexpression of ALS. In vitro expression studies were useful toclassify the IGFALS variants as pathogenic or benign.