Human ALS deficiency: clinical, endocrine and metabolic consequences

HORACIO DOMENÉ

New York

Congreso; LWPES/ESPE 8th Joint Meeting Paediatric Endocrinology in collaboration with APEG, APPES, JSPE and SLEP; 2009

LWPES/ES¨PE

PL3-02 Plenary IIIPlenary III Human ALS deficiency: clinical, endocrine and metabolic consequences Horacio M Domené1Horacio M Domené1 1Centro de Investigaciones Endocrinológicas (CEDIE-CONICET), Hospital de Niños R. Gutiérrez, Buenos Aires, ArgentinaCentro de Investigaciones Endocrinológicas (CEDIE-CONICET), Hospital de Niños R. Gutiérrez, Buenos Aires, Argentina The majority of IGF-I (and IGF-II) circulates in the serum as a complex with IGFBP-3 or IGFBP-5, and an acid labile subunit (ALS). The well-established function of ALS is to prolong the half-life of the IGFs-IGFBP-3/IGFBP-5 binary complexes. From the description of the first case of ALS deficiency, the number of mutations identified in the IGFALS gene has rapidly increased, suggesting that ALS deficiency may be prevalent in a subset of patients with extraordinarily low serum levels of IGF-I and IGFBP-3 that remain abnormally low upon GH stimulation. Fourteen different mutations of the human IGFALS gene have been identified in the seventeen patients identified to date. Eleven patients were found to be homozygous and six were compound heterozygous. The mutations showed an autosomal recessive pattern of inheritance. Postnatal growth was clearly affected. Commonly, height SDS before puberty was between -2 and -3, and were approximately 1.4 SD shorter than the midparental height SDS. Adult height SDS was higher than prepubertal height, but still 1.0 SD lower than the midparental height SDS. Pubertal delay was found in 50% of the male patients, while in the remaining, puberty started relatively late. Human ALS deficiency results in a peculiar IGF-I deficiency. Whereas circulating levels of IGF-I decrease dramatically, local production appears to be preserved. In addition to IGF-I other members of the circulating IGF system are also affected. Circulating IGF-II, IGFBP-1, -2, and -3 levels were all reduced, with the greatest reduction observed for IGFBP-3. Insulin resistance, characterized by normal glucose levels, hyperinsulinemia and low levels of IGFBP-1, was a common finding. In addition, some patients presented low bone mineral density (BMD). The pathophysiological mechanisms explaining these findings are still only partially understood. In summary, human ALS deficiency, the first monogenic defect involving an insulin-like growth factor binding protein, represents a unique condition in which the lack of ALS protein results in the disruption of the entire IGF circulating system. Despite a profound circulating IGF-I deficiency, there is only a mild impact on postnatal growth. Perhaps, the preserved expression of locally produced IGF-I under the stimulation of normal or even increased GH levels, might be responsible for the preservation of linear growth near or within normal limits.IGFALS gene has rapidly increased, suggesting that ALS deficiency may be prevalent in a subset of patients with extraordinarily low serum levels of IGF-I and IGFBP-3 that remain abnormally low upon GH stimulation. Fourteen different mutations of the human IGFALS gene have been identified in the seventeen patients identified to date. Eleven patients were found to be homozygous and six were compound heterozygous. The mutations showed an autosomal recessive pattern of inheritance. Postnatal growth was clearly affected. Commonly, height SDS before puberty was between -2 and -3, and were approximately 1.4 SD shorter than the midparental height SDS. Adult height SDS was higher than prepubertal height, but still 1.0 SD lower than the midparental height SDS. Pubertal delay was found in 50% of the male patients, while in the remaining, puberty started relatively late. Human ALS deficiency results in a peculiar IGF-I deficiency. Whereas circulating levels of IGF-I decrease dramatically, local production appears to be preserved. In addition to IGF-I other members of the circulating IGF system are also affected. Circulating IGF-II, IGFBP-1, -2, and -3 levels were all reduced, with the greatest reduction observed for IGFBP-3. Insulin resistance, characterized by normal glucose levels, hyperinsulinemia and low levels of IGFBP-1, was a common finding. In addition, some patients presented low bone mineral density (BMD). The pathophysiological mechanisms explaining these findings are still only partially understood. In summary, human ALS deficiency, the first monogenic defect involving an insulin-like growth factor binding protein, represents a unique condition in which the lack of ALS protein results in the disruption of the entire IGF circulating system. Despite a profound circulating IGF-I deficiency, there is only a mild impact on postnatal growth. Perhaps, the preserved expression of locally produced IGF-I under the stimulation of normal or even increased GH levels, might be responsible for the preservation of linear growth near or within normal limits.