Pubertal origin of growth retardation in inborn errors of protein metabolism: A longitudinal cohort study.

Inherited amino-acid metabolism disorders (IAAMDs) require lifelong protein-restricted diet. We aimed to investigate: 1/ whether IAAMDs was associated with growth, pubertal, bone mineral apparent density (BMAD) or body composition impairments; 2/ associations linking height, amino-acid mixture (AAM), plasma amino-acids and IGF1 concentrations. Retrospective longitudinal study of 213 patients with neonatal-onset urea cycle disorders (UCD, n = 77), organic aciduria (OA, n = 89), maple syrup urine disease (MSUD, n = 34), or tyrosinaemia type 1 (n = 13). We collected growth parameters, pubertal status, BMAD, body composition, protein-intake, and IGF1 throughout growth. Overall final height (n = 69) was below target height (TH): −0.9(1.4) vs. -0.1(0.9) SD, p < 0.001. Final height was ≤ TH-2SD in 12 (21%) patients. Height ≤ − 2SD was more frequent during puberty than during early-infancy and pre-puberty: 23.5% vs. 6.9%, p = 0.002; and vs. 10.7%, p < 0.001. Pubertal delay was frequent (26.7%). Height (SD) was positively associated with isoleucine concentration: β, 0.008; 95%CI, 0.003 to 0.012; p = 0.001. In the pubertal subgroup, height (SD) was lower in patients with vs. without AAM supplementation: −1.22 (1.40) vs. -0.63 (1.46) (p = 0.02). In OA, height and median (IQR) isoleucine and valine concentrations(μmol/L) during puberty were lower in patients with vs. without AAM supplementation: −1.75 (1.30) vs. −0.33 (1.55) SD, p < 0.001; and 40 (23) vs. 60 (25) (p = 0.02) and 138 (92) vs. 191 (63) (p = 0.01), respectively. No correlation was found with IGF1. Lean-mass index was lower than fat-mass index: −2.03 (1.15) vs. -0.44 (0.89), p < 0.001. In IAAMDs, growth retardation worsened during puberty which was delayed in all disease subgroups. Height seems linked to the disease, AAM composition and lower isoleucine concentration, independently of the GH-IGF1 pathway. We recommend close monitoring of diet during puberty. • Growth and final height are impaired in inborn errors of protein metabolism with protein-restricted diet, notably in male. • Growth retardation worsened during puberty with no subsequent catch-up gains. • Delayed puberty is noted in a quarter of patients and was more common in males. • Dietary proteins are associated with growth retardation. Their composition differed according to aetiologies and age group. [ABSTRACT FROM AUTHOR]