Bone mass in Rett syndrome: association with clinical parameters and MECP2 mutations

Abstract

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the MECP2 gene. In 49 female RTT children, aged 1.9-17 y, bone mass was assessed and correlated with clinical parameters and mutations involving the MECP2 gene. We also studied five adult females, aged 20-33 y, and one male child, aged 6 y. Lumbar spine bone mineral content (BMC) and bone mineral density (BMD) were correlated with weight, height, BMI, clinical severity, degree of scoliosis, use of anticonvulsants, and ambulatory status. L1-L4 BMD and BMC showed that 48.9% of them had BMD values >2 SD below age-related norms. BMD values were in the osteoporotic range in the five adult females with RTT. Eleven percent of the children and adults with RTT experienced fractures. Low bone mass was correlated with marginal significance to clinical severity and ambulation but not to scoliosis or anticonvulsant use. Lowest bone mass occurred in patients with T158M or R270X mutations but without statistical significance. Studies in a murine model of RTT confirmed low bone mass as an inherent component of this syndrome. MECP2 mutations and clinical parameters impact bone mass in RTT, but an association with a specific mutation was not demonstrable.

Figure 1

(A) DXA L1-L4 BMC values compared to age related normal. The 10 th, 50 th and 90 th percentiles for normal females are illustrated. The hollow circle shows BMC for the 6 year old RTT male. (B)Bone mineral content (BMC) is plotted against age, ages 2 to 16 years. There is a linear relationship with a correlation coefficient of r =0.617.

Figure 2

(A) DXA L1-L4 BMD results plotted on the Hologic 4500 database. The chart shows mean values ± 2 standard deviations.(B) Bone mineral density (BMD) is plotted against age, 2 to 14 years. There is a linear relationship with a correlation coefficient of r= 0.651.

Figure 3

DXA values for L1–L4 plotted against the Hologic 4500 data base for 5 females with RTT syndrome. The chart shows mean values + or − 2 standard deviations.

Figure 4

(A): L1–L4 BMC, and (S): BMD is shown for individual MeCP2 mutations. The bars represent the range ± 2 standard deviations for lumbar spine BMD. The differences in BMC and BMD were not statistically different for any mutation.

Figure 5

Trendlines relating age- associated effects of ambulation (green) vs. non ambulation (red) on Lumbar Spine (LS) BMC (g) in RTT. This illustrates the differences between these groups as well as the trend for increasing BMD (g/cm² ) with age (years).

Figure 6

Radiographs of 7 week old mice. Wild type and male null (knock-out mouse) illustrating differences in cortical thickness, mineralization of the medullary cavity in long bones and spine bone density.