Aneuploidy and Skeletal Health

Abstract

The normal human chromosome complement consists of 46 chromosomes comprising 22 morphologically different pairs of autosomes and one pair of sex chromosomes. Variations in either chromosome number and/or structure frequently result in significant mental impairment, and/or a variety of other clinical problems, among them, altered bone mass and strength. Chromosomal syndromes associated with specific chromosomal abnormalities are classified as either numerical or structural and may involve more than one chromosome. Aneuploidy refers to the presence of an extra copy of a specific chromosome, or trisomy, as seen in Down’s syndrome (trisomy 21), or the absence of a single chromosome, or monosomy, as seen in Turner syndrome (a single X chromosome in females: 45, X). Aneuploidies have diverse phenotypic consequences, ranging from severe mental retardation and developmental abnormalities to increased susceptibility to various neoplasms and premature death. In fact, trisomy 21 is the prototypical aneuploidy in humans, is the most common genetic abnormality associated with longevity and is one of the most widespread genetic causes of intellectual disability. In this review, the impact of trisomy 21 on the bone mass, architecture, skeletal health and quality of life of people with Down syndrome will be discussed.

Sclerostin Antibody Treatment Stimulates Bone Formation to Normalize Bone Mass in Male Down Syndrome Mice

“…At present, there are no medical treatments for the low bone mass in DS approved by the US Food and Drug Administration. Therefore, low BMD in DS is currently managed by a combination of calcium and vitamin D supplements, physiotherapy, nutritional effects, exercise, and off‐label (and contraindicated) oral bisphosphonate use . Thus, there is an urgent need for alternative treatments to increase bone mass and strength in this vulnerable population.…”

“…In particular, it was noted that cardiac ischemic events and cerebrovascular events were likely driving this imbalance, although further evaluation is needed to determine the cause . This may be an important finding in the context of DS, with a minority of DS individuals having congenital heart malformations . In the event of the clinical use of SclAb in DS, close attention to potential cardiac events would certainly need to be addressed, as would further investigation of the function of sclerostin in the vasculature.…”

“…Down syndrome (DS), the trisomy of human chromosome (Hsa) 21, is the most common symptomatic chromosomal abnormality compatible with survival into adulthood . The likelihood of trisomy 21 is strongly associated with maternal age, although chromosomal copy of trisomy 21 can originate maternally or paternally.…”

Skeletal Deficits in Male and Female down Syndrome Model Mice Arise Independent of Normalized Dyrk1a Expression in Osteoblasts

“…Further investigations of bone phenotypes in humans with DS measured biochemical markers, which revealed that P1NP (marker of bone formation) was reduced in DS without significant differences in CTx (marker of bone resorption) [21]. Low bone mass and BMD phenotypes have been attributed to decreased bone turnover, with an imbalance between bone formation and resorption seen in both humans with DS and DS model mice [21,25,28,32].…”

Spina bifida-predisposing heterozygous mutations in Planar Cell Polarity genes and Zic2 reduce bone mass in young mice

“…Progress has been made in delineating the genetic and pathophysiological basis of osteoporosis-related fragility fractures in the elderly 4 , 5 , whereas fractures during childhood have been less intensively studied. A number of genetic conditions presenting in childhood with primary skeletal disorders, such as osteogenesis imperfecta associated with mutations in the Wingless homology (Wnt) ligand Wnt1 6 , are now recognised, while multigenic disorders such as Down’s syndrome are also directly associated with skeletal effects 7 .…”