Fig. 7.20 ). A set of genes on the maternal chromosome at 15q12 is imprinted (and hence silenced), so the paternal chromosome provides the only functional alleles. When these are lost as a result of a deletion (in the paternal chromosome), the patient develops Prader-Willi syndrome. Among the set of genes that are deleted in Prader-Willi syndrome, the most likely culprit is believed to be a gene cluster encoding multiple distinct small nucleolar RNAs (snoRNAs), which are involved in messenger RNA processing. Conversely, a distinct gene, UBE3A, that also maps to the same region of chromosome 15 isimprinted on thepaternalchromosome. UBE3A encodes for a ubiquitin ligase, a family of enzymes that targets other cellular proteins for proteasomal degradation (Chapter 1) through the addition of ubiquitin moieties. Only the maternally derived allele of the gene normally is active. Deletion of this maternal gene on chromosome 15 gives rise to the Angelman syndrome. The neurologic manifestations of Angelman are principally because of a lack of UBE3A expression in specific regions of the brain.
Molecular studies of cytogenetically normal patients with Prader-Willi syndrome have shown that in some cases, both of the structurally normal copies of chromosome 15 are derived from the mother. Inheritance of both chromosomes of a pair from one parent is called uniparental disomy. The net effect is the same (i.e., the patient does not have a functional set of genes from the [nonimprinted] paternal chromosome 15). Angelman syndrome, as might be expected, also can result from uniparental disomy of paternal chromosome 15.
Site of deletion
Site of deletion Imprinted Angelman Active Angelman gene gene
Fig. 7.20 GeneticsofAngelmanandPrader-Willisyndromes.
http://ebooksmedicine.net •Imprintinginvolvestranscriptionalsilencingofthepaternalormaternalcopiesofcertaingenesduringgametogenesis.Forsuchgenesonlyonefunctionalcopyexistsintheindividual.Lossofthefunctionalallele(notimprinted)bydeletionsgivesrisetodiseases.
As mentioned earlier and as illustrated by several examples, many diseases of infancy and childhood are of genetic origin. Others, although not genetic, either are unique to children or take distinctive forms in this patient population and thus merit the designation pediatric diseases. During each stage of development, infants and children are prey to a somewhat different group of diseases (
Table 7.5 ). Clearly, diseases of infancy (i.e., in the first year of life) pose the highest risk of death. During this phase, the neonatal period (the first 4 weeks of life) is unquestionably the most hazardous time.
After the infant survives the first year of life, the outlook brightens considerably. However, it is sobering to note that between 1 year and 14 years of age, injuries resulting from accidents are the leading cause of death. Not all conditions listed in
Table 7.5 are described in this chapter; only a select few that are most common are considered here. Although general principles of neoplastic disease and specific tumors are discussed elsewhere, a few tumors of children are described, to highlight the differences between pediatric and adult neoplasms.
Table 7.5 Causes of Death by Age
Prader-Willisyndromeresultsfromdeletionofpaternalchromosomalregion15q12andischaracterizedbymentalretardation,shortstature,hypotonia,obesity,andhypogonadism.
Angelmansyndromeresultsfromdeletionofmaternalchromosomalregion15q12andischaracterizedbymentalretardation,ataxia,seizures,andinappropriatelaughter.