Chromosomal Disorders and Disorders of DNA
Marc C. Patterson
INTRODUCTION
Rearrangements of the human genome, ranging from grossly disordered chromosome number to submicroscopic variations in copy numbers can profoundly affect development and function of the nervous system. Likewise, defects in the machinery that maintain the integrity and duplication fidelity of DNA lead to a family of rare disorders characterized by varying combinations of neurodegeneration, premature aging, immunodeficiency, and susceptibility to malignancy.
CHROMOSOMAL DISORDERS
Human chromosomal anomalies are manifested as change in the total number of chromosomes, structural rearrangements, imprinting abnormalities, or variations in copy number. Examples of abnormal chromosome number (i.e., aneuploidy) are sex-chromosomal aneuploidy, such as 45,X (Turner syndrome), and autosomal aneuploidy, such as 47,XX × 21 (trisomy 21, Down syndrome). Structural abnormalities include regional deletions or insertions, segmental translocations (i.e., reciprocal or Robertsonian) or inversions (i.e., pericentric or paracentric), duplications, and ring chromosomes. There are many chromosomal syndromes, which result primarily from these numeric or segmental anomalies, producing a functional change of gene dosage; gene imprinting is also recognized as a critical modifier of expression. The most common manifestation of chromosomal anomalies is intellectual disability. Congenital malformations occur with variable frequency and differences in severity. In the sex-chromosome disorders, infertility is the most common feature. Table 135.1 summarizes the features of several classic chromosome disorders as examples: trisomy 21 syndrome, Prader-Willi syndrome (PWS), Angelman syndrome (AS), and a common idiopathic intellectual disability syndrome caused by subtelomeric anomalies of chromosomes. A variety of mechanisms underlie these disorders. Trisomy 21 results from chromosomal nondisjunction (maternal 80%, paternal 20%), an age-related phenomenon in most cases, and unbalanced translocation in the remainder. PWS and AS result from loss of paternally or maternally imprinted alleles in the same chromosomal region (15 q11-13); such loss may reflect abnormal imprinting (methylation— see the following section), chromosomal deletion, translocation or inversion, or point mutations in a specific gene (UBE3A for AS). CATCH-22 is a deletion syndrome—the manifestations are at least in part a reflection of the amount of genetic material that is lost.
GENOMIC IMPRINTING
Genomic imprinting is an epigenetic phenomenon that permits nonmendelian inheritance in the mammalian genome. Several autosomal genes are inherited, in a silent state, on one parental allele and in an active state on the other parental allele. This parentof-origin-specific gene expression is called genomic imprinting. The diseases that arise from these genes are mostly caused by mutation of the active allele, duplication of the nonactive allele, or imprinting errors resulting in silencing of the active allele. Over 20 imprinted genes have now been identified in the mouse genome; many of them have human homologs. For example, the IGF-2 gene is paternally active, and only when the gene defect is inherited from the father do the offspring express the dwarfing phenotype. In PWS and AS, deletions in the PWS critical region on the paternal chromosome, or maternal uniparental disomy, result in silencing the paternally active allele and the PWS phenotype, whereas deletion of the AS critical region on the maternal chromosome, or paternal uniparental disomy, results in the silencing of the maternal allele and the AS phenotype.
The molecular mechanism of genomic imprinting is incompletely understood. The isolation of a cis-acting imprinting center, located upstream to the promotor region of the SNRPN gene, has helped us understand the molecular basis of genomic imprinting. Deletions or mutations in this imprinting center have been shown to associate with PWS or AS, depending on the origin of parental germ lines. It is postulated that the imprinting center confers a male or female imprint by use of an imprinting switch during gametogenesis. In the female germ line, the imprinting switch is needed to reset the male chromosome from the maternal grandfather to confer the characteristics of a female chromosome. In the male germ line, the same process is needed to reset the female chromosome from the paternal grandmother to confer the characteristics of a male chromosome. This epigenetic mark is thought to be achieved by DNA methylation. In the case of PWS, the inactive allele on the maternal chromosome is hypermethylated, which suppresses gene transcription. The hypermethylated cytosine residues on the DNA sequences may repel the transcription factors needed for the activation of gene transcription. In other imprinted genes such as the IGF-2 receptor, DNA methylation is associated with the active allele on the maternal chromosome. Therefore, other factors in addition to DNA methylation may be involved in genomic imprinting.
AUTISM SPECTRUM DISORDER AND GENOMIC IMPRINTING
Autism is a neurodevelopmental disorder characterized by language and social impairments and prominent repetitive, stereotypic behaviors (see also Chapter 138). Interstitial duplication of maternal chromosome 15q11-13 region is one of the more common chromosomal anomalies in autism. Clinically, there are some phenotypic overlaps between autism spectrum disorders (ASDs) and PWS. Interestingly, among the children with PWS, those who express two maternally imprinted alleles are twice more likely to have ASD than those with PWS caused by deletion of paternally imprinted alleles. The identification of mutations in the methyl CpG-binding protein 2 (MeCP2) gene as the major cause of Rett syndrome suggested that DNA methylation (and hence genomic imprinting) may play important roles in other neurodevelopmental disorders.
TABLE 135.1 Common Chromosomal Disorders | ||||||||||||||||||
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Subtle chromosomal anomalies such as subtelomeric and submicroscopic deletion or duplication frequently give rise to neurologic phenotypes, without necessarily causing somatic manifestations. Techniques using subtelomeric probes led the way in improving cytogenetic diagnosis but have been largely supplanted by array comparative genomic hybridization (CGH) in the investigation of idiopathic intellectual disability and cancers.
INTELLECTUAL DISABILITY ASSOCIATED WITH SUBTELOMERIC CHROMOSOMAL DELETION
Telomeres are the chromosome ends that contain complex DNA protein structures. The DNA sequence is a repetitivehexanucleotide motif, TTAGGG, ranging from 2 to 15 kb in length. This repetitive sequence and its specific DNA-binding proteins form a cap structure at the chromosome ends. This cap structure enables cells to distinguish chromosome ends, prevents fusion or degradation of chromosomes, and facilitates chromosomal segregations during cellular divisions. A reverse transcriptase named telomerase recognizes this terminal repetitive DNA sequence and works to maintain the chromosomal integrity by adding telomeric DNA onto chromosome ends, when a lagging strand is created during replication. Anomalies of these DNA protein structures change the chromosomal length. Shortening of telomeric length is seen in normal aging of somatic cells, whereas unchecked telomerase activation results in chromosomal fusion, as is often seen in cancer cells. Intellectual disability is a common developmental disorder. The etiology of about 30% to 40% of moderate to severe intellectual disability (IQ <50) remains unknown, despite extensive diagnostic testing. These patients have a normal karyotype using routine- or high-resolution chromosomal-banding techniques.
Since the early 1990s, researchers have developed DNA probes to detect subtle subtelomeric chromosomal anomalies in humans. At least 5% of children with idiopathic intellectual disability harbor subtelomeric chromosomal rearrangements, detected by a set of subtelomeric probes in different fluorescent in situ hybridization (FISH) studies. These rearrangements include subtelomeric deletions, duplications, or derivative chromosomes resulting in partial monosomy-trisomy states. The positive detection rate increases when screening criteria include severe intellectual disability, positive family history of intellectual disability, and at least one physical dysmorphism. These results suggest that subtelomeric FISH study remains a useful tool for identifying the etiology of the disorders of patients with idiopathic intellectual disability. More recently, single nucleotide polymorphism (SNP) arrays have been recommended as an efficient screening test in populations
with intellectual disability, with a diagnostic yield greater than 10% in one study.
with intellectual disability, with a diagnostic yield greater than 10% in one study.
IDENTIFICATION OF DNA COPY NUMBER VARIATIONS BY ARRAY COMPARATIVE GENOMIC HYBRIDIZATION
Chromosomal disorders arising from segmental deletion or duplication contribute to variations of copy numbers of DNA fragments. These fragments are often not visualized by current high-resolution chromosomal banding. This submicroscopic genomic copy number variation is thought to be the most common cause of idiopathic developmental delay, including intellectual disability. Recent advances in high-throughput microarray technology, coupled with sophisticated data analysis, have allowed rapid and accurate detection of these submicroscopic genomic copy number variations. In CGH, the patient’s DNA is hybridized to arrayed genomic DNA targets (genomic clones or oligonucleotides) on a glass slide or gene chip. The signal intensities of each hybridized genomic target are compared with those of the control standards (or the parents). Variation of copy numbers can be readily detected. This new genetic diagnostic tool has led to the identification of an ever-growing family of novel microdeletion syndromes. The repetitive observation of microscopic chromosomal anomalies and their correlation with certain clinical phenotypes is likely to identify the genetic causes of many idiopathic neurodevelopmental disorders whose cause is currently unknown. Investigators have reported relatively high yields of CGH in cohorts with intellectual disability and autism in both children and adults.
DISORDERS OF DNA MAINTENANCE, TRANSCRIPTION, AND TRANSLATION
Except for components of the respiratory chain encoded by DNA, the DNA of the nucleus is responsible for the production of the molecules essential to the cellular economy. Disorders that impair the maintenance of the integrity of DNA, or its timely and accurate transcription and translation, frequently lead to neurodegeneration, impaired growth, premature aging, and a propensity to develop malignancies. The brain is particularly vulnerable to these disorders because cerebral neurons are, for practical purposes, irreplaceable and their high metabolic rate mandates high levels of oxygen consumption; both of these factors render the CNS more susceptible to damage by reactive oxygen species and other metabolites than less richly endowed tissues.
This section provides an introduction to the processes involved and the rare diseases resulting from derangement of these controls. It is likely that the number of these disorders will continue to grow in parallel with the relevant basic science. Neurologists in the 21st century must have a firm grasp of the essential principles to diagnose and manage people with these diseases.
DNA MAINTENANCE AND TRANSCRIPTION
DNA is subject to errors in its duplication during cell division and during the process of repair following exposure to a variety of mutagens (environmental, toxic, and therapeutic). The elaborate machinery includes helicases that unwind the strands of DNA in preparation for transcription into RNA, RNA polymerase, which directs the formation of mRNA on the DNA template, and DNA polymerase, which catalyses the duplication of DNA. The process is fine-tuned by a large family of transcription factors; investigators are constantly adding to their number. This process is highly dependent on sites of replication origin, which change during development and in the face of disease.
A complex system has evolved to correct errors in nucleic acid duplication. When single bases are incorrectly inserted into the new DNA molecules, they are removed by the process of base excision repair, mediated by specific DNA glycosylases and endonucleases and DNA polymerases and ligases. Longer segments of 25 to 32 bases are frequently damaged by exposure to ultraviolet radiation and are removed by nucleotide excision repair, which requires its own family of proteins. Breaks of double-stranded DNA activate a mechanism that requires the participation of DNA protein kinase and recombination proteins. The processes are even more complex than is implied by this brief overview, because many of the involved proteins play multiple, mutually modifying roles in repair and transcription.
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