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Chromosomal Disorders: Background and Neuroradiology

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Chromosomal Disorders: Background and Neuroradiology Chromosomal Disorders: Background and Neuroradiology Ashok J. Kumar, 1 Thomas P. Naidich, Gail Stetten, Allan L. Reiss, Henry Wang, George H. Thomas, and OrestHurko From the Division of Neuroradiology (AJK, HW), Departments of Neurology (OH), Psychiatry (ALR), and Gynecology and Obstetrics (GS), The Johns Hopkins University School of Medicine; and the Kennedy Institutes, Baltimore, MD (GHT) and Baptist Hospital (TPN), Miami, FL Chromosomal aberrations, and their associated malities can be detected by neuroimaging. 2) syndromes of dysmorphism and malformations Most of the clinical syndromes associated with of multiple organ systems, have been long rec­ chromosomal abnormalities are notoriously vari­ ognized as significant causes of severe mental able, requiring individual assessment of each pa­ impairment. With a few major exceptions, these tient. Incompletely overlapping partial aneu­ clinical syndromes have only recently been cat­ ploidies, for example, give rise to broadly similar alogued as systematically ( 1, 2) as have been syndromes, but slight differences in their extent single-gene disorders. The neuropathologic fea­ may considerably alter the resultant phenotype. tures of many of these syndromes have been Neuroimaging can help to characterize the asso­ characterized only broadly, if at all. Not surpris­ ciated CNS pathology and facilitate proper man­ ingly, there is no detailed compendium of the agement of the patient. neuroradiologic features of the malformations of It is our purpose to introduce the chromosomal the central nervous system (CNS) associated with disorders to the general neuroradiologist by con­ various chromosomal aberrations. centrating on basic concepts and by giving spe­ Certain chromosomal aberrations, such as tri­ cific illustrations of some of the more commonly somy 21 and the associated Down syndrome, are encountered syndromes. Limitations of space and encountered with sufficient frequency to permit of current knowledge preclude an encyclopedic systematic study of their effects on the CNS. treatment. These studies show that disruption of the nervous system is nearly a universal feature of these syndromes, particularly those involving auto­ Genes and Chromosome Structure somes. Neuroradiologic investigations of these The fundamental unit of inheritance is the conditions are becoming increasingly important gene, a linear array of DNA consisting of exon in their characterization for two reasons: 1) In sequences encoding the structure of a single some cases, admittedly few, CNS effects are protein, noncoding intron sequences interspersed mediated in part by surgically remediable struc­ between the exons, and regulatory regions both tural abnormalities, such as hydrocephalus or upstream and downstream (3). It is estimated that atlantoaxial instability. These structural abnor- the human genetic complement consists of 100,000 such genes, as well as other DNA se­ quences, some encoding transfer and ribosomal Supported in part by NICHD Mental Retardation Center Core Grant RNA, others with no known coding function. In HD 24061 and Program Project Grant, "Mapping the Chromosomes of Man." humans, these genes are arranged like beads on 1 Address reprint requests to Dr Kumar, Division of Neuroradiology, 23 pairs of string-like chromosomes, in a char­ Johns Hopkins Hospital, 600 N. Wolfe St. , Baltimore, MD 21205. acteristic order. Each chromosome is composed Index terms: Chromosomes, abnormalities and anomalies; Trisom y syn­ of a continuous DNA double helix, as well as dromes; Pediatric neuroradiology associated histone and nonhistone (acidic) pro­ AJNR 13:577-593, Mar/ Apr 1992 0195-6108/ 92/ 1302-0577 teins. Of these 23 chromosome pairs, 22 pairs © American Society of Neuroradiology are autosomes that are represented equally in 577 578 AJNR: 13, March/ April 1992 Kusick's Mendelian inheritance in man (4). As of ' ) this writing, this continuously updated catalogue \ 'b II I )~ ll contains over 5000 entries. ~.. ~.. .lp » )r Many human disorders-such as schizophre­ ... 5 1 2 3 [f nia, hypertension, and diabetes-are thought to be polygenic, resulting from the summed effects ~, ~~ :, !~ fl,(t •• j : • of multiple genes dispersed widely on different .... ~ \i )~ ~l if'" -·a . ·' u chromosomes. Our understanding of such disor­ X 10 11. 1 2 ders in humans remains quite sketchy, although . i (\ .. i ~ there is a well developed theory of such Galtonian g ., ..,~ §~ t n ."" :i . , transmission, that has been applied successfully 18 19 20 1 3 14 15 16 17 by plant and animal breeders (5). ~ . ~~ Chromosomal disorders, the topic of this pa­ ••2 1 22 per, are defined by the presence of microscopi­ A cally visible alterations in the number or structure of chromosomes. These diseases appear to result ~J »~ «8 ~0 no from the overrepresentation or underrepresenta­ 4 5 tion of hundreds or thousands of contiguous I 1 2 3 I A B genes. A useful compendium of these disorders is to be found in Schinzel's Catalogue of unbal­ 8 KH X3 ~K U& iii iiX ~~ anced chromosome aberrations in man ( 1). x- -6----- 7------8 ----- 9-----10- ----11 -----12 I c Diagnosis of Chromosomal Disorders 6h 6/Hul XX iHi X~ It~ XI{ 13 --14 --15 16 17---18 I 19--20 Microscopic examination of the chromosomes D E F is called karyotype analysis. Karyotype analysis ,..,.,. can only detect gross structural alterations in­ I •y 21 --22 G volving long stretches of chromosomes contain­ ing hundreds to thousands of genes. Karyotype 8 analysis is not generally applicable to Mendelian Fig. 1. Normal karyotypes. A, A normal female karyotype (46, or polygenic disorders, but it is useful to define XX) . B, A normal male karyotype (46, XY) . the grosser chromosomal disorders. Karyotype analysis is performed clinically on preparations of chromosomes from peripheral blood lympho­ both sexes, and one pair is the sex chromosomes, cytes or fibroblasts that have been arrested in the XX for the female (Fig. 1A) and XY for the male metaphase stage of the cell cycle. Such analysis (Fig. 18). A normal count of 23 pairs, ie, 46 can be performed on cells from amniotic fluid or chromosomes total, is known as the (2n) diploid from a chorionic villus biopsy for prenatal kary­ number. A haploid number-one copy from each otyping. It can also be performed on tumor cells, of the 23 pairs, (1n)-arises normally during which invariably have marked karyotypic abnor­ meiosis, in the formation of eggs and sperm. malities that distinguish them from the nonmalig­ nant cells of the same individual. However, the chromosomal aberrations that we will be discuss­ Genetic Diseases ing usually affect every cell in a given individual­ Most genetic diseases can be considered to a different category of disorder. occur in three broad categories: Mendelian, Each human chromosome has a visible con­ polygenic, and chromosomal disorders. Each striction called the centromere that separates its class has its own classification system and theory. short arm (designated p) from its long arm (q). The Mendelian disorders, named after the genet­ The size and position of the centromere are char­ icist who described the theory underlying the acteristic for each chromosome. Chromosomes inheritance of such traits, are the best understood are first identified by the size and position of the of these diseases. Each of these diseases results centromere and then subdivided further by their from alteration at one gene locus. These disorders banding patterns. The banding pattern reflects are most comprehensively catalogued in Me- differences in the staining intensity of each seg- AJNR: 13, March/April 1992 579 A B c D E F Fig. 2. Diagrammatic illustration of various structural abnormalities involving a chromosome (Reproduced with modification from Robbins et al (6), pp 126-125.) A, Deletion; B, balanced reciprocal translocation; C, Robertsonian translocation; D, inversions; E, ring chromosome; F, actual Ring chromosome (arrow). (Diagramatic illustrations by Brent A. Bauer, MFA, of the Department of Art as Applied to Medicine of the Johns Hopkins School of Medicine.) ment of the chromosome with any of a large has a limited resolution. Two chromosomes that variety of chromogenic or fluorescent dyes. appear to have identical deletions karyotypically Banding permits identification of those chromo­ may in fact differ by scores of genes. somes or subchromosomal regions that may be Using karyotypes, the cytogeneticist can define altered in a given patient. However, even with the several different types of disorder. Euploidy refers use of special techniques (eg, prometaphase to the normal state of having a balanced set of banding, which allows examination of extended chromosomes. Aneuploidy is a general term re­ chromosomes that have not yet fully condensed ferring to any deviation from an exact multiple into their metaphase configuration), karyology of the haploid number. Except in tumor cells or 580 AJNR: 13, March/Aprill992 spontaneous abortuses, the clinician usually en­ sions, and translocations (Fig. 2A). A terminal counters aneuploidy involving only a single chro­ deletion can occur when there is a single break mosome-more extensive alterations being in­ in the arm of a chromosome. An interstitial dele­ compatible with life (Fig. 3). Such aneuploidy can tion results when there are two breaks on a given be either an additional copy of a chromosome or chromosomal arm, with rejoining of the distal and one chromosome too few. For example, if auto­ proximal fragments. In either case, those chro­ some 18 is present in three copies rather than mosomal fragments that are no longer physically the expected two, this aneuploidy is referred to connected to a centromere are lost in the next as trisomy 18; if chromosome 5 is present only cell division. One can specify in which region and in one copy rather than the expected two, then at what band the break and deletion have oc­ there is monosomy 5; if only a part of a chro­ curred. For example, 46 XV, del(15) q11-q14 mosome is overrepresented or underrepresented, indicates a male individual with a normal total this is a partial aneuploidy. number of chromosomes but a deletion of bands 11 to 14 on the long (q) arm of one chromosome 15.
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