A multilevel analysis of cognitive dysfunction and psychopathology associated with chromosome 22q11.2 deletion syndrome in children.

摘要: In recent years, a great deal has been learned about disorder that is one of the most common genetic causes developmental disability, mental retardation, and psychopathology. Resulting from 1.5- to 3-Mb microdeletion on long (q) arm chromosome 22 (Driscoll, Budarf, & Emanuel, 1992; Driscoll et al., 1992), this accurately characterized as “chromosome 22q11.2 deletion syndrome” (DS22q11.2). Thus defined, encompasses previously described phenotypes including DiGeorge (1965), velocardiofacial (Shprintzen, Goldberg, Lewin, Sidoti, Berkman, Argamaso, Young, 1978), conotruncal anomaly face (Burn, Takao, Wilson, Cross, Momma, Wadey, Scambler, Goodship, 1993) syndromes, some cases Cayler cardiofacial syndrome (Giannotti, Digilio, Marino, Mingarelli, Dallapiccola, 1994) Opitz G/BBB (McDonald–McGinn, Driscoll, Bason, Christensen, Lynch, Sullivan, Canning, Zavod, Quinn, Rome, 1995). A molecular fluorescence in situ hybridization probe for set prevalence at 1 4,000 live births (Burn 1996), an estimate currently thought be quite conservative (e.g., Shashi, Muddasani, Santos, Berry, Kwapil, Lewandowski, Keshavan, 2004). Furthermore, several factors point significant growth identified population individuals with DS22q11.2 near future. One major cause mortality syndrome, congenital heart defects, now routinely resolved surgically. Another that, because contiguous gene no effect reproductive fitness, adults will have 50% chance having affected child. third growing knowledge increasing rates early identification diagnosis. Given typically produces disability frequently results serious psychopathology it essential develop deep understanding cognitive behavioral phenotype. That should improve clinical management may provide important clues into gene–brain–behavior relationships. Investigation neuroscience perspective can valuable information basic research scientists clinicians. For example, studies are likely help explicate neural bases processes disturbed other disorders produce characteristic impairments visuospatial numerical cognition fragile X, Turner, Williams–Beuren syndromes). Such involving children also shed light developing brain structure/function relationships what extent these account observable impairments. investigations like complement role variation individual differences function (for review, see Parasuraman Greenwood, 2004), well etiology complex neuropsychiatric disorders. contrast traditional psychiatric genetics studies, which begins cluster symptoms (i.e., diagnosis) attempts map traits specific loci, here we investigating phenotypic manifestations known, homogeneous etiology. The effects known alteration system ability catechol-O-methyltransferase [COMT] enzyme, affects regulation synaptic dopamine particularly prefrontal cortex), thus studied terms its theoretically motivated question mediation dysfunction executive cognition). As shall make clear below, multiple levels approach such prove fruitful way integrate findings neurocognitive basis psychopathology. Most progress was related physical (see Figure image child deletion). These involve cleft palate and/or velopharyngeal insufficiency, immune deficiencies, neonatal hypocalcemia, aforementioned facial dysmorphisms (Emanuel, McDonald–McGinn, Saitta, Zackai, 2001; McDonald–McGinn al, 1999). Although many present understood effectively treated managed, far less apparent changes structure function, their relation range reported. first reports aspects phenotype came standardized tests intellectual academic achievement, parent-report measures. study 33 reported mean full-scale IQ borderline functioning (71.2 ± 12.8), Verbal 77.5 (±14.9), performance 69.1 (±12.0; Moss, Batshaw, Solot, Gerdes, Emmanuel, Wang, Similar were Belgian sample extended age infancy older (Swillen, Devriendt, Legius, Prinzie, Vogels, Ghesquiere, Fryns, With regard Moss al. math composite scores (from Wechsler Achievement Scales) significantly lower than spelling reading (80.1 15.2 vs. 88.3 16.4 86.7 18.2, respectively). Analyses enlarged samples same generally replicated pattern Woodin, Aleman, 2001). addition, within-subject comparisons memory indicated rote verbal higher those (Bearden, Emannuel, Cannon, This consistent Kreps–Falk, (2000) who, arithmetical found poorer test short-term auditory number recall. Figure 1 A 4-year-old girl DS22q11.2. With psychosocial functioning, Swillen, Eyskens, Dumoulin, Gewillig, Fryns (1997) Child Behavior Checklist, indicating elevated “social problems,” “attention “withdrawn” sub-scales. focusing younger (13 63 months) (Gerdes 1999) not only typical delayed language, speech, motor development, but 75% toddlers exhibited behaviors during testing judged “highly active, emotional disorganized,” measured by Bayley Scale Infant Development (Bayley, 1969), whereas one-quarter “behaviorally inhibited.” It possible childhood problems do more chronic, severe illnesses adolescence adulthood. Indeed, highest risk date schizophrenia, order 25–30% adult patients (Bassett Chow, 1999; Bassett, Hodgkinson, Correia, Scutt, Weksberg, 1998; Murphy, Jones, Owen, 1999). However, whether observed DS22q11.2. bipolar (Papolos, Faedda, Veit, Morrow, Kucherlapati, Shprintzen, anxiety attention-deficit/hyperactivity (ADHD; Niklasson, Rasmussen, Oskarsdottir, Gillberg, ADHD (particularly inattentive or combined type, rather hyperactive type) appears morbidity adolescents DS22q11.2, 35–55% patients. There estimates autistic spectrum between 14 31% (Fine, Weissman, Pinto–Martin, press; Oppositional defiant 8–43% (Arnold, Siegel–Bartelt, Cytrynbaum, Teshima, Schachar, Feinstein, Eliez, Blasey, Reiss, 2002; 2001, Papolos one-third meet criteria obsessive–compulsive (OCD; Gothelf reason present.