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Neurofibromatosis Type 1 is a common multisystem disorder of autosomal dominant inheritance that affects approximately one in 3000 individuals of all ethnic groups. Cognitive dysfunction associated with NF1 is a complicated and incompletely understood aspect of the disease. Modernization of neuroimaging methods and genetic techniques have made significant advances in this realm possible.
Neurofibromatosis Type 1 is a common multisystem disorder of autosomal dominant inheritance that affects approximately one in 3000 individuals of all ethnic groups. Cognitive dysfunction associated with NF1 is a complicated and incompletely understood aspect of the disease. Modernization of neuroimaging methods and genetic techniques have made significant advances in this realm possible.
Neurofibromatosis Type 1 is a common multisystem disorder of autosomal dominant inheritance that affects approximately one in 3000 individuals of all ethnic groups. Cognitive dysfunction associated with NF1 is a complicated and incompletely understood aspect of the disease. Modernization of neuroimaging methods and genetic techniques have made significant advances in this realm possible.
Tena L. Rosser, MD, and Roger J. Packer, MD Address Department of Neurology, Children's National Medical Center, 111 Michigan Avenue NW, Washington, DC 20010, USA. E-mail: trosser@cnmc.org Current Neurology and Neuroscience Reports 2003, 3:129136 Current Science Inc. ISSN 15284042 Copyright 2003 by Current Science Inc. Introduction Neurofibromatosis type 1 (NF1) is a common multisys- tem disorder of autosomal dominant inheritance that affects approximately one in 3000 individuals of all eth- nic groups [1]. The physical manifestations of NF1, such as caf au lait spots, axillary freckling, iris hamartomas (Lisch nodules), osseous lesions (sphenoid wing dyspla- sia, pseudarthrosis) and benign as well as malignant neu- ral tumors (neurofibromas, optic gliomas), are well recognized (Table 1) [2]. In addition, cognitive difficul- ties and learning disabilities of varying degrees have been noted in 30% to 65% of patients [3]. The cognitive dys- function associated with NF1 is a complicated and incompletely understood aspect of the disease. It also represents an important source of morbidity, as an indi- vidual's cognitive abilities have a major lifelong impact on educational prospects, future employment, self- image, relationships with peers, and overall ability to function in society. Over the past decade, much research has been devoted to unraveling the mystery of cognitive dysfunction in NF1, with the goals of defining the specific deficits, deter- mining the underlying causes, and eventually discovering effective treatments. Modernization of neuroimaging methods and genetic techniques has made significant advances in this realm possible. Important recent devel- opments have included expanded research into the rela- tionship between brain structure and cognitive function, better understanding of the NF1 gene on chromosome 17, identification of several functions of neurofibromin (the protein product of the NF1 gene), and the develop- ment of animal models with cognitive deficits similar to those in humans with NF1. Background: What Do We Already Know? Mental retardation and IQ Recent data based on objective testing measures have revealed that the NF1 population has a slightly increased incidence of mental retardation, defined as a full-scale IQ score of less than 70. Between 4% and 8% of individuals with NF1 fall into the mentally retarded IQ range, whereas approximately 3% of the general population has mental retardation [3,4]. Across numerous studies of the NF1 pop- ulation, mean full-scale IQ scores vary from 87 to 100 on Wechsler Intelligence Scales (WISC) [5]. The vast majority of studies have shown no discrepancy between perfor- mance and verbal IQ scores [613]. Debate remains regarding whether the lowering of IQ applies to the NF1 population as a whole or if it repre- sents only a subset of NF1 patients [4,5]. There is some preliminary evidence to suggest that a bimodal pattern exists, indicating that there are two distinct groups, those with cognitive impairment and those without [6,14,15]. However, further research is required to substantiate these suspicions. Visual-spatial skills Deficits in visual-spatial skills are well documented in NF1. Since the 1980s, when these difficulties were first identi- fied, multiple studies have evaluated visual-spatial skills using various measures including Bender visual-motor gestalt testing, dot localization, facial recognition, Hooper visual organizational testing, judgement of line orientation (JLO), Rey-Osterreith complex figure copying, visual- The cognitive dysfunction associated with neurofibroma- tosis type 1 (NF1) is an intriguing aspect of this phenotyp- ically heterogeneous genetic neurocutaneous disorder. A broad range of both nonverbal and verbal learning disabil- ities are evident in approximately 30% to 65% of children with NF1. Deficits in IQ, executive function, attention, and motor skills have also been documented. Current challenges lie in discovering the underlying multifactorial etiologies of the cognitive abnormalities found in NF1. Likely answers lie in neuroanatomic correlates as seen on neuroimaging as well as in molecular and genetic advances into the role of neurofibromin, the protein product of the NF1 gene. The development of NF1 animal models with learning and memory difficulties similar to those seen in humans demonstrates promising preliminary evidence that medical treatment of cognitive abnormalities may one day be possible. 130 Pediatric Neurology motor integration, visual form discrimination, visual-per- ceptual skills testing, as well as others [6,7,1012,1618]. The JLO test stands out among studies as being consis- tently abnormal [4,6,7,9,10,1618]. Thus, the JLO is believed to be an important indicator of neurocognitive dysfunction in NF1 [4]. Two studies have documented that the visual-spatial deficits found in NF1 are somewhat unique. Cutting et al. [19], expanding initial research by Eliason [16], compared children with NF1 with learning-disabled children without NF1 and with a normal control group. The NF1 group scored significantly lower on visual-spa- tial tests than the learning-disabled group; however, there was no significant difference between the NF1 and the control groups. The authors concluded that the visual-spatial deficits in children with NF1 are different than those found in otherwise healthy learning-dis- abled children [19]. Language function Although the initial focus was on describing the nonverbal deficits in NF1, it was presumed that language function was relatively spared in these children. However, the vast body of research performed most recently has demon- strated a variety of language impairments in the realms of reading, spelling, vocabulary, naming, verbal reasoning, wri t t en mat hemat i cs, and wri t t en l anguage [6,7,10,12,16,17,19]. Dyslexia, a specific reading disability, has also been identified in children with NF1 in some studies [7,10,17]. Verbal disabilities do not frequently occur alone in children with NF1. They may be less severe than, but coexist with, visual-spatial difficulties [4,5]. Eliason [16], for example, evaluated 23 children with NF1. He identi- fied isolated visual-perceptual disabilities in 56% and concomitant language dysfunction in 30%. The exact nature of the overlap between visual-spatial abnormali- ties and language dysfunction in children with NF1 is still incompletely understood. Learning disabilities and the cognitive phenotype Reports of the frequency of learning disabilities (LD) in NF1 range from 30% to 65%, which is significantly higher than the estimates of 7% to 10% of LD seen in the general population [3,19]. A learning disability represents a dis- crepancy between ability (IQ) and achievement (perfor- mance on reading, writing, spelling, or math testing) [4]. Both Ozonoff [5] and North [4] have noted in recent review articles that estimates of learning disabilities in the NF1 population require cautious interpretation secondary to confounding factors. There are differing definitions of LD, lack of appropriate control groups, and frequently no accommodation for the lowering of IQ seen in the NF1 population among studies [4,5]. Cutting et al. [19] have made another interesting point regarding the interpreting of studies of cognition. When comparing three groups of children (NF1, learn- ing disabled without NF1, and normal control groups), several visual-spatial and language tasks previously found to be deficient in sibling-matched designs were not present when comparing the NF1 group and the no- diagnosis control group [19]. Thus, these authors have emphasized that broad genetic and familial influences must be taken into account when considering the influ- ence of NF1 on cognition. Early work into the learning disabilities associated with NF1 attempted to describe an NF1 cognitive phenotype [7]. Researchers now know that a spectrum of nonverbal as well as verbal learning disabilities exist in children with NF1. Thus, there does not appear to be a specific profile of cognitive dysfunction in the NF1 population [3]. This real- ization has implications for treatment, as neurocognitive evaluation and management must then be individualized for every child with NF1 and LD. Executive functioning Executive functioning requires goal-directed behavior and the use of numerous complex intellectual skills, such as organization, planning, attention, inhibition, and self- monitoring [5]. Although less well studied than other aspects of the cognitive dysfunction in NF1, executive functioning is impaired in some individuals with NF1. The majority of studies have focused on children with NF1. For example, in the initial works of the 1980s, Stine and Adams [20] noted "weaknesses related to cortical organization and distracti- bility." [20]. Later, others revealed poor problem solving skills, strategy generation, and expression of ideas [14]. There is also evidence to suggest that these difficulties persist into adulthood. In evaluating adults with NF1, Zol- ler et al. [21] found that NF1 had a negative impact on a variety of intellectual skills, such as inductive reasoning, logical abstraction, short-term memory, attention, and mental flexibility. This raises the question of whether spe- cific interventions during childhood could impact these Table 1. National Institutes of Health diagnostic criteria for NF1 Two or more of the following features must be present for the diagnosis of NF1: 6 or more caf au lait spots with a diameter greater than 0.5 cm before puberty and 1.5 cm after puberty Axillary or inguinal freckling 2 or more neurofibromas or a single plexiform neurofibroma 2 or more Lisch nodules (iris hamartomas) Optic glioma A distinctive osseous lesion such as sphenoid bone dysplasia or thinning of long bone cortex A first-degree relative with NF1 by the above criteria NF1neurofibromatosis type 1. Neurocognitive Dysfunction in Children with Neurofibromatosis Type 1 Rosser and Packer 131 mental functions later in life and underscores the impor- tance of further research into this area of cognition. Attention deficits Attention has been one of the better-analyzed aspects of executive functioning in the NF1 population and is an area of keen interest in NF1 research at this time (Table 2). As noted previously, multiple studies have suggested that there is an association between NF1 and attention deficit hyperactivity disorder (ADHD), defined by the DSM-IV cri- teria as a constellation of inattention, hyperactivity, and impulsivity [13,14,16,2022]. Some researchers have shown, however, that children with NF1 may be more likely to fulfill diagnostic criteria for attention deficit disor- der without hyperactivity [14]. Although the exact incidence is unknown, recent work suggests that ADHD may be present in approximately one third to one half of children with NF1, a marked increase above the estimates of ADHD in the general pediatric pop- ulation (5%) [7,23,24]. More specifically, in agreement with earlier reports by Hofman et al. [7], Kayl et al. [23] found that 12 of 36 (33%) of their NF1 pediatric study population met diagnostic criteria for ADHD by rating scales. Mautner et al. [24] have found an even higher incidence, documenting that 46 of 93 (49.5%) of their pediatric NF1 study population satisfied DSM-IV ADHD diagnostic criteria. Koth et al. [25] have raised the question of whether ADHD is part of the NF1 phenotype or a separate, unre- lated disorder. Controlling for genetic and environmental factors by comparing the ADHD status of children with NF1 to their unaffected siblings and biologic parents, the authors findings support the theory that ADHD is indeed a component of the NF1 behavioral and cognitive pheno- type [25]. Motor skills Both gross and fine motor delays are commonly found in children with NF1. A determination of the precise inci- dence of motor delays in the pediatric NF1 population is difficult to discern from the literature. However, deficits of manual dexterity, coordination, balance, gait, and ball skills have been noted in children with NF1 when com- pared with published age-related norms, unaffected sib- lings, and IQ-matched learning-disabled control subjects [7,14,17]. Psychomotor slowing on motor tasks has also been demonstrated [26]. These motor impairments may impact upon a child's ability to interact with their environ- ment and, as with cognitive delays, warrant prompt evalua- ti on and i nterventi on. Tabl e 3 summari zes the neurocognitive deficits in children with NF1. Relating Structure to Function Although many researchers have focused on defining the neurocognitive deficiencies in NF1, others have investi- gated the possible underlying mechanisms by attempting to relate brain function to its structure (Table 4). Subtle abnormalities of brain structure in NF1, such as macro- cephaly, which occurs in approximately 50% of individuals with NF1, were recognized early in the study of this disease [1]. The advent of modern neuroimaging with magnetic resonance imaging (MRI) led to the discovery of T2- weighted signal abnormalities or unidentified bright Table 2. Results of studies on ADHD in children with NF1 Study/year Patients with NF1, n NF1 children with ADHD* Comparison population Conclusions Kayl et al. [23] / 2000 36 33% 18 normal control subjects NF1 patients had increased total corpus callosum area compared with control subjects, but there were no differences between NF1 and NF1+ADHD groups. Increased severity of attention difficulties in NF1+ADHD group was related to smaller splenial and total callosal area. Koth et al. [25] / 2000 31 42% NF1-unaffected siblings and biologic parents ADHD may be a component of NF1 phenotype rather than a separate, unrelated disorder. Mautner et al. [24] / 2002 93 49.50% 26 children with NF1 + no ADHD, 14 children with ADHD + no NF1, 14 control subjects First systematic evaluation of effectiveness of stimulant medication in 20 children with NF1+ADHD. Showed methylphenidate improved attention and impulse control on TOVA test. Methylphenidate also improved learning ability and social behavior at 1 year of follow-up by the CBCL. *Children who meet diagnostic criteria for ADHD by DSM III-R of DSM-IV criteria. ADHDattention deficit hyperactivity disorder; CBCLchild behavior checklist; NF1neurofibromatosis type 1; TOVAtest of variables of attention. 132 Pediatric Neurology objects (UBOs) and to the development of morphometric and volumetric brain analyses, which have been helpful in further advancing our understanding of cognition in NF1. Functional MRI will likely bring the next wave of new insights in this area. Unidentified bright objects and magnetic resonance imaging in neurofibromatosis type 1 Unidentified bright objects represent areas of high T2- weighted signal on MRI and, by definition, demonstrate no mass effect, edema, or enhancement with contrast (Fig. 1) [1]. Only one case report has linked a UBO to a focal neurologic abnormality. A 13-year-old girl with NF1 and a thalamic/subthalamic T2 signal hyperintensity was reported to have a contralateral hand dystonia that improved over 2 years as her radiologic abnormality resolved [27]. UBOs occur primarily in the basal ganglia, cerebellum, brainstem, and subcortical white matter of approximately 43% to 79% of children with NF1 [4]. In addition, UBOs are not static in nature, typically resolving by early adulthood [3]. This may partially explain the wide range of reported incidence of UBOs in the literature [3]. Histologically, UBOs demonstrate dysplastic or hyperplas- tic glial proliferation and white matter spongiform change that is believed to represent intramyelinic edema. It has been postulated that myelin abnormalities may then be at least partially responsible for the cognitive difficulties seen in NF1 [28]. A tremendous amount of research has been devoted to determining how cognition might be related to the number, size, volume, and precise location of UBOs, with little consensus reached among studies. Initial work by Dunn and Roos [29], Duffner et al. [30], and Ferner et al. [31] showed no association between T2 hyperintensities and cognition, but this work was criti- cally flawed by not performing IQ testing in all patients. However, better designed follow-up studies using more systematic, quantitative neurocognitive evaluations also produced conflicting data. The results of several of these studies are discussed to demonstrate the difficulty in drawing firm conclusions from over a decade of research in this area. North et al. [6] showed lowering of IQ as well as language and visual-spatial deficits in children with T2 hyperintensities. Lowering of global IQ in addition to deficiencies of attention, visual-spatial skills, and exec- utive functioning were demonstrated in children with UBOs in the work of Joy et al. [9]. The number of UBOs correlated with IQ deficits in a study by Hofman et al. [7]. Denckla et al. [32] found that lower IQ scores in children with NF1 were related to the presence and dis- tribution of UBOs [32]. In contrast, work performed by Legius et al. [33] and Moore et al. [13] showed no sig- nificant difference in IQ scores of the T2-positive and T2-negative groups, although lower IQ was associated with T2 lesions of the thalamus in the study by Moore et al. [13]. In summary, evidence suggests that a relationship between T2 hyperintensities and cognition in NF1 exists, but the precise impact of UBOs on different areas of cogni- tion is still controversial. MRI T2 hyperintensities, thus, cannot be considered a radiographic marker or predictor of cognitive dysfunction in NF1 at this time [4]. Other neuroanatomic correlates Questions regarding how other structural aspects of the brain in individuals with NF1 may be linked to cogni- tive function have also arisen. Morphometric and volu- metric MRI have made exploration of the phenomenon of macrocephaly, as well as assessment of corpus cal- losal area and sylvian fissure morphology in the NF1 population, possible. Table 3. Summary of neurocognitive deficits in children with NF1 Realms affected Comments Mental retardation Full-scale IQ less than 70 occurs in 4%8% of individuals with NF1. No consistent discrepancy between performance and verbal IQ among studies. IQ may follow a bimodal pattern in NF1. Visual-spatial skills The most common type of neurocognitive deficit. JLO test is consistently abnormal between studies. May be different in children with NF1 and unaffected children with LD. Language skills A variety of verbal impairments may be seen. Usually coexist with visual-spatial difficulties. Learning disabilities Occur in 30%65% of children with NF1, a marked increase from the incidence of LD in the general population. Cognitive phenotype Children with NF1 have a range of nonverbal and verbal disabilities. At this time, a specific NF1 cognitive phenotype is not recognized. Executive functioning Deficits of goal-directed behavior and intellectual skills such as organization, planning, attention, inhibition, and self-monitoring have been noted but are less well characterized than other aspects of cognitive dysfunction in NF1. Attention Recent research shows that ADHD or ADD may occur in 33%49.5% of children with NF1. Stimulant medications are effective in controlling symptoms. Motor skills Gross and fine motor delays as well as psychomotor slowing are common. ADDattention deficit disorder; ADHDattention deficit hyperactivity disorder; JLOjudgement of line orientation; LDlearning disability; NF1neurofibromatosis type 1. Neurocognitive Dysfunction in Children with Neurofibromatosis Type 1 Rosser and Packer 133 Preliminary work has demonstrated that brain vol- ume is significantly larger in children with NF1 compared with control subjects, suggesting that megalen- cephaly is responsible for macrocephaly in these patients. There is conflicting evidence, however, as to how macro- cephaly correlates with cognitive dysfunction [18,34,35]. Although Ferner et al. [26] and North et al. [6] found no association, Cutting et al. [35] found significant vocabu- lary impairments in a macrocephalic NF1 population compared with a normocephalic NF1 population. Of note though, Cutting et al. [35] did not identify a strong relationship between macrocephaly and the origin of NF1 (familial versus sporadic), UBOs (presence versus absence), or extent of cognitive impairment. Moore et al. [18] undertook further study of this sub- ject, finding that gray matter volume was greater in chil- dren with NF1 compared with control subjects and correlated with the degree of learning disability in the NF1 study population. Corpus callosum size was also larger in NF1 subjects and was related to lower scores on measures of academic achievement in addition to visual- spatial and motor skills [18]. The authors conclude by proposing that delayed neuronal apoptosis may be responsible for macrocephaly and delayed neuronal con- nections in children with NF1, suggesting that these underlying structural abnormalities are related to cogni- tive impairment in NF1 [18]. Billingsley et al. [36] speculated that individuals with NF1 might demonstrate cortical abnormalities simi- lar to those seen in the reading-disabled general popula- tion, becoming the first to evaluate sylvian fissure morphology specifically in children with NF1. Several intriguing findings regarding planum temporale (PT) structure were documented. The left PT in boys had a smaller surface area and gray matter volume compared with NF1 girls and control subjects. In addition, boys with NF1 showed greater left-right PT symmetry, similar to what is reported in the general reading-disabled popu- lation. Reading and math intelligence-based discrepancy scores were related to PT asymmetry in the NF1 group compared with control subjects. Less leftward PT asym- metry in the NF1 population was associated with poorer reading and math achievement relative to full-scale IQ. The authors conclude that the susceptibility of reading and other learning disabilities in NF1 may be related to sylvian fissure development and morphology [36]. Attention deficit hyperactivity disorder and brain morphology in neurofibromatosis type 1 Research in non-NF1 populations suggests that the under- lying etiology of ADHD can at least partially be explained by brain morphology [23]. Several recent studies have spe- cifically examined the correlation between brain morphol- ogy and ADHD in children with NF1. A recent MRI study by Cutting et al. [37] suggests that megalencephaly in NF1 may be related to ADHD. Mega- lencephaly was present in boys with NF1 and no ADHD. In contrast, boys with NF1 and ADHD were normocephalic, suggesting that somehow a diagnosis of ADHD in NF1 cor- rects for megalencephaly [37]. A relationship between anterior and posterior corpus callosum structure and ADHD versus normal control sub- jects is also believed to exist [23]. Kayl et al. [23] evaluated the cross-sectional areas of seven regions of the corpus cal- losum in children with NF1 to determine how morphol- ogy was related to ADHD symptoms. The authors demonstrated that children with NF1 had increased corpus callosal areas over control subjects, but there were no dis- cernable differences in callosal area between the NF1 and NF1/ADHD groups. However, unexpectedly, an increase in severity of attention deficits was associated with a smaller splenial and total corpus callosum area in the NF1/ADHD children [23]. Management of Learning-disabled Children with Neurofibromatosis Type 1 Although no well-defined NF1 cognitive phenotype has emerged, it is currently understood that individuals with NF1 may experience a variety of nonverbal and verbal neu- rocognitive deficits that can adversely affect their educa- tional experience and have a large impact on their overall Table 4. Neuroanatomic structures possibly related to cognitive dysfunction in NF1 Presence, location, and number of unidentified bright objects Macrocephaly/megalencephaly Corpus callosal area Planum temporale NF1neurofibromatosis type 1. Figure 1. Brain magnetic resonance imaging fluid attenuated inver- sion recovery image demonstrates unidentified bright objects in the white matter of the cerebellum, middle cerebellar peduncle, and pons of a 3-year-old girl with neurofibromatosis type 1. 134 Pediatric Neurology quality of life. Cognitive dysfunction in children may at times be subtle and may often masquerade as behavioral problems, attention difficulties, or laziness. Thus, physi- cians and other individuals involved in the care of children with NF1 should have a very high index of suspicion for learning disabilities. Formal neurocognitive evaluation is warranted in any child who shows possible cognitive impairment. Gross and fine motor delays deserve the same attention, as intervention with physical and occupational therapy can improve motor skills and coordination. Recognition and diagnosis of comorbid ADHD in chil- dren with NF1 is also critically important because effective treatment with stimulant medication and behavioral mod- ification techniques are available. Mautner et al. [24] have published the first systematic study of the use of stim- ulant medication in the NF1 pediatric population, sub- stantiating suspicions of effectiveness that were previously primarily anecdotal in nature. Low-dose methylphenidate (range, 5 to 15 mg; average of 7.5 mg) improved attention, behavior control, and social problems in the NF1/ADHD study population. At 1-year follow-up, these benefits were still demonstrable and statistically significant on both par- ent and teacher Child Behavior Checklists [24]. Thus, used in conjunction with nonmedical therapies such as behavioral modification, stimulant medications may help maximize academic as well as social abilities in children with concomitant NF1 and ADHD. Anticipatory guidance with regard to physical as well as cognitive complications should also be provided to parents of children with NF1 so that prompt intervention may be undertaken when problems arise [3]. Specific educational protocols are not currently available for learning-disabled children with NF1, but they may be developed in the future as the cognitive dysfunction associated with NF1 is better understood. Pathophysiology and the Role of Neurofibromin Understanding the underlying genetic defect of NF1 has become critical to explaining the spectrum of clinical man- ifestations of this disease, from benign and malignant tumor growth to cognitive dysfunction. Neurofibromin is the protein product of the NF1 gene, which is located on chromosome 17q11.2 [38]. In adults, neurofibromin is expressed in neurons, Schwann cells, and oligodendro- cytes, as well as in many non-neural cell types [39]. Although the function of neurofibromin is incompletely understood, it clearly plays a role in multiple intracellular processes, including regulation of the ras tumor suppressor gene, modulation of adenylyl cyclase and cyclic adenosine monophosphate (cAMP) pathways, as well as cytoskeletal assembly [40,4144]. The effect of neurofibromin on the ras gene has been most clearly defined. More specifically, a domain of the NF1 gene contains GTPase-activating protein (GAP) activ- ity which down-regulates ras, a plasma membrane protein involved in cellular growth and differentiation [41]. The ras protein has active and inactive forms. Ras is active when bound to GTP and inactive when GTP is hydrolyzed to GDP [45]. In the active state, ras promotes cell prolifera- tion. GAP proteins, such as neurofibromin, regulate ras by stimulating the conversion of active to inactive ras. Thus, mutations in the NF1 gene produce inactive neurofibro- min, and the resulting deficiency of normal intracellular neurofibromin causes excessive ras activity with subse- quent unregulated cell growth [46]. Animal Models of Cognitive Dysfunction in Neurofibromatosis Type 1 Mouse models The development of knockout mouse models has allowed researchers to apply their knowledge of the pathogenesis of NF1 and of the functions of neurofibromin to investigate cognition dysfunction at molecular and cellular levels. Building on the initial work of Silva et al. [47], two recent articles published by Costa et al. [48,49] have been instrumental in specifically linking the learning process in NF1 to the interaction between neurofibromin and ras. Initial mouse model studies demonstrated that mice homozygous for a null mutation in the NF1 gene showed mid-gestation lethality. However, mice heterozygous for the same null mutation were viable, showing an increased predisposition to tumor formation as well as learning defi- cits [47,48]. It was also determined that an alternatively spliced exon 23a modifies the GAP domain of the NF1 gene [48]. Exclusion of exon 23a produces the type I iso- form of neurofibromin, whereas inclusion of the exon 23a results in the type II isoform of neurofibromin. To further investigate the function of the type II isoform, Costa et al. [48] developed a mouse model specifically lacking exon 23a (NF1 23a-/-). They found that although mice homozy- gous for this mutation survived without physical impair- ment or increased tumor predisposition, specific learning deficits were apparent. Cognitive deficits were most nota- ble on hippocampal-dependent tasks, such as the Morris water maze and contextual discrimination, and were simi- lar to those seen earlier in heterozygous null mice. The authors concluded that the type II isoform of neurofibro- min is essential for normal cognitive function and that the GAP-related domain of neurofibromin plays an important role in learning and memory. In addition, they proposed that hyperactive ras may have been responsible for the NF1 exon 23a-/- learning-disabled phenotype [48]. Research has suggested that abnormal up-regulation of ras activity, caused by loss of neurofibromin, may play a crucial role in cognitive dysfunction in mice, as well as humans, with NF1 [49]. In their second paper, to better define the function of the ras protein in hippocampal- dependent visual-spatial task learning, Costa et al. [49] evaluated mice heterozygous for the NF1 gene null muta- Neurocognitive Dysfunction in Children with Neurofibromatosis Type 1 Rosser and Packer 135 tion using a water maze test. The authors were able to dem- onstrate improved spatial learning deficits in NF1 mice by manipulating ras activity genetically as well as pharmaco- logically. Specifically, NF1 mice (with presumed increased ras activity) crossed with mice genetically engineered to be deficient in ras activity did not have visual-spatial learning difficulties. Also, administration of an oral farnesyl-trans- ferase inhibitor, a medication that decreases ras signaling by altering the post-translational step of farnesylation, to adult NF1 mice corrected their learning deficits [49]. This study further evaluated the long-term potentiation (LTP) of hippocampal CA1 neurons in these mice, and found that the NF1 mice had a deficit of synaptic plasticity [49]. LTP is a form of synaptic plasticity that is believed to be involved in hippocampal-related learning paradigms [40]. As with the learning deficits, the genetically engi- neered NF1 mice with deficient ras activity had normal LTP, suggesting that hyperactive ras may also contribute to decreased synaptic plasticity [40,49]. Furthermore, the authors showed that increased gamma-aminobutyric acid (GABA)-mediated inhibition may cause decreased synaptic plasticity, and thus may be related to the underlying cogni- tive difficulties associated with NF1 [49]. Not yet testable in humans, these experiments have outlined certain important parallels between the cognitive deficits in mice and humans with NF1 and have relevant implications for the development of treatment strategies for cognitive dysfunction through modification of ras activity or GABA mediation [49]. Drosophila models The NF1 protein product in Drosophila, the fruit fly, con- tains a 2802-amino acid sequence that is 60% identical to that of human neurofibromin [42]. Thus, the Drosophila model has been useful in exploring additional mecha- nisms involved in learning and memory in NF1. Guo et al. [50] demonstrated that G-proteinactivated adenylyl cyclase activity appears to have NF1-dependent and NF1-independent components in Drosophila. The NF1- dependent activation of the rut-adenylyl cyclase pathway was required for olfactory learning and memory in the NF1 Drosophila, demonstrating a novel mechanism for how G- proteins activate cAMP pathways during the normal learn- ing process [50]. Although it is not yet clear how these new insights apply to humans, they again highlight the fact that neurofibromin's role in cognitive function is extremely complicated and that multiple biochemical pathways are most likely involved. Conclusions Although many questions regarding cognition in children with NF1 remain, we have begun to understand the com- plex mechanisms at play over the past two decades, making great progress in defining a range of nonverbal and verbal cognitive dysfunction, as well as behavioral and motor impairments, in children with NF1. Research into the mul- tiple functions of neurofibromin and the development of NF1 animal models with similar learning and memory dis- abilities have laid the foundation for explaining cognitive dysfunction on molecular and cellular levels. Targeting specific biochemical pathways to improve cognitive abili- ties both genetically and pharmacologically has now been realized in mouse models and holds potential for similar treatments in humans. Importantly, the developments in our understanding are not just relevant to NF1, but have implications for unlocking the mysteries of cognitive func- tion in humankind. 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