Sporadic and Familial Variants in NF1: An Explanation of the Wide Variability in Neurocognitive Phenotype?

Background: Cognitive impairment is the most common neurological manifestation in NF1 and occurs in 30-70% of NF1 cases. The onset and severity of each specific cognitive deficit varies greatly from child to child, with no apparent external causes. The wide variability of phenotype is the most complex aspect in terms of management and care. Despite multiple research, the mechanism underlying the high heterogeneity in NF1 has not yet been elucidated. While many studies have focused on the effects of specific and precise genetic mutations on the NF1 phenotype, little has been done on the impact of NF1 transmission (sporadic vs. familial cases). We used a complete neuropsychological evaluation designed to assess five large cognitive areas: general cognitive functions (WISC-IV and EVIP); reading skills ("L'Alouette," ODEDYS-2 and Lobrot French reading tests); phonological process (ODEDYS-2 test); visual perceptual skills (JLO, Thurstone and Corsi block tests) and attention (CPT-II), as well as psychosocial adjustments (CBCL) to explore the impact of NF1 transmission on cognitive disease manifestation in 96 children affected by NF1 [55 sporadic cases (29♀, 26♂); 41 familial cases (24♀, 17♂)]. Results: Familial and Sporadic form of NF1 only differ in IQ expression. The families' socioeconomic status (SES) impacts IQ performance but not differently between sporadic and familial variants. However, SES is lower in familial variants than in the sporadic variant of NF1. No other cognitive differences emerge between sporadic and familial NF1. Conclusions: Inheritance in NF1 failed to explain the phenotype variability in its entirety. IQ differences between groups seems in part linked to the environment where the child grows up. Children with NF1, and especially those that have early diagnoses (most often in inherited cases), must obtain careful monitoring from their early childhood, at home to strengthen investment in education and in school to early detect emerging academic problems and to quickly place them into care. Trial Registration: IDRCB, IDRCB2008-A01444-51. Registered 19 January 2009.

Deficit in phonological processes: a characteristic of the neuropsychological profile of children with NF1.

Learning disabilities are one of the most frequent complications of neurofibromatosis type 1 (NF1) in children. Studies of the effects of the neurocognitive deficit on academic performance are relatively rare, owing to the small size of the populations concerned. However, research is needed to develop effective rehabilitation programs. In the present study, we explored the impact of a possible phonological deficit on the reading abilities of children with NF1. A multicenter, cross-sectional study was conducted in France on two groups of 75 children with or without NF1 aged 8-12 years, matched for age, sex, handedness, and reading level. All participants underwent a neuropsychological evaluation to assess their general cognitive level, reading skills, phonological processes, visuoperceptual abilities, and attentional capacity. Phonological skills were assessed by means of two phonological awareness tasks and one short-term memory task. In the group of children with NF1, 41% had reading difficulties. Phonological processes were impaired in this group, compared with the children without NF1. Similar differences were found for a phoneme deletion task after adjustment for reading difficulties, IQ level, and visuoperceptual abilities. Phonological awareness, but not phonological short-term memory, was impaired in children with NF1, and not just those whose reading was impaired. Results suggest that children with NF1 have a phonological awareness deficit, whatever their reading level. Identification of reduced phonological skills may warrant the implementation of a specific rehabilitation program before early reading difficulties emerge.

Neuropsychological status of French children with developmental dyslexia and/or developmental coordination disorder: Are both necessarily worse than one?

Developmental dyslexia (DD) and developmental coordination disorder (DCD) co-occur frequently, raising the underlying question of shared etiological bases. We investigated the cognitive profile of children with DD, children with DCD, and children with the dual association (DD + DCD) to determine the inherent characteristics of each disorder and explore the possible additional impact of co-morbidity on intellectual, attentional, and psychosocial functioning. The participants were 8- to 12-year-olds (20 DD, 22 DCD, and 23 DD + DCD). Cognitive abilities were assessed by the Wechsler Intelligence Scale for Children - Fourth Edition (WISC-IV) and the Continuous Performance Test - Second Edition (CPT-II) and behavioral impairments were evaluated by the Child Behavior Checklist (CBCL). No differences were found between the three groups on attention testing (CPT-II) or psychosocial characteristics (CBCL), but a higher percentage of DD + DCD children had pathological scores on psychosocial scales. Significant between-group differences were observed on Processing Speed Index scores and the block design and symbol search subtests, where DD children fared better than DCD children. No significant differences were evident between the co-morbid vs. the pure groups. Our results clearly show significant differences between children with DD only and children with DCD only. In particular, visuo-spatial disabilities and heterogeneity of intellectual profile seem to be good markers of DCD. However, it should be noted that despite these distinct and separate characteristics, a common cognitive profile (weaknesses and strengths) is likely shared by both neurodevelopmental disorders. Surprisingly, concerning co-morbidity, DD + DCD association is not associated with a decrease in intellectual or attentional capacities.