Levels of cerebrospinal fluid nerve-growth factor differ in infantile autism and Rett syndrome

Riikonen, Raili; Vanhala, Raija

doi:10.1017/s0012162299000328

Cited by 39 publications

(15 citation statements)

References 45 publications

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“…34 Prior to this study, very little research has linked NGF to ASD. Riikonen and Vanhala 35 showed that NGF levels were normal in children with infantile autism and low to negligible in children with Rett syndrome, however, they did not examine these levels during earlier or later time points. Nelson et al 36 examined and compared archived newborn blood samples in children that developed ASD ( n = 69), mental retardation without ASD ( n = 60), cerebral palsy ( n = 63) and control children ( n = 54).…”

Section: Discussionmentioning

confidence: 98%

QTL replication and targeted association highlight the nerve growth factor gene for nonverbal communication deficits in autism spectrum disorders

Yoon

Geschwind

et al. 2011

Mol Psychiatry

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Autism Spectrum Disorder (ASD) has a heterogeneous etiology that is genetically complex. It is defined by deficits in communication and social skills and the presence of restricted and repetitive behaviors. Genetic analyses of heritable quantitative traits that correlate with ASD may reduce heterogeneity. With this in mind, deficits in nonverbal communication (NVC) were quantified based on items from the Autism Diagnostic Interview Revised. Our previous analysis of 228 families from the Autism Genetics Research Exchange (AGRE) repository reported 5 potential quantitative trait loci (QTL). Here we report an NVC QTL replication study in an independent sample of 213 AGRE families. One QTL was replicated (P < 0.0004). It was investigated using a targeted-association analysis of 476 haplotype blocks with 708 AGRE families using the Family Based Association Test (FBAT). Blocks in two QTL genes were associated with NVC with a P-value of 0.001. Three associated haplotype blocks were intronic to the Nerve Growth Factor (NGF) gene (P= 0.001, 0.001, 0.002), and one was intronic to KCND3 (P= 0.001). Individual haplotypes within the associated blocks drove the associations (0.003, 0.0004 and 0.0002) for NGF and 0.0001 for KCND3. Using the same methods, these genes were tested for association with NVC in an independent sample of 1517 families from an Autism Genome Project (AGP). NVC was associated with a haplotype in an adjacent NGF block (P= 0.0005) and one 46 kb away from the associated block in KCND3 (0.008). These analyses illustrate the value of QTL and targeted association studies for genetically complex disorders such as ASD. NGF is a promising risk gene for NVC deficits.

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Section: Discussionmentioning

confidence: 98%

QTL replication and targeted association highlight the nerve growth factor gene for nonverbal communication deficits in autism spectrum disorders

Yoon

Geschwind

et al. 2011

Mol Psychiatry

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“…At the clinical level, the role of neurotrophins such as BDNF in Rett syndrome is also unclear. Initial studies described lower levels of NGF in blood serum or cerebral spinal fluid of RTT patients compared to non-RTT individuals, but no differences in BDNF levels (Lappalainen et al, 1996; Riikonen, 2003; Riikonen and Vanhala, 1999; Vanhala et al, 1998). However, a recent study reports that BDNF mRNA levels are reduced in brain samples from RTT patients (Abuhatzira et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Bdnf overexpression in hippocampal neurons prevents dendritic atrophy caused by Rett-associated MECP2 mutations

Larimore

Chapleau

Kudo

et al. 2009

Neurobiology of Disease

114

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The expression of the methylated DNA-binding protein MeCP2 increases during neuronal development, which suggests that this epigenetic factor is crucial for neuronal terminal differentiation. We evaluated dendritic and axonal development in embryonic day-18 hippocampal neurons in culture by measuring total length and counting branch point numbers at 4 days in vitro, well before synapse formation. Pyramidal neurons transfected with a plasmid encoding a small hairpin RNA (shRNA) to knockdown endogenous Mecp2 had shorter dendrites than control untransfected neurons, without detectable changes in axonal morphology. On the other hand, overexpression of wildtype (wt) human MECP2 increased dendritic branching, in addition to axonal branching and length. Consistent with reduced neuronal growth and complexity in Rett syndrome (RTT) brains, overexpression of human MECP2 carrying missense mutations common in RTT individuals (R106W or T158M) reduced dendritic and axonal length. One of the targets of MeCP2 transcriptional control is the Bdnf gene. Indeed, endogenous Mecp2 knockdown increased the intracellular levels of BDNF protein compared to untransfected neurons, suggesting that MeCP2 represses Bdnf transcription. Surprisingly, overexpression of wt MECP2 also increased BDNF levels, while overexpression of RTT-associated MECP2 mutants failed to affect BDNF levels. The extracellular BDNF scavenger TrkB-Fc prevented dendritic overgrowth in wt MECP2-overexpressing neurons, while overexpression of the Bdnf gene reverted the dendritic atrophy caused by Mecp2-knockdown. However, this effect was only partial, since Bdnf increased dendritic length only to control levels in mutant MECP2-overexpressing neurons, but not as much as in Bdnftransfected cells. Our results demonstrate that MeCP2 plays varied roles in dendritic and axonal development during neuronal terminal differentiation, and that some of these effects are mediated by autocrine actions of BDNF.

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“…Animal studies have shown that alterations in endogenous NGF levels during the early postnatal stage influences the development of learning and memory capacities in rodents (Calamandrei et al 1996). As for human studies, low levels of NGF have been detected in the CSF of children with Rett and West syndromes: two neurological disorders associated with mental impairment (Lappalainen et al 1996, Riikonen et al 1997, Riikonen and Vanhala 1999. It has been suggested that altered production of specific neurotrophins during critical developmental phases may be involved in the pathogenesis of some psychiatric disorders as well as of syndromes associated with learning disability (Bersani et al 1996).…”

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confidence: 99%

Serum NGF levels in children and adolescents with either Williams syndrome or Down syndrome

Calamandrei

Alleva

Cirulli

et al. 2000

Develop Med Child Neuro

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The neurotrophin nerve growth factor (NGF) is a major regulator of peripheral and central nervous system development. Serum NGF was measured in normally developing control children (n=26) and in individuals affected by congenital syndromes associated with learning disability: either Williams syndrome (WS; n=12) or Down syndrome (DS; n=21). Participants were assessed at three distinct developmental stages: early childhood (2 to 6 years), childhood (8 to 12 years), and adolescence (14 to 20 years). A sample was taken only once from each individual. Serum NGF levels were markedly higher in participants with WS, than DS and control participants. In addition, different developmental profiles emerged in the three groups: while in normally developing individuals NGF levels were higher in early childhood than later on, children with WS showed constantly elevated NGF levels. When compared to control participants, those with DS showed lower NGF levels only during early childhood. Neuropsychological assessment confirmed previously reported differences among the three groups in the development of linguistic/cognitive abilities. Some features of individuals with WS, such as hyperacusis and hypertension, could be related to high‐circulating NGF levels.

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Levels of cerebrospinal fluid nerve-growth factor differ in infantile autism and Rett syndrome

Cited by 39 publications

References 45 publications

QTL replication and targeted association highlight the nerve growth factor gene for nonverbal communication deficits in autism spectrum disorders

QTL replication and targeted association highlight the nerve growth factor gene for nonverbal communication deficits in autism spectrum disorders

Bdnf overexpression in hippocampal neurons prevents dendritic atrophy caused by Rett-associated MECP2 mutations

Serum NGF levels in children and adolescents with either Williams syndrome or Down syndrome

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