Marie Gomot

X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the Neuroligin family

A large French family including members affected by nonspecific X-linked mental retardation, with or without autism or pervasive developmental disorder in affected male patients, has been found to have a 2-base-pair deletion in the Neuroligin 4 gene (NLGN4) located at Xp22.33. This mutation leads to a premature stop codon in the middle of the sequence of the normal protein and is thought to suppress the transmembrane domain and sequences important for the dimerization of neuroligins that are required for proper cell-cell interaction through binding to beta-neurexins. As the neuroligins are mostly enriched at excitatory synapses, these results suggest that a defect in synaptogenesis may lead to deficits in cognitive development and communication processes. The fact that the deletion was present in both autistic and nonautistic mentally retarded males suggests that the NLGN4 gene is not only involved in autism, as previously described, but also in mental retardation, indicating that some types of autistic disorder and mental retardation may have common genetic origins.

Hypersensitivity to acoustic change in children with autism: electrophysiological evidence of left frontal cortex dysfunctioning.

Exaggerated reactions to even small changes in the environment and abnormal behaviors in response to auditory stimuli are frequently observed in children with autism (CWA). Brain mechanisms involved in the automatic detection of auditory frequency change were studied using scalp potential and scalp current density (SCD) mapping of mismatch negativity (MMN) in 15 CWA matched with 15 healthy children. Compared with the response in controls, MMN recorded at the Fz site in CWA showed significantly shorter latency and was followed by a P3a wave. Mapping of potentials indicated significant intergroup differences. Moreover, SCD mapping demonstrated the dynamics of the different MMN generators: Although temporal component was evidenced bilaterally in both groups, it occurred earlier on the left hemisphere in CWA, preceded by an abnormal early left frontal component. The electrophysiological pattern reported here emphasized a left frontal cortex dysfunctioning that might also be implicated in cognitive and behavioral impairment characteristic, of this complex neurodevelopmental disorder.

Maturation of frontal and temporal components of mismatch negativity (MMN) in children.

The mismatch negativity (MMN) response of auditory ERPs in adults appears to result from several overlapping components involving both frontal and temporal brain areas. Our aim was to test whether a similar configuration could be observed in children, and to examine the maturation rates of the different components. MMN (standard tones: 1000 Hz, deviants: 1100 Hz) was recorded from 28 scalp electrodes in 24 healthy children aged from 5 to 10 and in eight adults for comparison. Scalp current density analysis revealed both temporal and frontal components in children of all ages as well as in adults. Moreover the amplitudes of the temporal components were significantly greater in children than in adults, whereas the frontal components were similar at all ages. The results strongly suggest that MMN is mediated by at least two separate neural systems, and that the frontal system matures earlier than the sensory-specific system.

FACL4, encoding fatty acid-CoA ligase 4, is mutated in nonspecific X-linked mental retardation.

X-linked mental retardation (XLMR) is an inherited condition that causes failure to develop cognitive abilities, owing to mutations in a gene on the X chromosome. The latest XLMR update lists up to 136 conditions leading to syndromic, or specific, mental retardation (MRXS) and 66 entries leading to nonspecific mental retardation (MRX). For 9 of the 66 MRX entries, the causative gene has been identified. Our recent discovery of the contiguous gene deletion syndrome ATS-MR (previously known as Alport syndrome, mental retardation, midface hypoplasia, elliptocytosis, OMIM #300194), characterized by Alport syndrome (ATS) and mental retardation (MR), indicated Xq22.3 as a region containing one mental retardation gene. Comparing the extent of deletion between individuals with ATS-MR and individuals with ATS alone allowed us to define a critical region for mental retardation of approximately 380 kb, containing four genes. Here we report the identification of two point mutations, one missense and one splice-site change, in the gene FACL4 in two families with nonspecific mental retardation. Analysis of enzymatic activity in lymphoblastoid cell lines from affected individuals of both families revealed low levels compared with normal cells, indicating that both mutations are null mutations. All carrier females with either point mutations or genomic deletions in FACL4 showed a completely skewed X-inactivation, suggesting that the gene influences survival advantage. FACL4 is the first gene shown to be involved in nonspecific mental retardation and fatty-acid metabolism.

Cortical auditory processing and communication in children with autism: electrophysiological/behavioral relations

The purpose of the present study was to investigate the relations between late auditory evoked potentials (AEPs) recorded at temporal sites (the N1c wave or Tb) and verbal and non-verbal abilities in children with autism. The study was performed in 26 mentally retarded children with autism (AUT) aged 4-8 years (mean age +/- S.E.M. = 71 +/- 2 months; mean verbal and non-verbal developmental quotient +/- S.E.M. = 36 +/- 4 and 48 +/- 3). The stimuli used were 750 Hz tone bursts of 200 ms duration delivered binaurally at different intensity levels (50, 60, 70, 80 dB SPL) with 3-5 s interstimulus intervals. Temporal AEPs were first compared to those of a group of 16 normal children (NOR) in the same age range (mean age +/- S.E.M. = 69 +/- 3 months). We then focused on the AUT group and considered relations between temporal AEPs and the severity of disorders of verbal and non-verbal communication assessed using a behavior rating scale. AEPs recorded on left and right temporal sites were of smaller amplitude in the AUT group than in the NOR group. Increasing intensity-related amplitude was observed on both sides in NOR and only on the right side in AUT. The lack of intensity effect on the left side resulted in a particular pattern of asymmetry at the highest level of intensity (80 dB SPL) with greater N1c amplitude on the right than on the left side (the reverse was found in the NOR group). Electro-clinical correlations indicated that the greater the amplitude of the right temporal N1c responses, the higher the verbal and non-verbal communication abilities. This suggests a developmental reorganization of left-right hemisphere functions in autism, with preferential activation of the right hemisphere for functions usually allocated to the left hemisphere, particularly those involving the secondary auditory areas situated on the lateral surface of the superior temporal gyrus where the N1c/Tb wave is generated.

Candidate electrophysiological endophenotypes of hyper-reactivity to change in autism.

Although resistance to change is a main feature of autism, the brain processes underlying this aspect of the disorder remain poorly understood. The aims of this study were to examine neural basis of auditory change-detection in children with autism spectrum disorders (ASD; Nxa0=xa027) through electrophysiological patterns (MMN, P3a) and to test whether these are quantitatively related to intolerance of change (using the BSE-R scale). ASD displayed significantly shorter MMN latency and larger P3a than controls, indicating a greater tendency to switch attention to deviant events. These electrophysiological abnormalities were significantly more marked in children who displayed greater difficulties in tolerating change. The atypical neurophysiological mechanism of change perception identified might thus be associated with one of the hallmark behavioural manifestations of autism.

Specific clinical and brain MRI features in mentally retarded patients with mutations in the Oligophrenin-1 gene.

Oligophrenin‐1 (OPHN‐1) gene disruption is known as responsible for so called “non‐specific” X‐linked mental retardation (MR) Billuart et al. [1998: Nature 392:923–926]. In order to search for a possible specific clinical and radiological profile for mutation in the OPHN‐1 gene, clinical and 3D brain MRI studies were performed in the two families with a known mutation in OPHN‐1 reported so far: a 19‐year‐old female with an X;12 balanced translocation encompassing OPHN‐1, and four affected males of family MRX60 sharing a frameshift mutation in OPHN‐1. Clinical data shared by affected individuals were neonatal hypotonia with motor delay but no obvious ataxia, marked strabismus, early onset complex partial seizures, and moderate to severe MR. Brain MRIs performed in three individuals exhibited a specific vermian dysgenesis including an incomplete sulcation of anterior and posterior vermis with the most prominent defect in lobules VI and VII. In addition, a non‐specific cerebral cortico‐subcortical atrophy was also observed. These clinical and radiological features suggest a distinct clinico‐radiological syndrome. These preliminary data need to be confirmed in other families and will be helpful for further targeted mutation screening of the OPHN‐1 gene in male patients with similar clinico‐radiological features. In addition, OPHN‐1 inactivation should be considered as a relevant model of developmental vermis disorganization, leading to a better understanding of the possible role of the cerebellum in MR.

MECP2 gene mutations in non-syndromic X-linked mental retardation: Phenotype–genotype correlation†

Non‐syndromic X‐linked mental retardation (MRX) is a frequent cause of inherited mental retardation. It is a heterogeneous condition in which the first 12 genes discovered to date explain no more than 15% of the MRX situations ascertained by recurrence in multiplex families. In Rett syndrome (RTT), an X‐linked dominant condition mostly sporadic and usually lethal in males, most affected females have been shown to be mutated in the Methyl–CpG binding protein 2 gene (MECP2) that maps at Xq28. Some mentally retarded males related to RTT females carry the same mutation. Several MRX families mapping to Xq28 were subsequently tested for MECP2 and a causative mutation was discovered in three families, suggesting that it could be one of the main genes involved in MRX. We report here the corresponding phenotypes in these three families of increasing severity. In family 1, an in‐frame deletion ΔP387‐M466 was found in the 3′ region. The patients had severe to mild non‐progressive MR, with better motor skills than verbal abilities. In family 2, an Arg to Trp substitution (R167W) was found between the transcription repression domain (TRD) and the methyl binding domain (MBD). The patients had brisk reflexes and essential tremor with mild and non‐progressive MR, poor motor co‐ordination and written language difficulties. In the third family (MRX16), a Glu to Gly substitution (E137G) was found in the MBD. The patients had manifestations similar to those of family 2, but MR was mild to moderate, speech articulation was poor and some had verbal stereotypies. Regression of language skills was suspected in three patients. Phenotype–genotype correlation could thus be suspected and is discussed in these three families.

Bioclinical profiles of autism and other developmental disorders using a multivariate statistical approach.

To study the relationships between clinical and biological data that are necessary for physiopathological analysis in the field of developmental disorders, we developed a quantified grouping system, based on four developmental assessment parameters. Parallel with this clinical research, we developed electrophysiological procedures adapted to the pathology of autism. In this paper, we report the utilization of an original multivariate descriptive statistical approach (correspondence analysis followed by cluster analysis) that allowed us to identify different bioclinical profiles using these clinical and electrophysiological data conjointly. These profiles are believed to be evidence for different underlying cerebral dysfunctions. This procedure proved effective in identifying two main bioclinical dimensions in a population of 145 developmentally disordered children. These dimensions reflect the association of intellectual impairment and centroparietal electrophysiological reactivity on the one hand, and autistic behavior and temporal electrophysiological reactivity on the other. This study, performed on a large population of children using objective methods of data analysis, provides validation of numerous multidisciplinary studies of autism and other developmental disorders carried out on small samples of children.

Comportements répétés et restreints (C2R) dans les troubles autistiques: évaluation clinique

INTRODUCTIONnRestricted and repetitive behaviours (RRB) represent a common problem throughout the autistic spectrum. They comprise a wide range of behavioural manifestations that persist over time and resist therapeutics. Furthermore, degrees of heterogeneity have been reported in the clinical expression of autistic syndrome, particularly in the restricted and repetitive aspects. Advances are needed in the understanding of this complex and heterogeneous clinical dimension of autism to improve efficacy of therapeutics.nnnLITERATURE FINDINGSnMost clinical studies have subdivided RRB into lower-level sensory-motor behaviours and higher-level behaviours, which are more complex and characteristic features of autism. However, none of these studies have taken into account all the forms of RRB. To date, there is no specific and thorough tool to evaluate this dimension of autism. From the analysis of the literature, we proposed a list of 43 behaviours covering the full range of repetitive, restricted and stereotyped activities observed in autism.nnnAIM OF THE STUDYnThe aim of the present study was to test the relevance of these 43 RRB in a family context.nnnCLINICAL SETTINGSnThe participants were 14 children with an autism spectrum disorder, aged from six to 16 years. Circumscribed interests were the most commonly reported RRB, and motor stereotypies, aggressive and body-focused behaviours were the least expressed behaviours.nnnRESULTSnMultivariate statistical analysis identified three groups of children with different behavioural profiles and three clusters of RRB, i.e. repetitive motor behaviours, repetitive sensory-vocal behaviours and restricted ideational behaviours.nnnDISCUSSIONnAlthough these preliminary results need to be validated in a wider population, the list of 43 RRB allowed us to describe accurately this symptomatology of autism and to confirm the heterogeneity of this dimension of autistic disorders. The identification of clinical subgroups, possibly underlain by different psychopathological or physiopathological factors would help research and contribute to the development of specific new therapeutic strategies which are still needed to improve quality of life of patients with autistic disorder and their families.