Clinical and experimental evidence suggest a link between KIF7 and C5orf42-related ciliopathies through Sonic Hedgehog signaling.

Acrocallosal syndrome (ACLS) is an autosomal recessive neurodevelopmental disorder caused by KIF7 defects and belongs to the heterogeneous group of ciliopathies related to Joubert syndrome (JBTS). While ACLS is characterized by macrocephaly, prominent forehead, depressed nasal bridge, and hypertelorism, facial dysmorphism has not been emphasized in JBTS cohorts with molecular diagnosis. To evaluate the specificity and etiology of ACLS craniofacial features, we performed whole exome or targeted Sanger sequencing in patients with the aforementioned overlapping craniofacial appearance but variable additional ciliopathy features followed by functional studies. We found (likely) pathogenic variants of KIF7 in 5 out of 9 families, including the original ACLS patients, and delineated 1000 to 4000-year-old Swiss founder alleles. Three of the remaining families had (likely) pathogenic variants in the JBTS gene C5orf42, and one patient had a novel de novo frameshift variant in SHH known to cause autosomal dominant holoprosencephaly. In accordance with the patients' craniofacial anomalies, we showed facial midline widening after silencing of C5orf42 in chicken embryos. We further supported the link between KIF7, SHH, and C5orf42 by demonstrating abnormal primary cilia and diminished response to a SHH agonist in fibroblasts of C5orf42-mutated patients, as well as axonal pathfinding errors in C5orf42-silenced chicken embryos similar to those observed after perturbation of Shh signaling. Our findings, therefore, suggest that beside the neurodevelopmental features, macrocephaly and facial widening are likely more general signs of disturbed SHH signaling. Nevertheless, long-term follow-up revealed that C5orf42-mutated patients showed catch-up development and fainting of facial features contrary to KIF7-mutated patients.

Cerebellum enlargement and corpus callosum agenesis: a longitudinal case report.

Macrocerebellum, a neuroradiological and clinical entity of unknown etiology characterized by an isolated, disproportionately large cerebellum, has to date been reported in only a few cases. It has been suggested that the condition could represent a marker for disturbed cerebral development, however, longitudinal reports are lacking. We describe a 19-month-old patient with agenesis of the corpus callosum, who developed enlargement of the cerebellum without clinical signs of cerebellar impairment, a picture that has not been previously described.

KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes.

KIF7, the human ortholog of Drosophila Costal2, is a key component of the Hedgehog signaling pathway. Here we report mutations in KIF7 in individuals with hydrolethalus and acrocallosal syndromes, two multiple malformation disorders with overlapping features that include polydactyly, brain abnormalities and cleft palate. Consistent with a role of KIF7 in Hedgehog signaling, we show deregulation of most GLI transcription factor targets and impaired GLI3 processing in tissues from individuals with KIF7 mutations. KIF7 is also a likely contributor of alleles across the ciliopathy spectrum, as sequencing of a diverse cohort identified several missense mutations detrimental to protein function. In addition, in vivo genetic interaction studies indicated that knockdown of KIF7 could exacerbate the phenotype induced by knockdown of other ciliopathy transcripts. Our data show the role of KIF7 in human primary cilia, especially in the Hedgehog pathway through the regulation of GLI targets, and expand the clinical spectrum of ciliopathies.

The FG syndrome from a pathological perspective.

We report on a case of FG syndrome in an almost 6-year-old boy, diagnosed post-mortem. The description of the intellectual and behavior phenotype provided by the mother, together with the evidence gathered at autopsy, were sufficient to reach a clinical diagnosis. The mother had mild manifestations, including a symptomatic tethered cord, which established her as a carrier of the putative mutation causing the syndrome in the son. The propositus' phenotype did not suggest involvement of the MED12 gene.

Toriello Carey syndrome: genetic, clinical, and oral considerations: a case report.

Toriello Carey syndrome is a rare recessive autosomal disease whose clinical manifestations are more evident in males. Some authors report that the general characteristics of this disease are agenesis of the corpus callosum, mental disability, convulsions, atrial septal defect, pulmonary artery stenosis, pyloric stenosis, and hypospadias. Facial and cranial alterations may occur, including hypertelorism, telecanthus, divergent strabismus, malformed ears, anteverted nares, retrognathism, and cleft palate. This paper reports on a 13-year-old male with Toriello Carey syndrome and leucoderma, and describes his oral problems and his dental care.

Language lateralization in individuals with callosal agenesis: an fMRI study.

Since the seminal work of Broca in 1861, it is well established that language is essentially processed in the left hemisphere. However, the origin of hemispheric specialization remains controversial. Some authors posit that language lateralization is genetically determined, while others have suggested that hemispheric specialization develops with age. Tenants of the latter view have further suggested that the adult pattern of left hemispheric specialization is achieved by means of callosal inhibition of homologous speech areas in the right hemisphere during ontogeny. According to this hypothesis, one would expect language to develop bilaterally in the acallosal brain. A recent functional magnetic resonance imaging (fMRI) study in one patient with agenesis of the corpus callosum suggests that this might indeed be the case (Riecker et al., 2007). However, given the large anatomic and functional variability in the population of subjects with agenesis of the corpus callosum, this finding needs to be more extensively replicated. In the present study, we explored language lateralization in six individuals with agenesis of the corpus callosum using an fMRI protocol which included a syntactic decision task and a sub-vocal verbal fluency task. Two neurologically intact control groups, one comparable to the acallosals in terms of IQ, age and education (n=6) and one group with a high IQ (n=5), performed the same tasks. No differences were found between language lateralization of the subjects with agenesis of the corpus callosum and the control groups in the receptive speech task. However, for expressive speech, the groups differed with respect to frontal activations, with the acallosal participants showing a more bilateral pattern of activation than the high-IQ participants only. No differences were found for temporal regions. Overall, these results indicate that the corpus callosum is not essential for the establishment of lateralized language functions.

Diffusion MRI abnormalities in pediatric neurological disorders.

Diffusion-weighted imaging (DWI) makes it possible to measure early changes in cellular function in the central nervous system. The purpose of this article is to discuss the diagnostic value of diffusion-weighted and diffusion tensor imaging (DTI) in different pediatric cerebral disorders. First, the principles of DWI and DTI are briefly reviewed. The clinical usefulness of these imaging techniques is then discussed using cases with pediatric neurological disorders, such as hypoxic-ischemic encephalopathy in neonates, trauma (shaken baby syndrome), encephalopathy or encephalitis in infants, posterior reversible encephalopathy syndrome and congenital brain anomaly (callosal dysgenesis). In addition, using DTI, we evaluate normal brain development, particularly in the corpus callosum and cortico-spinal tract, and discuss the application of DTI to the study of white matter in the developing brain.

Acrocallosal syndrome in a young hypertensive male.

Acrocallosal syndrome is an extremely rare genetic disorder with autosomal recessive inheritance. It is characterised by moderate to severe mental retardation, hypotonia, agenesis of the corpus callosum and preaxial polydactyly involving both feet and the facial features like broad forehead and hypertelorism. The authors report a case of a young hypertensive male who presented with unprovoked seizures for the first time who had multiple craniofacial, digital dysmorphic features with moderate mental retardation. The diagnosis of acrocallosal syndrome was arrived at after neuroimaging showed agenesis of corpus callosum with interhemispheric cysts.

[Agenesis of corpus callosum - a review].

The subject herein discussed is malformations about which information abounds. This is due to constant improvements in approaches to obtaining such information through images generated by modern imaging technology. As the examination of structures at hand progresses, so does the possibility for precise imaging diagnostics. Agenesis of the corpus callosum is one those subtle and difficult to detect malformations which are currently becoming subjects of research. Agenesis of the corpus callosum is a brain anomaly with incidence of occurrence from 0.05 to 0.7%. It could be either observed in 49% of cases unaccompanied by other conditions or accompanied by other anomaly syndromes. This cerebral malformation is usually diagnosed post partum in children suffering from epilepsy or behaviour or cognitive disorders. In consideration of the necessity of early fetal abnormality detection and the conduct of the obstetrician in a social aspect, the above-mentioned is a prerequisite which makes discussions necessary. Constant up-dating and discussions allow periodic revision and optimizations of prenatal diagnostics.

[Impact of prenatal corpus callosum agenesis diagnosis on pregnancy outcome. Evaluation of 155 cases between 2000 and 2006]. / Impact du dépistage anténatal des agénésies du corps calleux sur le devenir des grossesses. Etude de 155 dossiers de 2000 à 2006.

The purpose of this study was to investigate the changes between 2000 and 2006 in pregnancy outcome when a diagnosis of either isolated or associated fetal corpus callosum agenesis (CCA) was made, given that beginning in 2003, the information provided to couples facing this problem related a good prognosis in nearly 80 % of cases of isolated CCA and a poor prognosis in 20 % of cases. We retrospectively analyzed all pregnancies with a fetal diagnosis of CCA between 2000 and 2006 (n=155) and compared two periods: the first group from 2000 to June 2003, the second from July 2003 to 2006. For each group, we analyzed the type of CCA during pregnancy - either isolated or associated - and the outcome of pregnancy. We compared the rate of pregnancy termination before and after 2003 and analyzed the accuracy of the prenatal CCA diagnosis. Of the 155 patients studied, 62 terminated the pregnancy. The overall rate of termination decreased from 31/70 to 31/85. When CCA was said to be isolated prenatally, the rate of pregnancy termination fell from 13/35 to 9/44 (-17 %) (p<0.05). Nine diagnoses of CCA were corrected after birth or by postmortem examination. Improvement of prenatal diagnosis requires better quality of prenatal screening, with a more systematic study of dysmorphic features, a study of correlations between the type of CCA and the neurological prognosis, and more genetic studies.

Social cognition in individuals with agenesis of the corpus callosum.

Past research has revealed that individuals with agenesis of the corpus callosum (ACC) have deficits in interhemispheric transfer, complex novel problem-solving, and the comprehension of paralinguistic aspects of language. Case studies and family reports also suggest problems in social cognition. The performance of 11 individuals with complete ACC and with normal intelligence was compared to that of 13 IQ- and age-matched controls on three measures of social cognition. Individuals with ACC were indistinguishable from controls on the Happe Theory of Mind Stories and the Adult Faux Pas Test, but performed significantly worse on various portions of the Thames Awareness of Social Inference Test (TASIT) involving interpretations of videotaped social vignettes. Further analysis of the TASIT indicated that individuals with ACC showed deficiency in the recognition of emotion, weakness in understanding paradoxical sarcasm, and particular difficulty interpreting textual versus visual social cues. These results suggest that the tendency for deficient social cognition in individuals with ACC stems from a combination of difficulty integrating information from multiple sources, using paralinguistic cues for emotion, and understanding nonliteral speech. Together, these deficits would contribute to a less robust theory of mind.

Benefits of examination by post mortem performed magnetic resonance imaging of foetus: haemorrhage in germinal matrix.

Post mortem magnetic resonance imaging is demonstrated as a supplementary method to classic pathological-anatomical autopsy in determining anomalies of the foetus. Frequently it plays a key role; primarily where the possibilities of performing autopsy are somehow limited (autolysis, ventricular dilatation). Specification of the final diagnosis subsequently enables us to improve prenatal diagnostics, both by means of magnetic resonance imaging and primarily by correlation with the prenatal ultrasound scan; this feedback improves the later method. This case report demonstrated that post mortem magnetic resonance imaging, in contrast with prenatal ultrasound examination, showed extensive haemorrhage in the germinal matrix, and also illustrated indirect symptoms testifying to agenesis of the corpus callosum. Prenatal ultrasound examination showed only hydrocephalus and absence of septum pellucidum. Pathological-anatomical autopsy of the brain was insufficient with regard to advanced autolysis and brain haemorrhage.

Assessment of sulcation of the fetal brain in cases of isolated agenesis of the corpus callosum using in utero MR imaging.

BACKGROUND AND PURPOSE: There is gathering evidence to suggest that agenesis of the corpus callosum is associated with delayed fetal sulcation; it is possible that the corpus callosum facilitates normal gyral development. In this paper we sought to confirm whether delayed sulcation is found in fetuses with isolated agenesis of the corpus callosum as judged by in utero MR imaging. MATERIALS AND METHODS: Retrospective analysis of 20 fetuses with isolated corpus callosum agenesis investigated by in utero MR imaging and 20 aged-matched normal fetuses was performed in the second or third trimester. All fetuses were singleton pregnancies with known gestational age, imaged on a 1.5T superconducting MR system. Estimation of sulcation maturity was made with reference to a standard atlas and subgroup analysis of earlier gestation (group 1, 21-26 weeks) and later gestation (group 2, 30-34 weeks) fetuses was performed. RESULTS: Group 1 (n = 12) did not show a statistically significant difference between the 2 subgroups (P = .44) in terms of sulcation. A significant difference was demonstrated in the later gestation, group 2 (n = 8) fetal analyses; mean difference between consensus and actual gestation for normal fetuses was 0.9 weeks (SD of 1.5 weeks) versus -0.5 weeks (SD of 1.1 weeks) for the agenesis of corpus callosum cases (P = .046), suggestive of delayed sulcation in callosal agenesis. CONCLUSIONS: Delayed sulcation encountered in third trimester fetuses with agenesis of the corpus callosum may be seen and does not in itself imply an additional brain abnormality.

Diffusion-weighted imaging in fetuses with unilateral cortical malformations and callosal agenesis.

DWI was performed in fetuses with callosal agenesis and unilateral cortical malformations. ADC values were retrospectively measured in the developing white matter underlying the cortical malformation and compared with the corresponding contralateral white matter. In all 3 patients, ADC values were lower under the areas of cortical malformation compared with the normal contralateral side. Our findings suggest that there are structural differences in the developing white matter underlying areas of cortical malformation.

Transient neuronal populations are required to guide callosal axons: a role for semaphorin 3C.

The corpus callosum (CC) is the main pathway responsible for interhemispheric communication. CC agenesis is associated with numerous human pathologies, suggesting that a range of developmental defects can result in abnormalities in this structure. Midline glial cells are known to play a role in CC development, but we here show that two transient populations of midline neurons also make major contributions to the formation of this commissure. We report that these two neuronal populations enter the CC midline prior to the arrival of callosal pioneer axons. Using a combination of mutant analysis and in vitro assays, we demonstrate that CC neurons are necessary for normal callosal axon navigation. They exert an attractive influence on callosal axons, in part via Semaphorin 3C and its receptor Neuropilin-1. By revealing a novel and essential role for these neuronal populations in the pathfinding of a major cerebral commissure, our study brings new perspectives to pathophysiological mechanisms altering CC formation.

Understanding the mechanisms of callosal development through the use of transgenic mouse models.

The cerebral cortex is the area of the brain where higher-order cognitive processing occurs. The 2 hemispheres of the cerebral cortex communicate through one of the largest fiber tracts in the brain, the corpus callosum. Malformation of the corpus callosum in human beings occurs in 1 in 4000 live births, and those afflicted experience an extensive range of neurologic disorders, from relatively mild to severe cognitive deficits. Understanding the molecular and cellular processes involved in these disorders would therefore assist in the development of prognostic tools and therapies. During the past 3 decades, mouse models have been used extensively to determine which molecules play a role in the complex regulation of corpus callosum development. This review provides an update on these studies, as well as highlights the value of using mouse models with the goal of developing therapies for human acallosal syndromes.

Aicardi syndrome in a 47, XXY male neonate with lissencephaly and holoprosencephaly.

Aicardi syndrome (AS) is a rare neuro-ophthalmic disorder first described by Jean Aicardi in 1965 with a characteristic triad of corpus callosal agenesis (CCA), chorioretinal lacunae (CRL), and infantile spasms (IS). All known cases of AS have been sporadic and a responsible gene has not been identified. With 5 exceptional males, potential X-linked dominant genetic mutation characterizes AS occurring almost exclusively in girls. Most of male AS cases were still debatable in diagnosis either for their 46 XY karyotype or too atypical presentations to fit the formerly stricter diagnostic criteria. We report a 47, XXY male neonate presenting some undisputable, but otherwise some regarded as atypical features in AS. We compare his distinctively clinical pictures with previously reported male cases and find CRL is less pathognomonic and lissencephaly appears frequently among male AS. Because of insufficient genetic and biochemical markers for definite diagnosis at this moment, we suggest the experience of a relatively rare male case would help to shed light on the underlying genetic pathogenesis of AS.