Characterizing White Matter Tract Organization in Polymicrogyria and Lissencephaly: A Multifiber Diffusion MRI Modeling and Tractography Study.

BACKGROUND AND PURPOSE: Polymicrogyria and lissencephaly may be associated with abnormal organization of the undelying white matter tracts that have been rarely investigated so far. Our aim was to characterize white matter tract organization in polymicrogyria and lissencephaly using constrained spherical deconvolution, a multifiber diffusion MR imaging modeling technique for white matter tractography reconstruction. MATERIALS AND METHODS: We retrospectively reviewed 50 patients (mean age, 8.3 ± 5.4 years; range, 1.4-21.2 years; 27 males) with different polymicrogyria (n = 42) and lissencephaly (n = 8) subtypes. The fiber direction-encoded color maps and 6 different white matter tracts reconstructed from each patient were visually compared with corresponding images reconstructed from 7 age-matched, healthy control WM templates. Each white matter tract was assessed by 2 experienced pediatric neuroradiologists and scored in consensus on the basis of the severity of the structural abnormality, ranging from the white matter tracts being absent to thickened. The results were summarized by different polymicrogyria and lissencephaly subgroups. RESULTS: More abnormal-appearing white matter tracts were identified in patients with lissencephaly compared with those with polymicrogyria (79.2% versus 37.3%). In lissencephaly, structural abnormalities were identified in all studied white matter tracts. In polymicrogyria, the more frequently affected white matter tracts were the cingulum, superior longitudinal fasciculus, inferior longitudinal fasciculus, and optic radiation-posterior corona radiata. The severity of superior longitudinal fasciculus and cingulum abnormalities was associated with the polymicrogyria distribution and extent. A thickened superior fronto-occipital fasciculus was demonstrated in 3 patients. CONCLUSIONS: We demonstrated a range of white matter tract structural abnormalities in patients with polymicrogyria and lissencephaly. The patterns of white matter tract involvement are related to polymicrogyria and lissencephaly subgroups, distribution, and, possibly, their underlying etiologies.

Developmental care, neonatal behavior and postnatal maternal depressive symptomatology predict internalizing problems at 18 months for very preterm children.

OBJECTIVE: To provide a prospective developmental model for behavioral outcomes in preterm infants in relation to developmental care (DC) practices and postnatal maternal depression. STUDY DESIGN: A longitudinal, multicenter, follow-up study conducted in 25 Italian tertiary neonatal intensive care units (NICUs). Participants were 162 healthy very preterm infants and their mothers. The level of quality of DC was assessed for each hospital. Infant's neurobehavioral profile was evaluated twice: at discharge (T1) and at 18 months for behavioral problems (T3). Maternal depressive symptomatology was measured at T1 and at 6 months (T2). RESULTS: Low-quality DC in NICUs was associated with lower levels of infant neurobehavioral adaptability and higher levels of maternal depressive symptoms. Maternal depressive symptomatology in conjunction with higher infant dysregulation predicted more internalizing problems at 18 months of age. CONCLUSION: DC interventions and postnatal maternal depression, as well as infant behavior have an impact on short- and long-term infant outcomes.

Anterior Mesencephalic Cap Dysplasia: Novel Brain Stem Malformative Features Associated with Joubert Syndrome.

In Joubert syndrome, the "molar tooth" sign can be associated with several additional supra- and infratentorial malformations. Here we report on 3 subjects (2 siblings, 8-14 years of age) with Joubert syndrome, showing an abnormal thick bulging of the anterior profile of the mesencephalon causing a complete obliteration of the interpeduncular fossa. DTI revealed that the abnormal tissue consisted of an ectopic white matter tract with a laterolateral transverse orientation. Tractographic reconstructions support the hypothesis of impaired axonal guidance mechanisms responsible for the malformation. The 2 siblings were compound heterozygous for 2 missense variants in the TMEM67 gene, while no mutations in a panel of 120 ciliary genes were detected in the third patient. The name "anterior mesencephalic cap dysplasia," referring to the peculiar aspect of the mesencephalon on sagittal MR imaging, is proposed for this new malformative feature.

Greater brain response to emotional expressions of their own children in mothers of preterm infants: an fMRI study.

OBJECTIVE: The birth of a preterm infant and Neonatal Intensive Care Unit hospitalization constitute a potentially traumatic experience for mothers. Although behavioral studies investigated the parenting stress in preterm mothers, no study focused on the underlying neural mechanisms. We examined the effect of preterm births in mothers, by comparing brain activation in mothers of preterm and full-term infants. STUDY DESIGN: We used functional magnetic resonance imaging to measure the cerebral response of 10 first-time mothers of preterm infants (gestational age <32 weeks and/or birth weight <1500) and 11 mothers of full-term infants, viewing happy-, neutral- and distress-face images of their own infant, along with a matched unknown infant. RESULTS: While viewing own infant's face preterm mothers showed increased activation in emotional processing area (i.e., inferior frontal gyrus) and social cognition (i.e., supramarginal gyrus) and affiliative behavior (i.e., insula). CONCLUSION: Differential brain activation patterns in mothers appears to be a function of the atypical parenthood transition related to prematurity.

When one is Enough: Impaired Multisensory Integration in Cerebellar Agenesis.

In the last two decades, an intriguing shift in the understanding of the cerebellum has led to consider the nonmotor functions of this structure. Although various aspects of perceptual and sensory processing have been linked to the cerebellar activity, whether the cerebellum is essential for binding information from different sensory modalities remains uninvestigated. Multisensory integration (MSI) appears very early in the ontogenesis and is critical in several perceptual, cognitive, and social domains. For the first time, we investigated MSI in a rare case of cerebellar agenesis without any other associated brain malformations. To this aim, we measured reaction times (RTs) after the presentation of visual, auditory, and audiovisual stimuli. A group of neurotypical age-matched individuals was used as controls. Although we observed the typical advantage of the auditory modality relative to the visual modality in our patient, a clear impairment in MSI was found. Beyond the obvious prudence necessary for inferring definitive conclusions from this single-case picture, this finding is of interest in the light of reduced MSI abilities reported in several neurodevelopmental and psychiatric disorders-such as autism, dyslexia, and schizophrenia-in which the cerebellum has been implicated.

Language outcomes at 36 months in prematurely born children is associated with the quality of developmental care in NICUs.

OBJECTIVE: The aim of this study was to examine the relationship between the quality levels of NICU developmental care (DC) and language skills at 36 months in very preterm (VPT) children. STUDY DESIGN: Language skills of 78 VPT children from 19 NICUs and 90 full-term controls was assessed using a standardized language test. We compared children' language task performance by splitting NICUs into units with high- and low-quality of DC according to two main factors: (1) infant centered care (ICC), and (2) infant pain management (IPM). RESULTS: VPT children from low-care units with respect to ICC obtained lower scores in sentence comprehension, compared to children from high-care units. No differences were found between preterm children from high-quality ICC NICUs and full-term children. CONCLUSIONS: Findings suggest that higher quality of DC related to infant centered care can mitigate delays in language skills at 36 months in children born VPT.

Neonatal developmental care in infant pain management and internalizing behaviours at 18 months in prematurely born children.

BACKGROUND: Very preterm infants are exposed to adverse stressful experiences, which may result in long-term behavioural outcomes. The developmental care practices, including pain management and environmental support, can minimize the effects of stress exposure. However, developmental care quality levels may vary among Neonatal Intensive Care Units (NICUs) and little is known about how differences in developmental care quality affect long-term behavioural outcomes. The aim of this study was to examine the relation between quality levels NICUs developmental care and behaviour problems at 18 months corrected age in preterm children. METHODS: The behaviour of 134 preterm children from 22 NICUs and 123 full-term controls was examined using the questionnaire Child Behaviour Checklist 1½-5. We compared the behavioural profile of children by splitting NICUs into units with high- and low quality of developmental care according to two main care factors: (1) infant centered care (ICC) index, and (2) infant pain management (IPM) index. RESULTS: Preterm children from low-care units in IPM group reported higher scores in Internalizing Problems, compared to children from high-care units. No differences were found between preterm children from high-care in IPM and full-term children. No significant IPM effect was found for externalizing problems. No significant ICC effect emerged both for internalizing and externalizing problems. CONCLUSIONS: Findings suggest that higher quality of developmental care related to infant pain management can mitigate behavioural problems at 18 months in children born preterm, to such an extent that preterm children exhibit a behavioural profile similar to that displayed by full-term children.

Behavioural features of Italian infants and young adults with Williams-Beuren syndrome.

BACKGROUND: The increased interest in social interaction in Williams-Beuren syndrome (WBS) is evident from infancy onwards, together not only with increased empathy, positive interpersonal bias, but also with social disinhibition. Previous studies have described behavioural and emotional problems as being widely represented in WBS. There is limited scope for comparisons between literature data because of the variety of instruments used to assess behaviour. METHOD: Forty-one children and young adults with WBS were enrolled and underwent general cognitive assessment. In order to compare our data with the literature, we used standardised questionnaires used in previous studies (Developmental Behaviour Checklist: DBC-P). General cognitive abilities, gender and age were included in the analysis. RESULTS: Behavioural problems were more relevant than expected according to intellectual impairment. Some features were present at any age: inattention, anxiety, disruptive behaviours. Antisocial conduct was almost absent; perseverative conduct, a poor sense of danger and, more generally, self-absorbed behaviours tended to diminish along with age and to be linked to more pronounced cognitive impairment. CONCLUSION: As previously described for other countries, behaviour disturbances occur frequently in the Italian WBS population. Our data could support the existence of some 'intrinsic' behavioural characteristics in WBS such as inattention and anxiety, which are detectable and important at any age; both learning and social exposure to a structured context such as school could help diminish self-absorbed behaviour.

Novel splice-site mutations and a large intragenic deletion in PLA2G6 associated with a severe and rapidly progressive form of infantile neuroaxonal dystrophy.

Infantile neuroaxonal dystrophy, INAD, is a severe progressive psychomotor disorder with infantile onset and characterized by the presence of axonal spheroids throughout the central and peripheral nervous systems. A subset of INAD patients shows also brain iron accumulation which represents instead the distinctive feature of the idiopathic neurodegeneration with brain iron accumulation, NBIA. These diseases share the same causative gene, PLA2G6, encoding iPLA2-VIA, a calcium-independent phospholipase. Mutations that lead to a complete absence of protein are associated with a severe INAD profile, while compound heterozygous mutations with possibly a residual protein activity are instead associated with the less severe NBIA phenotype. Here we describe two INAD patients both with an unusually rapid disease progression and a peculiar neuroradiological presentation in one of them. Compound heterozygosity for a large intragenic deletion and a nonsense mutation was found in one of them while the other is carrying two novel splice-site mutations. Breakpoint-sequence analysis suggests a non-allelic-homologous-recombination (NAHR) event, probably underlying the rearrangement. These findings, while supporting the genotype-phenotype correlation already observed in INAD patients, provide the first sequence characterization of a genomic rearrangement in PLA2G6 gene, thus orienting the search for missing mutant alleles in PLA2G6 related diseases.

Academic performance in children with rolandic epilepsy.

The aim of this study was to investigate the frequency of reading, writing, and calculation disabilities in children with typical rolandic epilepsy (RE) and healthy control children. We also aimed to define the possible electroclinical markers of specific cognitive dysfunctions in RE. School abilities were evaluated and compared in 20 children (eight males, 12 females; mean age 10y 3mo [SD 1y 7mo]; range 7y 9mo-12y 9mo) consecutively diagnosed with typical RE, and a group of 21 healthy controls (nine males, 12 females; mean age 10y 4mo [SD 1y 8mo]; range 7y 6mo-13y 3mo). All the children received standardized neuropsychological tests. For each patient an exhaustive seizure diary was kept and all the sleep electroencephalogram (EEG) recordings were reviewed. Specific difficulties with reading, writing, and calculation (diagnosed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition) were found in nine out of 20 children with RE and two out of 21 healthy controls (chi2=0.01). The specific learning disabilities in the RE group were correlated with a marked increase in epileptiform discharges during sleep (chi2=0.02) and an early onset of epilepsy (chi2=0.02). Our findings suggest that seizure onset before age 8 years and epileptiform discharges (more than 50% of the sleep EEG recording) in several tracings over more than a year are relevant markers for identifying patients at risk of developing academic difficulties.

Clinical and molecular characteristics of 1qter microdeletion syndrome: delineating a critical region for corpus callosum agenesis/hypogenesis.

BACKGROUND: Patients with a microscopically visible deletion of the distal part of the long arm of chromosome 1 have a recognisable phenotype, including mental retardation, microcephaly, growth retardation, a distinct facial appearance and various midline defects including corpus callosum abnormalities, cardiac, gastro-oesophageal and urogenital defects, as well as various central nervous system anomalies. Patients with a submicroscopic, subtelomeric 1qter deletion have a similar phenotype, suggesting that the main phenotype of these patients is caused by haploinsufficiency of genes in this region. OBJECTIVE: To describe the clinical presentation of 13 new patients with a submicroscopic deletion of 1q43q44, of which nine were interstitial, and to report on the molecular characterisation of the deletion size. RESULTS AND CONCLUSIONS: The clinical presentation of these patients has clear similarities with previously reported cases with a terminal 1q deletion. Corpus callosum abnormalities were present in 10 of our patients. The AKT3 gene has been reported as an important candidate gene causing this abnormality. However, through detailed molecular analysis of the deletion sizes in our patient cohort, we were able to delineate the critical region for corpus callosum abnormalities to a 360 kb genomic segment which contains four possible candidate genes, but excluding the AKT3 gene.

Indicators of theory of mind in narrative production: a comparison between individuals with genetic syndromes and typically developing children.

It is a matter of debate whether the development of theory of mind (ToM) depends on linguistic development or is, rather, an expression of cognitive development. The study of genetic syndromes, which are characterized by intellectual impairment as well as by different linguistic profiles, may provide useful information with respect to this issue. The present study compares indicators of ToM in the narrative production of individuals with Cornelia de Lange syndrome, Down syndrome, Williams syndrome and typically developing children, matched on sex and mental age. Statistical comparisons of data obtained from a qualitative analysis of the narrative production of the different groups confirm the presence of distinctive patterns, mainly related to the effective use of personal pronouns. The analysis of correlations among story-telling variables and other cognitive and linguistic variables suggests that the relationship between language development, cognitive development, and the emergence of ToM cannot be reduced to unidirectional causal links.

A novel mutation in KCNQ2 associated with BFNC, drug resistant epilepsy, and mental retardation.

BACKGROUND: Benign familial neonatal convulsion (BFNC) is a rare autosomal dominant disorder caused by mutations in two genes, KCNQ2 and KCNQ3, encoding for potassium channel subunits underlying the M-current. This current limits neuronal hyperexcitability by causing spike-frequency adaptation. METHODS: The authors describe a BFNC family with four affected members: two of them exhibit BFNC only while the other two, in addition to BFNC, present either with a severe epileptic encephalopathy or with focal seizures and mental retardation. RESULTS: All affected members of this family carry a novel missense mutation in the KCNQ2 gene (K526N), disrupting the tri-dimensional conformation of a C-terminal region of the channel subunit involved in accessory protein binding. When heterologously expressed in CHO cells, potassium channels containing mutant subunits in homomeric or heteromeric configuration with wild-type KCNQ2 and KCNQ3 subunits exhibit an altered voltage-dependence of activation, without changes in intracellular trafficking and plasma membrane expression. CONCLUSION: The KCNQ2 K526N mutation may affect M-channel function by disrupting the complex biochemical signaling involving KCNQ2 C-terminus. Genetic rather than acquired factors may be involved in the pathophysiology of the phenotypic variability of the neurologic symptoms associated with BFNC in the described family.

Long-term neuropsychological deficits after cerebellar infarctions in two young adult twins.

Two young adult dizygotic twins with high schooling suffered two strokes at the ages of 26 and 30 years. On the first occasion, Case 2 suffered a stroke only a few months after Case 1; on the second occasion, Case 1 suffered a second stroke a few months after Case 2. In Case 1, lesions were mainly localized to the left cerebellar hemisphere in both stroke episodes. Case 2 suffered lesions localized to the right cerebellar hemisphere in the first stroke episode, and multiple lesions in both cerebellar hemispheres and the vermis, right pons and left thalamus during the second stroke episode. Seven years after the second stroke, despite full recovery of motor functions, the patients still show mild, yet selective, linguistic deficits (syntactic comprehension deficits, mild agrammatism, reading and writing disorders) without speech disturbances. They also present with selective dysfunctions in visuospatial short-term memory. Language disorders are ascribed to a dysfunction of the cerebellum in Case 1, while in Case 2 a dysfunction of the cerebellum and the thalamus is considered as both structures are part of the so-called 'frontal lobe system', which supports language generation. Visuospatial short-term memory disorders are attributed to an impaired ability to appreciate the organizing structure of the visual task and to poor planning strategies, which are in turn ascribed to cerebellar lesions. The role of the cerebellum in cognitive and linguistic functions is discussed.

Retrospective diagnosis of congenital cytomegalovirus infection and cortical maldevelopment.

Congenital cytomegalovirus (CMV) infection can cause malformations of cortical development (MCD). It is difficult to establish CMV as a cause of MCD several months postpartum. This can now be done by detection of CMV DNA in dried blood spots (DBS test) on Guthrie cards. The authors used DBS tests to assess 10 patients with MCD of unknown cause. Four of the 10 patients were positive for CMV.

Low-dose desmopressin infusion: renal action in healthy women in moderate salt retention and depletion, and interactions with prostanoids.

Studies were carried out to evaluate the influence of variations in sodium balance on the renal response to low-dose infusion of 1-desamino-8- D -arginine vasopressin (dDAVP), and the functional interaction between dDAVP and renal prostanoids. The studies were performed on healthy women in conditions of extracellular fluid volume expansion (SR group, n =9) and depletion (SD2 group, n=6), respectively. The study protocol included hypotonic polyuria (induced by oral water load) and subsequent antidiuresis (induced by low-dose infusion of dDAVP). Three 60-min clearance (cl.) periods were performed during polyuria (cl. P), early (cl. A1) and late (cl. A2) antidiuresis. The urinary concentrations of prostaglandin (PG) E(2) and the stable metabolites of PGI(2) and thromboxane (Tx) A(2), 6-keto-PGF(1alpha) (6KPGF) and TxB(2), were estimated. Paired renal functional explorations were performed in salt retention and salt depletion both in absence and presence of indomethacin (SR.I and SD2.I groups). In both paired and unpaired studies, the early and late effects of dDAVP on the functional excretory variables and the excretion of prostanoids were assessed as percentage variations, (A1-P)% P and (A2-A1)% A1. (I) dDAVP in salt retention and depletion. During early infusion dDAVP produced in both conditions a significant reduction in urinary flow rate, creatinine cl., absolute and fractional excretions of sodium, chloride and potassium; during late infusion dDAVP was effective in inducing a further significant reduction in urinary flow rate. In salt retention compared to depletion the early reductions in sodium and chloride (absolute and fractional) excretions were significantly lower. (II) Indomethacin pretreatment. During early infusion the dDAVP-induced reductions in the urinary flow rate and 6KPGF excretion were enhanced in both conditions. In salt depletion the dDAVP effects in reduction of creatinine cl. and urinary electrolyte excretions were also enhanced. During late infusion the antidiuretic effect of dDAVP was suppressed in salt retention, while in salt depletion creatinine cl., the urinary excretions of electrolytes and both 6KPGF and TxB(2) showed increases significantly different from the dDAVP effects in the absence of indomethacin. In conclusion, (a) the salt-retaining effect of dDAVP was less effective in salt retention compared to depletion. (b) Indomethacin pretreatment affected the renal action of dDAVP in a time-dependent pattern. The early effects in both conditions were consistent with an inhibited synthesis of modulator PGs. On the contrary, the late effects were consistent with the occurrence, at least in salt depletion, of an escape from dDAVP renal action. This escape phenomenon probably depended on a partial regression of the pharmacological inhibition of the modulating PGs.

Seckel's syndrome and malformations of cortical development: report of three new cases and review of the literature.

Seckel's syndrome is a rare form of primordial dwarfism, characterized by peculiar facial appearance. In the past, this condition was overdiagnosed, and most attention was given to the facial and skeletal features to define more precise diagnostic criteria. The presence of mental retardation and neurologic signs is one of the peculiar features of this syndrome, but only recently were rare cases of malformation of cortical development described, as documented by magnetic resonance imaging (MRI). Here, we present three new cases of Seckel's syndrome showing different malformations of cortical development (one gyral hypoplasia, one macrogyria and partial corpus callosum agenesis, and one bilateral opercular macrogyria). We hypothesize that the different types of clinical expression of our patients could be explained by different malformation of cortical development types. We think that MRI studies could be performed in malformative syndromes because of the possible correlations between type and extent of the lesion and the clinical picture of any individual case.

Disruption of the ProSAP2 gene in a t(12;22)(q24.1;q13.3) is associated with the 22q13.3 deletion syndrome.

The terminal 22q13.3 deletion syndrome is characterized by severe expressive-language delay, mild mental retardation, hypotonia, joint laxity, dolichocephaly, and minor facial dysmorphisms. We identified a child with all the features of 22q13.3 deletion syndrome. The patient's karyotype showed a de novo balanced translocation between chromosomes 12 and 22, with the breakpoint in the 22q13.3 critical region of the 22q distal deletion syndrome [46, XY, t(12;22)(q24.1;q13.3)]. FISH investigations revealed that the translocation was reciprocal, with the chromosome 22 breakpoint within the 22q subtelomeric cosmid 106G1220 and the chromosome 12q breakpoint near STS D12S317. Using Southern blot analysis and inverse PCR, we located the chromosome 12 breakpoint in an intron of the FLJ10659 gene and located the chromosome 22 breakpoint within exon 21 of the human homologue of the ProSAP2 gene. Short homologous sequences (5-bp, CTG[C/A]C) were found at the breakpoint on both derivative chromosomes. The translocation does not lead to the loss of any portion of DNA. Northern blot analysis of human tissues, using the rat ProSAP2 cDNA, showed that full-length transcripts were found only in the cerebral cortex and the cerebellum. The FLJ10659 gene is expressed in various tissues and does not show tissue-specific isoforms. The finding that ProSAP2 is included in the critical region of the 22q deletion syndrome and that our proband displays all signs and symptoms of the syndrome suggests that ProSAP2 haploinsufficiency is the cause of the 22q13.3 deletion syndrome. ProSAP2 is a good candidate for this syndrome, because it is preferentially expressed in the cerebral cortex and the cerebellum and encodes a scaffold protein involved in the postsynaptic density of excitatory synapses.