ABSTRACT
BACKGROUND AND PURPOSE: Zhu-Tokita-Takenouchi-Kim syndrome is a severe multisystem malformation disorder characterized by developmental delay and a diverse array of congenital abnormalities. However, these currently identified phenotypic components provide limited guidance in diagnostic situations, due to both the nonspecificity and variability of these features. Here we report a case series of 7 individuals with a molecular diagnosis of Zhu-Tokita-Takenouchi-Kim syndrome, 5 ascertained by their presentation with the neuronal migration disorder, periventricular nodular heterotopia. MATERIALS AND METHODS: Individuals with a molecular diagnosis of Zhu-Tokita-Takenouchi-Kim syndrome were recruited from 2 sources, a high-throughput sequencing study of individuals with periventricular nodular heterotopia or from clinical diagnostic sequencing studies. We analyzed available brain MR images of recruited individuals to characterize periventricular nodular heterotopia distribution and to identify the presence of any additional brain abnormalities. RESULTS: Pathogenic variants in SON, causative of Zhu-Tokita-Takenouchi-Kim syndrome, were identified in 7 individuals. Brain MR images from these individuals were re-analyzed. A characteristic set of imaging anomalies in addition to periventricular nodular heterotopia was identified, including the elongation of the pituitary stalk, cerebellar enlargement with an abnormally shaped posterior fossa, rounding of the caudate nuclei, hippocampal malformations, and cortical anomalies including polymicrogyria or dysgyria. CONCLUSIONS: The recurrent neuroradiologic changes identified here represent an opportunity to guide diagnostic formulation of Zhu-Tokita-Takenouchi-Kim syndrome on the basis of brain MR imaging evaluation.
Subject(s)
Brain Diseases , Intellectual Disability , Periventricular Nodular Heterotopia , Humans , Brain/pathology , Magnetic Resonance Imaging , Brain Diseases/pathology , Intellectual Disability/pathologyABSTRACT
BACKGROUND: Next generation sequencing studies have revealed an ever-increasing number of causes for genetic disorders of central nervous system white matter. A substantial number of disorders are identifiable from their specific pattern of biochemical and/or imaging findings for which single gene testing may be indicated. Beyond this group, the causes of genetic white matter disorders are unclear and a broader approach to genomic testing is recommended. AIM: This study aimed to identify the genetic causes for a group of individuals with unclassified white matter disorders with suspected genetic aetiology and highlight the investigations required when the initial testing is non-diagnostic. METHODS: Twenty-six individuals from 22 families with unclassified white matter disorders underwent deep phenotyping and genome sequencing performed on trio, or larger, family groups. Functional studies and transcriptomics were used to resolve variants of uncertain significance with potential clinical relevance. RESULTS: Causative or candidate variants were identified in 15/22 (68.2%) families. Six of the 15 implicated genes had been previously associated with white matter disease (COL4A1, NDUFV1, SLC17A5, TUBB4A, BOLA3, DARS2). Patients with variants in the latter two presented with an atypical phenotype. The other nine genes had not been specifically associated with white matter disease at the time of diagnosis and included genes associated with monogenic syndromes, developmental disorders, and developmental and epileptic encephalopathies (STAG2, LSS, FIG4, GLS, PMPCA, SPTBN1, AGO2, SCN2A, SCN8A). Consequently, only 46% of the diagnoses would have been made via a current leukodystrophy gene panel test. DISCUSSION: These results confirm the importance of broad genomic testing for patients with white matter disorders. The high diagnostic yield reflects the integration of deep phenotyping, whole genome sequencing, trio analysis, functional studies, and transcriptomic analyses. CONCLUSIONS: Genetic white matter disorders are genetically and phenotypically heterogeneous. Deep phenotyping together with a range of genomic technologies underpin the identification of causes of unclassified white matter disease. A molecular diagnosis is essential for prognostication, appropriate management, and accurate reproductive counseling.
Subject(s)
Leukoencephalopathies , White Matter , Flavoproteins , Genetic Testing/methods , High-Throughput Nucleotide Sequencing , Humans , Leukoencephalopathies/diagnostic imaging , Leukoencephalopathies/genetics , Mitochondrial Proteins , Phenotype , Phosphoric Monoester Hydrolases , Tubulin , White Matter/diagnostic imagingABSTRACT
BACKGROUND AND PURPOSE: Pathogenic variants in the ACTA2 gene cause a distinctive arterial phenotype that has recently been described to be associated with brain malformation. Our objective was to further characterize gyral abnormalities in patients with ACTA2 pathogenic variants as per the 2020 consensus recommendations for the definition and classification of malformations of cortical development. MATERIALS AND METHODS: We performed a retrospective, multicentric review of patients with proved ACTA2 pathogenic variants, searching for the presence of malformations of cortical development. A consensus read was performed for all patients, and the type and location of cortical malformation were noted in each. The presence of the typical ACTA2 arterial phenotype as well as demographic and relevant clinical data was obtained. RESULTS: We included 13 patients with ACTA2 pathogenic variants (Arg179His mutation, n = 11, and Arg179Cys mutation, n = 2). Ninety-two percent (12/13) of patients had peri-Sylvian dysgyria, 77% (10/13) had frontal dysgyria, and 15% (2/13) had generalized dysgyria. The peri-Sylvian location was involved in all patients with dysgyria (12/12). All patients with dysgyria had a characteristic arterial phenotype described in ACTA2 pathogenic variants. One patient did not have dysgyria or the characteristic arterial phenotype. CONCLUSIONS: Dysgyria is common in patients with ACTA2 pathogenic variants, with a peri-Sylvian and frontal predominance, and was seen in all our patients who also had the typical ACTA2 arterial phenotype.
Subject(s)
Nervous System Malformations , Actins/genetics , Humans , Mutation , Phenotype , Retrospective StudiesABSTRACT
OBJECTIVES: To describe the prenatal neuroimaging spectrum of rhombencephalosynapsis (RES) and criteria for its classification according to the severity of vermian anomaly. METHODS: In this multicenter retrospective study of fetuses with RES between 2002 and 2020, the medical records and brain ultrasound and magnetic resonance images were evaluated comprehensively to determine the severity of the vermian anomaly and the presence of associated brain findings. RES was classified, according to the pattern of vermian agenesis and the extent of the fusion of the hemispheres, as complete RES (complete absence of the vermis) or partial RES (further classified according to the part of the vermis that was missing and, consequently, the region of hemispheric fusion, as anterior, posterior, severe or mixed RES). Findings were compared between cases with complete and those with partial RES. RESULTS: Included in the study were 62 fetuses with a gestational age ranging between 12 and 37 weeks. Most had complete absence of the vermis (complete RES, 77.4% of cases), a 'round-shaped' cerebellum on axial views (72.6%) and a transverse cerebellar diameter (TCD) < 3rd centile (87.1%). Among the 22.6% of cases with partial RES, 6.5% were classified as severe partial, 6.5% as partial anterior, 8.1% as partial mixed and 1.6% as partial posterior. Half of these cases presented with normal or nearly normal cerebellar morphology and 28.5% had a TCD within the normal limits. Infratentorially, the fourth ventricle was abnormal in 88.7% of cases overall, and anomalies of the midbrain and pons were frequent (93.5% and 77.4%, respectively). Ventriculomegaly was observed in 80.6% of all cases, being more severe in cases with complete RES than in those with partial RES, with high rates of parenchymal and septal disruption. CONCLUSIONS: This study provides prenatal neuroimaging criteria for the diagnosis and classification of RES, and identification of related features, using ultrasound and magnetic resonance imaging. According to our findings, a diagnosis of RES should be considered in fetuses with a small TCD (severe cerebellar hypoplasia) and/or a round-shaped cerebellum on axial views, during the second or third trimester, especially when associated with ventriculomegaly. Partial RES is more common than previously thought, but presents an extreme diagnostic challenge, especially in cases with normal or nearly-normal cerebellar morphobiometric features. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.
Subject(s)
Abnormalities, Multiple/diagnostic imaging , Cerebellar Vermis/abnormalities , Cerebellum/abnormalities , Eye Abnormalities/diagnostic imaging , Kidney Diseases, Cystic/diagnostic imaging , Nervous System Malformations/diagnostic imaging , Neuroimaging , Prenatal Diagnosis/methods , Retina/abnormalities , Rhombencephalon/abnormalities , Abnormalities, Multiple/embryology , Adult , Cerebellar Vermis/diagnostic imaging , Cerebellar Vermis/embryology , Cerebellum/diagnostic imaging , Cerebellum/embryology , Eye Abnormalities/embryology , Female , Gestational Age , Humans , Kidney Diseases, Cystic/embryology , Magnetic Resonance Imaging , Multimodal Imaging , Nervous System Malformations/embryology , Pregnancy , Retina/diagnostic imaging , Retina/embryology , Retrospective Studies , Rhombencephalon/diagnostic imaging , Rhombencephalon/embryology , Severity of Illness Index , Ultrasonography, PrenatalABSTRACT
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.
Subject(s)
Brain/diagnostic imaging , Diffusion Tensor Imaging/methods , Lissencephaly/diagnostic imaging , Polymicrogyria/diagnostic imaging , White Matter/diagnostic imaging , Adolescent , Brain/pathology , Child , Child, Preschool , Female , Humans , Infant , Lissencephaly/diagnosis , Lissencephaly/pathology , Male , Polymicrogyria/pathology , Retrospective Studies , White Matter/pathology , Young AdultABSTRACT
BACKGROUND AND PURPOSE: Antibodies to myelin oligodendrocyte glycoprotein (MOG) have been identified in both children and adults with demyelination, with a strong association with bilateral or recurrent optic neuritis (ON). However, the full clinical spectrum of this newly described condition is unknown. We sought to describe non-ON inflammatory ophthalmological presentations such as uveitis and optic perineuritis in the context of MOG antibody seropositivity. METHODS: Using a live cell-based assay analysed by flow cytometry, we identified seropositive patients referred for MOG antibody testing in Australasia between 2014 and 2017. We identified four MOG antibody-positive patients with non-ON inflammatory ophthalmological presentations and present their detailed clinical information in this case series. RESULTS: Three patients had uveitis either in association with, or remote from, ON. One patient had optic perineuritis and peripheral ulcerative keratitis. We describe the presentation, examination, investigation findings and clinical course of these four patients. CONCLUSIONS: Recognition of these novel clinical associations may expand the clinical spectrum of MOG antibody-associated presentations. An expedited diagnosis may guide the management of these complex patients.
Subject(s)
Autoantibodies/immunology , Myelin-Oligodendrocyte Glycoprotein/immunology , Optic Neuritis/diagnosis , Uveitis/diagnosis , Adult , Child, Preschool , Female , Humans , Male , Middle Aged , Optic Neuritis/immunology , Uveitis/immunologyABSTRACT
AIM: To identify the genetic aetiology of a distinct leukoencephalopathy causing acute neurological regression in infancy with apparently complete clinical recovery. METHODS: We performed trio whole genome sequencing (WGS) to determine the genetic basis of the disorder. Mitochondrial function analysis in cultured patient fibroblasts was undertaken to confirm the pathogenicity of candidate variants. RESULTS: The patient presented at 18 months with acute hemiplegia and cognitive regression without obvious trigger. This was followed by clinical recovery over 4 years. MRI at disease onset revealed bilateral T2 hyperintensity involving the periventricular and deep white matter and MR spectroscopy of frontal white matter demonstrated a lactate doublet. Lactate levels and mitochondrial respiratory chain enzyme activity in muscle, liver and fibroblasts were normal. Plasma glycine was elevated. The MRI abnormalities improved. WGS identified compound heterozygous variants in BOLA3: one previously reported (c.136C>T, p.Arg46*) and one novel variant (c.176G>A, p.Cys59Tyr). Analysis of cultured patient fibroblasts demonstrated deficient pyruvate dehydrogenase (PDH) activity and reduced quantity of protein subunits of mitochondrial complexes I and II, consistent with BOLA3 dysfunction. Previously reported cases of multiple mitochondrial dysfunctions syndrome 2 (MMDS2) with hyperglycinaemia caused by BOLA3 mutations have leukodystrophy with severe, progressive neurological and multisystem disease. CONCLUSIONS: We report a novel phenotype for MMDS2 associated with apparently complete clinical recovery and partial resolution of MRI abnormalities. We have identified a novel disease-causing variant in BOLA3 validated by functional cellular studies. Our patient's clinical course broadens the phenotypic spectrum of MMDS2 and highlights the potential for some genetic leukoencephalopathies to spontaneously improve.
ABSTRACT
The ability to temporarily maintain relevant information in mind in the presence of interference or distracting information, also called working memory (WM), is critical for higher cognitive functions and cognitive development. In typically developing (TD) children, WM is underpinned by a fronto-parietal network of interacting left and right brain regions. Developmental absence (agenesis) of the corpus callosum (AgCC) is a congenital brain malformation resulting from disruption of corpus callosum formation. This study aims to investigate functional organisation of WM in children and adolescents with AgCC using functional magnetic resonance imaging (fMRI). Nine children with AgCC and a comparison group of sixteen TD children aged 8-17 years completed an fMRI WM paradigm designed to enable investigation of different WM processes, i.e., encoding, maintenance and retrieval. We found that AgCC children recruited globally similar brain regions as the TD comparison group during the WM task, despite significant disparity in brain development, i.e., bilateral occipito-frontal activations during verbal encoding, and bilateral fronto-parietal executive control network during retrieval. However, compared to their TD peers, children with AgCC seemed less able to engage lateralised brain systems specialised for particular memory material (i.e. less supramarginal activations for verbal material and less fusiform activations for face processing) and particular memory process (i.e. absence of right-predominant activations during retrieval). Group differences in the pattern of activation might also reflect different cognitive strategies to cope with competition in processing resources with different susceptibility to concurrent tasks (verbal vs visual), such as differential recruitment of associative visual areas and executive prefrontal regions in the AgCC compared with the TD group depending on the concurrent task completed during maintenance. This study provides a first step towards a better understanding of functional brain networks underlying higher cognitive functions in children with AgCC.
Subject(s)
Agenesis of Corpus Callosum/complications , Agenesis of Corpus Callosum/diagnostic imaging , Brain Mapping , Magnetic Resonance Imaging , Memory Disorders/diagnostic imaging , Memory Disorders/etiology , Adolescent , Child , Female , Functional Laterality , Humans , Image Processing, Computer-Assisted , Male , Movement , Oxygen/blood , Statistics, Nonparametric , Time Factors , Verbal LearningABSTRACT
BACKGROUND AND PURPOSE: Clusters of acute limb weakness in paediatric patients have been linked to outbreaks of non-polio enteroviruses, termed acute flaccid myelitis (AFM). Outside these clusters, in countries where polio is not endemic, this poliomyelitic-like illness is rare in childhood and its natural history is not well defined. We describe presenting features, investigation findings and long-term outcome of a series of children with AFM. METHODS: This was a retrospective cohort study. RESULTS: Eight children (six females) aged 3 months to 8 years (median age 5 years) met case criteria. Initial symptoms were pain (n = 7) followed by limb weakness with hypotonia (n = 8). Flaccid paralysis occurred in only three patients. Two had cranial nerve dysfunction. Magnetic resonance imaging of the spinal cord demonstrated grey matter involvement particularly affecting the anterior cord, with longitudinally extensive changes in three children. Cerebrospinal fluid examination showed pleocytosis in six children with raised cerebrospinal fluid protein in five. Nerve conduction and electromyography findings were consistent with a motor neuronopathy. Residual deficits were common, with moderate to severe weakness seen in five patients. Median follow-up was 28 months (range 17-108 months, 30.4 patient years in total). CONCLUSIONS: Acute flaccid myelitis is an uncommon condition in childhood with a high rate of significant long-term morbidity. AFM should be considered in children presenting with acute limb pain and weakness.
Subject(s)
Myelitis/diagnosis , Paralysis/diagnosis , Spinal Cord/diagnostic imaging , Child , Child, Preschool , Electrodiagnosis , Female , Humans , Infant , Magnetic Resonance Imaging , Male , Myelitis/diagnostic imaging , Myelitis/pathology , Neural Conduction/physiology , Paralysis/diagnostic imaging , Paralysis/pathology , Retrospective Studies , Spinal Cord/pathologySubject(s)
Anticonvulsants/therapeutic use , Epilepsy/drug therapy , Child , Electroencephalography , Humans , Risk AssessmentABSTRACT
BACKGROUND AND PURPOSE: Bilateral posterior PNH is a distinctive complex malformation with imaging features distinguishing it from classic bilateral PNH associated with FLNA mutations. The purpose of this study was to define the imaging features of posterior bilateral periventricular nodular heterotopia and to determine whether associated brain malformations suggest specific subcategories. MATERIALS AND METHODS: We identified a cohort of 50 patients (31 females; mean age, 13 years) with bilateral posterior PNH and systematically reviewed and documented associated MR imaging abnormalities. Patients were negative for mutations of FLNA. RESULTS: Nodules were often noncontiguous (n = 28) and asymmetric (n = 31). All except 1 patient showed associated developmental brain abnormalities involving a spectrum of posterior structures. A range of posterior fossa abnormalities affected the cerebellum, including cerebellar malformations and posterior fossa cysts (n = 38). Corpus callosum abnormalities (n = 40) ranged from mild dysplasia to agenesis. Posterior white matter volume was decreased (n = 22), and colpocephaly was frequent (n = 26). Most (n = 40) had associated cortical abnormalities ranging from minor to major (polymicrogyria), typically located in the cortex overlying the PNH. Abnormal Sylvian fissure morphology was common (n = 27), and hippocampal abnormalities were frequent (n = 37). Four family cases were identified-2 with concordant malformation patterns and 2 with discordant malformation patterns. CONCLUSIONS: The associations of bilateral posterior PNH encompass a range of abnormalities involving brain structures inferior to the Sylvian fissures. We were unable to identify specific subgroups and therefore conceptualize bilateral posterior PNH as a continuum of infrasylvian malformations involving the posterior cerebral and hindbrain structures.
Subject(s)
Brain Diseases/pathology , Lateral Ventricles/abnormalities , Magnetic Resonance Imaging , Malformations of Cortical Development/pathology , Periventricular Nodular Heterotopia/pathology , Adolescent , Adult , Aged , Cerebral Cortex/abnormalities , Child , Child, Preschool , Cohort Studies , Contractile Proteins/genetics , Corpus Callosum/pathology , Female , Fetal Diseases/genetics , Fetal Diseases/pathology , Filamins , Hippocampus/abnormalities , Humans , Infant , Infant, Newborn , Lateral Ventricles/pathology , Male , Microfilament Proteins/genetics , Middle Aged , Periventricular Nodular Heterotopia/genetics , Pregnancy , Rhombencephalon/abnormalities , Siblings , Twins, Monozygotic , Young AdultABSTRACT
Periventricular heterotopia (PH) is a brain malformation characterised by heterotopic nodules of neurons lining the walls of the cerebral ventricles. Mutations in FLNA account for 20-24% of instances but a majority have no identifiable genetic aetiology. Often the co-occurrence of PH with a chromosomal anomaly is used to infer a new locus for a Mendelian form of PH. This study reports four PH patients with three different microdeletion syndromes, each characterised by high-resolution genomic microarray. In three patients the deletions at 1p36 and 22q11 are conventional in size, whilst a fourth child had a deletion at 7q11.23 that was larger in extent than is typically seen in Williams syndrome. Although some instances of PH associated with chromosomal deletions could be attributed to the unmasking of a recessive allele or be indicative of more prevalent subclinical migrational anomalies, the rarity of PH in these three microdeletion syndromes and the description of other non-recurrent chromosomal defects do suggest that PH may be a manifestation of multiple different forms of chromosomal imbalance. In many, but possibly not all, instances the co-occurrence of PH with a chromosomal deletion is not necessarily indicative of uncharacterised underlying monogenic loci for this particular neuronal migrational anomaly.
ABSTRACT
Ciliopathies are an expanding group of rare conditions characterized by multiorgan involvement, that are caused by mutations in genes encoding for proteins of the primary cilium or its apparatus. Among these genes, CEP290 bears an intriguing allelic spectrum, being commonly mutated in Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS), Senior-Loken syndrome and isolated Leber congenital amaurosis (LCA). Although these conditions are recessively inherited, in a subset of patients only one CEP290 mutation could be detected. To assess whether genomic rearrangements involving the CEP290 gene could represent a possible mutational mechanism in these cases, exon dosage analysis on genomic DNA was performed in two groups of CEP290 heterozygous patients, including five JSRD/MKS cases and four LCA, respectively. In one JSRD patient, we identified a large heterozygous deletion encompassing CEP290 C-terminus that resulted in marked reduction of mRNA expression. No copy number alterations were identified in the remaining probands. The present work expands the CEP290 genotypic spectrum to include multiexon deletions. Although this mechanism does not appear to be frequent, screening for genomic rearrangements should be considered in patients in whom a single CEP290 mutated allele was identified.
Subject(s)
Abnormalities, Multiple/genetics , Antigens, Neoplasm/genetics , Cilia , Neoplasm Proteins/genetics , Antigens, Neoplasm/metabolism , Base Sequence , Cell Cycle Proteins , Cilia/genetics , Cilia/pathology , Cytoskeletal Proteins , DNA Mutational Analysis , Female , Fetus/metabolism , Fetus/pathology , Gene Deletion , Genetic Testing , Humans , Neoplasm Proteins/metabolism , RNA, Messenger/analysis , SyndromeABSTRACT
BACKGROUND AND PURPOSE: Malformations of the brain stem are uncommon. We present MR imaging and diffusion tensor imaging (DTI) features of 6 patients with pontine tegmental cap dysplasia, characterized by ventral pontine hypoplasia and a dorsal "bump," and speculate on potential mechanisms by which it forms. MATERIALS AND METHODS: Birth and developmental records of 6 patients were reviewed. We reviewed MR imaging studies of all patients and DTIs of patient 3. Potential developmental causes were evaluated. RESULTS: All patients were born uneventfully after normal pregnancies except patient 6 (in utero growth retardation). They presented with multiple cranial neuropathies and evidence of cerebellar dysfunction. Variable hypotonia and motor dysfunction were present. Imaging revealed ventral pontine hypoplasia and mild cerebellar vermian hypoplasia, in addition to an unusual rounded to beaklike "bump" on the dorsal surface of the pons, extending into the fourth ventricle. Color fractional anisotropy maps showed the bump to consist of a bundle of axons directed horizontally (left-right). The bump appeared, on morphologic images, to be continuous with the middle cerebellar peduncles (MCPs), which were slightly diminished in size compared with those in healthy infants. Analysis of the DTI was, however, inconclusive regarding the connections of these axons. The decussation of the MCPs, transverse pontine fibers, and longitudinal brain stem axonal pathways was also abnormal. CONCLUSIONS: Our data suggest that the dorsal transverse axonal band in these disorders results from abnormal axonal pathfinding, abnormal neuronal migration, or a combination of the 2 processes.
Subject(s)
Axons/pathology , Brain Stem/abnormalities , Brain Stem/pathology , Diffusion Magnetic Resonance Imaging/methods , Female , Humans , Infant, Newborn , MaleABSTRACT
In contrast to malformations, cerebellar disruptions have attracted little interest in the literature. We draw attention for the first time to the hypothesis that cerebellar clefts are residual changes following a prenatal cerebellar insult, and represent disruptions. We reviewed the clinical records and MR findings of six patients with a cerebellar cleft, two of whom also had prenatal MRI at 24 weeks of gestation. The clefts were located in the left cerebellar hemisphere in five cases, in the right in one patient. Other typical findings included disorderly alignment of the cerebellar folia and fissures, irregular gray/white matter junction, and abnormal arborization of the white matter in all patients. The cerebellar cleft extended into the fourth ventricle in three cases, and in two children cystic cortical lesions were seen. Supratentorial schizencephaly was found in two patients. In two patients there was a documented fetal cerebellar hemorrhage at 24 weeks of gestation. We conclude that cerebellar clefts are residual changes resulting from a prenatal cerebellar insult and consequently represent disruptions rather than primary malformations. The supratentorial findings are also in agreement with an acquired lesion. The outcome in these children was variable, mainly depending of the presence of supratentorial lesions.
Subject(s)
Cerebellum/abnormalities , Dilatation, Pathologic/etiology , Fetal Diseases/diagnosis , Prenatal Diagnosis/methods , Child , Child, Preschool , Dilatation, Pathologic/diagnosis , Female , Gestational Age , Humans , Image Processing, Computer-Assisted , Infant , Intracranial Hemorrhages/complications , Intracranial Hemorrhages/pathology , Magnetic Resonance Imaging , Male , Malformations of Cortical Development/complications , Malformations of Cortical Development/pathology , PregnancyABSTRACT
Our understanding of the neuropsychological effects of encephalitis has largely come from studies in which the level of premorbid functioning is estimated. Moreover, data on the neuropsychological effects of encephalitogenic pathogens other than the herpes simplex virus (HSV) are scant. We present the case of a 7-year-old girl who had intellectual and language assessment seven months prior to the onset of non-HSV encephalitis (possible aetiology: Mycoplasma pneumoniae), and again post-encephalitis. MRI post-illness demonstrated basal frontal, temporal and (limited) parietal damage. Details of speech, psychological and neuropsychological assessments were also documented. Pervasive changes were apparent in the domains of personality, behaviour, emotionality, attention, executive function, speech, language and memory. The patient's profile appears to differ most from that seen following typical HSV encephalitis with respect to marked executive and attentional difficulties. Her deficits appear to reflect both her acute basal brain injury and more diffuse insult, probably caused by postinfectious encephalitis.
Subject(s)
Cognition Disorders/etiology , Encephalitis, Herpes Simplex/complications , Simplexvirus/pathogenicity , Attention , Child , Cognition Disorders/virology , Female , Humans , Learning , Magnetic Resonance Imaging/methods , Neuropsychological Tests , Problem Solving , Psychomotor PerformanceABSTRACT
OBJECTIVE: To define the clinical, radiologic, and genetic features of periventricular heterotopia (PH) with Ehlers-Danlos syndrome (EDS). METHODS: Exonic sequencing and single stranded conformational polymorphism (SSCP) analysis was performed on affected individuals. Linkage analysis using microsatellite markers on the X-chromosome was performed on a single pedigree. Western blotting evaluated for loss of filamin A (FLNA) protein and Southern blotting assessed for any potential chromosome rearrangement in this region. RESULTS: The authors report two familial cases and nine additional sporadic cases of the EDS-variant form of PH, which is characterized by nodular brain heterotopia, joint hypermobility, and development of aortic dilatation in early adulthood. MRI typically demonstrated bilateral nodular PH, indistinguishable from PH due to FLNA mutations. Exonic sequencing or SSCP analyses of FLNA revealed a 2762 delG single base pair deletion in one affected female. Another affected female harbored a C116 single point mutation, resulting in an A39G change. A third affected female had a 4147 delG single base pair deletion. One pedigree with no detectable exonic mutation demonstrated positive linkage to the FLNA locus Xq28, an affected individual in this family also had no detectable FLNA protein, but no chromosomal rearrangement was detected. CONCLUSION: These results suggest that the Ehlers-Danlos variant of periventricular heterotopia (PH), in part, represents an overlapping syndrome with X-linked dominant PH due to filamin A mutations.
Subject(s)
Brain/abnormalities , Contractile Proteins/deficiency , Ehlers-Danlos Syndrome/genetics , Microfilament Proteins/deficiency , Point Mutation , Sequence Deletion , Adolescent , Adult , Amino Acid Substitution , Child , Chromosomes, Human, X/genetics , Contractile Proteins/genetics , Contractile Proteins/physiology , DNA Mutational Analysis , Ehlers-Danlos Syndrome/pathology , Epilepsy/etiology , Exons/genetics , Female , Filamins , Humans , Infant , Magnetic Resonance Imaging , Male , Microfilament Proteins/genetics , Microfilament Proteins/physiology , Microsatellite Repeats , Middle Aged , Mutation, Missense , Pedigree , Phenotype , Polymorphism, Single-Stranded ConformationalABSTRACT
BACKGROUND: Syndromes of bilateral symmetric polymicrogyria include an autosomal recessive form of bilateral frontoparietal polymicrogyria (BFPP), in which the malformation is most severe rostrally. The authors describe a new syndrome they have termed "bilateral generalized polymicrogyria" (BGP), in which the malformation occurs in a generalized distribution but is often most severe in the perisylvian regions. METHODS: Patients with bilateral polymicrogyria were identified from multiple medical centers worldwide. The diagnosis of BGP was based on findings from conventional spin echo MRI and, in one case, postmortem neuropathologic findings. Genetic analysis was performed for those patients from consanguineous pedigrees and those with multiple affected siblings to rule out linkage to the BFPP locus on chromosome 16q. RESULTS: Twelve patients were identified with BGP. Clinical features included cognitive and motor delay as well as seizures. Some specific features characteristic of other known bilateral polymicrogyria syndromes, such as pseudobulbar palsy and dysconjugate gaze, were not commonly seen in these patients. Radiologically, polymicrogyria appeared widespread but was often most severe in the perisylvian regions. Pathologic examination in one case revealed a diffusely thin and excessively folded cerebral cortex lacking normal six-layered architecture. Seven patients subjected to genetic analysis did not demonstrate linkage to the BFPP locus. CONCLUSIONS: BGP is a distinct syndrome of cortical malformation. Several features allow BGP to be distinguished from other disorders on the growing list of bilateral symmetric polymicrogyria syndromes.
Subject(s)
Cerebral Cortex/abnormalities , Developmental Disabilities/etiology , Intellectual Disability/etiology , Abnormalities, Multiple/genetics , Cerebral Ventricles/abnormalities , Child , Child, Preschool , Chromosomes, Human, Pair 16/genetics , Consanguinity , Developmental Disabilities/genetics , Epilepsies, Partial/etiology , Epilepsies, Partial/genetics , Fatal Outcome , Female , Genes, Recessive , Genetic Heterogeneity , Humans , Infant , Intellectual Disability/genetics , Magnetic Resonance Imaging , Male , Microsatellite Repeats , Nervous System Malformations/classification , Nervous System Malformations/diagnosis , Nervous System Malformations/genetics , Neuromuscular Diseases/genetics , Phenotype , Quadriplegia/genetics , SyndromeABSTRACT
BACKGROUND: Classical lissencephaly is a disorder of neuroblast migration with most patients having mutations of either the LIS1 or DCX genes. Most patients with lissencephaly secondary to LIS1 mutations have a severe malformation consisting of generalized agyria and pachygyria. However, increasing experience suggests that the phenotypic spectrum is wider than previously thought. METHODS: The authors describe the clinical and imaging features and mutation data of the five known patients with missense mutations of the LIS1 gene and emphasize one patient with normal intelligence. RESULTS: Patients with a missense mutation of the LIS1 gene have a wider and milder spectrum of cortical malformations and clinical sequelae compared with patients with other mutation types. CONCLUSION: Milder and more variable phenotypes seen in patients with missense mutations of LIS1 are likely a consequence of suboptimal function of the mutant LIS1 protein, rather than complete loss of function of this protein. The authors suggest that the few patients found thus far with missense mutations of LIS1 results from an underascertainment of patients with more subtle malformations and that abnormalities of the LIS1 gene may account for a greater spectrum of neurologic problems in childhood than has previously been appreciated.
Subject(s)
Brain Diseases/genetics , Brain Diseases/pathology , Brain/abnormalities , Brain/pathology , Intelligence/genetics , Microtubule-Associated Proteins/genetics , Mutation, Missense/genetics , 1-Alkyl-2-acetylglycerophosphocholine Esterase , Child , Child, Preschool , Female , Humans , Infant , Magnetic Resonance Imaging , Male , PhenotypeABSTRACT
The LIS1 gene was cloned following the study of children with lissencephaly and cytogenetic abnormalities involving chromosome 17p, however, the role of the LIS1 protein in normal cortical development is not precisely defined. LIS1 is a component of evolutionarily conserved intracellular multiprotein complexes and recent literature shows that these complexes are essential, not only for neuronal migration, but they might also be fundamental components of the machinery for cell proliferation and intracellular transport.