Congenital Neuronal Ceroid Lipofuscinosis with a Novel CTSD Gene Mutation: A Rare Cause of Neonatal-Onset Neurodegenerative Disorder.

Neuronal ceroid lipofuscinoses represent a heterogeneous group of early onset neurodegenerative disorders that are characterized by progressive cognitive and motor function decline, visual loss, and epilepsy. The age of onset has been historically used for the phenotypic classification of this group of disorders, but their molecular genetic delineation has now enabled a better characterization, demonstrating significant genetic heterogeneity even among individuals with a similar phenotype. The rare Congenital Neuronal Ceroid Lipofuscinosis (CLN10) caused by mutations in the CTSD gene encoding for cathepsin D is associated with a dramatic presentation with onset before or around birth. We report on a female born to consanguineous parents who presented at birth with severe neonatal encephalopathy with massive cerebral and cerebellar shrinking on magnetic resonance imaging. Whole exome sequencing with targeted bioinformatic analysis of a panel of genes associated with prenatal/perinatal onset of neurodegenerative disease was performed and revealed the presence of a novel homozygous in-frame deletion in CTSD. Additional functional studies further confirmed the pathogenic character of this variant and established the diagnosis of CLN10 in the patient.

Further evidence that de novo missense and truncating variants in ZBTB18 cause intellectual disability with variable features.

Identification of rare genetic variants in patients with intellectual disability (ID) has been greatly accelerated by advances in next generation sequencing technologies. However, due to small numbers of patients, the complete phenotypic spectrum associated with pathogenic variants in single genes is still emerging. Among these genes is ZBTB18 (ZNF238), which is deleted in patients with 1q43q44 microdeletions who typically present with ID, microcephaly, corpus callosum (CC) abnormalities, and seizures. Here we provide additional evidence for haploinsufficiency or dysfunction of the ZBTB18 gene as the cause of ID in five unrelated patients with variable syndromic features who underwent whole exome sequencing revealing separate de novo pathogenic or likely pathogenic variants in ZBTB18 (two missense alterations and three truncating alterations). The neuroimaging findings in our cohort (CC hypoplasia seen in 4/4 of our patients who underwent MRI) lend further support for ZBTB18 as a critical gene for CC abnormalities. A similar phenotype of microcephaly, CC agenesis, and cerebellar vermis hypoplasia has been reported in mice with central nervous system-specific knockout of Zbtb18. Our five patients, in addition to the previously described cases of de novo ZBTB18 variants, add to knowledge about the phenotypic spectrum associated with ZBTB18 haploinsufficiency/dysfunction.

Susceptibility weighted imaging of the neonatal brain.

Susceptibility weighted imaging (SWI) is a well-established magnetic resonance technique, which is highly sensitive for blood, iron, and calcium depositions in the brain and has been implemented in the routine clinical use in both children and neonates. SWI in neonates might provide valuable additional diagnostic and prognostic information for a wide spectrum of neonatal neurological disorders. To date, there are few articles available on the application of SWI in neonatal neurological disorders. The purpose of this article is to illustrate and describe the characteristic SWI findings in various typical neonatal neurological disorders.

Leukoencephalopathy with vanishing white matter: serial MRI of the brain and spinal cord including diffusion tensor imaging.

Vanishing white matter disease (VWM) is one of the most frequent inherited childhood white matter disorders. We present the brain and spinal cord disease progression on serial conventional magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) in a 4-year-old boy. Consecutive MRI examinations demonstrated a progression of the signal abnormalities in the cerebral white matter. Globally, apparent diffusion coefficient (ADC) values as well as axial and radial diffusivity increased over time, while fractional anisotropy (FA) values decreased. Involvement of the cervical posterior spinal tracts and mild global spinal cord atrophy was found. In conclusion, serial MRI and DTI studies may help to better understand the selective injury of the myelin and axons in VWM disease. These data may help in monitoring disease progression. Our data also show that complete neuroimaging work-up in VWM should also include the spinal cord.

Prenatal MR diffusion tractography in a fetus with complete corpus callosum agenesis.

Diffusion tensor imaging (DTI) in combination with 3D-tractography reconstructions allows studying the neuro-architecture of complex brain malformations in vivo. Prenatal, in utero DTI has been limited by long acquisition times, poor signal to noise ratio and multiple artifacts. Recent developments in hard- and software allow collection of high quality DTI data sets in utero. We report on the DTI and tractography data of a fetus with a corpus callosum agenesis. Our case shows that nowadays the neuro-architecture of the fetal brain can be studied in excellent detail. Prenatal DTI and tractography may help to improve our understanding of complex brain malformations.

Tecto-cerebellar dysraphism with occipital encephalocele: not a distinct disorder, but part of the Joubert syndrome spectrum?

Magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) findings in a 4-year-old child with occipital encephalocele, cerebellar vermis hypogenesis, and tectal malformation are presented. The neuroimaging findings are reminiscent of tectocerebellar dysraphism with an occipital encephalocele (TCD-OE). Additionally, elongated, thickened, and horizontally orientated superior cerebellar peduncles, an abnormally deepened interpeduncular fossa, subependymal heterotopia, and focal cortical dysplasia were noted. Color-coded fractional anisotropy (FA) maps revealed an absence of the decussation of the superior cerebellar peduncles. These findings are highly suggestive of Joubert syndrome and related disorders (JSRD). Our report and the review of the published cases suggest that TCD-OE is not a nosological entity, but may represent the structural manifestation of heterogeneous disorders such as the JSRD spectrum. DTI may be very helpful to differentiate between similar midbrain-hindbrain malformations.

Susceptibility-weighted imaging (SWI): a potential non-invasive imaging tool for characterizing ischemic brain injury?

Susceptibility-weighted imaging (SWI) is a new high-resolution magnetic resonance imaging (MRI) tool that uses the paramagnetic susceptibility effects of deoxygenated blood to study the intracranial venous vasculature. We present SWI imaging findings in two children who suffered from acute arterial ischemia. Various patterns of normal/altered venous drainage could be identified. Our case study suggests that SWI assisted mapping of the regional changes of the cerebral venous drainage and correlation with diffusion weighted MRI may identify critically perfused brain at risk for infarct progression. Prospective studies are mandatory to further validate the value of SWI.

Postnatal in-vivo MRI findings in anencephaly.

We report on the MRI findings of an anencephalic infant who survived 10 weeks postnatally. MRI showed absence of the cranial vault, all supratentorial structures, and the cerebellum. A brainstem primordium without pontine prominence was present. The brainstem was surrounded by the area cerebrovasculosa. The absence of a pontine prominence in an anencephalic infant without cerebellar tissue supports the hypothesis that absent pontine prominence is found in children with a prenatal loss of cerebellar tissue.

Normal cognitive functions in joubert syndrome.

Developmental delay and subsequent impaired cognitive functions are present in almost all patients with Joubert syndrome (JS). We report on a 20-year-old woman with mild clinical signs of JS (minimal truncal ataxia and oculomotor apraxia) but typical molar tooth sign on neuroimaging, normal full scale (IQ=93), verbal (IQ=93), and performance intelligence quotient (IQ=94). Only minor difficulties in visual-spatial organization and in some executive functions could be detected. This pattern of deficits is partly reminiscent of the cerebellar cognitive affective syndrome. Her diagnosis was only reached following the diagnosis of JS in two brothers with severe cognitive impairment. Molecular investigations demonstrated a homozygous mutation in the INPP5E gene. This exceptional observation confirms that normal cognitive functions are possible in JS and corroborates the well known intrafamilial variability.

Pontine tegmental cap dysplasia: the severe end of the clinical spectrum.

Pontine tegmental cap dysplasia (PTCD) is a newly described hindbrain malformation with distinct neuroradiological findings. Only 12 cases of PTCD have been described so far, all sporadic. We report 2 further patients. Both children presented after birth with significant feeding problems due to impaired mouth opening (previously not reported) and sucking difficulties. Facial, cochlear, and glossopharyngeal nerves were involved resulting in bilateral sensory deafness and a significant swallowing disorder requiring a gastrostomy. In one patient the trigeminal sensory nerve was also involved causing severe bilateral corneal clouding with impaired vision. Both patients showed only minimal developmental progress since birth and had no speech production. Furthermore, they had vertebral and rib anomalies. The patients died at the age of 15 and 32 months, respectively, due to intercurrent infections. The majority of patients reported previously were affected less severely. The presented patients may represent the severe end of the spectrum.

Cerebellar cleft: confirmation of the neuroimaging pattern.

We recently described the neuroimaging and clinical findings in 6 children with cerebellar clefts and proposed that they result from disruptive changes following prenatal cerebellar hemorrhage. We now report an additional series of 9 patients analyzing the clinical and neuroimaging findings. The clefts were located in the left cerebellar hemisphere in 5 cases, in the right in 3, and bilaterally in one child who had bilateral cerebellar hemorrhages as a preterm infant at 30 weeks gestation. In one patient born at 24 weeks of gestation a unilateral cerebellar hemorrhage has been found at the age of 4 months. Other findings included disordered alignment of the folia and fissures, an irregular gray/white matter junction, and abnormal arborization of the white matter in all cases. Supratentorial abnormalities were found in 4 cases. All but 2 patients were born at term. We confirm the distinct neuroimaging pattern of cerebellar clefts. Considering the documented fetal cerebellar hemorrhage in our first series, we postulate that cerebellar clefts usually represent residual disruptive changes after a prenatal cerebellar hemorrhage. Exceptionally, as now documented in 2 patients, cerebellar clefts can be found after neonatal cerebellar hemorrhages in preterm infants. The short-term outcome in these children was variable.

Fetal magnetic resonance imaging in midline malformations of the central nervous system and review of the literature.

Fetal magnetic resonance imaging (MRI) is a well-established second line imaging modality in identifying complex pathologies of the central nervous system (CNS), especially when ultrasound (US) findings are equivocal. It may enable an early and precise diagnosis, which is essential in terms of management of pregnancy and pre-, peri- and postnatal care. We present three cases with rare complex midline malformations of the CNS, diagnosed prenatally by fetal MRI. Two cases revealed holoprosencephaly; one case demonstrated rhombencephalosynapsis. In addition, we reviewed the literature and provide a summary of recent findings regarding cerebral midline development and discuss the advantages of fetal MRI.

Diffusion tensor imaging in Joubert syndrome.

BACKGROUND AND PURPOSE: Neuropathologic findings and preliminary imaging studies demonstrated the absence of pyramidal tract and superior cerebellar peduncular decussation in individual patients with Joubert syndrome (JS). We hypothesized that functional-structural neuroimaging findings do not differ between the genetic forms of JS. MATERIALS AND METHODS: MR imaging was performed with a 3T MR imaging-unit. Multiplanar T2- and T1-weighted imaging was followed by diffusion tensor imaging (DTI). Isotropic diffusion-weighted images, apparent diffusion coefficient maps, and color-coded fractional anisotropy maps, including tractography, were subsequently calculated. RESULTS: In all 6 patients studied, DTI showed that the fibers of the superior cerebellar peduncles did not decussate in the mesencephalon and the corticospinal tract failed to cross in the caudal medulla. The patients represented various genetic forms of JS. CONCLUSION: In JS, the fibers of the pyramidal tract and the superior cerebellar peduncles do not cross, irrespective of the underlying mutation.

Diffusion Tractography Biomarkers of Pediatric Cerebellar Hypoplasia/Atrophy: Preliminary Results Using Constrained Spherical Deconvolution.

BACKGROUND AND PURPOSE: Advances in MR imaging modeling have improved the feasibility of reconstructing crossing fibers, with increasing benefits in delineating angulated tracts such as cerebellar tracts by using tractography. We hypothesized that constrained spherical deconvolution-based probabilistic tractography could successfully reconstruct cerebellar tracts in children with cerebellar hypoplasia/atrophy and that diffusion scalars of the reconstructed tracts could differentiate pontocerebellar hypoplasia, nonprogressive cerebellar hypoplasia, and progressive cerebellar atrophy. MATERIALS AND METHODS: Fifteen children with cerebellar ataxia and pontocerebellar hypoplasia, nonprogressive cerebellar hypoplasia or progressive cerebellar atrophy and 7 controls were included in this study. Cerebellar and corticospinal tracts were reconstructed by using constrained spherical deconvolution. Scalar measures (fractional anisotropy and mean, axial and radial diffusivity) were calculated. A general linear model was used to determine differences among groups for diffusion MR imaging scalar measures, and post hoc pair-wise comparisons were performed. RESULTS: Cerebellar and corticospinal tracts were successfully reconstructed in all subjects. Significant differences in diffusion MR imaging scalars were found among groups, with fractional anisotropy explaining the highest variability. All groups with cerebellar pathologies showed lower fractional anisotropy compared with controls, with the exception of cerebellar hypoplasia. CONCLUSIONS: This study shows the feasibility of constrained spherical deconvolution to reconstruct cerebellar and corticospinal tracts in children with morphologic cerebellar pathologies. In addition, the preliminary results show the potential utility of quantitative analysis of scalars of the cerebellar white matter tracts in children with cerebellar pathologies such as cerebellar hypoplasia and atrophy. Further studies with larger cohorts of patients are needed to validate the clinical significance of our preliminary results.

Cerebral Reorganization after Hemispherectomy: A DTI Study.

BACKGROUND AND PURPOSE: Hemispherectomy is a neurosurgical procedure to treat children with intractable seizures. Postsurgical improvement of cognitive and behavioral functions is observed in children after hemispherectomy suggesting plastic reorganization of the brain. Our aim was to characterize changes in DTI scalars in WM tracts of the remaining hemisphere in children after hemispherectomy, assess the associations between WM DTI scalars and age at the operation and time since the operation, and evaluate the changes in GM fractional anisotropy values in patients compared with controls. MATERIALS AND METHODS: Patients with congenital or acquired neurologic diseases who required hemispherectomy and had high-quality postsurgical DTI data available were included in this study. Atlas- and voxel-based analyses of DTI raw data of the remaining hemisphere were performed. Fractional anisotropy and mean, axial, and radial diffusivity values were calculated for WM and GM regions. A linear regression model was used for correlation between DTI scalars and age at and time since the operation. RESULTS: Nineteen patients after hemispherectomy and 21 controls were included. In patients, a decrease in fractional anisotropy and axial diffusivity values and an increase in mean diffusivity and radial diffusivity values of WM regions were observed compared with controls (P < .05, corrected for multiple comparisons). In patients with acquired pathologies, time since the operation had a significant positive correlation with white matter fractional anisotropy values. In all patients, an increase in cortical GM fractional anisotropy values was found compared with controls (P < .05). CONCLUSIONS: Changes in DTI metrics likely reflect Wallerian and/or transneuronal degeneration of the WM tracts within the remaining hemisphere. In patients with acquired pathologies, postsurgical fractional anisotropy values correlated positively with elapsed time since the operation, suggesting a higher ability to recover compared with patients with congenital pathologies leading to hemispherectomy.

Transfontanellar duplex brain ultrasonography resistive indices as a prognostic tool in neonatal hypoxic-ischemic encephalopathy before and after treatment with therapeutic hypothermia.

OBJECTIVE: Prior to therapeutic hypothermia (that is, cooling), transfontanellar duplex brain sonography resistive indices (RI) were studied as a bedside non-invasive measures of cerebral hemodynamics in neonates who suffered from hypoxic-ischemic encephalopathy (HIE). We compared pre- and post-cooling RI values and examined the relationships between RI values and specific long-term neurodevelopmental outcomes. STUDY DESIGN: Transfontanellar duplex brain sonography, including RI, were obtained for 28 neonates prior to cooling and for 20 neonates following cooling. All RI values were sampled in the anterior cerebral artery at the beginning of each ultrasound study. Neurodevelopmental assessment was conducted between ages 20-32 months with the Mullen Scale of Early Learning. The relationships between pre- and post-cooling RI and cognitive and motor outcomes were studied. RESULT: Neonates with RI values <0.60 prior to and following cooling were more likely to die or have severe neurodevelopmental disability by ages 20-32 months than those with RI>0.60. Lower RI values were associated with specific neurodevelopmental deficits in motor skill attainment. CONCLUSION: Pre- and post-cooling transfontanellar duplex brain sonography RI values may be a useful prognostic tool, in conjunction with other clinical information, for neonates diagnosed with HIE. The results of this study suggest that further study of the prognostic value of RI values for short- and long-term outcomes is warranted.

Susceptibility-weighted imaging in pediatric arterial ischemic stroke: a valuable alternative for the noninvasive evaluation of altered cerebral hemodynamics.

BACKGROUND AND PURPOSE: SWI provides information about blood oxygenation levels in intracranial vessels. Prior reports have shown that SWI focusing on venous drainage can provide noninvasive information about the degree of brain perfusion in pediatric arterial ischemic stroke. We aimed to evaluate the influence of the SWI venous signal pattern in predicting stroke evolution and the development of malignant edema in a large cohort of children with arterial ischemic stroke. MATERIALS AND METHODS: A semiquantitative analysis of venous signal intensity on SWI and diffusion characteristics on DTI was performed in 16 vascular territories. The mismatch between areas with SWI-hypointense venous signal and restricted diffusion was correlated with stroke progression on follow-up. SWI-hyperintense signal was correlated with the development of malignant edema. RESULTS: We included 24 children with a confirmed diagnosis of pediatric arterial ischemic stroke. Follow-up images were available for 14/24 children. MCA stroke progression on follow-up was observed in 5/6 children, with 2/8 children without mismatch between areas of initial SWI hypointense venous signal and areas of restricted diffusion on DTI. This mismatch showed a statistically significant association (P = .03) for infarct progression. Postischemic malignant edema developed in 2/10 children with and 0/14 children without SWI-hyperintense venous signal on initial SWI (P = .07). CONCLUSIONS: SWI-DTI mismatch predicts stroke progression in pediatric arterial ischemic stroke. SWI-hyperintense signal is not useful for predicting the development of malignant edema. SWI should be routinely added to the neuroimaging diagnostic protocol of pediatric arterial ischemic stroke.

Apparent diffusion coefficient scalars correlate with near-infrared spectroscopy markers of cerebrovascular autoregulation in neonates cooled for perinatal hypoxic-ischemic injury.

BACKGROUND AND PURPOSE: Neurologic morbidity remains high in neonates with perinatal hypoxic-ischemic injury despite therapeutic hypothermia. DTI provides qualitative and quantitative information about the microstructure of the brain, and a near-infrared spectroscopy index can assess cerebrovascular autoregulation. We hypothesized that lower ADC values would correlate with worse autoregulatory function. MATERIALS AND METHODS: Thirty-one neonates with hypoxic-ischemic injury were enrolled. ADC scalars were measured in 27 neonates (age range, 4-15 days) in the anterior and posterior centrum semiovale, basal ganglia, thalamus, posterior limb of the internal capsule, pons, and middle cerebellar peduncle on MRI obtained after completion of therapeutic hypothermia. The blood pressure range of each neonate with the most robust autoregulation was identified by using a near-infrared spectroscopy index. Autoregulatory function was measured by blood pressure deviation below the range with optimal autoregulation. RESULTS: In neonates who had MRI on day of life ≥10, lower ADC scalars in the posterior centrum semiovale (r = -0.87, P = .003, n = 9) and the posterior limb of the internal capsule (r = -0.68, P = .04, n = 9) correlated with blood pressure deviation below the range with optimal autoregulation during hypothermia. Lower ADC scalars in the basal ganglia correlated with worse autoregulation during rewarming (r = -0.71, P = .05, n = 8). CONCLUSIONS: Blood pressure deviation from the optimal autoregulatory range may be an early biomarker of injury in the posterior centrum semiovale, posterior limb of the internal capsule, and basal ganglia. Optimizing blood pressure to support autoregulation may decrease the risk of brain injury in cooled neonates with hypoxic-ischemic injury.

Neonatal neuroimaging findings in congenital myotonic dystrophy.

We report on a preterm neonate of 30 weeks gestational age who presented with marked muscular hypotonia and severe respiratory failure at birth and was diagnosed with congenital myotonic dystrophy. Neuroimaging at 36 gestational weeks demonstrated diffuse T2-hyperintense signal of the supratentorial white matter and a simplified gyration and sulcation pattern. Follow-up imaging showed progressive myelination, brain maturation and decrease in T2-signal of the white matter. We discuss possible pathomechanisms for white matter signal abnormalities in this neonate.