Spectrum Of Brain Abnormalities Research Articles

ZBTB11 dysfunction: spectrum of brain abnormalities, biochemical signature and cellular consequences.

Bi-allelic pathogenic variants in ZBTB11 have been associated with intellectual developmental disorder, autosomal recessive 69 (MRT69; OMIM 618383). We report five patients from three families with novel, bi-allelic variants in ZBTB11. We have expanded the clinical phenotype of MRT69, documenting varied severity of atrophy affecting different brain regions and described combined malonic and methylmalonic aciduria as a biochemical manifestation.As ZBTB11 encodes for a transcriptional regulator, we performeded chromatin immunoprecipitation–sequencing targeting ZBTB11 in fibroblasts from patients and controls. Chromatin immunoprecipitation–sequencing revealed binding of wild-type ZBTB11 to promoters in 238 genes, among which genes encoding proteins involved in mitochondrial functions and RNA processing are over-represented. Mutated ZBTB11 showed reduced binding to 61 of the targeted genes, indicating that the variants act as loss of function. Most of these genes are related to mitochondrial functions. Transcriptome analysis of the patient fibroblasts revealed dysregulation of mitochondrial functions. In addition, we uncovered that reduced binding of the mutated ZBTB11 to ACSF3 leads to decreased ACSF3 transcript level, explaining combined malonic and methylmalonic aciduria.Collectively, these results expand the clinical spectrum of ZBTB11-related neurological disease and give insight into the pathophysiology in which the dysfunctional ZBTB11 affect mitochondrial functions and RNA processing contributing to the neurological and biochemical phenotypes.

Urine Organic Acid Analysis: Key Diagnostic Test for Fumaric Aciduria in a Sri Lankan Child.

Fumaric aciduria resulting from fumarate hydratase deficiency is a rare inherited disorder of the Krebs tricarboxylic acid cycle that is characterized by neurologic manifestations, a spectrum of brain abnormalities, and the excretion of fumaric acid in urine. We describe a 3 year old Sri Lankan boy who was referred at age 10 months with poor weight gain and hypotonia for further laboratory investigations. In addition to global developmental delay, there were noticeable dysmorphic features with a prominent forehead, low-set ears, micrognathia, and hypertelorism with persistent neutropenia. Urine organic acid assay revealed a massive elevation of fumaric acid on 2 occasions. Molecular analysis revealed a homozygous likely pathogenic missense variant, NM000143.3:c.1048C>T p. (Arg350Trp), in the FH gene, confirming the biochemical diagnosis. Our patient was the first patient in Sri Lanka molecularly diagnosed with fumaric aciduria. This case study highlights the importance of performing organic acid assays in children presenting with neurologic manifestations especially when these are suspected to have a metabolic basis.

Congenital Zika Virus Infection: a Review with Emphasis on the Spectrum of Brain Abnormalities.

Purpose of ReviewIn 2016, the World Health Organization declared the Zika virus (ZIKV) outbreak a Public Health Emergency of International Concern following a cluster of associated neurological disorders and neonatal malformations. Our aim is to review the clinical and neuroimaging findings seen in congenital Zika syndrome.Recent FindingsZIKV injures neural progenitor cells in the hippocampus, a brain region important for learning, memory, cognition, and emotion/stress response. Positron emission tomography has revealed global neuroinflammation in ZIKV infection in animal models.SummaryCongenital Zika syndrome is associated with a spectrum of brain abnormalities, including microcephaly, parenchymal calcifications, malformations of cortical development and defective neuronal migration, corpus callosum abnormalities, ventriculomegaly, and brainstem and cerebellar abnormalities.

Fumarase Deficiency: A Safe and Potentially Disease Modifying Effect of High Fat/Low Carbohydrate Diet.

Fumarate hydratase deficiency (FHD) caused by biallelic alterations of the FH (fumarate hydratase) gene is a rare disorder of the tricarboxylic acid cycle, classically characterized by encephalopathy, profound psychomotor retardation, seizures, a spectrum of brain abnormalities and early death in childhood. Less common milder phenotypes with moderate cognitive impairment and long-term survival have been reported. In addition, heterozygous mutations of the FH gene are responsible for hereditary leiomyomatosis and renal cell cancer (HLRCC). There is currently no recommended disease modifying treatment for FHD and only isolated reports of unsuccessful dietary modifications. Herein, we describe the safe and possibly disease modifying effect of a high fat, low carbohydrate diet in a 14-year-old female with severe FHD.

Sudden Death in the Septo-Optic Dysplasia Spectrum

Septo-optic dysplasia (SOD) is a rare entity in which a variable spectrum of brain abnormalities, classically involving midline structures septum pellucidum (SP) and/or corpus callosum (CC) are associated with optic nerve hypoplasia (ONH) and hypothalamic-pituitary dysfunction. Sudden unexpected death (SUD) in the setting of SOD is recognized but there is a paucity of postmortem studies of this patient population. A retrospective clinicopathological analysis of seven autopsy cases of pediatric patients (ages: ten weeks to 17 years) with SOD was performed. Six patients were found vital signs absent at home. The seventh child was admitted to the hospital in shock, and died after being maintained on life support for 16 days. At autopsy, in all cases there were central nervous system (CNS) abnormalities and stigmata of panhypopituitarism (PHP), confirming the underlying diagnosis of SOD. Infectious or other acute pathological processes to account for sudden death were not identified. Forensic pathologists need to be aware of SOD because it predisposes to SUD and an appreciation of the underlying neuroendocrine complexities of the disorder is required for proper death certification.

Spectrum of brain abnormalities detected on whole body F-18 FDG PET/CT in patients undergoing evaluation for non-CNS malignancies

We present the pattern of metabolic brain abnormalities detected in patients undergoing whole body (WB) F-18 flurodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) examination for non-central nervous system (CNS) malignancies. Knowledge of the PET/CT appearance of various intracranial metabolic abnormalities enables correct interpretation of PET scans in oncological patients where differentiation of metastasis from benign intracranial pathologies is important and improves specificity of the PET study. A complete clinical history and correlation with CT and MRI greatly helps in arriving at a correct imaging diagnosis.

Differential effects on white-matter systems in high-functioning autism and Asperger's syndrome

Whether autism spectrum maps onto a spectrum of brain abnormalities and whether Asperger's syndrome (ASP) is distinct from high-functioning autism (HFA) are debated. White-matter maldevelopment is associated with autism and disconnectivity theories of autism are compelling. However, it is unknown whether children with ASP and HFA have distinct white-matter abnormalities. Voxel-based morphometry mapped white-matter volumes across the whole brain in 91 children. Thirty-six had autism spectrum disorder. A history of delay in phrase speech defined half with HFA; those without delay formed the ASP group. The rest were typically developing children, balanced for age, IQ, gender, maternal language and ethnicity. White-matter volumes in HFA and ASP were compared and each contrasted with controls. White-matter volumes around the basal ganglia were higher in the HFA group than ASP and higher in both autism groups than controls. Compared with controls, children with HFA had less frontal and corpus callosal white matter in the left hemisphere; those with ASP had less frontal and corpus callosal white matter in the right hemisphere with more white matter in the left parietal lobe. HFA involved mainly left hemisphere white-matter systems; ASP affected predominantly right hemisphere white-matter systems. The impact of HFA on basal ganglia white matter was greater than ASP. This implies that aetiological factors and management options for autism spectrum disorders may be distinct. History of language acquisition is a potentially valuable marker to refine our search for causes and treatments in autism spectrum.

Model of Cerebral Palsy in the Perinatal Rabbit

Perinatal brain injury results in one of the highest burdens of disease in view of the lifelong consequences and is of enormous cost to society. This makes it imperative to develop better animal models that mimic the human condition. Many neurodevelopmental deficits, such as cerebral palsy, are believed to be a result of prenatal hypoxia-ischemia in humans. Fetal global hypoxia-ischemia is most commonly a consequence of acute placental insufficiency. Our laboratory has modeled in utero sustained and repetitive hypoxia-ischemia in the pregnant rabbit to mimic the insults of abruptio placenta and labor, respectively. Sustained hypoxia-ischemia at 70% (22 days' gestation) and 79% (25 days' gestation) and repetitive hypoxia-ischemia at 90% gestation (28 days' gestation) caused stillbirths and multiple deficits in the postnatal survivors. The deficits included impairment in multiple tests of spontaneous locomotion, reflex motor activity, motor responses to olfactory stimuli, and the coordination of suck and swallow. Hypertonia was observed in the 22 and 25 days' gestation survivors but not in the 28 days' gestation group. Hypertonic survivors were artificially fed and found to have the motor deficits persist for at least 11 postnatal days. A spectrum of brain abnormalities is found on magnetic resonance imaging. This is the first animal model to mimic cerebral palsy. The findings also suggest a window of vulnerability during brain development when the injury results in hypertonia in newborn pups.

Orofaciodigital syndrome type I in a patient with severe CNS defects

A female patient with orofaciodigital syndrome type I associated with pachygyria, heterotopic gray matter, interhemispheric cyst, agenesis of the corpus callosum, and a Dandy-Walker anomaly is reported. Because some of these defects have been described in patients with different types of orofaciodigital syndromes, we recommend caution when using neuroradiologic criteria to separate these syndromes. Given the severe spectrum of brain abnormalities displayed by our patient, and considering their similarity with the brain defects formerly described in other X-linked dominant conditions with male lethality localized to Xp22, the use of DNA probes from Xp22 is advised in identifying the gene(s) causing orofaciodigital syndrome type I.

The prevalence and spectrum of brain abnormalities in congenital choanal atresia.

Over the past few years there has been increasing awareness of the association of congenital choanal atresia (CCA) with other congenital defects, including brain abnormalities. We obtained CT scans of the brain in twenty-three consecutive patients with CCA (10 boys and 13 girls) to determine the prevalence and the scope of associated brain abnormalities. CCA was associated with known syndromes or different congenital abnormalities in 7 and 10 patients, respectively, and was an isolated finding in 6 patients. Six patients (26%) had brain abnormalities including alobar holoprosencephaly, absent corpus callosum, benign enlargement of the subarachnoid space of infancy, cerebral calcification, small right hemisphere, small ventricles and microcephaly. None of the brain abnormalities were suspected clinically. Brain abnormalities were more common in boys compared to girls (40% vs 15.4%, p = 0.18), in bilateral compared to unilateral CCA (31.3% vs 14%, p = 0.38), and in membranous compared to bony CCA (75% vs 15.7%, p = 0.02). Brain abnormalities associated with CCA may be more common than generally recognized and more so in certain subgroups of patients. Obtaining a CT scan of the brain should be considered in all patients with CCA.