ABSTRACT
The blood-brain barrier ensures CNS homeostasis and protection from injury. Claudin-5 (CLDN5), an important component of tight junctions, is critical for the integrity of the blood-brain barrier. We have identified de novo heterozygous missense variants in CLDN5 in 15 unrelated patients who presented with a shared constellation of features including developmental delay, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognizable pattern of pontine atrophy and brain calcifications. All variants clustered in one subregion/domain of the CLDN5 gene and the recurrent variants demonstrate genotype-phenotype correlations. We modelled both patient variants and loss of function alleles in the zebrafish to show that the variants analogous to those in patients probably result in a novel aberrant function in CLDN5. In total, human patient and zebrafish data provide parallel evidence that pathogenic sequence variants in CLDN5 cause a novel neurodevelopmental disorder involving disruption of the blood-brain barrier and impaired neuronal function.
Subject(s)
Microcephaly , Animals , Humans , Microcephaly/genetics , Claudin-5/genetics , Claudin-5/metabolism , Zebrafish/metabolism , Blood-Brain Barrier/metabolism , Seizures/genetics , SyndromeABSTRACT
OBJECTIVE: To describe the association between prenatal imaging and neurodevelopmental outcomes of fetuses with rhombencephalosynapsis (RES). STUDY DESIGN: Thirty-four pregnancies complicated by RES were identified from our institutional databases based on US and/or MRI findings. Genetic testing results were gathered. In cases of termination of pregnancy, we studied the association between prenatal imaging and neuropathologic findings. For those who opted for expectant management, comprehensive developmental assessments and postnatal MRI imaging were evaluated. RESULTS: Over one third of fetuses in our cohort had complete RES. Common intracranial anomalies identified were mesencephalosynapsis, aqueduct stenosis and diencephalosynapsis. The degree of RES was not associated with the frequency of additional central nervous system anomalies. MRI had a good correlation with neuropathologic findings with regard to the degree of RES, aqueduct stenosis and mesencephalosynapsis. Postmortem autopsy showed that one third of our cases had VACTERL-H and almost all of those had complete RES. All liveborn neonates(n = 6) had aqueduct stenosis requiring ventriculoperitoneal shunting within days of delivery (median 5 days). While a large proportion of prenatally suspected complete RES were found to have partial RES on postnatal imaging, prenatal diagnosis of aqueduct stenosis remained unchanged. All children that were at least 2 years old (n = 3) had global developmental delay. CONCLUSION: Prenatal assessment of the RES severity is challenging and may be unreliable. Nevertheless, postnatal prognosis is poor for both complete and partial RES. Associated aqueductal stenosis, can be reliably assessed prenatally and this may contribute to worse postnatal prognosis than the degree of RES.
ABSTRACT
Autosomal recessive microcephaly and chorioretinopathy-1 (MCCRP1) is a rare Mendelian disorder resulting from biallelic loss of function variants in Tubulin-Gamma Complex Associated Protein 6 (TUBGCP6, MIM#610053). Clinical features of this disorder include microcephaly, cognitive impairment, dysmorphic features, and variable ophthalmological anomalies including chorioretinopathy. Microcephaly can be recognized prenatally and visual impairment becomes evident during the first year of life. The clinical presentation resembles the findings in some acquired conditions such as congenital toxoplasmosis and cytomegalovirus infections; thus, it is important to recognize and diagnose this syndrome in view of its impact on patient health management and familial reproductive plans. To date, only seven molecularly confirmed patients from five unrelated families have been reported. We report an additional four unrelated patients with TUBGCP6 variants including one prenatal diagnosis and review the clinical phenotypes and genotypes of all the known cases. This report expands the molecular and phenotypic spectrum of TUBGCP6 and includes additional prenatal findings associated with MCCRP1.
Subject(s)
Microcephaly , Retinal Diseases , Pregnancy , Humans , Female , Microcephaly/diagnosis , Microcephaly/genetics , Microcephaly/complications , Genotype , Phenotype , Microtubule-Associated Proteins/geneticsABSTRACT
Sensorineural hearing loss results from abnormalities that affect the hair cells of the membranous labyrinth, inner ear malformations, and conditions affecting the auditory pathway from the cochlear nerve to the processing centers of the brain. Cochlear implantation is increasingly being performed for hearing rehabilitation owing to expanding indications and a growing number of children and adults with sensorineural hearing loss. An adequate understanding of the temporal bone anatomy and diseases that affect the inner ear is paramount for alerting the operating surgeon about variants and imaging findings that can influence the surgical technique, affect the choice of cochlear implant and electrode type, and help avoid inadvertent complications. In this article, imaging protocols for sensorineural hearing loss and the normal inner ear anatomy are reviewed, with a brief description of cochlear implant devices and surgical techniques. In addition, congenital inner ear malformations and acquired causes of sensorineural hearing loss are discussed, with a focus on imaging findings that may affect surgical planning and outcomes. The anatomic factors and variations that are associated with surgical challenges and may predispose patients to periprocedural complications also are highlighted. © RSNA, 2023 Quiz questions for this article are available through the Online Learning Center. Online supplemental material and the slide presentation from the RSNA Annual Meeting are available for this article.
Subject(s)
Cochlear Implantation , Cochlear Implants , Ear, Inner , Hearing Loss, Sensorineural , Child , Adult , Humans , Cochlear Implantation/adverse effects , Cochlear Implantation/methods , Hearing Loss, Sensorineural/diagnostic imaging , Hearing Loss, Sensorineural/surgery , Hearing Loss, Sensorineural/etiology , Ear, Inner/abnormalities , Ear, Inner/surgery , Cochlear Implants/adverse effects , Temporal Bone/anatomy & histologyABSTRACT
Macrocephaly means a large head and is defined as a head circumference (HC) above the 98th percentile or greater than +2SD above the mean for gestational age. Macrocephaly can be primary and due to increased brain tissue (megalocephaly), which in most cases is familial and benign or secondary. The latter may be due to various causes, including but not limited to communicating or non-communicating hydrocephalus, cerebral edema, focal and pericerebral increased fluid collections, thickened calvarium and brain tumors. Megalocephaly can be syndromic or non-syndromic. In the former, gyral and structural CNS anomalies are common. It is important to exercise caution when considering a diagnosis of megalocephaly due to limitations in the accuracy of HC measurement, lack of nomograms for specific populations, inconsistencies between prenatal and postnatal HC growth curves and progression over time. The degree of macrocephaly is important, with mild macrocephaly ≤2.5SD carrying a good prognosis, especially when one of the parents has macrocephaly and normal development. Cases in which the patient history and/or physical exam are positive or when parental HC are normal are more worrisome and warrant a neurosonogram, fetal MRI and genetic testing to better delineate the underlying etiology and provide appropriate counseling.
Subject(s)
Megalencephaly , Prenatal Diagnosis , Pregnancy , Female , Humans , Megalencephaly/diagnosis , Megalencephaly/therapy , Genetic Testing , Gestational Age , Magnetic Resonance ImagingABSTRACT
OBJECTIVE: To evaluate the short- and long-term outcome of fetuses with evidence of extension of the choroid plexus into the frontal horns. METHODS: This is a retrospective cohort study of fetuses diagnosed with isolated choroid plexi extending into the frontal horns. Fetuses with major central nervous system anomalies were excluded. Ultrasound and fetal/postnatal magnetic resonance imaging (MRI) were evaluated. Postnatal outcomes, including developmental assessment, were obtained. RESULTS: Twenty nine fetuses were diagnosed with choroid plexus extension (22 unilateral and 7 bilateral). Gestational age at diagnosis was 19.3 weeks. Three cases (10.3%) presented with nonspecific extra-CNS findings. At presentation, 8/29 (28%) cases had single/multiple choroid plexus cysts (CPC). Twenty-six (89.6%) cases underwent antenatal MRI. On MRI, four cases had punctate susceptibility weighted imaging (SWI) foci suggesting trace hemosiderin and two cases had ventriculomegaly. Antenatal follow-up demonstrated resolution of the choroid plexus extension in 90% (18/20). Gestational age at delivery was 39.6 weeks. All had normal neurologic examinations within 24 h of life. Postnatal MRI studies were notable for deep venous differences in seven cases. Long-term clinical outcome was assessed in 14 cases with a median follow-up of 1.75 years, with normal neurodevelopment reported in 13/14 (92.8%). CONCLUSIONS: Most fetuses with an anterior extension of the choroid plexus as the sole sonographic finding had favorable outcomes.
Subject(s)
Fetal Diseases , Nervous System Malformations , Pregnancy , Female , Humans , Infant , Choroid Plexus/diagnostic imaging , Retrospective Studies , Fetal Diseases/diagnosis , Ultrasonography, Prenatal/methods , Fetus , Cerebral Ventricles/diagnostic imagingABSTRACT
OBJECTIVES: To determine simple prenatal imaging parameters that can easily be acquired to predict the need for postnatal CSF diversion (PCD) surgery in fetuses undergoing open fetal surgery for open spina bifida (OSB). METHODS: All fetuses with OSB that underwent open fetal surgery between June 2017 and June 2021 with available follow-up outcomes were included. Imaging parameters including clivus-supraocciput angle (CSA) on magnetic resonance imaging, transcerebellar diameter (TCD) and lateral ventricle size (Vp) on ultrasound (US), were collected pre- and postoperatively. The requirement for PCD surgery was determined at 1 year of age. The predictive strength of each parameter was determined by Receiver Operating Characteristic curve analysis. RESULTS: Among 36 babies eligible for the analyses, 41.7% required PCD by one year of age. Pre-operative Vp (AUC 0.71; 95% confidence interval [CI] 0.54-0.88; p = 0.03), TCD (AUC 0.72; 95% CI 0.55-0.89; p = 0.02) and CSA (AUC 0.72; 95% CI 0.51-0.93; p = 0.04) were fair predictors for PCD surgery. After fetal surgery, TCD (AUC 0.93; 95% CI 0.83-1.00; p < 0.0001) and CSA (AUC 0.94; 95% CI 0.83-1.00; p = 0.0005) were outstanding predictors of PCD, whereas post-operative Vp was a fair predictor (AUC 0.71, 95% CI 0.54-0.88, p = 0.03). CONCLUSION: Post-operative CSA and TCD were outstanding predictors for the need for PCD surgery.
Subject(s)
Spina Bifida Cystica , Spinal Dysraphism , Pregnancy , Infant , Female , Humans , Gestational Age , Spinal Dysraphism/diagnostic imaging , Spinal Dysraphism/surgery , Fetus , Spina Bifida Cystica/diagnostic imaging , Spina Bifida Cystica/surgery , Prenatal Care , Ultrasonography, PrenatalABSTRACT
Lissencephaly comprises a spectrum of malformations of cortical development. This spectrum includes agyria, pachygyria, and subcortical band heterotopia; each represents anatomical malformations of brain cortical development caused by neuronal migration defects. The molecular etiologies of neuronal migration anomalies are highly enriched for genes encoding microtubules and microtubule-associated proteins, and this enrichment highlights the critical role for these genes in cortical growth and gyrification. Using exome sequencing and family based rare variant analyses, we identified a homozygous variant (c.997C>T [p.Arg333Cys]) in TUBGCP2, encoding gamma-tubulin complex protein 2 (GCP2), in two individuals from a consanguineous family; both individuals presented with microcephaly and developmental delay. GCP2 forms the multiprotein γ-tubulin ring complex (γ-TuRC) together with γ-tubulin and other GCPs to regulate the assembly of microtubules. By querying clinical exome sequencing cases and through GeneMatcher-facilitated collaborations, we found three additional families with bi-allelic variation and similarly affected phenotypes including a homozygous variant (c.1843G>C [p.Ala615Pro]) in two families and compound heterozygous variants consisting of one missense variant (c.889C>T [p.Arg297Cys]) and one splice variant (c.2025-2A>G) in another family. Brain imaging from all five affected individuals revealed varying degrees of cortical malformations including pachygyria and subcortical band heterotopia, presumably caused by disruption of neuronal migration. Our data demonstrate that pathogenic variants in TUBGCP2 cause an autosomal recessive neurodevelopmental trait consisting of a neuronal migration disorder, and our data implicate GCP2 as a core component of γ-TuRC in neuronal migrating cells.
Subject(s)
Genetic Variation/genetics , Lissencephaly/genetics , Microcephaly/genetics , Microtubule-Associated Proteins/genetics , Alleles , Brain/metabolism , Cell Movement/genetics , Child , Exome/genetics , Female , Homozygote , Humans , Male , Microtubules/genetics , Nervous System Malformations/genetics , Neurons/metabolism , Phenotype , Tubulin/geneticsABSTRACT
Nicotinamide adenine dinucleotide (NAD) is an essential coenzyme involved in over 400 cellular reactions. During embryogenesis, mammals synthesize NAD de novo from dietary l -tryptophan via the kynurenine pathway. Biallelic, inactivating variants in three genes encoding enzymes of this biosynthesis pathway (KYNU, HAAO, and NADSYN1) disrupt NAD synthesis and have been identified in patients with multiple malformations of the heart, kidney, vertebrae, and limbs; these patients have Congenital NAD Deficiency Disorder HAAO and four families with biallelic variants in KYNU. These patients present similarly with multiple malformations of the heart, kidney, vertebrae, and limbs, of variable severity. We show that each variant identified in these patients results in loss-of-function, revealed by a significant reduction in NAD levels via yeast genetic complementation assays. For the first time, missense mutations are identified as a cause of malformation and shown to disrupt enzyme function. These missense and frameshift variants cause moderate to severe NAD deficiency in yeast, analogous to insufficient synthesized NAD in patients. We hereby expand the genotypic and corresponding phenotypic spectrum of Congenital NAD Deficiency Disorder.
Subject(s)
NAD , Spine , Animals , Genotype , Humans , Mammals , Mutation, Missense , Spine/abnormalitiesABSTRACT
LonP1 is crucial for maintaining mitochondrial proteostasis and mitigating cell stress. We identified a novel homozygous missense LONP1 variant, c.2282 C > T, (p.Pro761Leu), by whole-exome and Sanger sequencing in two siblings born to healthy consanguineous parents. Both siblings presented with stepwise regression during infancy, profound hypotonia and muscle weakness, severe intellectual disability and progressive cerebellar atrophy on brain imaging. Muscle biopsy revealed the absence of ragged-red fibers, however, scattered cytochrome c oxidase-negative staining and electron dense mitochondrial inclusions were observed. Primary cultured fibroblasts from the siblings showed normal levels of mtDNA and mitochondrial transcripts, and normal activities of oxidative phosphorylation complexes I through V. Interestingly, fibroblasts of both siblings showed glucose-repressed oxygen consumption compared to their mother, whereas galactose and palmitic acid utilization were similar. Notably, the siblings' fibroblasts had reduced pyruvate dehydrogenase (PDH) activity and elevated intracellular lactate:pyruvate ratios, whereas plasma ratios were normal. We demonstrated that in the siblings' fibroblasts, PDH dysfunction was caused by increased levels of the phosphorylated E1α subunit of PDH, which inhibits enzyme activity. Blocking E1α phosphorylation activated PDH and reduced intracellular lactate concentrations. In addition, overexpressing wild-type LonP1 in the siblings' fibroblasts down-regulated phosphoE1α. Furthermore, in vitro studies demonstrated that purified LonP1-P761L failed to degrade phosphorylated E1α, in contrast to wild-type LonP1. We propose a novel mechanism whereby homozygous expression of the LonP1-P761L variant leads to PDH deficiency and energy metabolism dysfunction, which promotes severe neurologic impairment and neurodegeneration.
Subject(s)
ATP-Dependent Proteases/genetics , Cerebellar Diseases/genetics , Mitochondrial Proteins/genetics , Mutation , Neurodegenerative Diseases/genetics , Pyruvate Dehydrogenase Complex Deficiency Disease/genetics , Alleles , Cerebellar Diseases/enzymology , DNA, Mitochondrial/metabolism , Homozygote , Humans , Infant, Newborn , Lactates/metabolism , Male , Neurodegenerative Diseases/enzymology , Pedigree , Phosphorylation , Protein Subunits/metabolism , Proteolysis , Pyruvate Dehydrogenase Complex Deficiency Disease/pathologyABSTRACT
Variants in JAM3 have been reported in four families manifesting a severe autosomal recessive disorder characterized by hemorrhagic destruction of the brain, subependymal calcification, and cataracts. We describe a 7-year-old male with a similar presentation found by research-based quad genome sequencing to have two novel splicing variants in trans in JAM3, including one deep intronic variant (NM_032801.4: c.256+1260G>C) not detectable by standard exome sequencing. Targeted sequencing of RNA isolated from transformed lymphoblastoid cell lines confirmed that each of the two variants has a deleterious effect on JAM3 mRNA splicing. The role for genome sequencing as a clinical diagnostic test extends to those patients with phenotypes strongly suggestive of a specific Mendelian disorder, especially when the causal genetic variant(s) are not found by a more targeted approach. Barriers to diagnosis via identification of pathogenic deep intronic variation include lack of laboratory consensus regarding in silico splicing prediction tools and limited access to clinically validated confirmatory RNA experiments.
Subject(s)
Brain Diseases/genetics , Cell Adhesion Molecules/genetics , Hemorrhagic Disorders/genetics , RNA Splicing/genetics , Adult , Brain Diseases/diagnosis , Brain Diseases/diagnostic imaging , Brain Diseases/pathology , Child , Female , Hemorrhagic Disorders/diagnosis , Hemorrhagic Disorders/diagnostic imaging , Hemorrhagic Disorders/pathology , Humans , Introns/genetics , Male , Mutation/genetics , Pedigree , Protein Isoforms/genetics , Exome SequencingABSTRACT
Human post-natal neurodevelopmental delay is often associated with cerebral alterations that can lead, by themselves or associated with peripheral deficits, to premature death. Here, we report the clinical features of 10 patients from six independent families with mutations in the autosomal YIF1B gene encoding a ubiquitous protein involved in anterograde traffic from the endoplasmic reticulum to the cell membrane, and in Golgi apparatus morphology. The patients displayed global developmental delay, motor delay, visual deficits with brain MRI evidence of ventricle enlargement, myelination alterations and cerebellar atrophy. A similar profile was observed in the Yif1b knockout (KO) mouse model developed to identify the cellular alterations involved in the clinical defects. In the CNS, mice lacking Yif1b displayed neuronal reduction, altered myelination of the motor cortex, cerebellar atrophy, enlargement of the ventricles, and subcellular alterations of endoplasmic reticulum and Golgi apparatus compartments. Remarkably, although YIF1B was not detected in primary cilia, biallelic YIF1B mutations caused primary cilia abnormalities in skin fibroblasts from both patients and Yif1b-KO mice, and in ciliary architectural components in the Yif1b-KO brain. Consequently, our findings identify YIF1B as an essential gene in early post-natal development in human, and provide a new genetic target that should be tested in patients developing a neurodevelopmental delay during the first year of life. Thus, our work is the first description of a functional deficit linking Golgipathies and ciliopathies, diseases so far associated exclusively to mutations in genes coding for proteins expressed within the primary cilium or related ultrastructures. We therefore propose that these pathologies should be considered as belonging to a larger class of neurodevelopmental diseases depending on proteins involved in the trafficking of proteins towards specific cell membrane compartments.
Subject(s)
Cilia/genetics , Golgi Apparatus/genetics , Mutation/genetics , Neurodevelopmental Disorders/genetics , Vesicular Transport Proteins/genetics , Animals , Cells, Cultured , Cilia/pathology , Female , Golgi Apparatus/pathology , Humans , Male , Mice , Mice, Knockout , Neurodevelopmental Disorders/diagnostic imagingABSTRACT
INTRODUCTION: Although fetal brain injury due to COL4A1 gene mutation is well documented, fetal central nervous system (CNS) and placental histopathology lack description. We report CNS and placental pathology in fetal cases with symptomatic COL4A1 mutation. METHODS: We retrieved four autopsy cases of COL4A1 related disease, confirmed by genetic sequencing after fetal brain injury was detected. RESULTS: One case was a midgestation fetus with residua of ventricular zone hemorrhage and normal placental villi. Three cases were 30-32 week gestation fetuses: two demonstrated CNS small vessel thrombosis, with CNS injury. Both demonstrated high grade placental fetal vascular malperfusion (FVM). One additionally showed villous dysmorphism, the other demonstrated mild villous immaturity. The fetus whose placenta demonstrated high grade FVM was growth restricted. A fourth fetus demonstrated schizencephaly with a CNS arteriopathy with smooth muscle cell degeneration and cerebral infarcts; the placenta demonstrated severe villous dysmorphism and low grade FVM. DISCUSSION: These cases confirm that small vessel disease is important in producing intracranial pathology in COL4A1mutation. We report an arteriopathy distinct from microvascular thrombosis and demonstrate that placental pathology is common in fetal COL4A1 related disease. This tentatively suggests that placental pathology may contribute to CNS abnormalities by affecting circulatory sufficiency.
Subject(s)
Brain/abnormalities , Collagen Type IV/genetics , Fetus/abnormalities , Placenta Diseases/genetics , Placenta/pathology , Female , Humans , Mutation , Placenta Diseases/pathology , PregnancyABSTRACT
Traumatic brain injury is responsible for approximately half of all childhood deaths from infancy to puberty, the majority of which are attributable to abusive head trauma (AHT). Due to the broad way patients present and the lack of a clear mechanism of injury in some cases, neuroimaging plays an integral role in the diagnostic pathway of these children. However, this nonspecific nature also presages the existence of numerous conditions that mimic both the clinical and neuroimaging findings seen in AHT. This propensity for misdiagnosis is compounded by the lack of pathognomonic patterns and clear diagnostic criteria. The repercussions of this are severe and have a profound stigmatic effect. The authors present an exhaustive review of the literature complemented by illustrative cases from their institutions with the aim of providing a framework with which to approach the neuroimaging and diagnosis of AHT.
Subject(s)
Child Abuse , Craniocerebral Trauma , Child , Child Abuse/diagnosis , Craniocerebral Trauma/diagnostic imaging , Humans , Infant , NeuroimagingABSTRACT
BACKGROUND: Brain injury, impaired brain growth, and long-term neurodevelopmental problems are common in children with transposition of the great arteries. We sought to identify clinical risk factors for brain injury and poor brain growth in infants with transposition of the great arteries undergoing the arterial switch operation, and to examine their relationship with neurodevelopmental outcome. METHODS: The brains of 45 infants with transposition of the great arteries undergoing surgical repair were imaged pre- and postoperatively using magnetic resonance imaging. Brain weight z scores were calculated based on brain volume and autopsy reference data. Brain injury scores were determined as previously described. Neurodevelopment was assessed at 18 months using the Bayley-III scores of infant development. The relationships between clinical variables, brain injury, perioperative brain growth, and 18-month Bayley-III scores were analyzed. RESULTS: On preoperative imaging, moderate or severe white matter injury was present in 10 of 45 patients, whereas stroke was seen in 4 of 45. A similar prevalence of injury was seen on postoperative imaging, and we were unable to identify any clinical risk factors for brain injury. Brain weight z scores decreased perioperatively in 35 of 45 patients. The presence of a ventricular septal defect ( P=0.009) and older age at surgery ( P=0.007) were associated with impaired perioperative brain growth. When patients were divided into those undergoing surgery during the first 2 weeks of life (32/45) versus those being repaired later (13/45), infants repaired later had significantly worse perioperative brain growth (late repair postoperative brain weight z = -1.0±0.90 versus early repair z = -0.33±0.64; P=0.008). Bayley-III testing scores fell within the normal range for all patients, although age at repair ( P=0.03) and days of open chest ( P=0.03) were associated with a lower composite language score, and length of stay was associated with a lower composite cognitive score ( P=0.02). CONCLUSIONS: Surgery beyond 2 weeks of age is associated with impaired brain growth and slower language development in infants with transposition of the great arteries cared for at our center. Although the mechanisms underlying this association are still unclear, extended periods of cyanosis and pulmonary overcirculation may adversely impact brain growth and subsequent neurodevelopment.
Subject(s)
Arterial Switch Operation , Brain Diseases/etiology , Brain/growth & development , Child Development , Transposition of Great Vessels/surgery , Age Factors , Autopsy , Brain/diagnostic imaging , Brain Diseases/diagnostic imaging , Brain Diseases/physiopathology , Child Language , Diffusion Magnetic Resonance Imaging , Humans , Infant , Infant Behavior , Infant, Newborn , Ontario , Organ Size , Prospective Studies , Time Factors , Transposition of Great Vessels/complications , Transposition of Great Vessels/diagnostic imaging , Treatment OutcomeABSTRACT
Glutamine synthetase (GS) is the enzyme responsible for the biosynthesis of glutamine, providing the only source of endogenous glutamine necessary for several critical metabolic and developmental pathways. GS deficiency, caused by pathogenic variants in the glutamate-ammonia ligase (GLUL) gene, is a rare autosomal recessive inborn error of metabolism characterized by systemic glutamine deficiency, persistent moderate hyperammonemia, and clinically devastating seizures and multi-organ failure shortly after birth. The four cases reported thus far were caused by homozygous GLUL missense variants. We report a case of GS deficiency caused by homozygous GLUL gene deletion, diagnosed prenatally and likely representing the most severe end of the spectrum. We expand the known phenotype of this rare condition with novel dysmorphic, radiographic and neuropathologic features identified on post-mortem examination. The biallelic deletion identified in this case also included the RNASEL gene and was associated with immune dysfunction in the fetus. This case demonstrates that total absence of the GLUL gene in humans is viable beyond the embryonic period, despite the early embryonic lethality found in GLUL animal models.
Subject(s)
Amino Acid Metabolism, Inborn Errors/genetics , Glutamate-Ammonia Ligase/deficiency , Glutamate-Ammonia Ligase/genetics , Adult , Amino Acid Metabolism, Inborn Errors/pathology , Female , Fetus , Glutamine/genetics , Homozygote , Humans , Infant, Newborn , Male , Metabolic Diseases/genetics , Metabolic Diseases/pathologyABSTRACT
Our improved tools to identify the aetiologies in patients with multiple abnormalities resulted in the finding that some patients have more than a single genetic condition and that some of the diagnoses made in the past are acquired rather than inherited. However, limited knowledge has been accumulated regarding the phenotypic outcome of the interaction between different genetic conditions identified in the same patients. We report a newborn girl with brachytelephalangic chondrodysplasia punctata (BCDP) as well as frontonasal dysplasia, ptosis, bilateral hearing loss, vertebral anomalies, and pulmonary hypoplasia who was found, by whole exome sequencing, to have a de novo pathogenic variant in RAF1 (c.770C>T, [p.Ser257Leu]) and a likely pathogenic variant in SIX2 (c.760G>A [p.A254T]), as well as maternal systemic lupus erythematosus (SLE). This case shows that BCDP is most probably not a diagnostic entity and can be associated with various conditions associated with CDP including maternal SLE.
Subject(s)
Abnormalities, Multiple/genetics , Chondrodysplasia Punctata/genetics , Homeodomain Proteins/genetics , Nerve Tissue Proteins/genetics , Proto-Oncogene Proteins c-raf/genetics , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/pathology , Chondrodysplasia Punctata/diagnosis , Chondrodysplasia Punctata/pathology , Craniofacial Abnormalities/diagnosis , Craniofacial Abnormalities/genetics , Craniofacial Abnormalities/pathology , Face/abnormalities , Face/pathology , Female , Genetic Predisposition to Disease , Hernia, Diaphragmatic/diagnosis , Hernia, Diaphragmatic/genetics , Humans , Infant, NewbornABSTRACT
The RASopathies are a group of genetic disorders that result from germline pathogenic variants affecting RAS-mitogen activated protein kinase (MAPK) pathway genes. RASopathies share RAS/MAPK pathway dysregulation and share phenotypic manifestations affecting numerous organ systems, causing lifelong and at times life-limiting medical complications. RASopathies may benefit from precision medicine approaches. For this reason, the Sixth International RASopathies Symposium focused on exploring precision medicine. This meeting brought together basic science researchers, clinicians, clinician scientists, patient advocates, and representatives from pharmaceutical companies and the National Institutes of Health. Novel RASopathy genes, variants, and animal models were discussed in the context of medication trials and drug development. Attempts to define and measure meaningful endpoints for treatment trials were discussed, as was drug availability to patients after trial completion.
Subject(s)
Genetic Diseases, Inborn/genetics , Mitogen-Activated Protein Kinase Kinases/genetics , ras Proteins/genetics , Genetic Diseases, Inborn/pathology , Germ-Line Mutation/genetics , Humans , Signal Transduction/geneticsABSTRACT
OBJECTIVES: The aims of this study were to: i) determine the spectrum of brain injury and ii) compare brain volumes between pre- and postoperative brain MRI in the infants receiving extracorporeal membrane oxygenation compared with those who did not require extracorporeal membrane oxygenation. DESIGN: Cohort study of infants with D-transposition of the great arteries or single ventricle physiology. Brain volume (cm) was measured using a segmentation of a volumetric T1-weighted gradient echo sequence. Brain imaging findings (intraventricular hemorrhage, white matter injuries, and stroke) were analyzed with respect to known clinical risk factors for brain injury and adverse neurodevelopmental outcomes. Clinical factors were collected by retrospective chart review. The association between brain volume and extracorporeal membrane oxygenation was evaluated using generalized estimating equations to account for repeated measures. SETTING: Prospective and single-centered study. PATIENTS: One hundred nine infants (median gestational age, 39.1 wk) with D-transposition of the great arteries (n = 77) or single ventricle physiology (n = 32) were studied pre- and postoperatively with MRI as per clinical protocol. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 28 infants (26%) receiving extracorporeal membrane oxygenation, 19 (68%) were supported with extracorporeal membrane oxygenation once, and nine (32%) were supported 2-4 times. On postoperative MRI, new white matter injury was found in only five (17%) of the extracorporeal membrane oxygenation infants versus 40 (49%) in the non-extracorporeal membrane oxygenation group (p = 0.073). The rate of stroke (9% vs 10%), intraventricular hemorrhage (24% vs 29%), and hypoxic ischemia (3% vs 14%) did not differ between the non-extracorporeal membrane oxygenation and extracorporeal membrane oxygenation groups (all p > 0.5). Accounting for D-transposition of the great arteries or single ventricle physiology diagnosis, infants requiring extracorporeal membrane oxygenation had slower brain volume with single (ß = -1.67) or multiple extracorporeal membrane oxygenation runs ([ß = -6.54]; overall interaction p = 0.012). CONCLUSIONS: Patients with d-transposition of the great arteries or single ventricle physiology undergoing extracorporeal membrane oxygenation at our center have a similar incidence of brain injury but more significant impairment of perioperative brain volumes than those not requiring extracorporeal membrane oxygenation.
Subject(s)
Extracorporeal Membrane Oxygenation , Heart Defects, Congenital , Transposition of Great Vessels , Adult , Brain/diagnostic imaging , Cohort Studies , Extracorporeal Membrane Oxygenation/adverse effects , Humans , Infant , Prospective Studies , Retrospective StudiesABSTRACT
OBJECTIVES: To assess the natural evolution of the size of the fetal lateral ventricles throughout pregnancy in fetuses with callosal anomalies. METHODS: Cases of fetal callosal anomalies were retrospectively classified as isolated or complex based on the presence of other structural or genetic anomalies. Longitudinal ultrasound studies were reviewed, and postnatal outcomes were retrieved for isolated cases. RESULTS: In 135 fetuses, those who first presented after 24 weeks' gestation were more likely to have ventriculomegaly (n = 58 of 68 [85%]) than those who presented before 24 weeks (n = 39 of 67 [58%]; P < .001). In 79 cases that had longitudinal follow-up, the mean increase in ventricular width was 0.6 mm/wk, without a significant difference between isolated and complex cases (mean ± SD, 0.6 ± 1.5 versus 0.6 ± 1.1 mm; P = .45). CONCLUSIONS: Callosal anomalies are associated with progressive ventriculomegaly on prenatal ultrasound imaging, without a difference between isolated and complex anomalies. This feature should be considered part of the disease spectrum. The consequence of progressive ventriculomegaly on the long-term neurodevelopmental outcome is still unknown, and further studies should be aimed at obtaining long-term follow-up of these cases.