Fetal and neonatal neuroimaging in twin-twin transfusion syndrome.

OBJECTIVES: To describe the types of brain injury and subsequent neurodevelopmental outcome in fetuses and neonates from pregnancies with twin-twin transfusion syndrome (TTTS). Additionally, to determine risk factors for brain injury and to review the use of neuroimaging modalities in these cases. METHODS: This was a retrospective cohort study of consecutive TTTS pregnancies treated with laser surgery in a single fetal therapy center between January 2010 and January 2020. The primary outcome was the incidence of brain injury, classified into predefined groups. Secondary outcomes included adverse outcome (perinatal mortality or neurodevelopmental impairment), risk factors for brain injury and the number of magnetic resonance imaging (MRI) scans. RESULTS: Cranial ultrasound was performed in all 466 TTTS pregnancies and in 685/749 (91%) liveborn neonates. MRI was performed in 3% of pregnancies and 4% of neonates. Brain injury was diagnosed in 16/935 (2%) fetuses and 37/685 (5%) neonates and all predefined injury groups were represented. Four fetal and four neonatal cases of cerebellar hemorrhage were detected. Among those with brain injury, perinatal mortality occurred in 11/16 (69%) fetuses and 8/37 (22%) neonates. Follow-up was available for 29/34 (85%) long-term survivors with brain injury and the mean age at follow-up was 46 months. Neurodevelopmental impairment was present in 9/29 (31%) survivors with brain injury. Adverse outcome occurred in 28/53 (53%) TTTS individuals with brain injury. The risk of brain injury was increased after recurrent TTTS/post-laser twin anemia-polycythemia sequence (TAPS) (odds ratio (OR), 3.095 (95% CI, 1.581-6.059); P = 0.001) and lower gestational age at birth (OR per 1-week decrease in gestational age, 1.381 (95% CI, 1.238-1.541); P < 0.001). CONCLUSIONS: Based on dedicated neurosonography and limited use of MRI, brain injury was diagnosed in 2% of fetuses and 5% of neonates with TTTS. Adverse outcome was seen in over half of cases with brain injury. Brain injury was related to recurrent TTTS/post-laser TAPS and a lower gestational age at birth. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Scoring of brain magnetic resonance imaging and neurodevelopmental outcomes in infants with congenital heart disease.

BACKGROUND: Advances in surgical techniques to tackle critical congenital heart diseases (CHD) have enhanced the survival rates and life expectancy of children born with heart disease. Studies to better acknowledge their neurodevelopmental trajectory have paramount implications. OBJECTIVE: The aim of this study is to examine the nature of brain MRI findings in infants born with critical congenital heart diseases needing intervention in the first 6 months of life, with the help of an MRI scoring system and correlation with long term neurodevelopmental outcomes. METHODS: Brain MRI scans of eligible infants were extracted from database, reexamined to categorize, and score them into three main functional areas: cognitive/grey matter, motor/white matter, and visual. The scoring system also included stage of myelination and presence of punctate hemorrhages. The correlation of individual and total MRI scores with neurodevelopmental assessment using Bayley Scales for Infant and Toddler Development- version 3 (BSID III) were examined via logistic regression models while controlling for confounding variables. RESULT: Median (IQR) MRI score was 6 (4-7) with grey matter score of 2 (1-4). Initial BSID III scores were 80 ± 15, 80 ± 18, and 81 ± 19 for cognitive, motor and language components, respectively. The MRI cognitive score had direct correlation with respiratory index prior to surgery (cc = 0.47, p = 0.03) and cross-clamping time (cc = 0.65, p = 0.001). It displayed a significant inverse correlation with language scores for BSID III at 9 months (R = -0.42, p = 0.04) which lost significance in subsequent visits. CONCLUSION: This pilot study proved the feasibility of correlating structural brain abnormalities in MRI with later brain developmental deficits in infants with CHD. We envision establishing a standardized MRI scoring system to be performed on a large multi-center cohort that would help better predict and measure brain injury in infants with CHDs.

Relationship between the Quantitative Indicators of Cranial MRI and the Early Neurodevelopment of Preterm Infants.

AIM: To explore the relationship between the quantitative indicators (biparietal width, interhemispheric distance) of the cranial MRI for preterm infants at 37 weeks of postmenstrual age (PMA) and neurodevelopment at 6 months of corrected age. METHODS: A total of 113 preterm infants (gestational age < 37 weeks) delivered in the Obstetrics Department of the First People's Hospital of Lianyungang from September 2018 to February 2020 and directly transferred to the Neonatology Department for treatment were enrolled in this study. Based on their development quotient (DQ), the patients were divided into the normal (DQ ≥ 85, n = 76) group and the abnormal (DQ < 85, n = 37) group. Routine cranial MRI (cMRI) was performed at 37 weeks of PMA to measure the biparietal width (BPW) and interhemispheric distance (IHD). At the corrected age of 6 months, Development Screening Test (for children under six) was used to assess the participants' neurodevelopment. RESULTS: Univariate analysis showed statistically significant differences in BPW, IHD, and the incidence of bronchopulmonary dysplasia between the normal and the abnormal groups (P < 0.05), while no statistically significant differences were found in maternal complications and other clinical conditions between the two groups (P > 0.05). Binary logistic regression analysis demonstrated statistically significant differences in IHD and BPW between the normal and the abnormal groups (95% CI: 1.629-12.651 and 0.570-0.805, respectively; P = 0.004 and P < 0.001, respectively), while no significant differences were found in the incidence of bronchopulmonary dysplasia between the two groups (95% CI: 0.669-77.227, P = 0.104). Receiver operating characteristic curve revealed that the area under the curve of BPW, IHD, and the joint predictor (BPW + IHD) were 0.867, 0.805, and 0.881, respectively (95% CI: 0.800-0.933, 0.710-0.900, and 0.819-0.943, respectively; all P values < 0.001). CONCLUSION: BPW and IHD, the two quantitative indicators acquired by cMRI, could predict the neurodevelopmental outcome of preterm infants at the corrected age of 6 months. The combination of the two indicators showed an even higher predictive value.

Association between Term Equivalent Brain Magnetic Resonance Imaging and 2-Year Outcomes in Extremely Preterm Infants: A Report from the Preterm Erythropoietin Neuroprotection Trial Cohort.

OBJECTIVES: To compare the term equivalent brain magnetic resonance imaging (MRI) findings between erythropoietin (Epo) treated and placebo control groups in infants 240/7-276/7 weeks of gestational age and to assess the associations between MRI findings and neurodevelopmental outcomes at 2 years corrected age. STUDY DESIGN: The association between brain abnormality scores and Bayley Scales of Infant Development, Third Edition at 2 years corrected age was explored in a subset of infants enrolled in the Preterm Erythropoietin Neuroprotection Trial. Potential risk factors for neurodevelopmental outcomes such as treatment assignment, recruitment site, gestational age, inpatient complications, and treatments were examined using generalized estimating equation models. RESULTS: One hundred ten infants were assigned to Epo and 110 to placebo groups. 27% of MRI scans were rated as normal, and 60%, 10%, and 2% were rated as having mild, moderate, or severe abnormality. Brain abnormality scores did not significantly differ between the treatment groups. Factors that increased the risk of higher brain injury scores included intubation; bronchopulmonary dysplasia; retinopathy of prematurity; opioid, benzodiazepine, or antibiotic treatment >7 days; and periventricular leukomalacia or severe intraventricular hemorrhage diagnosed on cranial ultrasound. Increased global brain abnormality and white matter injury scores at term equivalent were associated with reductions in cognitive, motor, and language abilities at 2 years of corrected age. CONCLUSIONS: Evidence of brain injury on brain MRIs obtained at term equivalent correlated with adverse neurodevelopmental outcomes as assessed by the Bayley Scales of Infant and Toddler Development, Third Edition at 2 years corrected age. Early Epo treatment had no effect on the MRI brain injury scores compared with the placebo group.

A novel TUBG1 mutation with neurodevelopmental disorder caused by malformations of cortical development.

Neurodevelopmental disorder caused by malformations of cortical development is a rare neurological disease. Heterozygous missense variants in the TUBG1 gene lead to malformations of human cortical development, which further result in intellectual disability, developmental retardation, and epilepsy. To the best of our knowledge, only thirteen patients and a total of nine pathogenic TUBG1 variants have been described in the published literature. This study reports the case details and genetic data analysis of a girl (aged 8 years, 9 months) with developmental delay, psychomotor regression, epilepsy, and left external ear deformity. A novel TUBG1 mutation was identified by whole-exome sequencing and Sanger sequencing, confirming that this mutation may be the cause of the neurodevelopmental disorders. This case report characterizes the phenotypic spectrum, molecular genetic findings, and functional consequences of novel pathogenic TUBG1 variants in neurodevelopmental disorders caused by cortical development malformations.

Neurodevelopmental disorder in an Egyptian family with a biallelic ALKBH8 variant.

Alkylated DNA repair protein AlkB homolog 8 (ALKBH8) is a member of the AlkB family of dioxygenases. ALKBH8 is a methyltransferase of the highly variable wobble nucleoside position in the anticodon loop of tRNA and thus plays a critical role in tRNA modification by preserving codon recognition and preventing errors in amino acid incorporation during translation. Moreover, its activity catalyzes uridine modifications that are proposed to be critical for accurate protein translation. Previously, two distinct homozygous truncating variants in the final exon of ALKBH8 were described in two unrelated large Saudi Arabian kindreds with intellectual developmental disorder and autosomal recessive 71 (MRT71) syndrome (MIM# 618504). Here, we report a third family-of Egyptian descent-harboring a novel homozygous frame-shift variant in the last exon of ALKBH8. Two affected siblings in this family exhibit global developmental delay and intellectual disability as shared characteristic features of MRT71 syndrome, and we further characterize their observed dysmorphic features and brain MRI findings. This description of a third family with a truncating ALKBH8 variant from a distinct population broadens the phenotypic and genotypic spectrum of MRT71 syndrome, affirms that perturbations in tRNA biogenesis can contribute to neurogenetic disease traits, and firmly establishes ALKBH8 as a novel neurodevelopmental disease gene.

Longitudinal neurodevelopmental outcomes in preterm twins.

BACKGROUND: Several factors contribute to neurodevelopmental outcomes in preterm infants. The aim of this study was to examine the genetic and environmental influences on long-term outcomes in preterm twins. METHODS: From a prospective cohort of 225 preterm neonates studied with MRI, 24 monozygotic and 52 dizygotic twins were included. Neurodevelopmental outcomes at 1.5 and 3 years were assessed with the Bayley-III and at 4.5 years with The Movement Assessment Battery for Children and The Wechsler Preschool and Primary Scale of Intelligence-III. RESULTS: Preterm monozygotic and dizygotic twin pairs (N = 76 neonates) had similar neurodevelopmental outcomes at all time points. Monozygotic twins (N = 24) did not show greater agreement for outcomes relative to dizygotic twins (N = 52). Twin pairs who were discordant in development (N = 12) were born at a lower gestational age and had a higher incidence of bronchopulmonary dysplasia and retinopathy of prematurity. Discordant twins become more similar in cognitive and language outcomes over time. CONCLUSIONS: Neurodevelopmental outcomes in preterm twins may relate more strongly to environmental factors than genetics. Discordant twins were born earlier and had more perinatal morbidities. Despite the initial discordance, these twin pairs become similar in outcomes over time, which may reflect the positive impact of home environment or early intervention programs. IMPACT: Neurodevelopmental outcomes in preterm twins relate more strongly to environmental factors than genetics. Monozygotic twins did not show greater agreement in outcomes relative to dizygotic twins suggesting a stronger environmental, rather than genetic, influence on development. Twin pairs who were discordant in development were born at a lower gestational age and had a higher incidence of perinatal morbidities. Despite the initial discordance, these twin pairs become more similar in cognitive and language outcomes over time, which may reflect the positive impact of early intervention programs or home environment. Neurodevelopmental outcomes in preterm twins are influenced by exposure to early-life insults or environmental stressors. The initial variability in outcomes among preterm infants is not fixed, and efforts made post-discharge from the neonatal intensive care unit can have a substantial impact on long-term outcomes.

ODLURO syndrome: personal experience and review of the literature.

INTRODUCTION: The O'Donnell-Luria-Rodan (ODLURO) syndrome, caused by heterozygous mutation in the lysine N-methyltransferase2E (KMT2E) gene in chromosome 7q22, has been recently described. Mutation of KMT2E produces a protein-truncating variant gene that may be responsible for both developmental delay and intellectual disability disorders commonly defined by an Intelligence Quotient < 70 and usually unspecific pathologic brain features demonstrated by brain Magnetic Resonance imaging. The symptoms of ODLURO syndrome include variably developmental and speech delay, autism, seizures, hypotonia, and dysmorphic features. The aim of the study is to search for correlation between this specific gene mutation and clinical/radiological features, trying to provide new insights in this recently described pathological condition. METHODS: We reviewed the 38 cases collected by O'Donnel-Luria et al., adding three cases of a familial heterozygosis novel mutation in KMT2E gene; different degrees of neurological disorder, subtle dysmorphic features, intellectual disability, epilepsy, and various brain Magnetic Resonance features are described. RESULTS: Magnetic Resonance data were integrated by genetic analysis and clinical features. Brain Magnetic Resonance study of our patients confirmed peculiar pathologic features previously reported in ODLURO syndrome; cerebellar dysplasia was identified in one of them. All 3 patients had epilepsy, intellectual disability, and mild dysmorphisms. CONCLUSIONS: Our study adds 3 new patients genetically, clinically, and radiologically evaluated to the ODLURO syndrome case series. While CC hypoplasia and widening of subarachnoid spaces are already reported in literature, we document for the first time the presence of cerebellar dysplasia in ODLURO syndrome. We also highlight the extremely low IQ value and the presence of epilepsy in all 3 patients.

Surgery requiring general anesthesia in preterm infants is associated with altered brain volumes at term equivalent age and neurodevelopmental impairment.

BACKGROUND: The aim of the study was to describe and contrast the brain development and outcome among very preterm infants that were and were not exposed to surgery requiring general anesthesia prior to term equivalent age (TEA). METHODS: Preterm infants born ≤30 weeks' gestation who did (n = 25) and did not (n = 59) have surgery requiring general anesthesia during the preterm period were studied. At TEA, infants had MRI scans performed with measures of brain tissue volumes, cortical surface area, Gyrification Index, and white matter microstructure. Neurodevelopmental follow-up with the Bayley Scales of Infant and Toddler Development, Third Edition was undertaken at 2 years of corrected age. Multivariate models, adjusted for clinical and social risk factors, were used to compare the groups. RESULTS: After controlling for clinical and social variables, preterm infants exposed to surgical anesthesia demonstrated decreased relative white matter volumes at TEA and lower cognitive and motor composite scores at 2-year follow-up. Those with longer surgical exposure demonstrated the greatest decrease in white matter volumes and lower cognitive and motor outcomes at age 2 years. CONCLUSIONS: Very preterm infants who required surgery during the preterm period had lower white mater volumes at TEA and worse neurodevelopmental outcome at age 2 years. IMPACT: In very preterm infants, there is an association between surgery requiring general anesthesia during the preterm period and reduced white mater volume on MRI at TEA and lower cognitive and motor composite scores at age 2 years. It is known that the very preterm infant's brain undergoes rapid growth during the period corresponding to the third trimester. The current study suggests an association between surgery requiring general anesthesia during this period and worse outcomes.

Brain abnormalities on neuroimaging in Children with Congenital Zika Syndrome in Salvador, Brazil, and its possible implications on neuropsychological development.

OBJECTIVE: To characterize the spectrum of brain damages presented in children affected by Congenital Zika Syndrome (CZS), verify the existence of a co-occurrence pattern of these damages and discuss possible implications for the neuropsychological development. METHODS: Descriptive, quantitative, individualized, and cross-sectional study using secondary sources. We selected 136 children with CZS from the database of the Center of Strategic Information on Health Vigilance of the Municipal Office of Salvador, Brazil. We conducted descriptive and multiple correspondence analyses. RESULTS: Among the set of analyzed variables, microcephaly (51.5%), ventriculomegaly (57.4%), and brain calcifications (77.2%) were identified as the most frequent. The multiple correspondence analysis showed that the combination of these three variables (32.4%) was what better represented the spectrum of brain damages in the Central Nervous System. INTERPRETATION: Damage in the sensory-motor, cognitive and language development, as well as neurodevelopmental disorders, are described in the literature as impairments associated, either isolated or combined, with these damages, and it is worth highlighting that, in combined brain damages, impairments tend to be more severe. The findings of this study may contribute to understanding the repercussions of CZS on the neuropsychological development of children affected by the epidemic.

Neurodevelopmental and Psychiatric Symptoms in Patients with a Cyst Compressing the Cerebellum: an Ongoing Enigma.

A patient diagnosed with developmental delay, intellectual disability, and autistic and obsessive-compulsive symptoms was found to have a posterior fossa arachnoid cyst (PFAC) compressing the cerebellum. The patient was referred to our Ataxia Unit for consideration of surgical drainage of the cyst to improve his clinical constellation. This scenario led to an in-depth analysis including a literature review, functional resting-state MRI analysis of our patient compared to a group of controls, and genetic testing. While it is reasonable to consider that there may be a causal relationship between PFAC and neurodevelopmental or psychiatric symptoms in some patients, there is also a nontrivial prevalence of PFAC in the asymptomatic population and a significant possibility that many PFAC are incidental findings in the context of primary cognitive or psychiatric symptoms. Our functional MRI analysis is the first to examine brain function, and to report cerebellar dysfunction, in a patient presenting with cognitive/psychiatric symptoms found to have a structural abnormality compressing the cerebellum. These neuroimaging findings are inherently limited due to their correlational nature but provide unprecedented evidence suggesting that cerebellar compression may be associated with cerebellar dysfunction. Exome gene sequencing revealed additional etiological possibilities, highlighting the complexity of this field of cerebellar clinical and scientific practice. Our findings and discussion may guide future investigations addressing an important knowledge gap-namely, is there a link between cerebellar compression (including arachnoid cysts and possibly other forms of cerebellar compression such as Chiari malformation), cerebellar dysfunction (including fMRI abnormalities reported here), and neuropsychiatric symptoms?

MRI at term equivalent age for predicting long-term neurodevelopmental outcome in preterm infants - a cohort study.

Purpose: Preterm infants are at increased risk of adverse neurodevelopmental outcome (NDO). Cranial ultrasound has limited predictability. The purpose of the study is to evaluate whether magnetic resonance imaging (MRI) done at term equivalent age (TEA) predicts NDO at 18-22 months of corrected gestational age (CGA).Materials and methods: This cohort study of preterm infants born at ≤32 weeks of gestation and/or birth weight <1500 grams between April 2011 and August 2012 was conducted in a tertiary care institute in India. MRI done at TEA was reported using objective scoring. NDO at 18-22-month CGA was assessed using Bayley Scale of Infant Development (BSID) version III. Composite score (CS) < 85 in motor, language, or cognition domain was taken as adverse NDO. Association between individual MRI subscores and NDO was evaluated using multiple linear regressions by backward elimination method. Validity of MRI abnormality in predicting adverse NDO was assessed.Results: Out of 94 infants who had MRI at TEA, 56 (60%) underwent BSID III. Mean gestational age was 29.8 ± 2.1 weeks. Median CS of all domains was lower with higher total MRI score. Predictive accuracy for various subscores ranged from 55 to 73%. By multiple regression analysis, signal abnormality was associated with motor delay (ß -8.4; p .02) and cystic white matter (WM) changes with motor delay (ß -7.3; p .003) and cognitive delay (ß -6.1; p .005).Conclusions: Although specificity and negative predictive value were moderate to high across all subscores in MRI to predict the NDO, the accuracy has been only low to moderate, which limits its use as sole predictor.

The most useful cranial ultrasound predictor of neurodevelopmental outcome at 2 years for preterm infants.

AIM: To determine the most important cranial ultrasound predictors of abnormality associated with neurodevelopmental outcome at 2 years of age in preterm infants. MATERIALS AND METHODS: A total of 343 preterm infants born between 2005 and 2010 and cared for in KK Women's and Children's Hospital, a tertiary paediatric hospital, with birth weight ≤1,250 g were assessed in this retrospective study. Serial cranial ultrasound examinations were examined for intraventricular haemorrhage and cystic periventricular leukomalacia. Ventricular-brain ratio on term equivalent cranial ultrasound was measured. Neurodevelopmental outcome was assessed by the performance on Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-III) at 2 years corrected age. Mental delay was defined as having a combined Bayley-III score (the average of cognitive and language scores) <80. RESULTS: The mean cognitive, language, and motor scores on Bayley-III in this cohort were 93±15, 83±18, and 92±15, respectively. Twenty-six percent of the preterm infants had mental delay and 4% had cerebral palsy. Ventricular-brain ratio >0.35 was the most significant factor associated with mental delay (odds ratio 5.28, 95% CI: 1.49-18.71, p=0.01). Other significant risk factors for mental delay were male gender, postnatal steroids, and necrotising enterocolitis, whereas maternal tertiary education was a protective factor against adverse outcome. CONCLUSION: Ventricular-brain ratio >0.35 on term-equivalent cranial ultrasound in preterm infants is the strongest predictor for mental delay on Bayley score at 2 years of age.

TFE3-associated neurodevelopmental disorder: A distinct recognizable syndrome.

The transcription factor for immunoglobulin heavy-chain enhancer 3 (TFE3) gene encodes a transcription factor that regulates embryonic stem cell (ESC) differentiation. Its phosphorylation by the lysosomal Rag GTPase signaling pathway leads to cytoplasmic sequestration and inactivation promoting ESC differentiation and exit from pluripotency. Somatic translocations of this X-linked gene cause papillary renal cell carcinoma in which nuclear accumulation of the TFE3 oncoprotein is one of the most significant histopathologic characteristics. Early this year, Villegas et al. identified missense mutations in a TFE3 domain required for cytoplasmic inactivation as potentially causal for a mosaic human developmental disorder. They published five patients with de novo TFE3 nonsynonymous missense variants, four females and one male, with severe intellectual disability (5/5), coarse facial features (4/5), and Blaschkoid pigmentary mosaicism (4/5). The only male described has somatic mosaicism. All patients had normal brain Magnetic Resonance Imagings (MRIs). We present two unrelated females with this distinctive phenotype including the above triad along with other features not previously well described. Both were found to have de novo heterozygous variants in TFE3 on whole exome sequencing, one nonsynonymous missense, and one canonical splice site variant, thereby expanding the phenotypic and mutational spectrum for this disorder. Interestingly, due to significant coarsening of the facial features, both patients were initially thought to have a lysosomal storage disorder but enzyme screening and brain MRIs were negative.

Retinopathy of Prematurity and Bronchopulmonary Dysplasia are Independent Antecedents of Cortical Maturational Abnormalities in Very Preterm Infants.

Very preterm (VPT) infants are at high-risk for neurodevelopmental impairments, however there are few validated biomarkers at term-equivalent age that accurately measure abnormal brain development and predict future impairments. Our objectives were to quantify and contrast cortical features between full-term and VPT infants at term and to associate two key antecedent risk factors, bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP), with cortical maturational changes in VPT infants. We prospectively enrolled a population-based cohort of 110 VPT infants (gestational age ≤31 weeks) and 51 healthy full-term infants (gestational age 38-42 weeks). Structural brain MRI was performed at term. 94 VPT infants and 46 full-term infants with high-quality T2-weighted MRI were analyzed. As compared to full-term infants, VPT infants exhibited significant global cortical maturational abnormalities, including reduced surface area (-5.9%) and gyrification (-6.7%) and increased curvature (5.9%). In multivariable regression controlled for important covariates, BPD was significantly negatively correlated with lobar and global cortical surface area and ROP was significantly negatively correlated with lobar and global sulcal depth in VPT infants. Our cohort of VPT infants exhibited widespread cortical maturation abnormalities by term-equivalent age that were in part anteceded by two of the most potent neonatal diseases, BPD and ROP.

Expanding the Phenotype: Neurodevelopmental Disorder, Mitochondrial, With Abnormal Movements and Lactic Acidosis, With or Without Seizures (NEMMLAS) due to WARS2 Biallelic Variants, Encoding Mitochondrial Tryptophanyl-tRNA Synthase.

BACKGROUND: WARS2 encodes a tryptophanyl tRNA synthetase, which is involved in mitochondrial protein synthesis. Biallelic mutations in WARS2 are rare and have been associated with a spectrum of clinical presentations, including neurodevelopmental disorder with abnormal movements, lactic acidosis with or without seizures (NEMMLAS). CASE PRESENTATION: Here we present the case of an 8-year-old girl with ataxia and parkinsonism with periventricular white matter abnormalities on magnetic resonance imaging (MRI) and global developmental delay. The initial investigations revealed an elevated lactate level. Extensive metabolic testing, including a muscle biopsy, was inconclusive. Cerebrospinal fluid (CSF) neurotransmitter levels were low; however, a trial of levodopa was unremarkable. The chromosomal microarray and initial ataxia gene panel was normal. Zinc supplementation for a heterozygous variant of unknown significance in the CP gene on the ataxia exome panel was not effective in treating her symptoms. Reanalysis of the ataxia exome panel highlighted biallelic mutations in WARS2, which lead to the diagnosis of neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures (NEMMLAS). This lead to parental genetic testing, redirected therapy, and helped to expand the symptomology of this rare condition. CONCLUSION: Here we emphasize the importance of imminent and repeat expanded genetic testing to ensure early diagnosis and treatment for rare pediatric disorders. The patient is being trialed on a mitochondrial cocktail in an attempt to compensate for defects in mitochondrial protein synthesis associated with this variant. Longitudinal monitoring of disease manifestation will help establish the currently unknown natural history of this condition.

Altered neonatal white and gray matter microstructure is associated with neurodevelopmental impairments in very preterm infants with high-grade brain injury.

BACKGROUND: This study examines relationships between neonatal white and gray matter microstructure and neurodevelopment in very preterm (VPT) infants (≤30 weeks gestation) with high-grade brain injury (BI). METHODS: Term-equivalent diffusion tensor magnetic resonance imaging data were obtained in 32 VPT infants with high-grade BI spanning grade III/IV intraventricular hemorrhage, post-hemorrhagic hydrocephalus (PHH), and cystic periventricular leukomalacia (BI group); 69 VPT infants without high-grade injury (VPT group); and 55 term-born infants. The Bayley-III assessed neurodevelopmental outcomes at age 2 years. RESULTS: BI infants had lower fractional anisotropy (FA) in the posterior limb of the internal capsule (PLIC), cingulum, and corpus callosum, and higher mean diffusivity (MD) in the optic radiations and cingulum than VPT infants. PHH was associated with higher MD in the optic radiations and left PLIC, and higher FA in the right caudate. For BI infants, higher MD in the right optic radiation and lower FA in the right cingulum, PLIC, and corpus callosum were related to motor impairments. CONCLUSIONS: BI infants demonstrated altered white and gray matter microstructure in regions affected by injury in a manner dependent upon injury type. PHH infants demonstrated the greatest impairments. Aberrant white matter microstructure was related to motor impairment in BI infants.

Neuroimaging findings in newborns with congenital heart disease prior to surgery: an observational study.

OBJECTIVES: Neurodevelopmental impairment has become the most important comorbidity in infants with congenital heart disease (CHD). We aimed to (1) investigate the burden of brain lesions in infants with CHD prior to surgery and (2) explore clinical factors associated with injury. STUDY DESIGN: Prospective observational study. SETTING: Single centre UK tertiary neonatal intensive care unit. PATIENTS: 70 newborn infants with critical or serious CHD underwent brain MRI prior to surgery. MAIN OUTCOME MEASURES: Prevalence of cerebral injury including arterial ischaemic strokes (AIS), white matter injury (WMI) and intracranial haemorrhage. RESULTS: Brain lesions were observed in 39% of subjects (95% CI 28% to 50%). WMI was identified in 33% (95% CI 23% to 45%), subdural haemorrhage without mass effect in 33% (95% CI 23% to 45%), cerebellar haemorrhage in 9% (95% CI 4% to 18%) and AIS in 4% (95% CI 1.5% to 12%). WMI was distributed widely throughout the brain, particularly involving the frontal white matter, optic radiations and corona radiata. WMI exhibited restricted diffusion in 48% of cases. AIS was only observed in infants with transposition of the great arteries (TGA) who had previously undergone balloon atrial septostomy (BAS). AIS was identified in 23% (95% CI 8% to 50%) of infants with TGA who underwent BAS, compared with 0% (95% CI 0% to 20%) who did not. CONCLUSIONS: Cerebral injury in newborns with CHD prior to surgery is common.

Golden Exosomes Selectively Target Brain Pathologies in Neurodegenerative and Neurodevelopmental Disorders.

Exosomes, nanovesicles that are secreted by different cell types, enable intercellular communication at local or distant sites. Alhough they have been found to cross the blood brain barrier, their migration and homing abilities within the brain remain unstudied. We have recently developed a method for longitudinal and quantitative in vivo neuroimaging of exosomes based on the superior visualization abilities of classical X-ray computed tomography (CT), combined with gold nanoparticles as labeling agents. Here, we used this technique to track the migration and homing patterns of intranasally administrated exosomes derived from bone marrow mesenchymal stem cells (MSC-exo) in different brain pathologies, including stroke, autism, Parkinson's disease, and Alzheimer's disease. We found that MSC-exo specifically targeted and accumulated in pathologically relevant murine models brains regions up to 96 h post administration, while in healthy controls they showed a diffuse migration pattern and clearance by 24 h. The neuro-inflammatory signal in pathological brains was highly correlated with MSC-exo accumulation, suggesting that the homing mechanism is inflammatory-driven. In addition, MSC-exo were selectively uptaken by neuronal cells, but not glial cells, in the pathological regions. Taken together, these findings can significantly promote the application of exosomes for therapy and targeted drug delivery in various brain pathologies.