A form of muscular dystrophy associated with pathogenic variants in JAG2.

JAG2 encodes the Notch ligand Jagged2. The conserved Notch signaling pathway contributes to the development and homeostasis of multiple tissues, including skeletal muscle. We studied an international cohort of 23 individuals with genetically unsolved muscular dystrophy from 13 unrelated families. Whole-exome sequencing identified rare homozygous or compound heterozygous JAG2 variants in all 13 families. The identified bi-allelic variants include 10 missense variants that disrupt highly conserved amino acids, a nonsense variant, two frameshift variants, an in-frame deletion, and a microdeletion encompassing JAG2. Onset of muscle weakness occurred from infancy to young adulthood. Serum creatine kinase (CK) levels were normal or mildly elevated. Muscle histology was primarily dystrophic. MRI of the lower extremities revealed a distinct, slightly asymmetric pattern of muscle involvement with cores of preserved and affected muscles in quadriceps and tibialis anterior, in some cases resembling patterns seen in POGLUT1-associated muscular dystrophy. Transcriptome analysis of muscle tissue from two participants suggested misregulation of genes involved in myogenesis, including PAX7. In complementary studies, Jag2 downregulation in murine myoblasts led to downregulation of multiple components of the Notch pathway, including Megf10. Investigations in Drosophila suggested an interaction between Serrate and Drpr, the fly orthologs of JAG1/JAG2 and MEGF10, respectively. In silico analysis predicted that many Jagged2 missense variants are associated with structural changes and protein misfolding. In summary, we describe a muscular dystrophy associated with pathogenic variants in JAG2 and evidence suggests a disease mechanism related to Notch pathway dysfunction.

Rare pathogenic variants in WNK3 cause X-linked intellectual disability.

PURPOSE: WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown. METHOD: We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID). RESULTS: We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p.Pro204Arg, p.Leu300Ser, p.Glu607Val) in WNK3 in 14 male individuals from 6 unrelated families. Affected individuals had ID with variable presence of epilepsy and structural brain defects. WNK3 variants cosegregated with the disease in 3 different families with multiple affected individuals. This included 1 large family previously diagnosed with X-linked Prieto syndrome. WNK3 pathogenic missense variants localize to the catalytic domain and impede the inhibitory phosphorylation of the neuronal-specific chloride cotransporter KCC2 at threonine 1007, a site critically regulated during the development of synaptic inhibition. CONCLUSION: Pathogenic WNK3 variants cause a rare form of human X-linked ID with variable epilepsy and structural brain abnormalities and implicate impaired phospho-regulation of KCC2 as a pathogenic mechanism.

Ipsilesional volume loss of basal ganglia and thalamus is associated with poor hand function after ischemic perinatal stroke.

BACKGROUND: Perinatal stroke (PS) is the leading cause of hemiparetic cerebral palsy (CP). Involvement of the corticospinal tract on neonatal magnetic resonance imaging (MRI) is predictive of motor outcome in patients with hemiparetic CP. However, early MRI is not available in patients with delayed presentation of PS and prediction of hemiparesis severity remains a challenge. AIMS: To evaluate the volumes of the basal ganglia, amygdala, thalamus, and hippocampus following perinatal ischemic stroke in relation to hand motor function in children with a history of PS and to compare the volumes of subcortical structures in children with PS and in healthy controls. METHODS: Term born PS children with arterial ischemic stroke (AIS) (n = 16) and with periventricular venous infarction (PVI) (n = 18) were recruited from the Estonian Pediatric Stroke Database. MRI was accuired during childhood (4-18 years) and the volumes of the basal ganglia, thalamus, amygdala and hippocampus were calculated. The results of stroke patients were compared to the results of 42 age- and sex-matched healthy controls. Affected hand function was evaluated by Assisting Hand Assessment (AHA) and classified by the Manual Ability Classification System (MACS). RESULTS: Compared to the control group, children with AIS had smaller volumes of the ipsi- and contralesional thalami, ipsilesional globus pallidus, nucleus accumbens and hippocampus (p < 0.005). Affected hand function in children with AIS was correlated with smaller ipsilesional thalamus, putamen, globus pallidus, hippocampus, amygdala and contralesional amygdala (r > 0.5; p < 0.05) and larger volume of the contralesional putamen and hippocampus (r < - 0.5; p < 0.05). In children with PVI, size of the ipsilesional caudate nucleus, globus pallidus, thalamus (p ≤ 0.001) and hippocampus (p < 0.03) was smaller compared to controls. Smaller volume of the ipsi- and contralesional thalami and ipsilesional caudate nucleus was correlated with affected hand function (r > 0.55; p < 0.05) in children with PVI. CONCLUSIONS: Smaller volume of ipsilesional thalamus was associated with poor affected hand function regardless of the perinatal stroke subtype. The pattern of correlation between hand function and volume differences in the other subcortical structures varied between children with PVI and AIS. Evaluation of subcortical structures is important in predicting motor outcome following perinatal stroke.

Impact of obesity on vascular calcification in patients with chronic kidney disease.

AIM: The aim of this study was to compare vascular calcification (VC) in obese and non-obese chronic kidney disease (CKD) patients, using three methods for measuring VC. MATERIALS AND METHODS: The study included 168 consecutive patients with CKD. Patients were divided into two groups by body mass index (BMI) - group 1 (BMI ≥ 30 kg/m2) and group 2 (BMI < 30 kg/m2), and according to estimated glomerular filtration rate (eGFR) - subgroup A (eGFR < 45 mL/min/1.73m2) and subgroup B (eGFR < 45 mL/min/1.73m2). VC was assessed by measuring abdominal aortic calcification (AAC), ankle-brachial index (ABI) and echocardiography. RESULTS: Group 1 patients were older (p = 0.03). There was a relatively low number of diabetics in our study cohort: 41 patients, (24%). The number of diabetics was similar in both groups. The presence of AAC was more common in 1B and 2B than in 1A and 2A groups (p = 0.005 and p = 0.02) and in 1B group compared to 2B group (p = 0.05). In both groups, ABI ≥ 1.3 and ABI < 0.9 were more common in B subgroups. The presence of heart valvular lesions was very high in both groups. Spearman rank-order analysis of every cohort demonstrated significant correlation between AAC and heart valve lesions (Spearman R = 0.3; p = 0.01) and also between AAC and LVH (Spearman R = 0.3; p = 0.004). Analysis of variance of every cohort showed that in patients with ABI ≥ 1.3 and heart valve lesions, Kauppila score was significantly higher than in those with normal heart valves. CONCLUSION: Our study shows that obesity is not an independent predictor of VC in CKD patients. VC, assessed by three different methods, was more pronounced in obese patients with lower kidney function.

Variations in CT Utilization, Protocols, and Radiation Doses in COVID-19 Pneumonia: Results from 28 Countries in the IAEA Study.

Background There is lack of guidance on specific CT protocols for imaging patients with coronavirus disease 2019 (COVID-19) pneumonia. Purpose To assess international variations in CT utilization, protocols, and radiation doses in patients with COVID-19 pneumonia. Materials and Methods In this retrospective data collection study, the International Atomic Energy Agency coordinated a survey between May and July 2020 regarding CT utilization, protocols, and radiation doses from 62 health care sites in 34 countries across five continents for CT examinations performed in patients with COVID-19 pneumonia. The questionnaire obtained information on local prevalence, method of diagnosis, most frequent imaging, indications for CT, and specific policies on use of CT in COVID-19 pneumonia. Collected data included general information (patient age, weight, clinical indication), CT equipment (CT make and model, year of installation, number of detector rows), scan protocols (body region, scan phases, tube current and potential), and radiation dose descriptors (CT dose index and dose length product). Descriptive statistics and generalized estimating equations were performed. Results Data from 782 patients (median age, 59 years [interquartile range, 15 years]) from 54 health care sites in 28 countries were evaluated. Less than one-half of the health care sites used CT for initial diagnosis of COVID-19 pneumonia and three-fourths used CT for assessing disease severity. CT dose index varied based on CT vendors (7-11 mGy; P < .001), number of detector rows (8-9 mGy; P < .001), year of CT installation (7-10 mGy; P = .006), and reconstruction techniques (7-10 mGy; P = .03). Multiphase chest CT examinations performed at 20% of sites (11 of 54) were associated with higher dose length product compared with single-phase chest CT examinations performed in 80% of sites (43 of 54) (P = .008). Conclusion CT use, scan protocols, and radiation doses in patients with coronavirus disease 2019 pneumonia showed wide variation across health care sites within the same and between different countries. Many patients were imaged multiple times and/or with multiphase CT scan protocols. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Lee in this issue.

Clinical, neuroradiological, and biochemical features of SLC35A2-CDG patients.

SLC35A2-CDG is caused by mutations in the X-linked SLC35A2 gene encoding the UDP-galactose transporter. SLC35A2 mutations lead to hypogalactosylation of N-glycans. SLC35A2-CDG is characterized by severe neurological symptoms and, in many patients, early-onset epileptic encephalopathy. In view of the diagnostic challenges, we studied the clinical, neuroradiological, and biochemical features of 15 patients (11 females and 4 males) with SLC35A2-CDG from various centers. We describe nine novel pathogenic variations in SLC35A2. All affected individuals presented with a global developmental delay, and hypotonia, while 70% were nonambulatory. Epilepsy was present in 80% of the patients, and in EEG hypsarrhythmia and findings consistent with epileptic encephalopathy were frequently seen. The most common brain MRI abnormality was cerebral atrophy with delayed myelination and multifocal inhomogeneous abnormal patchy white matter hyperintensities, which seemed to be nonprogressive. Thin corpus callosum was also common, and all the patients had a corpus callosum shorter than normal for their age. Variable dysmorphic features and growth deficiency were noted. Biochemically, normal mucin type O-glycosylation and lipid glycosylation were found, while transferrin mass spectrometry was found to be more specific in the identification of SLC35A2-CDG, as compared to routine screening tests. Although normal glycosylation studies together with clinical variability and genetic results complicate the diagnosis of SLC35A2-CDG, our data indicate that the combination of these three elements can support the pathogenicity of mutations in SLC35A2.

CDKL5 Gene-Related Epileptic Encephalopathy in Estonia: Four Cases, One Novel Mutation Causing Severe Phenotype in a Boy, and Overview of the Literature.

Cyclin-dependent kinase-like 5 (CDKL5) gene mutations have mainly been found in females with early infantile epileptic encephalopathy (EIEE), severe intellectual disability, and Rett-like features. To date, only 22 boys have been reported, presenting with far more severe phenotypic features. We report the first cases of CDKL5 gene-related EIEE in Estonia diagnosed using panels of epilepsy-associated genes and describe the phenotype-genotype correlations in three male and one female patient. One of the mutations, identified in a male patient, was a novel de novo hemizygous frameshift mutation (NM_003159.2:c.2225_2228del (p.Glu742Afs*41)) in exon 15 of CDKL5. All boys have a more severe phenotype than the female patient. In boys with early onset of seizures and poor development with absent or poor eye contact, CDKL5 gene-related EIEE can be suspected and epilepsy-associated genes should be analyzed for early etiological diagnosis. Early genetic diagnosis would be the cornerstone in personalized treatment in the future.

Resting-State Functional Connectivity and Cognitive Impairment in Children with Perinatal Stroke.

Perinatal stroke is a leading cause of congenital hemiparesis and neurocognitive deficits in children. Dysfunctions in the large-scale resting-state functional networks may underlie cognitive and behavioral disability in these children. We studied resting-state functional connectivity in patients with perinatal stroke collected from the Estonian Pediatric Stroke Database. Neurodevelopment of children was assessed by the Pediatric Stroke Outcome Measurement and the Kaufman Assessment Battery. The study included 36 children (age range 7.6-17.9 years): 10 with periventricular venous infarction (PVI), 7 with arterial ischemic stroke (AIS), and 19 controls. There were no differences in severity of hemiparesis between the PVI and AIS groups. A significant increase in default mode network connectivity (FDR 0.1) and lower cognitive functions (p < 0.05) were found in children with AIS compared to the controls and the PVI group. The children with PVI had no significant differences in the resting-state networks compared to the controls and their cognitive functions were normal. Our findings demonstrate impairment in cognitive functions and neural network profile in hemiparetic children with AIS compared to children with PVI and controls. Changes in the resting-state networks found in children with AIS could possibly serve as the underlying derangements of cognitive brain functions in these children.

Vascular syndrome predicts the development and course of epilepsy after perinatal stroke.

OBJECTIVE: Epilepsy develops in one third of the patients after perinatal stroke. It is still unclear which vascular syndrome of ischemic stroke carries higher risk of epilepsy. The aim of the current study was to evaluate the risk of epilepsy according to the vascular syndrome of perinatal stroke. METHODS: The study included 39 children with perinatal arterial ischemic stroke (13 with anterior or posterior trunk of the distal middle cerebral artery occlusion, 23 with proximal or distal M1 middle cerebral artery occlusion and three with lenticulostriate arteria infarction), and 44 children with presumed perinatal venous infarction. Magnetic resonance imaging obtained at the chronic stage was used to evaluate the vascular syndrome of stroke. RESULTS: The median follow-up time was 15.1 years (95% CI: 12.4-16.5 years), epilepsy developed in 19/83 (22.9%) patients. The cumulative probability to be without epilepsy at 15 years was 75.4% (95% CI: 65.8-86.4). The probability of having epilepsy was higher in the group of proximal or distal M1 artery occlusion compared to patients with periventricular venous infarction (HR 7.2, 95% CI: 2.5-26, p = .0007). Patients with periventricular venous infarction had significantly more often status epilepticus or spike-wave activation in sleep ≥85% of it compared to patients with anterior or posterior trunk of the distal middle cerebral artery occlusion (OR = 81; 95% CI: 1.3-5046, p = .029). SIGNIFICANCE: The emphasis of this study is placed on classifying the vascular syndrome of perinatal stroke and on the targeted follow-up of patients for epilepsy until young adulthood. The risk for having epilepsy after perinatal stroke is the highest in children with proximal or distal M1 middle cerebral artery occlusion. Patients with periventricular venous infarction have a more severe course of epilepsy.

High Prevalence of Collagenopathies in Preterm- and Term-Born Children With Periventricular Venous Hemorrhagic Infarction.

INTRODUCTION: The aim of this study was to evaluate genetic risk factors in term-born children with antenatal periventricular hemorrhagic infarction (PVHI), presumed antenatal periventricular venous infarction and periventricular hemorrhagic infarction in preterm neonates. METHODS: Genetic analysis and magnetic resonance imaging were performed in 85 children: term-born children (≥36 gestational weeks) with antenatal periventricular hemorrhagic infarction (n = 6) or presumed antenatal (n = 40) periventricular venous infarction and preterm children (<36 gestational weeks) with periventricular hemorrhagic infarction (n = 39). Genetic testing was performed using exome or large gene panel (n = 6700 genes) sequencing. RESULTS: Pathogenic variants associated with stroke were found in 11 of 85 (12.9%) children with periventricular hemorrhagic infarction/periventricular venous infarction. Among the pathogenic variants, COL4A1/A2 and COL5A1 variants were found in 7 of 11 (63%) children. Additionally, 2 children had pathogenic variants associated with coagulopathy, whereas 2 other children had other variants associated with stroke. Children with collagenopathies had significantly more often bilateral multifocal stroke with severe white matter loss and diffuse hyperintensities in the white matter, moderate to severe hydrocephalus, moderate to severe decrease in size of the ipsilesional basal ganglia and thalamus compared to children with periventricular hemorrhagic infarction/periventricular venous infarction without genetic changes in the studied genes (P ≤ .01). Severe motor deficit and epilepsy developed more often in children with collagenopathies compared to children without genetic variants (P = .0013, odds ratio [OR] = 233, 95% confidence interval [CI]: 2.8-531; and P = .025, OR = 7.3, 95% CI: 1.3-41, respectively). CONCLUSIONS: Children with periventricular hemorrhagic infarction/periventricular venous infarction have high prevalence of pathogenic variants in collagene genes (COL4A1/A2 and COL5A1). Genetic testing should be considered for all children with periventricular hemorrhagic infarction/periventricular venous infarction; COL4A1/A2 and COL5A1/A2 genes should be investigated first.

The thalamus and basal ganglia are smaller in children with epilepsy after perinatal stroke.

Background: Epilepsy is one of the most serious consequences of perinatal stroke. Epilepsy itself has been proposed as a risk factor for impaired cognitive, language, and behavioral functioning. It is still unclear which children develop epilepsy after perinatal stroke. The current study aimed to evaluate the volume of the thalamus and the basal ganglia in children after perinatal stroke in relation to poststroke epilepsy. Methods: The follow-up study included 29 children with perinatal arterial ischemic stroke (AIS), 33 children with presumed periventricular venous infarction (PVI), and 46 age- and sex-matched healthy controls. Magnetic resonance imaging was performed in children between the ages of 4 and 18 years, and volumetric analysis by segmentation was used to evaluate the size of the thalamus, caudate nucleus, putamen, globus pallidus, hippocampus, amygdala, and nucleus accumbens. Results: During a median follow-up time of 12.8 years [interquartile range (IQR): 10.8-17.3] in the AIS group and 12.5 years (IQR: 9.3-14.8) in the PVI group (p = 0.32), epilepsy developed in 10 children (34.5%) with AIS and in 4 (12.1%) children with PVI, p = 0.036 [odds ratio (OR) = 3.8, 95%, confidence interval (CI): 1.04-14]. Epilepsy and interictal epileptiform discharges (IEDs) without clinical seizures were more often expressed in children with AIS (n = 16, 55%) than in children with PVI (n = 7, 21.2%), p = 0.0057 (OR = 3.8 95% CI: 1.04-14). In the AIS group, the ipsilesional and contralesional thalamus, ipsilesional caudate nucleus, and nucleus accumbens were significantly smaller in children with epilepsy compared to children without epilepsy. In the PVI group, the ipsilesional thalamus, caudate nucleus, and nucleus accumbens were smaller in the pooled group of epilepsy plus IED alone compared to children without epilepsy. Conclusion: In children with AIS, epilepsy or IED occurred more often compared to children with PVI. Both patients with AIS and PVI with severe damage to the basal ganglia and the thalamus have a higher risk of developing poststroke epilepsy and should be monitored more closely throughout childhood to initiate timely antiseizure medication and rehabilitation.

AXIN2-related oligodontia-colorectal cancer syndrome with cleft palate as a possible new feature.

BACKGROUND: Pathogenic variants in AXIN2 have been associated with tooth agenesis, colon polyps, and colon cancer. Given the rare nature of this phenotype, we set out to collect additional genotypic and phenotypic information. METHODS: Data were collected via a structured questionnaire. Sequencing was performed in these patients mostly due to diagnostic purpose. A little more than half of the AXIN2 variant carriers were identified by NGS; other six were family members. RESULTS: Here, we report 13 individuals with a heterozygous AXIN2 pathogenic/likely pathogenic variant who have a variable expression of oligodontia-colorectal cancer syndrome (OMIM 608615) or oligodontia-cancer predisposition syndrome (ORPHA 300576). Three individuals from one family also had cleft palate, which might represent a new clinical feature of AXIN2 phenotype, also given the fact that AXIN2 polymorphisms have been found in association with oral clefting in population studies. AXIN2 has already been added to multigene cancer panel tests; further research should be conducted to determine whether it should be added to cleft lip/palate multigene panels. CONCLUSION: More clarity about oligodontia-colorectal cancer syndrome, about the variable expression, and associated cancer risks is needed to improve clinical management and to establish guidelines for surveillance. We collected information about the surveillance that was advised, which might support clinical management of these patients.

Language lateralization and outcome in perinatal stroke patients with different vascular types.

Perinatal stroke affects child's language development and can change language lateralization. Language generation and comprehension tasks in functional magnetic resonance imaging were used to determine language lateralization in term born children with perinatal left-side arterial ischemic stroke (AIS) (n = 9, mean age (SD) 13.4 (3.1) y.) and periventricular venous infarction (PVI) (n = 12, 11.8 (2.8) y.), and in healthy right-handed controls (n = 30, 11.6 (2.6) y.). Lateralization index was calculated for the Broca and Wernicke areas and correlated with language and cognitive outcomes measured by the Kaufman Assessment Battery for Children II ed. Language outcome in children with perinatal stroke is poorer compared to healthy controls. Children with small AIS lesions and most children with PVI showed left-side language activation. Most children with large AIS lesions and one child with large PVI had language activation reorganized to the right hemisphere. Language reorganization to the unlesioned right hemisphere did not ensure normal language outcome.

Maternal Pyelonephritis as a Potential Cause of Perinatal Periventricular Venous Infarction in Term-Born Children.

Introduction: The study was designed to assess the prevalence of pregnancy and delivery associated risk factors in children suffering from neonatal or presumed periventricular venous infarction. Methods: Antenatal records and pregnancy outcome data were retrospectively assessed in children with presumed periventricular venous infarction (n = 43, born ≥36 gestational weeks) or neonatal periventricular venous infarction (n = 86, born <36 gestational weeks) and compared to a matched control group (n = 2168, ≥36 gestational weeks) from a prospective study. Results: Children with presumed periventricular venous infarction had significantly more maternal bacterial infections compared to the control group (47% vs 20%, respectively, P < .001), whereas no difference was found compared to the neonatal periventricular venous infarction group (49%, P = .80). Mothers with bacterial infection in the presumed periventricular venous infarction group had significantly more often pyelonephritis compared to the control group (50% vs 3.4%, respectively, P < .001). Conclusions: Our data show an increased risk for developing periventricular venous infarction in the case of maternal bacterial infections, especially between gestational weeks 21 and 31.

Predictive value of clinical and radiological findings in inflicted traumatic brain injury.

AIMS: The aim of this study is to evaluate the value of early radiological investigations in predicting the long-term neurodevelopmental outcome of infants with inflicted traumatic brain injury (ITBI). METHODS: Clinical and radiological investigations of 24 infants with ITBI were performed during the acute phase of injury (1-3 days), and during the early (4 days up to 3 months) and late (>9 months) postinjury phases. The clinical outcome in survivors (n = 22) was based on the Rankin Disability Scale and the Glasgow Outcome Score. RESULTS: Five out of 24 infants (21%) had a poor neurodevelopmental outcome (death and severe disability), 17 infants (71%) had different developmental problems and 2 infants were normal at the mean age of 62 (54-70) (95% CI) months. A low initial Glasgow Coma Scale score of 8 or below [p < 0.05, OR 13.0 (1.3-133.3)], the development of brain oedema [p < 0.005, OR 13.0 (1.6-773)], focal changes in the basal ganglia during the acute phase [p < 0.01, OR 45 (2.1-937.3)], the development of new intracerebral focal changes early postinjury [p < 0.05, OR 24.1(1.0-559.1)], a decrease in white matter [p < 0.01, OR 33 (1.37-793.4)] and the development of severe atrophy before 3 months postinjury [p < 0.05, OR 24 (11.0-559.1)] were significantly correlated with a poor neurodevelopmental outcome. CONCLUSIONS: Early clinical and radiological findings in ITBI are of prognostic value for neurodevelopmental outcome.

The Cost-Effectiveness of Abdominal Aortic Aneurysm Screening in Estonia.

OBJECTIVE: To assess the cost-effectiveness of population-based abdominal aortic aneurysm (AAA) screening in Estonia. METHODS: A Markov cohort model was used to evaluate the cost-effectiveness of population-based AAA screening compared with no screening. A hypothetical cohort of 6000 men aged 65 was followed for 35 years. Data for disease transition probabilities and quality of life outcomes were obtained from published literature; costs were calculated based on Estonian data. Analysis followed the healthcare payer's perspective using an annual discount rate of 5% for costs and effects. The model evaluated the number of avoidable AAA ruptures and AAA-related deaths and the differences in costs and quality-adjusted life-years (QALYs). RESULTS: The AAA screening would have prevented 10 AAA ruptures and 6 AAA-related deaths among the cohort of 6000 men, resulting in 23 QALYs gained (0.000378 QALYs per individual). The additional cost of the screening and treatment was €39 429 (€65.4 per individual) with the incremental cost-effectiveness ratio for screening compared with no screening being €17 303 per QALY gained. Although results were sensitive to assumptions regarding health-related quality of life and the models' time horizon, screening was found to be cost-effective with a 99% probability at a willingness-to-pay threshold of €30 000 per QALY. CONCLUSION: Population-based AAA screening of elderly men is likely to be a cost-effective measure in reducing the AAA-related disease burden. Given the increase in the overall costs, the actual policy decisions regarding implementing an AAA screening program in Estonia are likely to be influenced by availability of resources as well.

PEHO syndrome caused by compound heterozygote variants in ZNHIT3 gene.

PEHO syndrome is characterized by Progressive Encephalopathy with Edema, Hypsarrhythmia, and Optic atrophy, which was first described in Finnish patients. A homozygous missense substitution p.Ser31Leu in ZNHIT3 was recently identified as the primary cause of PEHO syndrome in Finland. Variants in ZNHIT3 have not been identified in patients with PEHO or PEHO-like syndrome in other populations. It has therefore been suggested that PEHO syndrome caused by ZNHIT3 variants does not occur outside of the Finnish population. We describe the first patient outside Finland who carries compound heterozygous variants in ZNHIT3 gene causing PEHO syndrome. Trio genome sequencing was carried out and the identified variants were confirmed by Sanger sequencing. The patient filled all diagnostic clinical criteria of PEHO syndrome. We identified biallelic missense variants in ZNHIT3 gene: the c.92C > T p.(Ser31Leu) variant (NM_004773.3), which is described previously as causing PEHO syndrome and the second novel variant c.41G > T p.(Cys14Phe). There are only eight heterozygous carriers of c.41G > T variant in the gnomAD database and it is predicted damaging by multiple in silico algorithms. The ZNHIT3-associated PEHO syndrome exists outside of the Finnish population.

Low cerebral blood flow velocity and head circumference in infants with severe hypoxic ischemic encephalopathy and poor outcome.

AIMS: To evaluate long-term changes in cerebral blood flow velocity (CBFV) and head circumference in asphyxiated infants. METHODS: CBFV was measured in 83 asphyxiated and 115 healthy term infants in anterior and middle cerebral, basilar and internal carotid artery (ICA) up to the age of 60-149 days. The psychomotor development and head circumference was followed for 18 months. RESULTS. Mean CBFV was increased (p < 0.05) during the first days after asphyxia in infants with severe hypoxic-ischemic encephalopathy (HIE) (n = 25) compared to control group or infants with mild to moderate HIE (n = 58) with maximum values found at the age of 36-71.9 h: in ICA (mean [95% CI]) 31.2 (25.5-36.6) cm/s in severe HIE infants compared to 13.0 (12.2-13.9) cm/s in controls. Decreased (p < 0.0001) mean CBFV developed in severe HIE infants by the age of 21-59 days: in ICA 14.1 (11.5-16.8) cm/s compared to 22.9 (21.4-24.4) cm/s in controls. Infants with severe HIE had similar mean height but lower head circumferences compared to controls (p < 0.05) at the age of 21-59 days. CONCLUSION: The high mean CBFV found in infants with severe HIE during the first days after asphyxia is temporary and low CBFV and head circumference develops by the age of 21-59 days.

Changes in cerebral and visceral blood flow velocities in asphyxiated term neonates with hypoxic-ischemic encephalopathy.

OBJECTIVE: The purpose of this study was to evaluate changes in the Doppler blood flow velocity (BFV) in the cerebral and visceral arteries in asphyxiated term neonates. METHODS: The BFV was measured in 47 asphyxiated and 37 healthy term neonates in the anterior cerebral artery, middle cerebral artery, basilar artery, internal carotid artery, celiac artery (CA), superior mesenteric artery (SMA), and renal artery (RA) up to the age of 60 to 149 days. RESULTS: At the age of 12 to 120 hours after asphyxia, the mean BFV had increased, and the resistive index (RI) had decreased (P < .05) in all cerebral arteries in neonates with severe hypoxic-ischemic encephalopathy (HIE) compared with the control group. In neonates with severe HIE, the mean BFV in the RA had significantly decreased at the age of 3 to 240 hours, and the RI had increased at the age of 24 to 240 hours, normalizing by the age of 21 to 59 days compared with the control group (P < .05). In the SMA, a decreased mean BFV was found in neonates with severe HIE compared with those with mild to moderate HIE only at the age of 24 to 36 hours. In neonates with mild to moderate HIE, the mean BFV had increased in the SMA and CA compared with the control group at the age of 2 to 11.9 hours. CONCLUSIONS: A severe alteration of the cerebral and visceral BFV takes place during the first days after asphyxia in neonates with different severities of HIE.