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We report a 9-year-old Spanish boy with severe psychomotor developmental delay, short stature, microcephaly and abnormalities of the brain morphology, including cerebellar atrophy. Whole-exome sequencing (WES) uncovered two novel de novo variants, a hemizygous variant in CASK (Calcium/Calmodulin Dependent Serine Protein Kinase) and a heterozygous variant in EEF2 (Eukaryotic Translation Elongation Factor 2). CASK gene encodes the peripheral plasma membrane protein CASK that is a scaffold protein located at the synapses in the brain. The c.2506-6 A > G CASK variant induced two alternative splicing events that account for the 80% of the total transcripts, which are likely to be degraded by NMD. Pathogenic variants in CASK have been associated with severe neurological disorders such as mental retardation with or without nystagmus also called FG syndrome 4 (FGS4), and intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH). Heterozygous variants in EEF2, which encodes the elongation factor 2 (eEF2), have been associated to Spinocerebellar ataxia 26 (SCA26) and more recently to a childhood-onset neurodevelopmental disorder with benign external hydrocephalus. The yeast model system used to investigate the functional consequences of the c.34 A > G EEF2 variant supported its pathogenicity by demonstrating it affects translational fidelity. In conclusion, the phenotype associated with the CASK variant is more severe and masks the milder phenotype of EEF2 variant., (© 2023. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Introduction: Few studies have examined the functional brain correlates of the performance of the Stroop task in bipolar disorder (BD). It is also not known whether it is associated with failure of de-activation in the default mode network, as has been found in studies using other tasks., Methods: Twenty-four BD patients and 48 age, sex and educationally estimated intellectual quotient (IQ) matched healthy subjects (HS) underwent a functional MRI during performance of the counting Stroop task. Task-related activations (incongruent versus congruent condition) and de-activations (incongruent versus fixation) were examined using whole-brain, voxel-based methodology., Results: Both the BD patients and the HS showed activation in a cluster encompassing the left dorsolateral and ventrolateral prefrontal cortex and the rostral anterior cingulate cortex and supplementary motor area, with no differences between them. The BD patients, however, showed significant failure of de-activation in the medial frontal cortex and the posterior cingulate cortex/precuneus., Conclusions: The failure to find activation differences between BD patients and controls suggests that the 'regulative' component of cognitive control remains intact in the disorder, at least outside episodes of illness. The failure of de-activation found adds to evidence documenting trait-like default mode network dysfunction in the disorder., Competing Interests: Conflict of interest Dr. R. Rodriguez-Jimenez has been a consultant for, spoken in activities of, or received grants from: Instituto de Salud Carlos III, Fondo de Investigación Sanitaria (FIS), Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid Regional Government (S2010/BMD-2422 AGES; S2017/BMD-3740), Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Ferrer, Juste, Takeda, Exeltis, Angelini, Casen-Recordati. Dr. N. Verdolini has received financial support for CME activities and travel funds from the following entities (unrelated to the present work): Angelini, Janssen-Cilag, Lundbeck, Otsuka. The other authors declare no financial or other conflicts of interest related to this study., (Copyright © 2023. Published by Elsevier B.V.)

Anterior shoulder instability remains one of the main indications for shoulder surgery. We present a modified way of treating anterior shoulder instability in the beach-chair position from an anterior arthroscopic approach through the rotator interval. This technique opens the rotator interval, which increases the working area and allows us to work without cannulae. Through this approach, we can treat all injuries comprehensively and, if necessary, switch to other arthroscopic techniques used for instability such as arthroscopic Latarjet or anterior ligamentoplasties., (© 2022 The Authors.)

We report the clinical and genetic features of a Caucasian girl who presented a severe neurodevelopmental disorder with drug-resistant epilepsy, hypotonia, severe gastro-esophageal reflux and brain magnetic resonance imaging anomalies. WES uncovered a novel variant in homozygosis (g.197092814_197092824delinsC) in HECW2 gene that encodes the E3 ubiquitin-protein ligase HECW2. This protein induces ubiquitination and is implicated in the regulation of several important pathways involved in neurodevelopment and neurogenesis. Furthermore, de novo heterozygous missense variants in this gene have been associated with neurodevelopmental disorder with hypotonia, seizures, and absent language (NDHSAL). The homozygous variant of our patient disrupts the splice donor site of intron 22 and causes the elimination of exon 22 (r.3766_3917+1del) leading to an in-frame deletion of the protein (p.Leu1256_Trp1306del). Functional studies showed a twofold increase of its RNA expression, while the protein expression level was reduced by 60%, suggesting a partial loss-of-function mechanism of pathogenesis. Thus, this is the first patient with NDHSAL caused by an autosomal recessive splicing variant in HECW2., (© 2022 Wiley Periodicals LLC.)

Background: Cytomegalovirus (CMV) is the leading cause of congenital infection worldwide. Up to 15%-20% of infected newborns will develop long-term sequelae such as hearing loss and neurologic abnormalities. The aim of this study was to investigate the prevalence of congenital CMV infection (cCMV) and associated clinical abnormalities in Spain., Methods: A prospective screening for cCMV by viral load in saliva was performed. Saliva samples were obtained within the first 72 hours of life in a maternity ward in Madrid (Spain), during a 1-year period. All positive screening tests were confirmed with viral load in urine. Clinical, laboratory, auditory, visual and cerebral imaging assessments were performed in all children with cCMV., Results: Of the 4097 neonates born during the study period, 3190 (78%) were included. CMV viral load in saliva was detectable in 24/3190 (0.75%) children, and congenital infection was confirmed in 15/3190 (0.47%, CI 95%: 0.29%-0.77%). Positive predictive value was 62.5% (CI 95%: 46.5%-76.1%). Two infants presented symptoms at birth. Eight (53.3%) children showed abnormalities in magnetic resonance imaging; most of them isolated white matter abnormalities. Newborns with abnormalities in magnetic resonance imaging showed higher viral loads in blood and saliva (P = 0.04)., Conclusions: One in 200 neonates born in our hospital presented a cCMV infection. CMV viral load in saliva has been shown to be a simple and highly accepted screening method but should be confirmed by CMV detection in urine. In spite of the fact that half of infected children had abnormalities in cerebral imaging, diagnosis during the neonatal period would have been impossible without a screening program in most cases.

Background: Apert syndrome is one of the most severe craniofacial disorders. This study aims to describe the craniofacial surgeries and central nervous system malformations of a cohort of children with Apert syndrome treated in the past 20 years and to compare these data with previously published data., Methods: Retrospective analysis of a series of patients with Apert syndrome treated between 1999 and 2019 in our hospital. Information was analyzed regarding craniofacial procedures, hydrocephalus and presence of shunts, Chiari malformation Type 1, and other brain malformations such as corpus callosum and septum pellucidum anomalies., Results: Thirty-seven patients were studied. Ventriculoperitoneal shunt prevalence was 24.3%, and 8.1% of patients required decompressive surgery for Chiari malformation. All of them needed at least one cranial vault remodeling procedure. The median age for this procedure was 8 months. In 69.7% of patients, the first cranial vault intervention was performed in the fronto-orbital region. In 36.4% of patients, a midface advancement had been performed at the time of this review, although this proportion was very dependent on the follow-up period and the age of the patients. The median age for the midface advancement procedure was 5.25 years. Anomalies of the corpus callosum and the septum pellucidum were reported in 43.2% and 59.5% of patients, respectively., Conclusion: Apert syndrome is a type of syndromic craniosynostosis, and patients usually require one or more cranial and facial surgeries. In comparison with other syndromic craniosynostosis types, Apert syndrome less frequently requires a VP shunt or treatment for a Chiari malformation., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Surgical Neurology International.)

We report the clinical and genetic findings in a Spanish boy who presented MEGDEL syndrome, a very rare inborn error of metabolism. Whole-exome sequencing uncovered a new homozygous mutation in the serine active site containing 1 (SERAC1) gene, which is essential for both mitochondrial function and intracellular cholesterol trafficking. Functional studies in patient fibroblasts showed that p.D224G mutation affects the intracellular cholesterol trafficking. Only three missense mutations in this gene have been described before, being p.D224G the first missense mutation outside of the SERAC1 serine-lipase domain. Therefore, we conclude that the defect in cholesterol trafficking is not limited to alterations in this specific part of the protein.

Background: Mutations in the LAMA2 gene cause autosomal recessive laminin α2 related congenital muscular dystrophy. In patients with partial laminin α2 deficiency the phenotype is usually milder than in those with absent protein. Apart from the typical white matter abnormalities, there is an increased risk of cerebral complications such as epilepsy and mental retardation, despite a structurally normal brain., Methods/results: We present a patient with primary partial laminin α2 deficiency due to a homozygous novel LAMA2 missense mutation who developed West syndrome in his first year of life. To our knowledge, this combination has not previously been reported. A 5 year-old boy exhibited global hypotonia with generalized muscle weakness from birth. At 8 months of age he presented infantile spasms and an EEG finding of hypsarrhythmia. Seizures were controlled in a few weeks with intramuscular synthetic ACTH, followed by valproic acid. Two years later antiepileptic medication was withdrawn. He achieved unsupported walking at the age of 4, but his cognitive status corresponded to a 2 year-old child. Epilepsy has not recurred and brain MRI showed the typical white matter abnormalities without associated neuronal migration defects., Conclusion: This report widens the clinical spectrum of cerebral manifestations related with mutations in LAMA2. The beginning of a severe epileptic encephalopathy modifies the natural history of the disease., (Copyright © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Background: Kearns-Sayre syndrome (KSS) is a mitochondrial DNA deletion syndrome that presents with profound cerebral folate deficiency and other features. Preliminary data support the notion that folinic acid therapy might be useful in the treatment of KSS patients. Our aim was to assess the clinical and neuroimaging outcomes of KSS patients receiving folinic acid therapy., Patients: We recruited eight patients with diagnoses of KSS. Four cases were treated at 12 de Octubre Hospital, and the other two cases were treated at Sant Joan de Déu Hospital. Two patients refused to participate in the treatment protocol., Methods: Clinical, biochemical and neuroimaging data (magnetic resonance imaging or computed tomography scan) were collected in baseline conditions and at different time points after the initiation of therapy. Cerebrospinal fluid 5-methyltetrahydrofolate levels were analysed with HPLC and fluorescence detection. Large-scale mitochondrial DNA deletions were analysed by Southern blot., Treatment Protocol: The follow-up periods ranged from one to eight years. Cases 1-4 received oral folinic acid at a dose of 1 mg/kg/day, and cases 6 and 8 received 3 mg/kg/day., Results: No adverse effects of folinic acid treatment were observed. Cerebral 5-methyltetrahydrofolate deficiencies were observed in all cases in the baseline conditions. Moreover, all three patients who accepted lumbar puncture after folinic acid therapy exhibited complete recoveries of their decreased basal cerebrospinal fluid 5-methyltetrahydrofolate levels to normal values. Two cases neurologically improved after folinic therapy. Disease worsened in the other patients. Post-treatment neuroimaging was performed for the 6 cases that received folinic acid therapy. One patient exhibited improvements in white matter abnormalities. The remaining patients displayed progressions in subcortical cerebral white matter, the cerebellum and cerebral atrophy., Conclusions: Four patients exhibited clinical and radiological progression of the disease following folinic acid treatment. Only one patient who was treated in an early stage of the disease exhibited both neurological and radiological improvements following elevated doses of folinic acid, and an additional patient experienced neurological improvement. Early treatment with high-dose folinic acid therapy seems to be advisable for the treatment of KSS., Trial Registration: Eudrac T2007-00-6748-23.

Carotid and vertebral artery dissection is a rarely reported cause of stroke in childhood and adolescence, especially if there is not a direct trauma to the neck. Four patients, under 15 years of age, presented with an internal carotid artery dissection, and one patient presented with a vertebral artery dissection. They were all making a physical effort when the event occurred. The five patients had ischemic symptoms, and in two the events were preceded by transient ischemic attacks. Headache was associated in four patients. The diagnosis was made by magnetic resonance imaging and angiography, which included transfemoral angiography in two patients. All improved before leaving the hospital, and four patients did not suffer recurrent episodes. The diagnostic accuracy of artery dissection has improved because of noninvasive neuroimaging testing, but it should still be suspected in any pediatric ischemic stroke, especially if there is headache or cervical pain associated.