Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy.

Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harbouring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20) and delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: (i) defective cell membrane expression; (ii) impaired LGI1-binding; and/or (iii) impaired interaction with the postsynaptic density protein PSD-95. We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics.

Recurrent Intracranial Hypertension in a Toddler with Graves' Disease.

INTRODUCTION: Idiopathic intracranial hypertension (IIH) is characterized by increased intracranial pressure without an evident cause. Obesity and the female sex have been recognized as risk factors for the development of this syndrome. Until now, Graves' disease has only been described in the literature as the probable cause of IIH in 7 patients. This report describes the case of a young girl with Graves' disease presenting with symptoms of intracranial hypertension (IH). CASE PRESENTATION: A 21-month-old girl presented with progressive symptoms of poor weight gain and bilateral exophthalmos. She also experienced difficulty sleeping, diarrhea multiple times per day, irritability, and heat intolerance. Laboratory investigation showed elevated free T4, fully suppressed TSH, and elevated anti-TSH antibodies, consistent with a diagnosis of new-onset Graves' disease. She was successfully treated with monotherapy thiamazole, titrated to the lowest possible dose of 1.25 mg once daily with normalization of thyroid function tests within 3 months of treatment initiation. After 18 months of treatment, her condition unexpectedly deteriorated as papilledema and slight esotropia were found at a routine checkup. An MRI and lumbar puncture showed increased intracranial pressure, but no underlying anatomical cause for the IH was found. Acetazolamide therapy was started, and papilledema in both eyes resolved within weeks. Unfortunately, papilledema has recurred several times over the following 2 years when attempts were made to decrease the acetazolamide dose. DISCUSSION/CONCLUSION: This case report is the first to describe a very young patient who developed significant IIH in the chronic stage of Graves' disease. IIH development seemed to be related to the progression of the Graves' ophthalmopathy, rather than initiation of thiamazole therapy or fluctuations in serum fT4 levels.

Classroom-evaluated school performance at nine years of age after very preterm birth.

OBJECTIVE: To determine classroom-evaluated school performance nine years after preterm birth, predicted by perinatal risk factors and neonatal brain abnormalities. STUDY DESIGN: Children were recruited from a consecutive cohort of 113 preterm infants (<32 weeks' gestation), participating in a longitudinal prospective study, investigating brain injury and neurodevelopmental outcome. Data on perinatal risk factors, presence of brain injury at term-equivalent age, and maternal education were collected. Information on school performance included enrollment in special (primary) education, grade repetition and school results from the nationwide standardized Dutch Pupil Monitoring System regarding reading comprehension, spelling, and mathematics. RESULTS: Information on school enrollment was available for 87 children (77%), of whom 7 (8%) were in special primary education and 19 (22%) repeated a grade. This was significantly higher compared to national rates (p ≤ .05). Results on school performance were available for 74 children (65%) and showed clearly below average scores in reading comprehension (p = .006), spelling (p = .014) and mathematics (p < .001). Univariate analysis showed that lower performance in reading comprehension was predicted by male sex and low maternal education; spelling by male sex; and mathematics by Bronchopulmonary Dysplasia, white matter injury and maternal education. In a multivariate model, male sex and maternal education were predictive for reading comprehension and white matter injury for mathematics. CONCLUSION: Preterm born children more often need special primary education and have higher grade repeat rates. They perform poorer on reading comprehension, spelling and mathematics. Regular follow-up remains important for preterm born children during school age.

Neuroprotective strategies following perinatal hypoxia-ischemia: Taking aim at NOS.

Perinatal asphyxia is characterized by oxygen deprivation and lack of perfusion in the perinatal period, leading to hypoxic-ischemic encephalopathy and sequelae such as cerebral palsy, mental retardation, cerebral visual impairment, epilepsy and learning disabilities. On cellular level PA is associated with a decrease in oxygen and glucose leading to ATP depletion and a compromised mitochondrial function. Upon reoxygenation and reperfusion, the renewed availability of oxygen gives rise to not only restoration of cell function, but also to the activation of multiple detrimental biochemical pathways, leading to secondary energy failure and ultimately, cell death. The formation of reactive oxygen species, nitric oxide and peroxynitrite plays a central role in the development of subsequent neurological damage. In this review we give insight into the pathophysiology of perinatal asphyxia, discuss its clinical relevance and summarize current neuroprotective strategies related to therapeutic hypothermia, ischemic postconditioning and pharmacological interventions. The review will also focus on the possible neuroprotective actions and molecular mechanisms of the selective neuronal and inducible nitric oxide synthase inhibitor 2-iminobiotin that may represent a novel therapeutic agent for the treatment of hypoxic-ischemic encephalopathy, both in combination with therapeutic hypothermia in middle- and high-income countries, as well as stand-alone treatment in low-income countries.

Intra-arterial treatment in a child with embolic stroke due to atrial myxoma.

Arterial ischaemic stroke is an important cause of morbidity in children. Timely diagnosis is necessary for acute stroke treatment but can be challenging in clinical practice. Due to a paucity of data there are no specific recommendations regarding the use of mechanical thrombectomy devices in current paediatric stroke guidelines. A 14-year-old boy presented with a severe acute left hemisphere stroke due to a proximal middle cerebral artery occlusion caused by emboli from an atrial myxoma. No clinical improvement was seen after administration of intravenous thrombolysis. Subsequent mechanical thrombectomy with a second-generation stent-based thrombectomy device resulted in successful recanalization and clinical improvement. To our knowledge, this is the first report of mechanical thrombectomy in a child with acute embolic stroke caused by atrial myxoma.

GPSM2 and Chudley-McCullough syndrome: a Dutch founder variant brought to North America.

Chudley-McCullough syndrome (CMS) is characterized by profound sensorineural hearing loss and brain anomalies. Variants in GPSM2 have recently been reported as a cause of CMS by Doherty et al. In this study we have performed exome sequencing of three CMS patients from two unrelated families from the same Dutch village. We identified one homozygous frameshift GPSM2 variants c.1473delG in all patients. We show that this variant arises from a shared, rare haplotype. Since the c.1473delG variant was found in Mennonite settlers, it likely originated in Europe. To support DNA diagnostics, we established an LOVD database for GPSM2 containing all variants thus far described.

Increased concentrations of both NMDA receptor co-agonists D-serine and glycine in global ischemia: a potential novel treatment target for perinatal asphyxia.

Worldwide, perinatal asphyxia is an important cause of morbidity and mortality among term-born children. Overactivation of the N-methyl-D-aspartate receptor (NMDAr) plays a central role in the pathogenesis of cerebral hypoxia-ischemia, but the role of both endogenous NMDAr co-agonists D-serine and glycine remains largely elusive. We investigated D-serine and glycine concentration changes in rat glioma cells, subjected to oxygen and glucose deprivation (OGD) and CSF from piglets exposed to hypoxia-ischemia by occlusion of both carotid arteries and hypoxia. We illustrated these findings with analyses of cerebrospinal fluid (CSF) from human newborns affected by perinatal asphyxia. Extracellular concentrations of glycine and D-serine were markedly increased in rat glioma cells exposed to OGD, presumably through increased synthesis from L-serine. Upon reperfusion glycine concentrations normalized and D-serine concentrations were significantly lowered. The in vivo studies corroborated the finding of initially elevated and then normalizing concentrations of glycine and decreased D-serine concentrations upon reperfusion These significant increases of both endogenous NMDAr co-agonists in combination with elevated glutamate concentrations, as induced by global cerebral ischemia, are bound to lead to massive NMDAr activation, excitotoxicity and neuronal damage. Influencing these NMDAr co-agonist concentrations provides an interesting treatment target for this common, devastating and currently poorly treatable condition.

Redox state of near infrared spectroscopy-measured cytochrome aa(3) correlates with delayed cerebral energy failure following perinatal hypoxia-ischaemia in the newborn pig.

Early detection of delayed cerebral energy failure may be important in the prevention of reperfusion injury of the brain after severe perinatal hypoxia-ischaemia (HI). This study investigated whether monitoring of the redox state of cytochrome aa(3) (Cytaa(3)) with near infrared spectroscopy (NIRS) after severe perinatal asphyxia may allow us to detect early a compromised energy metabolism of the developing brain. We therefore correlated serial Cytaa(3) measurements (to estimate mitochondrial oxygenation) simultaneously with the (31)phosphorous-magnetic resonance spectroscopy ((31)P-MRS)-measured phosphocreatin/inorganic phosphate (PCr/Pi) ratio (to estimate cerebral energy reserve) in newborn piglets before and after severe hypoxia-ischaemia. The animals were treated upon reperfusion with either allopurinol, deferoxamine, or 2-iminobiotin or with a vehicle to reduce post-HI reperfusion injury of the brain. Four sham-operated piglets served as controls. Before HI, the individual Cytaa(3) values ranged between -0.02 and 0.71 micromol/L (mean value: -0.07) relative to baseline. The pattern over post-HI time of the vehicle-treated animals was remarkably different from the other groups in as far Cytaa(3) became more oxidised from 3 h after start of HI onwards (increase of Cytaa(3) as compared with baseline), whereas the other groups showed a significant reduction over time (decrease of Cytaa(3) as compared with baseline: allopurinol and deferoxamine) or hardly any change (2-iminobiotin and sham-operated piglets). Vehicle-treated piglets showed a significant reduction in PCr/Pi at 24 h after start of HI, but the cerebral energy state was preserved in 2-iminobiotin-, allopurinol- and deferoxamine-treated piglets. With severe reduction in PCr/Pi-ratio, major changes in the redox-state of Cytaa(3) also occurred: Cytaa(3) was mostly either in a reduced state (down to -6.45 micromol/L) or in an oxidised state (up to 6.84 micromol/L) at these low PCr/Pi ratios. The positive predictive value (PPV) of Cytaa(3) to predict severe reduction of the PCr/Pi ratio was 42%; the negative PPV was 87%. A similar relation was found for Cytaa(3) with histologically determined loss of neurons.

Effects of allopurinol and deferoxamine on reperfusion injury of the brain in newborn piglets after neonatal hypoxia-ischemia.

The hypothesis was tested that treatment with allopurinol, a xanthine oxidase inhibitor, or deferoxamine, a chelator of nonprotein-bound iron, preserved cerebral energy metabolism, attenuated development of edema, and improved histologic outcome in the newborn piglet at 24 h after hypoxia-ischemia. Thirty-two newborn piglets were subjected to 1 h of hypoxia-ischemia by occluding both carotid arteries and reducing the fraction of inspired oxygen; five newborn piglets served as sham-operated controls. The depth of hypoxia-ischemia was controlled by phosphorous magnetic resonance spectroscopy. Upon reperfusion and reoxygenation, piglets received vehicle (n= 12), allopurinol (30 mg/kg/d, n = 10), or deferoxamine (12.5 mg/kg/d, n = 10). The cerebral energy status was determined with phosphorous magnetic resonance spectroscopy. The presence of vasogenic edema was assessed by T2-weighted magnetic resonance imaging. Brain cell injury was assessed with caspase-3 activity, histology, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end (TUNEL)-labeling. At 24 h after hypoxia-ischemia, the phosphocreatine/inorganic phosphate ratios were significantly decreased in vehicle-treated, but not in allopurinol- or deferoxamine-treated piglets. Water T2 values were significantly increased at 24 h after hypoxia-ischemia in cerebral cortex, thalamus, and striatum of vehicle-treated piglets, but not in allopurinol- and deferoxamine-treated piglets. No differences in caspase-3 activity, histologic outcome, or TUNEL-labeling were demonstrated between the three treatment groups. We suggest that allopurinol and deferoxamine may have an additional value in the treatment of perinatal hypoxia-ischemia with other neuroprotective agents or in combination with hypothermia.

Pharmacological interventions in the newborn piglet in the first 24 h after hypoxia-ischemia. A hemodynamic and electrophysiological perspective.

The purpose of this study was to investigate whether combined inhibition of neuronal and inducible nitric oxide synthase (NOS) by 2-iminobiotin, free radical scavenging by allopurinol, and non-protein-bound iron chelation with deferoxamine improved cerebral oxygenation, electrocortical brain activity, and brain energy status during the first 24 h after hypoxia-ischemia (HI) in the newborn piglet. Forty-three newborn piglets were subjected to 1 h of severe HI by occluding both carotid arteries and phosphorous magnetic resonance spectroscopy ((31)P-MRS)-guided hypoxia, whereas five served as sham-operated controls. Upon reperfusion, piglets received vehicle (n=12), 2-iminobiotin (n=11), allopurinol (n=10), or deferoxamine (n=10). Cerebral oxygenation was recorded with near-infrared spectrophotometry (NIRS), electrocortical brain activity was assessed with amplitude-integrated EEG (aEEG), and cerebral energy status with (31)P-MRS. The oxygenated hemoglobin (HbO(2)) and total hemoglobin (tHb) were significantly increased in vehicle-treated piglets compared with 2-iminobiotin-treated and deferoxamine-treated piglets. No change in deoxygenated Hb (HHb) was demonstrated over time. The aEEG was significantly preserved in 2-iminobiotin- and deferoxamine-treated piglets compared with vehicle-treated piglets. Allopurinol treatment was not as effective as 2-iminobiotin treatment after HI. Phosphocreatine/inorganic phosphate ratios (PCr/P(i)) were significantly decreased for vehicle-treated piglets at 24 h post-HI, whereas 2-iminobiotin, allopurinol, and deferoxamine prevented the development of secondary energy failure. We speculate that the beneficial effects, especially of 2-iminobiotin, but also of deferoxamine, are due to reduced peroxynitrite-mediated oxidation.

Effects of selective nitric oxide synthase inhibition on IGF-1, caspases and cytokines in a newborn piglet model of perinatal hypoxia-ischaemia.

Selective inhibition of neuronal and inducible nitric oxide synthase (NOS) with 2-iminobiotin previously showed a reduction in brain cell injury. In the present study, we investigated the effects of 2-iminobiotin treatment on insulin-like growth factor-1 (IGF-1) expression, caspase activity and cytokine expression in a newborn piglet model of perinatal hypoxia-ischaemia. Newborn piglets were subjected to 1 h of hypoxia-ischaemia and were treated intravenously with vehicle or 2-iminobiotin. Vehicle-treated piglets showed reduced IGF-1 mRNA expression and increased caspase-3 activity and DNA fragmentation. 2-Iminobiotin treatment, administered immediately upon reperfusion, prevented these observations. No differences in caspase-8 and -9 activity and cytokine [interleukin (IL)-1alpha/beta, IL-6, tumour necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta] mRNA expression were demonstrated between vehicle- and 2-iminobiotin-treated piglets at 24 h following hypoxia-ischaemia. IGF-1 mRNA correlated inversely with caspase-3 and transferase-mediated dUTP-biotin in situ nick end labelling score in the cortex, but positively with caspase-8. Cytokine mRNA did not correlate with IGF-1 mRNA, caspase-3 activity or DNA fragmentation. The present results indicate that the previously demonstrated neuroprotective effect of 2-iminobiotin treatment after perinatal hypoxia-ischaemia coincided with a preservation of the endogenous IGF-1 production and reduced caspase-3 activity, but not with a significant decrease in cytokine production.