Hyperkinetic Movement Disorder Caused by the Recurrent c.892C>T NACC1 Variant.

BACKGROUND: Genetic syndromes of hyperkinetic movement disorders associated with epileptic encephalopathy and intellectual disability are becoming increasingly recognized. Recently, a de novo heterozygous NACC1 (nucleus accumbens-associated 1) missense variant was described in a patient cohort including one patient with a combined mitochondrial oxidative phosphorylation (OXPHOS) deficiency. OBJECTIVES: The objective is to characterize the movement disorder in affected patients with the recurrent c.892C>T NACC1 variant and study the NACC1 protein and mitochondrial function at the cellular level. METHODS: The movement disorder was analyzed on four patients with the NACC1 c.892C>T (p.Arg298Trp) variant. Studies on NACC1 protein and mitochondrial function were performed on patient-derived fibroblasts. RESULTS: All patients had a generalized hyperkinetic movement disorder with chorea and dystonia, which occurred cyclically and during sleep. Complex I was found altered, whereas the other OXPHOS enzymes and the mitochondria network seemed intact in one patient. CONCLUSIONS: The movement disorder is a prominent feature of NACC1-related disease.

Radiotherapy-induced vascular cognitive impairment 20 years after childhood brain tumor.

BACKGROUND: Studies have established that radiotherapy for childhood brain tumors (BTs) increases the risk of cerebrovascular disease (CVD); however, it is unclear how this will affect cognitive function. This study aimed to investigate the associations between radiotherapy-induced CVD, white matter hyperintensities (WMHs), and neurocognitive outcomes in adult survivors of childhood BTs. METHODS: In a cross-sectional setting, we conducted a national cohort that included 68 radiotherapy-treated survivors of childhood BTs after a median follow-up of 20 years. Markers of CVD and WMHs were evaluated using brain MRI, and the sum of CVD-related findings was calculated. Additionally, the associations among CVD findings, WMHs, and neuropsychological test results were analyzed. RESULTS: Of the 68 childhood BT survivors, 54 (79%) were diagnosed with CVD and/or WMHs at a median age of 27 years. CVD and/or WMHs were associated with lower scores for verbal intelligence quotient, performance intelligence quotient (PIQ), executive function, memory, and visuospatial ability (P < .05). Additionally, survivors with microbleeds had greater impairments in the PIQ, processing speed, executive function, and visuospatial ability (P < .05). WMHs and CVD burden were associated with greater difficulties in memory function and visuospatial ability (P < .05). Small-vessel disease burden was associated with PIQ scores, processing speed, working memory, and visuospatial ability. CONCLUSIONS: The study results suggest that markers of radiotherapy-induced CVD, the additive effect of CVD markers, and risk factors of dementia are associated with cognitive impairment, which may suggest that the survivors are at a high risk of developing early-onset dementia.

DNA polymerase gamma variants and hepatotoxicity during maintenance therapy of childhood acute lymphoblastic leukemia: is there a causal relationship?

Hepatotoxicity is a frequent complication during maintenance therapy of acute lymphoblastic leukemia (ALL) with 6-mercaptopurine and methotrexate. Elevated levels of methylated 6-mercaptopurine metabolites (MeMP) are associated with hepatotoxicity. However, not all mechanisms are known that lead to liver failure in patients with ALL. Variants in the POLG gene, which encodes the catalytic subunit of mitochondrial DNA polymerase gamma (POLG1), have been related to drug-induced hepatotoxicity, for example, by sodium valproate. The association of common POLG variants with hepatotoxicity during maintenance therapy was studied in 34 patients with childhood ALL. Of the screened POLG variants, four different variants were detected in 12 patients. One patient developed severe hepatotoxicity without elevated MeMP levels and harbored a heterozygous POLG p.G517V variant, which was not found in the other patients.

Early disc degeneration in radiotherapy-treated childhood brain tumor survivors.

BACKGROUND: Childhood brain tumor (BT) survivors have an increased risk of treatment-related late effects, which can reduce health-related quality of life and increase morbidity. This study aimed to investigate lumbar disc degeneration in magnetic resonance imaging (MRI) in adult survivors of radiotherapy-treated childhood BT compared to age and sex-matched population controls. METHODS: In this cross-sectional comparative study, 127 survivors were identified from hospital registries. After a mean follow-up of 20.7 years (range 5-33.1), 67 survivors (mean age 28.4, range 16.2-43.5) were investigated with MRI and compared to 75 sex-matched population-based controls. Evaluated MRI phenotypes included Pfirrmann grading, , intervertebral disc protrusions, extrusions, and high-intensity-zone-lesions (HIZ). Groups were also compared for known risk factors of lumbar intervertebral disc (IVD) degeneration. RESULTS: Childhood BT survivors had higher Pfirrmann grades than controls at all lumbar levels (all p < 0.001). Lumbar disc protrusions at L4-5 (p = 0.02) and extrusions at L3-4 (p = 0.04), L4-5 (p = 0.004), and L5-S1 (p = 0.01) were significantly more common in the BT group compared to the control. The survivor cohort also had significantly more HIZ-lesons than the controls (n=13 and n=1, p=0.003). Age at diagnosis was associated with lower degree of IVD degeneration (p < 0.01). Blood pressure correlated with IVD degeneration (P < 0.05). CONCLUSIONS: Signs of early disc degeneration related to tumor treatment can be seen in the IVDs of survivors. Disc degeneration was more severe in children treated in adolescence.

Favourable long-term recovery after decompressive craniectomy: the Northern Finland experience with a predominantly adolescent patient cohort.

PURPOSE: Decompressive craniectomy (DC) is an effective treatment of intracranial hypertension. Correspondingly, the procedure is increasingly utilised worldwide. The number of patients rendered vegetative following surgery has been a concern-a matter especially important in children, due to long anticipated lifetime. Here, we report the long-term outcomes of all paediatric DC patients from an 11-year period in a tertiary-level centre that geographically serves half of Finland. METHODS: We identified all patients younger than 18 years who underwent DC in the Oulu University Hospital between the years 2009 and 2019. Outcomes and clinicoradiological variables were extracted from the patient records. RESULTS: Mean yearly prevalence of brain injury requiring DC was 1.34/100 000 children-twenty-four patients underwent DC during the study period and 21 (88%) survived. The median age of the patients was 16.0 years, and the median preoperative GCS was 5.0 (IQR 5.0). Fifteen patients (63%) had made a good recovery (Extended Glasgow Outcome Scale ≥ 7). Of the surviving patients, two (9.5%) had not returned to school. After traumatic brain injury (n = 20), the Rotterdam CT score (mean 3.0, range 1 to 5) was not associated with mortality, poor recovery or inability to continue school (p = 0.13, p = 0.41, p = 0.43, respectively). Absent basal cisterns were associated with mortality (p = 0.005), but not with poor recovery if the patient survived DC (p = 0.81). Hydrocephalus was associated with poor recovery and inability to continue school (p = 0.01 and p = 0.03, respectively). CONCLUSION: Most of our patients made a favourable recovery and were able to continue school. No late mortality was observed. Thus, even in clinically and radiologically severely brain-injured children, decompressive craniectomy appears to yield favourable outcomes.

Epidemiological, clinical, and genetic characteristics of paediatric genetic white matter disorders in Northern Finland.

AIM: To examine the epidemiological, clinical, and genetic characteristics of paediatric patients with genetic white matter disorders (GWMDs) in Northern Finland. METHOD: A longitudinal population-based cohort study was conducted in the tertiary catchment area of Oulu University Hospital from 1990 to 2019. Patients were identified retrospectively by International Statistical Classification of Diseases and Related Health Problems codes in hospital records and prospectively by attending physicians. Inclusion criteria were children younger than 18 years with defined GWMDs or genetic disorders associated with white matter abnormalities (WMAs) on brain magnetic resonance imaging. RESULTS: Eighty patients (mean age [SD] at the end of the study 11y [8y 6mo], range 0-35y; 45 males, 35 females) were diagnosed with a defined GWMD. The cumulative childhood incidence was 30 per 100 000 live births. Regarding those patients with 49 distinct GWMDs, 20% had classic leukodystrophies and 80% had genetic leukoencephalopathies. The most common leukodystrophies were cerebral adrenoleukodystrophy, Krabbe disease, and Salla disease. Additionally, 29 patients (36%) had genetic aetiologies not previously associated with brain WMAs or they had recently characterised GWMDs, including SAMD9L- and NHLRC2-related neurological disorders. Aetiology was mitochondrial in 21% of patients. The most common clinical findings were motor developmental delay, intellectual disability, hypotonia, and spasticity. INTERPRETATION: The cumulative childhood incidence of childhood-onset GWMDs was higher than previously described. Comprehensive epidemiological and natural history data are needed before future clinical trials are undertaken. What this paper adds Forty-nine distinct genetic white matter disorders (GWMDs) were identified, with 20% of cases being classic leukodystrophies. The cumulative childhood incidence of GWMDs was higher than described previously. A considerable proportion (36%) of GWMDs were previously undefined or recently characterised GWMDs. Mitochondrial aetiology was more common (21%) than previously reported.

Preoperative measurements on MRI in Chiari 1 patients fail to predict outcome after decompressive surgery.

BACKGROUND: The purpose of our study was to research the parameters of magnetic resonance imaging (MRI) that would predict the outcome of surgery in patients with Chiari 1 malformation (CM1) and to evaluate changes in MRI parameters after surgery. METHODS: Fifty-one patients (19 children, 13 adolescents, and 19 adults) operated on due to CM1 in Oulu University Hospital between 2004 and 2018 were evaluated. Seventeen parameters were measured from the preoperative MRI and 11 from the postoperative MRI. The correlations between the MRI parameters and the clinical variables before and after surgery were analyzed. RESULTS: The majority (88.2%) of the patients had favorable surgical outcomes. Postoperatively, subjective symptoms improved in 88.6% of the patients and syringomyelia in 81.8%. The location of the cerebellar tonsils, when measured in relation to the C2 synchondrosis or the end plate, postoperatively moved cranially in 51.0% (n = 26), did not change in 27.4% (n = 14), and moved caudally in 21.6% (n = 11) of the patients. However, neither the location of the tonsils nor any other parameters measured from pre- or postoperative MRI correlated with the patients' symptoms or surgical outcomes. CONCLUSIONS: No specific parameters on preoperative MRI evaluation were predictive of the outcome of surgery, emphasizing clinical examination in surgical decision-making. Furthermore, the postoperative MRI parameters did not correlate with the surgical outcomes. Thus, routine postoperative imaging is suggested only for patients with preoperatively diagnosed syringomyelia or worsening of symptoms.

Loss of DIAPH1 causes SCBMS, combined immunodeficiency, and mitochondrial dysfunction.

BACKGROUND: Homozygous loss of DIAPH1 results in seizures, cortical blindness, and microcephaly syndrome (SCBMS). We studied 5 Finnish and 2 Omani patients with loss of DIAPH1 presenting with SCBMS, mitochondrial dysfunction, and immunodeficiency. OBJECTIVE: We sought to further characterize phenotypes and disease mechanisms associated with loss of DIAPH1. METHODS: Exome sequencing, genotyping and haplotype analysis, B- and T-cell phenotyping, in vitro lymphocyte stimulation assays, analyses of mitochondrial function, immunofluorescence staining for cytoskeletal proteins and mitochondria, and CRISPR-Cas9 DIAPH1 knockout in heathy donor PBMCs were used. RESULTS: Genetic analyses found all Finnish patients homozygous for a rare DIAPH1 splice-variant (NM_005219:c.684+1G>A) enriched in the Finnish population, and Omani patients homozygous for a previously described pathogenic DIAPH1 frameshift-variant (NM_005219:c.2769delT;p.F923fs). In addition to microcephaly, epilepsy, and cortical blindness characteristic to SCBMS, the patients presented with infection susceptibility due to defective lymphocyte maturation and 3 patients developed B-cell lymphoma. Patients' immunophenotype was characterized by poor lymphocyte activation and proliferation, defective B-cell maturation, and lack of naive T cells. CRISPR-Cas9 knockout of DIAPH1 in PBMCs from healthy donors replicated the T-cell activation defect. Patient-derived peripheral blood T cells exhibited impaired adhesion and inefficient microtubule-organizing center repositioning to the immunologic synapse. The clinical symptoms and laboratory tests also suggested mitochondrial dysfunction. Experiments with immortalized, patient-derived fibroblasts indicated that DIAPH1 affects the amount of complex IV of the mitochondrial respiratory chain. CONCLUSIONS: Our data demonstrate that individuals with SCBMS can have combined immune deficiency and implicate defective cytoskeletal organization and mitochondrial dysfunction in SCBMS pathogenesis.

Model Selection Based Algorithm in Neonatal Chest EIT.

This paper presents a new method for selecting a patient specific forward model to compensate for anatomical variations in electrical impedance tomography (EIT) monitoring of neonates. The method uses a combination of shape sensors and absolute reconstruction. It takes advantage of a probabilistic approach which automatically selects the best estimated forward model fit from pre-stored library models. Absolute/static image reconstruction is performed as the core of the posterior probability calculations. The validity and reliability of the algorithm in detecting a suitable model in the presence of measurement noise is studied with simulated and measured data from 11 patients. The paper also demonstrates the potential improvements on the clinical parameters extracted from EIT images by considering a unique case study with a neonate patient undergoing computed tomography imaging as clinical indication prior to EIT monitoring. Two well-known image reconstruction techniques, namely GREIT and tSVD, are implemented to create the final tidal images. The impacts of appropriate model selection on the clinical extracted parameters such as center of ventilation and silent spaces are investigated. The results show significant improvements to the final reconstructed images and more importantly to the clinical EIT parameters extracted from the images that are crucial for decision-making and further interventions.

Is Brain MRI Needed in Diagnostic Evaluation of Mild Intellectual Disability?

AIM: The purpose of our study was to suggest an imaging strategy and guidelines for the selection of the children with mild intellectual disability (ID) for magnetic resonance imaging (MRI), to avoid unnecessary imaging. METHODS: The brain MRIs and patient reports of 471 children were reviewed for the imaging findings and ID severity. The correlation between the clinical and brain MRI findings was analyzed in the 305 children with mild ID. RESULTS: Thirty-eight (12.5%) of the children with mild ID had significant abnormal brain MRI findings. Thirty-five of these had other neurological symptoms or diseases in addition to ID, which were an indication for brain MRI. In the logistic regression analysis, seizures (in patients without an epilepsy diagnosis), epilepsy, movement disorders, dysmorphia, encephalitis, traumatic brain injury, and abnormal head size were statistically significant symptoms or comorbidities associated with abnormal MRI findings. Only three children (1.0%) with mild ID had a significant MRI finding without any other clinical symptoms or disease. CONCLUSION: Routine MRI in children with mild ID without specific neurological symptoms, dysmorphic features, or related diseases is not suggested for revealing an etiology of mild ID. Since children with ID usually need to be sedated for MRI, routine imaging in the diagnostic evaluation of mild ID should be carefully considered. Clinical examination, other symptoms, and related diseases should be carefully assessed to decide the need for MRI.

Radiation-induced accelerated aging of the brain vasculature in young adult survivors of childhood brain tumors.

BACKGROUND: Cranial radiotherapy may damage the cerebral vasculature. The aim of this study was to understand the prevalence and risk factors of cerebrovascular disease (CVD) and white matter hyperintensities (WMHs) in childhood brain tumors (CBT) survivors treated with radiotherapy. METHODS: Seventy CBT survivors who received radiotherapy were enrolled in a cross-sectional study at a median 20 years after radiotherapy cessation. The prevalence of and risk factors for CVD were investigated using MRI, MRA, and laboratory testing. Tumors, their treatment, and stroke-related data were retrieved from patients' files. RESULTS: Forty-four individuals (63%) had CVD at a median age of 27 years (range, 16-43 years). The prevalence rates at 20 years for CVD, small-vessel disease, and large-vessel disease were 52%, 38%, and 16%, respectively. Ischemic infarcts were diagnosed in 6 survivors, and cerebral hemorrhage in 2. Lacunar infarcts were present in 7, periventricular or deep WMHs in 34 (49%), and mineralizing microangiopathy in 21 (30%) survivors. Multiple pathologies were detected in 44% of the participants, and most lesions were located in a high-dose radiation area. Higher blood pressure was associated with CVD and a presence of WMHs. Higher cholesterol levels increased the risk of ischemic infarcts and WMHs, and lower levels of high-density lipoprotein and higher waist circumference increased the risk of lacunar infarcts. CONCLUSIONS: Treating CBTs with radiotherapy increases the risk of early CVD and WMHs in young adult survivors. These results suggest an urgent need for investigating CVD prevention in CBT patients.

Homozygous TAF1C variants are associated with a novel childhood-onset neurological phenotype.

TATA-box binding protein associated factor, RNA polymerase I subunit C (TAF1C) is a component of selectivity factor 1 belonging to RNA polymerase I (Pol I) transcription machinery. We report two unrelated patients with homozygous TAF1C missense variants and an early onset neurological phenotype with severe global developmental delay. Clinical features included lack of speech and ambulation and epilepsy. MRI of the brain demonstrated widespread cerebral atrophy and frontal periventricular white matter hyperintensity. The phenotype resembled that of a previously described variant of UBTF, which encodes another transcription factor of Pol I. TAF1C variants were located in two conserved amino acid positions and were predicted to be deleterious. In patient-derived fibroblasts, TAF1C mRNA and protein expression levels were substantially reduced compared with healthy controls. We propose that the variants impairing TAF1C expression are likely pathogenic and relate to a novel neurological disease. This study expands the disease spectrum related to Pol I transcription machinery, associating the TAF1C missense variants with a severe neurological phenotype for the first time.

PLS3 Mutations Cause Severe Age and Sex-Related Spinal Pathology.

Objective: Mutations in the X-chromosomal PLS3-gene, encoding Plastin 3, lead to severe early-onset osteoporosis, suggesting a major role for PLS3 in bone metabolism. However, the consequences of abnormal PLS3 function in bone and other tissues remain incompletely characterized. This study evaluated spinal consequences of aberrant PLS3 function in patients with PLS3 mutations. Design: A cross-sectional cohort study with spinal magnetic resonance imaging of 15 PLS3 mutation-positive (age range 9-77 years) and 13 mutation-negative (9-70 years) subjects. Images were reviewed for spinal alignment, vertebral heights and morphology, intervertebral disc changes and possible endplate deterioration. Results: Vertebral changes were significantly more prevalent in the mutation-positive subjects compared with the mutation-negative subjects; they were most abundant in upper thoracic spine, and in all age groups and both sexes, although more prominent in males. Difference in anterior vertebral height reduction was most significant in T5 and T6 (p = 0.046 and p = 0.041, respectively). Mid-vertebral height reduction was most significant in T3 and T5 (p = 0.037 and p = 0.005, respectively), and, for male mutation-positive subjects only, in T4 and T6-10 (p = 0.005-0.030 for each vertebra). Most of the abnormal vertebrae were biconcave in shape but thoracic kyphosis or lumbar lordosis were unchanged. Vertebral endplates were well-preserved in the mutation-positive subjects with even fewer Schmorl nodes than the mutation-negative subjects (10 vs. 16). Conclusions: Compromised PLS3 function introduces severe and progressive changes to spinal structures that are present already in childhood, in both sexes and most abundant in upper thoracic spine. Cartilaginous structures are well-preserved.

Medulloblastoma, macrocephaly, and a pathogenic germline PTEN variant: Cause or coincidence?

BACKGROUND: Medulloblastomas (MBs) are a heterogeneous group of childhood brain tumors with four consensus subgroups, namely MBSHH , MBWNT , MBGroup 3 , and MBGroup 4 , representing the second most common type of pediatric brain cancer after high-grade gliomas. They suffer from a high prevalence of genetic predisposition with up to 20% of MBSHH caused by germline mutations in only six genes. However, the spectrum of germline mutations in MBSHH remains incomplete. METHODS: Comprehensive Next-Generation Sequencing panels of both tumor and patient blood samples were performed as molecular genetic characterization. The panels cover genes that are known to predispose to cancer. RESULTS: Here, we report on a patient with a pathogenic germline PTEN variant resulting in an early stop codon p.(Glu7Argfs*4) (ClinVar ID: 480383). The patient developed macrocephaly and MBSHH , but reached remission with current treatment protocols. CONCLUSIONS: We propose that pathogenic PTEN variants may predispose to medulloblastoma, and show that remission was reached with current treatment protocols. The PTEN gene should be included in the genetic testing provided to patients who develop medulloblastoma at an early age. We recommend brain magnetic resonance imaging upon an unexpected acceleration of growth of head circumference for pediatric patients harboring pathogenic germline PTEN variants.

NIV NAVA versus Nasal CPAP in Premature Infants: A Randomized Clinical Trial.

BACKGROUND: Noninvasive ventilation is recommended for neonatal respiratory distress to avoid adverse effects of invasive ventilation. OBJECTIVE: The aim of this study was to compare the feasibility of noninvasive neurally adjusted ventilatory assist (NIV NAVA) and continuous positive airway pressure (CPAP) in preterm newborn infants. METHODS: Forty preterm infants (gestational age 28+0 to 36+6 weeks) requiring CPAP and supplemental oxygen (FiO2 >0.23) for respiratory distress at <48 h of postnatal age were randomized to NIV NAVA or CPAP. The primary endpoint was the inspired oxygen concentration 12 h after study inclusion. Secondary endpoints were the duration of oxygen treatment, total duration of respiratory support, parenteral nutrition, blood gas values, patient comfort, need for invasive ventilation, and treatment complications. RESULTS: The mean FiO2 at the time of study inclusion was 0.29 in both groups. After 12 h of treatment, FiO2 was 0.26 ± 0.07 and 0.26 ± 0.04 in the NIV NAVA and CPAP groups, respectively (difference 0.006, 95% CI -0.4 to 0.5), with no difference between the groups during the course of noninvasive ventilation (p = 0.80). Seven patients (35%) in the NIV NAVA group and 10 (50%) in the control group required intubation (difference 15%, 95% CI -15.5 to 4.3, p = 0.36). Time to intubation, gas exchange, vital parameters, pain scale, treatment complications, and neonatal outcome did not differ between the groups. CONCLUSIONS: In the present trial, NIV NAVA had no statistically significant effect on oxygen requirements or the need for invasive ventilation in preterm newborn infants.

Radiation-Induced Meningiomas After Childhood Brain Tumor: A Magnetic Resonance Imaging Screening Study.

Purpose: Childhood brain tumors (CBTs) and their treatment increase the risk of secondary neoplasms (SNs). We studied the incidence of secondary craniospinal tumors with magnetic resonance imaging (MRI) screening in a national cohort of survivors of CBT treated with radiotherapy, and we analyzed the Finnish Cancer Registry (FCR) data on SNs in survivors of CBT with radiotherapy registered as a part of the primary tumor treatment. Methods: A total of 73 survivors of CBT participated in the MRI study (mean follow-up of 19 ± 6.2 years). The incidence of SNs in a cohort of CBT patients (N = 569) was retrieved from the FCR (mean follow-up of 11 ± 12.9 years). Brain tumors were diagnosed at age ≤16 years between the years 1970 and 2008 in the clinical study and the years 1963 and 2010 in the FCR population. Results: Secondary brain tumors, meningiomas in all and schwannoma in one, were found in 6 of the 73 (8.2%) survivors with a mean of 23 ± 4.3 years after the diagnosis of the primary tumor. The cumulative incidence was 10.2% (95% confidence interval [CI] 3.9-25.1) in 25 years of follow-up. In the FCR data, the 25-year cumulative incidence of SNs was 2.4% (95% CI 1.3-4.1); only two brain tumors, no meningiomas, were registered. Conclusion: Survivors of CBT treated with radiotherapy have a high incidence of meningiomas, which are rarely registered in the FCR.

Novel variants and phenotypes widen the phenotypic spectrum of GABRG2-related disorders.

PURPOSE: Next-generation sequencing (NGS) has made genetic testing of patients with epileptic encephalopathies easier - novel variants are discovered and new phenotypes described. Variants in the same gene - even the same variant - can cause different types of epilepsy and neurodevelopmental disorders. Our aim was to identify the genetic causes of epileptic encephalopathies in paediatric patients with complex phenotypes. METHODS: NGS was carried out for three patients with epileptic encephalopathies. Detailed clinical features, brain magnetic resonance imaging and electroencephalography were analysed. We searched the Human Gene Mutation Database for the published GABRG2 variants with clinical description of patients and composed a summary of the variants and their phenotypic features. RESULTS: We identified two novel de novo GABRG2 variants, p.P282T and p.S306F, with new phenotypes including neuroradiological evidence of neurodegeneration and epilepsy of infancy with migrating focal seizures (EIMFS). One patient carried previously reported p.P83S variant with autism spectrum disorder (ASD) phenotype that has not yet been described related to GABRG2 disorders and a more severe epilepsy phenotype than reported earlier. In all, the literature search yielded twenty-two articles describing 27 different variants that were divided into two categories: those with self-limiting epilepsies and febrile seizures and those with more severe drug-resistant epileptic encephalopathies. CONCLUSION: This study further expands the genotypic and phenotypic spectrum of epilepsies associated with GABRG2 variants. More knowledge is still needed about the influence of the environment, genetic background and other epilepsy susceptibility genes on the phenotype of the specific GABRG2 variants.

The radiological and clinical follow-up of osteonecrosis in cancer patients.

BACKGROUND: In patients with cancer, osteonecrosis (ON) lesions can affect multiple sites throughout the skeleton, including the long and short bones and the joints. The aims of this study were to explore the natural course of ON in patients treated for cancer by using radiological classification suitable for multisite ON lesions and to assess correlations between the ON grade and surgical procedures. MATERIAL AND METHODS: Data were retrieved from hospital databases on 233 ON lesions in 54 patients (aged 2-73 years at cancer diagnosis; mean age: 25 years). ONs were graded according to the Niinimäki classification, based on magnetic resonance images. Medical records were reviewed to identify surgical procedures. RESULTS: A total of 14 different ON sites were detected; the hip was the most common site (n = 51), followed by the femur (n = 45), tibia (n = 41) and knee (n = 37). Among the 233 ON lesions, 78.1% did not require surgical procedures. The remaining lesions required total joint arthroplasty (TJA; 40/233, 17.2%), core decompression (3.4%) and arthroscopy (1.3%). Most TJAs (33/40, 82.5%) were performed on the hip. ONs of the knee required TJAs only once; grade 3 knee ONs frequently healed (58%, 11/19). None of the diaphyseal or metaphyseal (grade 1-2) ONs of the long bones required surgery, and no fractures of those bones were identified. CONCLUSIONS: In conclusion, the natural history of ONs varied by the grade and site. Based on our findings, we would not recommend routine radiological follow-ups for grades 1-2 ON lesions that do not affect the joints, because the clinical consequences of those lesions appear to be minimal, although pain relief would be warranted. In contrast, joint deformations (grade 5) require surgery; therefore, intervention studies should focus on grades 3-4 ON lesions.

Late vertebral side effects in long-term survivors of irradiated childhood brain tumor.

PURPOSE: Long-term side effects of the treatments are common in survivors of irradiated pediatric brain tumors. Ionizing radiation in combination with surgery and chemotherapy during childhood may reduce vertebral height and bone mineral density (BMD), and cause growth failure. The aim of this study was to evaluate the late consequences of tumor treatments on vertebrae in survivors of childhood brain tumors. METHODS: 72 adult survivors (mean age 27.8 years, standard deviation 6.7) of irradiated childhood brain tumor were studied by spinal magnetic resonance imaging (MRI) for vertebral abnormalities from the national cohort of Finland. Patients were treated in five university hospitals in Finland between the years 1970 and 2008. Subject height and weight were measured and body mass index (BMI) was calculated. The morphology and height/depth ratio of the vertebrae in the middle of the kyphotic thoracic curvature (Th8) and lumbar lordosis (L3) were examined. Vertebrae were analyzed by Genant's semiquantative (SQ) method and spinal deformity index (SDI) was calculated. BMD was measured by using dual X-ray absorptiometry. RESULTS: 4.2% (3/72) of the patients had undiagnosed asymptomatic vertebral fracture and 5.6% (4/72) of patients had radiation-induced decreased vertebral body height. Male patients had flatter vertebrae compared with females. Patient age at the time of irradiation, BMI and irradiation area correlated to vertebral morphology differentially in males and females. BMD had no association with the vertebral shape. Patients who had received craniospinal irradiation were shorter than the general population. CONCLUSION: Childhood brain tumor survivors had a high number of vertebral abnormalities in young adulthood. Irradiation was associated with abnormal vertebral morphology and compromised final height. Male gender may predispose vertebrae to the side effects of irradiation.

Neonatal Alexander Disease: Novel GFAP Mutation and Comparison to Previously Published Cases.

Alexander disease (AxD) is a genetic leukodystrophy caused by GFAP mutations leading to astrocyte dysfunction. Neonatal AxD is a rare phenotype with onset in the first month of life. The proband, belonging to a large pedigree with dominantly inherited benign familial neonatal epilepsy (BFNE), had a phenotype distinct from the rest of the family, with hypotonia and macrocephaly in addition to drug-resistant neonatal seizures. The patient deteriorated and passed away at 6 weeks of age. The pathological and neuroimaging data were consistent with the diagnosis of AxD. Genetic analysis of the proband identified a novel de novo GFAP missense mutation and a KCNQ2 splice site mutation segregating with the BFNE phenotype in the family. The GFAP mutation was located in the coil 2B region of GFAP protein, similar to most neonatal-onset AxD cases with an early death. The clinical and neuroradiological features of the previously published neonatal AxD patients are presented. This study further supports the classification of neonatal-onset AxD as a distinct phenotype based on the age of onset.