Low skeletal muscle mass and liver fibrosis in children with cerebral palsy.

The purpose of the study was to conduct a nutritional and metabolic assessment of children with cerebral palsy, including an investigation of liver status, body composition, and bone mineral density. In this cross-sectional study we included 22 children with cerebral palsy. By using ultrasound, transient elastography, dual x-ray absorptiometry (DXA) scan, blood samples, anthropometric measurements, and a three-day diet registration, the nutritional and metabolic status was evaluated. Liver fibrosis and steatosis were found in four patients (18.2%), all with severe motor impairments, low skeletal muscle mass, and epilepsy. All patients with liver involvement had normal liver-related blood samples. Decreased bone mineral density was found in 26.3%, and 91.0% had low skeletal muscle mass. Fat mass and muscle mass were significantly lower in the patients with severe motor impairments compared to the patients with less severe motor impairments. Within the children classified as 'underweight' or 'normal' according to body mass index, body fat determined by DXA scan was normal or high in 50% of these patients. CONCLUSIONS: This study is the first to report liver fibrosis and steatosis in children with cerebral palsy. Possible causes of liver fibrosis and/or steatosis are altered body composition with low skeletal muscle mass, decreased mobility and medical drug intake. Further investigations of liver involvement and risk factors are needed. WHAT IS KNOWN: • Children and adolescents with cerebral palsy are at risk of malnutrition and altered body composition, both of which can lead to fatty liver disease. • It is unknown whether children with cerebral palsy are at increased risk of metabolic disturbances such as fatty liver disease. WHAT IS NEW: • Altered body composition and low skeletal muscle mass, regardless of ambulation is present in 91% of the children with cerebral palsy. • Liver fibrosis and/or steatosis were found in 18.2% of the patients. Possible causes are altered body composition, decreased mobility and medical drug intake.

Metabolic assessment in children with neuromuscular disorders shows risk of liver enlargement, steatosis and fibrosis.

AIM: The aim of this study was to conduct a metabolic and nutritional assessment of children with neuromuscular disorders, including the investigation of the liver and bone mineral density. METHODS: In this observational study, we included 44 children with neuromuscular disorders. The nutritional status, bone health and liver were assessed by ultrasound, transient elastography, dual X-ray absorptiometry scan, blood samples, anthropometric measurements and 3-day diet registration. RESULTS: Liver involvement was found in 31.0%: liver enlargement in 7.1%, steatosis in 4.8%, fibrosis in 14.3% and liver enlargement together with steatosis or fibrosis was found in 4.8%. These changes were found in 9/23 patients with Duchenne muscular dystrophy, 4/9 patients with spinal muscular atrophy type II and 0/12 patients with other neuromuscular diagnoses. Low bone mineral density was found in 44.0% of the patients, though the majority used daily vitamin D and calcium supplements. Vitamin D insufficiency or deficiency was found in 22.6%. CONCLUSION: The metabolic assessment in children with neuromuscular disorders shows an increased risk of liver enlargement, steatosis and fibrosis. Possible causes are obesity, decreased mobility, low skeletal muscle mass and for a subgroup the use of glucocorticoids. The findings suggest that monitoring liver function should be part of the nutritional assessment in patients with neuromuscular disorders.

Employment, health visits, mental health, and mortality in parents with a chronically ill child: a Danish nationwide population-based cohort study.

Chronic diseases in children can impact their parents; this may be overlooked in a clinical setting. Our aim was to investigate associations of chronic diseases in children with their parents' employment, health care utilization, mental health, and mortality. In a matched cohort study using nationwide and population-based data in Denmark, we included parents to children (< 18 years) with acute disseminated encephalomyelitis, multiple sclerosis, type 1 diabetes, inflammatory bowel disease, and rheumatoid arthritis/juvenile idiopathic arthritis during 2008-2015. The reference group was parents to unaffected children. Outcomes were parental employment (early retirement, cash benefits, income), health care utilization (e.g., general practitioner, or hospital visits), mental health (visits to psychiatry/psychology clinics, antidepressant drug redemptions), and mortality. We included 13,769 parents with a chronically ill child and 138,606 control parents. Annual income was unaffected for two-parent families after the child's disease onset, but two-parent families had increased hazard of early retirement of 25% (95% CI = 1.01-1.54; p = 0.04). Parents with a chronically ill child had (a) increased rate of antidepressant drug redemptions or psychology/psychiatry visits (hazard ratio 1.37; 95% CI = 1.28-1.46 at 1-year follow-up); (b) increased health care utilization, with an increased marginal mean in primary care of 1% (95% CI = 1.00-1.02; p = 0.005), hospital-affiliated visits of 19% (95% CI = 1.14-1.24; p < 0.0001), and hospital admissions of 14% (95% CI = 1.09-1.20; p < 0.0001); and (c) 69% increased mortality hazard (95% CI = 1.30-2.18; p < 0.0001) in parents younger than 50 years with no comorbidities, albeit small in absolute numbers. CONCLUSION: Pediatric chronic diseases were negatively associated with parental employment, mental health, and mortality, and increased health care utilization. WHAT IS KNOWN: • Studies on the impact of pediatric chronic diseases on parental health are qualitative. • Knowledge is unavailable regarding the impact on parental work, health care utilization, and mortality. WHAT IS NEW: • Among 13,769 parents with a chronically ill child and 138,606 control parents, parents with a chronically ill child had 37% increased antidepressant drug redemptions, and these parents <50 years without comorbidities had 69% increased mortality hazard. • Medical doctors should consider the parental health condition and societal challenges related to having child with a chronic disease.

Infections seem to be more frequent before onset of pediatric multiple sclerosis: A Danish nationwide nested case-control study.

BACKGROUND: Infections are suspected environmental triggers for multiple sclerosis (MS). The relationship between the timing and cumulative number of childhood infections regarding pediatric MS risk is uninvestigated. OBJECTIVES: To investigate whether childhood infections contribute to pediatric MS. METHODS: A nationwide nested case-control study with detailed MS case ascertainment including chart review was undertaken. For each MS case, we selected five control children using density sampling from the entire Danish population, matching controls to children with MS by sex and birthdate. We analyzed data with the cumulative number of childhood infections as exposure and MS as outcome. Hazard ratios (HRs) including 95% confidence intervals (CIs) were estimated using Cox regression. RESULTS: We identified 212 children with MS and 1,060 controls. Median age at MS onset was 15.3 years (range: 7.6-17.8 years); 72% were girls. Each infection during the preceding 3 years increased the hazard for MS by 11% (95% CI = 1.01-1.22, p = 0.04); having 5+ infections compared with 0-4 infections in the preceding 3 years doubled the hazard for MS (HR: 2.18; 95% CI = 1.12-4.30, p = 0.02). CONCLUSION: Children with MS appeared to have more infections in the 3 years preceding MS clinical onset; accordingly, immune response to infections may influence MS pathogenesis.

Children with dyskinetic cerebral palsy are severely affected as compared to bilateral spastic cerebral palsy.

AIM: We aimed at describing clinical findings in children with dyskinetic as compared to bilateral spastic cerebral palsy (CP). METHODS: Data were extracted from the Danish nationwide CP register. Participants were born in 1999-2007 and were 5-6 years at ascertainment. RESULTS: The total number of CP cases was 1165 of which 92 had dyskinetic and 540 bilateral spastic CP. Prevalence of dyskinetic CP was 0.16 per 1000 live births. In participants with dyskinetic compared to bilateral spastic CP, there was more frequently an Apgar level less than five at five minutes (22.7% vs. 11.2%) and neonatal seizures (43.5% vs. 28.5%), but less respiratory deficiency, hyperbilirubinaemia and sepsis. Impairment based on gross motor function classification was more severe in dyskinetic CP (level III-V 90.0% vs. 66.0%). In dyskinetic CP, there was a high rate of reduced developmental quotient (68.1%), visual impairment (39.3%) and epilepsy (51.6%). Basal ganglia lesions were more prevalent in dyskinetic compared to bilateral spastic CP (27.7% vs. 12.8%). CONCLUSION: Cases of dyskinetic CP had overlapping clinical features with cases of bilateral spastic CP, but differed significantly in several perinatal risk factors. The children with dyskinetic CP had experienced more peri- or neonatal adverse events, and neurodevelopmental impairment was severe.

Pediatric-onset multiple sclerosis and other acquired demyelinating syndromes of the central nervous system in Denmark during 1977-2015: A nationwide population-based incidence study.

BACKGROUND: The incidence of acquired demyelinating syndromes (ADS) including multiple sclerosis (MS) has never been investigated in a Danish pediatric population. OBJECTIVES: We estimated the nationwide age- and sex-specific incidence of pediatric ADS including MS. METHODS: Data were sourced from the Danish Multiple Sclerosis Registry, providing cases of pediatric MS for 1977-2015, and the National Patient Register, providing cases of ADS during 2008-2015. All medical records were reviewed to validate the register-based diagnoses. RESULTS: We identified 364 cases of pediatric MS occurring during 1977-2015 (incidence rate = 0.79 per 100,000 person-years). MS was exceptionally rare before puberty, but the incidence rose considerably from 9 years in girls and 11 years in boys. The female-to-male ratio was 2.5; the median age at onset was 16 years (range = 7-17 years). The MS incidence rate was relatively stable through the study period. During 2008-2015, we identified 219 ADS cases. The incidence was 2.29 per 100,000 person-years with considerable differences in the age peaks for the separate ADS. CONCLUSION: The incidence rates of MS and other ADS in Denmark were higher than those reported for some other European countries. Referral bias and classification differences may account for this disparity, in particular the age-intervals and the definition of onset.

Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients.

BACKGROUND: The encephalomyopathic mtDNA depletion syndrome with methylmalonic aciduria is associated with deficiency of succinate-CoA ligase, caused by mutations in SUCLA2 or SUCLG1. We report here 25 new patients with succinate-CoA ligase deficiency, and review the clinical and molecular findings in these and 46 previously reported patients. PATIENTS AND RESULTS: Of the 71 patients, 50 had SUCLA2 mutations and 21 had SUCLG1 mutations. In the newly-reported 20 SUCLA2 patients we found 16 different mutations, of which nine were novel: two large gene deletions, a 1 bp duplication, two 1 bp deletions, a 3 bp insertion, a nonsense mutation and two missense mutations. In the newly-reported SUCLG1 patients, five missense mutations were identified, of which two were novel. The median onset of symptoms was two months for patients with SUCLA2 mutations and at birth for SUCLG1 patients. Median survival was 20 years for SUCLA2 and 20 months for SUCLG1. Notable clinical differences between the two groups were hepatopathy, found in 38% of SUCLG1 cases but not in SUCLA2 cases, and hypertrophic cardiomyopathy which was not reported in SUCLA2 patients, but documented in 14% of cases with SUCLG1 mutations. Long survival, to age 20 years or older, was reported in 12% of SUCLA2 and in 10% of SUCLG1 patients. The most frequent abnormality on neuroimaging was basal ganglia involvement, found in 69% of SUCLA2 and 80% of SUCLG1 patients. Analysis of respiratory chain enzyme activities in muscle generally showed a combined deficiency of complexes I and IV, but normal histological and biochemical findings in muscle did not preclude a diagnosis of succinate-CoA ligase deficiency. In five patients, the urinary excretion of methylmalonic acid was only marginally elevated, whereas elevated plasma methylmalonic acid was consistently found. CONCLUSIONS: To our knowledge, this is the largest study of patients with SUCLA2 and SUCLG1 deficiency. The most important findings were a significantly longer survival in patients with SUCLA2 mutations compared to SUCLG1 mutations and a trend towards longer survival in patients with missense mutations compared to loss-of-function mutations. Hypertrophic cardiomyopathy and liver involvement was exclusively found in patients with SUCLG1 mutations, whereas epilepsy was much more frequent in patients with SUCLA2 mutations compared to patients with SUCLG1 mutations. The mutation analysis revealed a number of novel mutations, including a homozygous deletion of the entire SUCLA2 gene, and we found evidence of two founder mutations in the Scandinavian population, in addition to the known SUCLA2 founder mutation in the Faroe Islands.

Mutations in COA3 cause isolated complex IV deficiency associated with neuropathy, exercise intolerance, obesity, and short stature.

BACKGROUND: We investigated a subject with an isolated cytochrome c oxidase (COX) deficiency presenting with an unusual phenotype characterised by neuropathy, exercise intolerance, obesity, and short stature. METHODS AND RESULTS: Blue-native polyacrylamide gel electrophoresis (BN-PAGE) analysis showed an almost complete lack of COX assembly in subject fibroblasts, consistent with the very low enzymatic activity, and pulse-labelling mitochondrial translation experiments showed a specific decrease in synthesis of the COX1 subunit, the core catalytic subunit that nucleates assembly of the holoenzyme. Whole exome sequencing identified compound heterozygous mutations (c.199dupC, c.215A>G) in COA3, a small inner membrane COX assembly factor, resulting in a pronounced decrease in the steady-state levels of COA3 protein. Retroviral expression of a wild-type COA3 cDNA completely rescued the COX assembly and mitochondrial translation defects, confirming the pathogenicity of the mutations, and resulted in increased steady-state levels of COX1 in control cells, demonstrating a role for COA3 in the stabilisation of this subunit. COA3 exists in an early COX assembly complex that contains COX1 and other COX assembly factors including COX14 (C12orf62), another single pass transmembrane protein that also plays a role in coupling COX1 synthesis with holoenzyme assembly. Immunoblot analysis showed that COX14 was undetectable in COA3 subject fibroblasts, and that COA3 was undetectable in fibroblasts from a COX14 subject, demonstrating the interdependence of these two COX assembly factors. CONCLUSIONS: The mild clinical course in this patient contrasts with nearly all other cases of severe COX assembly defects that are usually fatal early in life, and underscores the marked tissue-specific involvement in mitochondrial diseases.

LAMA2-related myopathy: Frequency among congenital and limb-girdle muscular dystrophies.

INTRODUCTION: Muscular dystrophy caused by LAMA2-gene mutations is an autosomal recessive disease typically presenting as a severe, early-onset congenital muscular dystrophy (CMD). However, milder cases with a limb-girdle type muscular dystrophy (LGMD) have been described. METHODS: In this study, we assessed the frequency and phenotypic spectrum of LAMA2-related muscular dystrophy in CMD (n = 18) and LGMD2 (n = 128) cohorts identified in the last 15 years in eastern Denmark. The medical history, brain-MRI, muscle pathology, muscle laminin-α2 expression, and genetic analyses were assessed. RESULTS: Molecular genetics revealed 2 pathogenic LAMA2 mutations in 5 of 18 CMD and 3 of 128 LGMD patients, corresponding to a LAMA2-mutation frequency of 28% in the CMD and 2.3% in the LGMD cohorts, respectively. CONCLUSIONS: This study demonstrates a wide clinical spectrum of LAMA2-related muscular dystrophy and its prevalence in an LGMD2 cohort, which indicates that LAMA2 muscular dystrophy should be included in the LGMD2 nomenclature.

Children and adolescents previously treated with glucocorticoids display lower verbal intellectual abilities.

AIM: Perinatal exposure to glucocorticoids has been associated with adverse cerebral effects, but little is known about their effect on cognitive development and exposure later in childhood. This study examined intellectual abilities, memory and behavioural problems in children previously treated with glucocorticoids. METHODS: We evaluated 38 children aged from seven to 16 years, who had been treated with glucocorticoids for rheumatic disease or nephrotic syndrome, together with 42 healthy controls matched for age, gender and parental education. The median cumulative dose of prednisolone equivalents was 158 mg/kg (range 21-723) and the mean time that had elapsed since treatment was three-and-a-half (standard deviation 2.2) years. Intellectual abilities were assessed with the Wechsler Intelligence Scale for Children and memory performance and behavioural problems with a pattern recognition memory task and the Child Behaviour Check List. RESULTS: There were no significant differences between the groups in pattern recognition memory, perceptual organisation index or behavioural problems, but patients had a significantly lower verbal comprehension index and this difference was present in both disease groups. There were no significant dose-response relationships regarding verbal intellectual abilities. CONCLUSION: Children and adolescents previously treated with glucocorticoids seemed to have lower intellectual verbal abilities than healthy controls.

Infrastructuring precision medicine: Making gene therapies for rare diseases workable in practice.

Long viewed by social scientists as a future imaginary, precision medicine is now materializing in many healthcare systems in the form of new diagnostic practices and novel treatment modalities, such as gene therapies. Based on an ethnographic study of the introduction of the first two clinically available in-vivo gene therapies in the Danish healthcare system, we investigate what it takes to make these therapies workable in practice. Drawing on social science literature on infrastructuring, we describe the many forms of mundane work required to fit these therapies into regulatory frameworks, political processes and daily work practices in the healthcare system. Further, we observe how the processes of infrastructuring required to introduce the gene therapies into clinical practice had transformative implications as they redistributed roles and responsibilities among clinicians, pharmacists, procurement agencies and pharmaceutical manufacturers.

Burden of Disease of Duchenne Muscular Dystrophy in Denmark - A National Register-Based Study of Individuals with Duchenne Muscular Dystrophy and their Closest Relatives.

Background: Duchenne Muscular Dystrophy (DMD) is a progressive genetic disease with a prevalence of 1 per 3,600-6,000 male births. Individuals with DMD are typically diagnosed at age 4-7 years; median survival is 30 years. They require multidisciplinary care, personal assistance, and often special education. Objective: The aim was to assess the burden of disease in DMD in Denmark. This includes incidence, prevalence, use of healthcare services, labour market participation, educational outcomes, and overall attributable costs due to DMD. Impact on the closest relatives (siblings and parents) was also investigated. Methods: The comprehensive Danish national health and administrative registers were used to assess the burden of disease following individuals with DMD and closest relatives from five years before, and up to 20 years after DMD diagnosis. Individuals with DMD (and relatives) from 1994-2021 were included. All outcomes were compared to matched control groups without the disease drawn from the Danish population. Results: 213 unique individuals with DMD were identified. They had lower grades in school, required more special education and more healthcare and home care compared to their control group. The extra costs of special education summed to EUR 180,900 over the course of 11 years elementary school. They had an annual average productivity loss of EUR 20,200 between the age of 18 to 30. The extra healthcare costs of DMD in the 20 years after diagnosis were estimated to EUR 1,524,000. If an individual with DMD lives to be 30, total extra costs sum to EUR 2,365,800. Conclusions: Using national register data this study presented detailed results on the burden of disease of DMD, including impact on closest relatives. With 60 additional hospital admissions and 200 extra outpatient contacts in 20 years healthcare costs, but also costs of home care and special education, increases as disease progresses.

Acetaminophen treatment in children and adults with spinal muscular atrophy: a lower tolerance and higher risk of hepatotoxicity.

Acute liver failure has been reported sporadically in patients with spinal muscular atrophy (SMA) and other neuromuscular disorders with low skeletal muscle mass receiving recommended dosages of acetaminophen. It is suggested that low skeletal muscle mass may add to the risk of toxicity. We aimed to describe the pharmacokinetics and safety of acetaminophen in patients with SMA. We analyzed acetaminophen metabolites and liver biomarkers in plasma from SMA patients and healthy controls (HC) every hour for six or eight hours on day 1 and day 3 of treatment with therapeutic doses of acetaminophen. Twelve patients with SMA (six adults and six children) and 11 HC participated in the study. Adult patients with SMA had significantly lower clearance of acetaminophen compared to HC (14.1 L/h vs. 21.5 L/h). Formation clearance of acetaminophen metabolites, glucuronide, sulfate, and oxidative metabolites were two-fold lower in the patients compared to HC. The liver transaminases and microRNAs increased nine-fold in one adult SMA patient after two days of treatment. The other patients and HC did not develop abnormal liver biomarkers. In this study, patients with SMA had lower clearance and slower metabolism of acetaminophen, and one patient developed liver involvement. We recommend giving 15 mg/kg/dose to SMA adults (with a maximum of 4000 mg/day) and monitoring standard liver biomarkers 48 h after first-time treatment of acetaminophen.

Homozygous splice variant (c.1741-6G>A) of the COL6A1 gene in three patients with Ullrich congenital muscular dystrophy.

The three major collagen VI genes: COL6A1, COL6A2, and COL6A3 encode microfibrillar components of extracellular matrices in multiple tissues including muscles and tendons. Pathogenic variants in the collagen VI genes cause collagen VI-related dystrophies representing a continuum of conditions from Bethlem myopathy at the milder end to Ullrich congenital muscular dystrophy at the more severe end. Here we describe a pathogenic variant in the COL6A1 gene (NM_001848.3; c.1741-6G>A) found in homozygosity in three patients with Ullrich congenital muscular dystrophy. The patients suffered from severe muscle impairment characterised by proximal weakness, distal hyperlaxity, joint contractures, wheelchair-dependency, and use of nocturnal non-invasive ventilation. The pathogenicity was verified by RNA analyses showing that the variant induced aberrant splicing leading to a frameshift and loss of function. The analyses were in line with immunocytochemistry studies of patient-derived skin fibroblasts and muscle tissue demonstrating impaired secretion of collagen VI into the extracellular matrix. Thereby, we add the variant c.1741-6G>A to the list of pathogenic, recessive, splice variants in COL6A1 causing Ullrich congenital muscular dystrophy. The variant is listed in ClinVar as of "uncertain significance" and "likely benign" and may presumably have been overlooked in other patients.

Nonpharmacological Interventions to Reduce Sedation and General Anesthesia in Pediatric MRI: A Meta-analysis.

CONTEXT: Nonpharmacological strategies are increasingly used in pediatric procedures, but in pediatric MRI, sedation and general anesthesia are still commonly required. OBJECTIVES: To evaluate the effectiveness of nonpharmacological interventions in reducing use of sedation and general anesthesia in pediatric patients undergoing MRI, and to investigate effects on scan time, image quality, and anxiety. DATA SOURCES: We searched Ovid Medline, CINAHL, Embase, and CENTRAL from inception through October 10, 2022. STUDY SELECTION: We included randomized controlled trials and quasi-experimental designs comparing the effect of a nonpharmacological intervention with standard care on use of sedation or general anesthesia, scan time, image quality, or child and parental anxiety among infants (<2 years), children, and adolescents (2-18 years) undergoing MRI. DATA EXTRACTION: Standardized instruments were used to extract data and assess study quality. RESULTS: Forty-six studies were eligible for the systematic review. Limited to studies on children and adolescents, the meta-analysis included 20 studies with 33 873 patients. Intervention versus comparator analysis showed that nonpharmacological interventions were associated with reduced need for sedation and general anesthesia in the randomized control trials (risk ratio, 0.68; 95% confidence interval, 0.48-0.95; l2 = 35%) and nonrandomized studies (risk ratio, 0.58; 95% confidence interval, 0.51-0.66; l2 = 91%). The effect was largest among children aged 3 to 10 years when compared with older children and adolescents aged 11 to 18 years. LIMITATIONS: There was substantial heterogeneity among nonrandomized studies. CONCLUSIONS: Nonpharmacological interventions must be considered as standard procedure in infants, children, and adolescents undergoing MRI.

School performance and psychiatric comorbidity in childhood absence epilepsy: A Danish cohort study.

The aim was to determine school performance and psychiatric comorbidity in children with childhood absence epilepsy (CAE). We reviewed the medical records in children with ICD-10 codes for idiopathic generalized epilepsy before 18 years of age, and pediatric neurologists confirmed the International League Against Epilepsy criteria for CAE were met. Control groups were the general pediatric population or children with non-neurological chronic disease. Outcomes were from nationwide and population-based registers on school performance and psychiatric comorbidity. We compared the mean grade point average using linear regression and estimated hazard ratios (HR) using Cox regression for the other outcomes. Analyses were adjusted for the child's sex, and year of birth, and parental highest education, receipt of cash benefits or early disability pension. We included 114 children with CAE with a median age at onset of 5.9 years (interquartile range = 4.5-7.3 years). Compared with both population controls and non-neurological chronically ill children, children with CAE had increased hazard of special needs education (HR = 2.7, 95% confidence interval (CI) = 1.8-4.1, p < 0.0001), lower grade point average at 9th grade by 1.7 grade points (95% CI = -2.5 to -1.0, p < 0.001), increased ADHD medicine use (HR = 4.4, 95% CI = 2.7-7.2, p < 0.001), increased sleep medicine use (HR = 2.7, 95% CI = 1.7-4.3, p < 0.001), and increased psychiatry visits (HR = 2.1, 95% CI = 1.1-4.0, p = 0.03). In conclusion, children with CAE have increased psychiatric comorbidity and a considerable proportion of these children receive special needs education in primary/secondary school, albeit insufficient to normalize their considerably lower grade point average in the 9th grade.

A novel RNASEH2B splice site mutation responsible for Aicardi-Goutieres syndrome in the Faroe Islands.

AIM: The aim of the study was to identify the genetic background for Aicardi-Goutieres syndrome (AGS) in the Faroe Islands. METHODS: Four patients with AGS were identified. The patients had a variable phenotype, from a severe prenatal form with intrauterine foetal death to a milder phenotype, albeit still with an early onset, within the first 2-3 months. RESULTS: A genome-wide search for homozygosity revealed one single 15.6 Mb region of homozygosity on chromosome 13, which included RNASEH2B, where a splice site mutation c.322-3C>G was identified. Screening of 170 anonymous Faroese controls revealed a carrier frequency of approximately 1.8%, corresponding to an incidence of AGS in the Faroe Islands of around 1 in 12,300. CONCLUSION: The previously identified RNASEH2B mutations comprise altogether 20 mutations (missense, nonsense and splice site) with all patients harbouring at least one missense mutation. The severe phenotype of the Faroese patients compared with the previously reported patients with RNASEH2B mutations may be caused by the presence of two null alleles (although some residual normal splicing cannot be ruled out), whereas patients with one or two missense mutations may have some, albeit abnormal, RNASEH2B proteins, and hence some residual activity of RNASEH2B, explaining their milder phenotype.

Validation of Pediatric Idiopathic Generalized Epilepsy Diagnoses from the Danish National Patient Register During 1994‒2019.

Objective: To identify pediatric idiopathic generalized epilepsy (IGE) during 1994-2019 using ICD-10 codes in the Danish National Patient Register and anti-seizure prescriptions in the Danish Prescription Database. Study Design and Setting: We reviewed the medical records in children with ICD-10 codes for IGE before 18 years of age, and pediatric neurologists confirmed that the International League Against Epilepsy criteria were met. We estimated positive predictive values (PPV) and sensitivity for ICD-10 alone, including combinations of codes, anti-seizure prescription, and age at first code registration using medical record-validated diagnoses as gold standard. Results: We validated the medical record in 969 children with an ICD-10 code of IGE, and 431 children had IGE (115 childhood absence epilepsy, 97 juvenile absence epilepsy, 192 juvenile myoclonic epilepsy, 27 generalized tonic-clonic seizures alone). By combining ICD-10 codes with antiseizure prescription and age at epilepsy code registration, we found a PPV for childhood absence epilepsy at 44% (95% confidence interval [CI]=34%‒54%) and for juvenile absence epilepsy at 44% (95% CI=36%-52%). However, ethosuximide prescription, age at ethosuximide code registration before age 8 years and a combination of ICD-10 codes yielded a PPV of 59% (95% CI=42%‒75%) for childhood absence epilepsy but the sensitivity was only 17% (20/115 children identified). For juvenile myoclonic epilepsy the highest PPV was 68% (95% CI=62%‒74%) using the code G40.3F plus antiseizure prescription and age at epilepsy code registration after age 8 years, with sensitivity of 85% (164/192 children identified). For generalized tonic-clonic seizures alone the highest PPV was 31% (95% CI=15%‒51%) using G40.3G during 2006-2019 plus antiseizure prescription and age at code registration after age 5 years. Conclusion: The Danish National Patient Register and the Danish Prescription Database are not suitable for identifying children with IGE subtypes, except for juvenile myoclonic epilepsy which can be identified with caution.

School performance and psychiatric comorbidity in juvenile absence epilepsy and juvenile myoclonic epilepsy: a Danish population-based cohort study.

BACKGROUND: We aimed to determine school performance and psychiatric comorbidity in juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and generalized tonic-clonic seizures (GTCS) alone. METHODS: All children (< 18 years) fulfilled International League Against Epilepsy criteria after review of their medical records. Control groups were the pediatric background population or children with non-neurological chronic disease. Outcomes were on school performance and psychiatric comorbidity. We compared mean grade point averages using linear regression and estimated hazard ratios using Cox regression in the remaining analyses. We adjusted for the child's sex, age, and year of birth; and parental highest education, receipt of cash benefits or early retirement. RESULTS: We included 92 JAE, 190 JME, 27 GTCS alone, 15,084 non-neurological chronic disease controls, and population controls. JAE had two times increased hazard for special needs education compared with age-matched population controls (hazard ratio 2.2, 95% CI = 1.1‒4.6, p = 0.03); this was not seen in JME. Compared with population controls, both JAE and JME had lower grade point average in secondary and high school (JME: 9th grade: - 0.5 points, 95% CI = -0.9 to -0.06, p = 0.03; high school: - 0.6 points, 95% CI = -1.3 to -0.1, p = 0.04), and 8% fewer JME and 15% fewer JAE attended high school. Both JME and JAE had higher hazard for redeeming sleep medication compared with non-neurological chronic disease; additionally, JAE had increased hazard for ADHD medicine redemptions. CONCLUSIONS: Both JAE and JME had marginally poorer school performance; performance seemed worse in JAE than in JME. Both JAE and JME had increased use of sleep medication.