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.

Ryanodine receptor 1 related myasthenia like myopathy responsive to pyridostigmine.

Disease causing variants in the Ryanodine receptor 1 (RYR1) gene are a common cause for congenital myopathy and for malignant hyperthermia susceptibility. We report a 17 year old boy with congenital muscle weakness progressing to a myasthenia like myopathy with muscle weakness, fatigability, ptosis, and ophthalmoplegia. Muscle biopsy showed predominance and atrophy of type 1 fibers. Whole-exome trio sequencing revealed three variants in the RYR1-gene in the patient: c.6721C > T,p.(Arg2241*) and c.2122G > A,p.(Asp708Asn) in cis position, and the c.325C > T,p.(Arg109Trp) variant in trans. Treatment with pyridostigmine improved symptoms. This case supports that a myasthenia like phenotype is part of the phenotypic spectrum of RYR1 related disorders, and that treatment with pyridostigmine can be beneficial for patients with this phenotype.

Mono-allelic loss of YTHDF3 and neurodevelopmental disorder: clinical features of four individuals with 8q12.3 deletions.

The YTH domain family member 3 gene (YTHDF3) encodes a reader of the abundant N6-methyladenosine (m6 A) modification of eukaryotic mRNA, which plays an essential role in regulating mRNA stability and is necessary to achieve normal development of the central nervous system in animal models. YTHDF3 has not previously been implicated in Mendelian disease despite a high probability of loss of function intolerance and statistical evidence of enrichment for gene-disruptive de novo variants in large-scale studies of individuals with intellectual disability and/or developmental delay. We report four individuals with deletion of 8q12.3, deletion size 1.38-2.60 Mb, encompassing YTHDF3, three of them were de novo, and in one case, the inheritance was unknown. Common features of the individuals (age range, 4-22 years) were developmental delay and/or intellectual disability. Two individuals underwent squint surgery. We suggest that haploinsufficiency of YTHDF3 causes a neurodevelopmental disorder with developmental delay and intellectual disability of variable degree.

Phenotypic heterogeneity and mosaicism in Xia-Gibbs syndrome: Five Danish patients with novel variants in AHDC1.

Xia-Gibbs syndrome (XGS) is a neurodevelopmental disorder characterized by intellectual disability, developmental delay, seizures, hypotonia, obstructive sleep apnoea and mild facial dysmorphism. Heterozygosity for loss-of-function variants in AHDC1, encoding the AT-hook DNA binding motif containing protein 1, were discovered in 2014 as the likely genetic cause of Xia-Gibbs syndrome. We present five patients with Xia-Gibbs syndrome caused by previously unreported variants in AHDC1. Two of the patients share a frameshift variant: c.2849del (p.(Pro950Argfs*192)) in AHDC1. Despite sharing this variant, the two patients show remarkable phenotypic differences underscoring the clinical heterogeneity of Xia-Gibbs syndrome. In addition, we present a case of Xia-Gibbs syndrome caused by mosaicism for an AHDC1 variant.

Parents' Assessment of Disability in Their Children With Down Syndrome.

AIM: To describe a population of children with Down syndrome and evaluate their parents' assessment of disability. METHODS: Medical records of a population of 80 children with Down syndrome aged 5 to 17 years were analyzed for genetic background and associated diagnoses. And 27 parents to their children agreed to assess disability by employing a set of 26 International Classification of Functioning, Disability and Health body function (b) codes and activity and participation (d) codes. Clinical data were gathered and analysis of parents' assessment of disability using psychometric and Rasch analysis was performed. RESULTS: Clinical data on 27 children assessed by their parents and 53 children not assessed had identical associated diagnoses. The 26 International Classification of Functioning, Disability and Health codes and qualifiers had a mean score of 2.67 (range 1.26-4.11) and corrected code-total correlations mean of 0.55 (range -1.17 to 0.82). Rasch analysis showed proper code MNSQ infit and outfit values with mean 1.03 and 1.06. CONCLUSION: Clinical data on 27 children assessed were similar to 53 children that were not evaluated. Parents' assessment of the 27 children showed good psychometric and Rasch analysis properties. Similar results might be expected in the total population of 80 children.

Is MED13L-related intellectual disability a recognizable syndrome?

INTRODUCTION: MED13L-related intellectual disability is characterized by moderate intellectual disability (ID), speech impairment, and dysmorphic facial features. We present 8 patients with MED13L-related intellectual disability and review the literature for phenotypical and genetic aspects of previously described patients. MATERIALS AND METHODS: In the search for genetic aberrations in individuals with ID, two of the patients were identified by chromosomal microarray analysis, and five by exome sequencing. One of the individuals, suspected of MED13L-related intellectual disability, based on clinical features, was identified by Sanger sequencing. RESULTS: All 8 individuals had de novo MED13L aberrations, including two intragenic microdeletions, two frameshift, three nonsense variants, and one missense variant. Phenotypically, they all had intellectual disability, speech and motor delay, and features of the mouth (open mouth appearance, macroglossia, and/or macrostomia). Two individuals were diagnosed with autism, and one had autistic features. One had complex congenital heart defect, and one had persistent foramen ovale. The literature was reviewed with respect to clinical and dysmorphic features, and genetic aberrations. CONCLUSIONS: Even if most clinical features of MED13L-related intellectual disability are rather non-specific, the syndrome may be suspected in some individuals based on the association of developmental delay, speech impairment, bulbous nasal tip, and macroglossia, macrostomia, or open mouth appearance.

Parents' Expressions of Concerns and Hopes for the Future and Their Concomitant Assessments of Disability in Their Children.

AIM: To assess parents' ability to express their concerns and hopes for the future in their children with disability and assess their children's disability as well as to analyse these data for consistency. METHOD: Parents of 162 children with spina bifida, spinal muscular atrophy, muscular disorders, cerebral palsy, visual impairment, hearing impairment, mental disability, or disability following brain tumours were asked to freely express their concerns and hopes for the future and to assess disability in their own children by employing a set of 26 International Classification of Functioning, Disability and Health, Children and Youth Version (ICF-CY) body function (b) codes and activity and participation (d) codes. A grounded theory approach was employed to systematize parents' expressions of concerns and hopes; then, parents scored qualifiers on a 5-step qualitative Likert scale. Parents assessed their children's disability in the same way using the ICF-CY 5-step qualifier scale. RESULTS: Altogether, 119 parents freely expressed their concerns and hopes, and 101 of them also assessed their children's disability using the 26 ICF-CY codes. A total of 475 expressions of concern and hopes (issues) were expressed and categorized into 34 areas of concern and hopes (subsections). The most frequently mentioned issues were education; understanding, goodwill, and communication between parents; and community support. Qualitative data on both 5-step qualifier scales showed good reliability. Rasch analysis maps on concerns and hopes for children as well as on the ICF-CY assessment demonstrated good alignment and a clinically relevant progression from the least to the most disabled children. CONCLUSION: Parents can express valid and reliable data on their concerns and hopes for the future and can reliably assess disability in their own children.

Parents' Assessments of Disability in Their Children Using World Health Organization International Classification of Functioning, Disability and Health, Child and Youth Version Joined Body Functions and Activity Codes Related to Everyday Life.

AIM: To help parents assess disability in their own children using World Health Organization (WHO) International Classification of Functioning, Disability and Health, Child and Youth Version (ICF-CY) code qualifier scoring and to assess the validity and reliability of the data sets obtained. METHOD: Parents of 162 children with spina bifida, spinal muscular atrophy, muscular disorders, cerebral palsy, visual impairment, hearing impairment, mental disability, or disability following brain tumours performed scoring for 26 body functions qualifiers (b codes) and activities and participation qualifiers (d codes). Scoring was repeated after 6 months. Psychometric and Rasch data analysis was undertaken. RESULTS: The initial and repeated data had Cronbach α of 0.96 and 0.97, respectively. Inter-code correlation was 0.54 (range: 0.23-0.91) and 0.76 (range: 0.20-0.92). The corrected code-total correlations were 0.72 (range: 0.49-0.83) and 0.75 (range: 0.50-0.87). When repeated, the ICF-CY code qualifier scoring showed a correlation R of 0.90. Rasch analysis of the selected ICF-CY code data demonstrated a mean measure of 0.00 and 0.00, respectively. Code qualifier infit mean square (MNSQ) had a mean of 1.01 and 1.00. The mean corresponding outfit MNSQ was 1.05 and 1.01. The ICF-CY code τ thresholds and category measures were continuous when assessed and reassessed by parents. Participating children had a mean of 56 codes scores (range: 26-130) before and a mean of 55.9 scores (range: 25-125) after repeat. Corresponding measures were -1.10 (range: -5.31 to 5.25) and -1.11 (range: -5.42 to 5.36), respectively. Based on measures obtained at the 2 occasions, the correlation coefficient R was 0.84. The child code map showed coherence of ICF-CY codes at each level. There was continuity in covering the range across disabilities. And, first and foremost, the distribution of codes reflexed a true continuity in disability with codes for motor functions activated first, then codes for cognitive functions, and, finally, codes for more complex functions. CONCLUSIONS: Parents can assess their own children in a valid and reliable way, and if the WHO ICF-CY second-level code data set is functioning in a clinically sound way, it can be employed as a tool for identifying the severity of disabilities and for monitoring changes in those disabilities over time. The ICF-CY codes selected in this study might be one cornerstone in forming a national or even international generic set of ICF-CY codes for the benefit of children with disabilities, their parents, and caregivers and for the whole community supporting with children with disabilities on a daily and perpetual basis.

Environmental needs in childhood disability analysed by the WHO ICF, Child and Youth Version.

INTRODUCTION: The WHO has launched a common classification for disabilities in children, the International Classification of Functioning, Disability and Health, Child and Youth Version (ICF-CY). We wanted to determine whether cat-egories of the environmental (e) and the body functions (b) components of the classification could address environmental needs in children with different disorders and various disability severities. METHODS: A set of 16 e categories and 47 b categories were selected and worded to best enable parents to describe children's everyday support needs and environmental influences through interviews in their own homes. RESULTS: Of the 367 invited parents, 332 (90.5%) participated, providing data on children with spina bifida, spinal muscular atrophy, muscular disorders, cerebral palsy, visual impairments, hearing impairments, mental disability and disabilities following brain tumour treatment. The mean age of children across disabilities was 9.4 years (range: 1.0-15.9). The mean e code score was 35.7 (range: 4.0-64.0), and the mean b code score was 32.2 (range: 0.0-159.0). The most urgent needs as detected by qualifier 4 environmental categories scores were common among children with complex disorders and issues related to health professionals, legal services and health services. CONCLUSIONS: Parents understand the environmental and body function components in a meaningful manner and the codes seem to be valid. Special emphasis should be given to environmental issues for children with more complex disabilities. There was no correlation between the severity of a disability and environmental issues, indicating that each child's needs were basically met, irrespective of disability severity. FUNDING: partnership project § 16, 21, 31 administered by the Danish Health Authority. TRIAL REGISTRATION: not relevant.

Positive experience with intrathecal baclofen treatment in children with severe cerebral palsy.

INTRODUCTION: Treatment of severe spasticity and dystonia with intrathecal baclofen (ITB) in children has been shown to be effective and has therefore been employed in the Region of Southern Denmark. The aim of this retrospective study was to analyse the efficacy and adverse events since ITB was introduced in 2003. METHODS: A total of 46 children who had a baclofen pump from April 2003 to January 2013 were included. The children's medical records were reviewed and clinical characteristics, efficacy and adverse events were registered. The efficacy of treatment experienced by parents was ascertained by telephone interviews, and data were rated on a Likert scale ranging from one to five, where one was no effect and five was marked improvement. RESULTS: After ITB, spasticity was reduced from a median of four to two in the upper extremities and from a median of four to one in the lower extremities. Baclofen infusion was 105.1-2,000 micrograms/day (mean 494.9 micrograms/day). Oral baclofen was reduced from 27.3 to 17.7 mg/day after ITB (p < 0.01). The parents' assessment of improvement in well-being, function and ease of care of their child had a mean score of 3.7, 2.2 and 3.4, respectively. 87.1% of parents stated that ITB had been worthwhile, and 90.3% would recommend it to other parents. Most infectious and mechanical adverse events were experienced during the first 200 days after pump implantation. The total complication rate was 0.40 per pump year. CONCLUSION: ITB resulted in reduced spasticity in children with severe spasticity and dystonia, and ITB could be considered safe. Parents' satisfaction with ITB was rated as good and most parents would recommend ITB to others. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

Assessing Children With Disabilities Using WHO International Classification of Functioning, Disability and Health Child and Youth Version Activities and Participation D Codes.

AIM: Evaluation of the International Classification of Functioning, Disability and Health child and youth version (ICF-CY) activities and participation d code functions in clinical practice with children across diagnoses, disabilities, ages, and genders. METHODS: A set of 57 codes were selected and worded to describe children's support needs in everyday life. Parents of children aged 1 to 15 years participated in interviews to discuss and rate their child's disability. RESULTS: Of 367 invited parents, 332 (90.5%) participated. The mean age of their children with disability was 9.4 years. The mean code scores were 50.67, the corrected code-total correlations were .76, intercode correlations had the mean of 0.61, and Cronbach's α was .98. As a result of Rasch analysis, graphical data for disability measures paralleled clinical expectations across the total population of 332 children. CONCLUSION: The World Health Organization International Classification of Functioning, Disability and Health child and youth version d code data can provide a coherent measure of severity of disability in children across various diagnoses, ages, and genders.

The Nordic Five to Fifteen questionnaire could provide the basis for a common neurological disability variable.

AIMS: Assessing disabilities in children is essential and Danish parents provide increasingly important feedback on how their child's disability affects daily living. The Nordic Five to Fifteen (FTF) parent questionnaire is widely used in Nordic countries to detect atypical or delayed development in children. Our study evaluated its internal validity and whether it could be used to generate a common disability variable across childhood neurological disorders and severities. METHODS: The 28-statement FTF questionnaire was completed by the parents of children with spina bifida, muscular disorders, spinal atrophy, cerebral palsy, blindness, deafness, mental retardation and disability, who received treatment for brain tumours. Psychometric analysis and Rasch analysis of the five FTF code qualifier level data were carried out. RESULTS: A total of 227 of 332 (68.4%) parents participated. The mean qualifier score was 3.06 (standard deviation 0.89, range 2.31-4.26), and the variances mean was 1.57 (range 0.87-2.38). The corrected code-total correlation was 0.65, and reliability was 0.96. The Rasch analysis demonstrated good fit alignment of codes. CONCLUSION: The FTF questionnaire can be used with children with neurological disabilities, and the Rasch scale analysis results indicate that it could form the analytical basis for developing a common disability variable.

[Neurofibroma of the larynx in a nine month-old child]. / Laryngeal neurofibromatose hos et ni måneder gammelt barn.

Neurofibroma of the larynx is a very rare condition. A nine month-old boy presented with airway obstruction due to a plexiform neurofibroma of the larynx. It also involved the proximal part of trachea and hypopharynx. Surgical excision was not a possibility. A tracheotomy was performed in order to secure the airways. The patient was doing well afterwards and has been followed with an MRI scan twice a year. Though neurofibroma of the larynx is rare, it should be considered when diagnosing of children with airway obstruction. Long-term follow-up is essential due to risk of malignant transformation.

Symptoms and time to diagnosis in children with brain tumours.

INTRODUCTION: Clinical symptoms in brain tumours in children are variable at onset and diagnosis is often delayed. Symptoms were investigated with regard to brain tumour localisation, prediagnostic symptomatic intervals and malignancy. MATERIAL AND METHODS: Clinical data from children aged 0-17 years from Southern Denmark were analysed retrospectively and the results were correlated with data on prehospital symptoms obtained from interviews with parents and general practitioners. RESULTS: A total of 55 children diagnosed during a period of five years were indentified and 31 interviews were obtained. A total of 19 (41%) of the tumours were supratentorial hemispheric and midline and 27 (59%) were infratentorial. At supratentorial localisations, 42% experienced vomiting as their first symptom followed by seizures in 37% and headache in 31%. At infratentorial localisations, headache occurred in 62%, vomiting in 55% and ataxia in 48% of the cases. The prediagnostic symptomatic interval had a median duration of 30 days with vomiting (range 3-330 days), a median of 75 days with headache (5-730 days) and a median of 75 days with ataxia (1-730 days). CONCLUSION: Diagnosis is often late in relation to the presenting symptoms. An earlier diagnosis may be achieved if a brain tumour is considered as soon as any child presents with the relevant symptoms. FUNDING: Not relevant. TRIAL REGISTRATION: ISRCTN88306789.

A dominant mutation in the gene encoding the erythroid transcription factor KLF1 causes a congenital dyserythropoietic anemia.

The congenital dyserythropoietic anemias (CDAs) are inherited red blood cell disorders whose hallmarks are ineffective erythropoiesis, hemolysis, and morphological abnormalities of erythroblasts in bone marrow. We have identified a missense mutation in KLF1 of patients with a hitherto unclassified CDA. KLF1 is an erythroid transcription factor, and extensive studies in mouse models have shown that it plays a critical role in the expression of globin genes, but also in the expression of a wide spectrum of genes potentially essential for erythropoiesis. The unique features of this CDA confirm the key role of KLF1 during human erythroid differentiation. Furthermore, we show that the mutation has a dominant-negative effect on KLF1 transcriptional activity and unexpectedly abolishes the expression of the water channel AQP1 and the adhesion molecule CD44. Thus, the study of this disease-causing mutation in KLF1 provides further insights into the roles of this transcription factor during erythropoiesis in humans.

Spinal cord injury at birth: a hidden causative factor.

UNLABELLED: A case of perinatally acquired spinal cord injury (SCI) is presented. The foetus was vigorous until birth, the breech presented and delivery was performed by a non-traumatic Caesarean section. The infant displayed symptoms of severe SCI but diagnosis was delayed due to severe co-morbidity. Diagnostic considerations are briefly reviewed. Ventilatory support was withdrawn at the age of 20 days when the infant had still not exhibited any respiratory effort or spontaneous movements. Autopsy revealed a serious congenital malalignment of the upper cervical vertebrae and at the histological examination extensive reactive changes were observed in the same area. To our knowledge such findings have not been published previously. CONCLUSION: In cases of serious perinatally acquired SCI, claim of malpractice is often apparent. In this case a hidden congenital malformation of the cervical vertebrae was revealed, highlighting the need of careful postmortem examinations in such cases.

[Oesteogenesis imperfecta--genetics, diagnosis and medical treatment]. / Osteogenesis imperfecta--genetik, diagnostik og medicinsk behandling.

The molecular background for osteogenesis imperfecta (OI) is mutations in one of the two genes (COL1A1 and COL1A2) encoding collagen I. The disease is characterised by varying degrees of fragile bones, retarded growth, bone deformities, tooth abnormalities, blue sclerae, and hearing loss. Treatment with bisphosphonates reduces the incidence of fractures in children with severe OI, while this still remains to be demonstrated in adults. Results from bone marrow transplantation and animal experiments may lead to alternative treatment in severe OI.

[Rhizotomy for children with severe spastic cerebral palsy]. / Rhizotomibehandling af børn med svaer spastisk cerebral parese.

INTRODUCTION: Severe spasticity is a limiting factor for motor development in children with spastic cerebral palsy. Botulinum toxin, intrathecal baclofen and peroral baclofen all reduce spasticity but might also limit improvements in functional development over time. In the selective dorsal or posterior rhizotomy (SDR) approach, afferent sensory nerve fibers are cut while efferent motor fibers are preserved. In this way spasticity is reduced and motor functions can improve. SDR is an established treatment method, and the first Danish study is reported. MATERIAL AND METHODS: Twenty Danish children with severe spastic cerebral palsy were evaluated, operated on and trained over a 10-year period from 1992 to 2002. Those on whom operation was performed ranged from 4 to 16 years of age (median 8 years), and training and follow-up took place during the ensuing 60 months. At time of operation, 20-40% of 100-120 dorsal root filaments were cut, corresponding to the II-V lumbar and I-II sacral nerve roots. RESULTS: Spasticity in the lower extremities measured before SDR showed an average Asworth score of 2.0-4.2 (median 3.1). Eighteen months after SDR, scores were 0.8-1.8 (median 1.0), and at 60 months 0.8-1.8 (median 1.0). Both post-operative values were significant (t-test, p < 0.001). Mobility improved over a longer period of time: the Illinois St. Louis scale values before SDR were 1-9 (median 6), while at 18 months post-operative they were 1-9 (median 5) and at 60 months post-operative 1-9 (median 4). At 18 months, scores were non-significant (t test, p > 0.05), but at 60 months they were significant (t < 0.05). According to the Montgomery scale, 4 children had worse post-operative scores and 12 children had better scores. When comparing age at operation with outcome, we observed a certain degree of concordance between relatively younger age and better post-operative muscular function (Pearson's r = 0.8). CONCLUSION: SDR resulted in early and lasting reduction in spasticity in all 20 children operated upon. Improved muscular function, however, required training and time. Not until 60 months after operation were functional measures significantly better than the preoperative values.

[Intrathecal baclofen in the treatment of severe spastic tetraplegia and dystonia in children and adolescents]. / Intratekal baclofenbehandling ved svaer spastisk tetraplegi og dystoni hos børn og unge.

INTRODUCTION: Continuous intrathecal baclofen has been used over the past years especially in adult patients with spasticity of spinal origin. Children and young adults with severe spasticity and dystonia of cerebral origin are difficult to treat in spite of optimal systemic antispasmotic therapy with baclofen, tizanidine, dantrolene and/or diazepam. Intrathecal baclofen has therefore been applied in a group of young patients. MATERIAL AND METHODS: Eight children and young adults from East Denmark with spasticity and 12 with dystonia aged 3-18 years (median 10.9 years) were tested, operated and treated with continuous intrathecal baclofen for a period of 2-64 months (median 22.2 months). Registration of efficacy, fillings, adjustments of baclofen and other therapies were performed in an out patient setting since 1995. RESULTS: Spasticity in lower extremities was reduced from Ashworth score 3.5-4.5 (median 4.2) to Ashworth score 2.5-4.0 (median 2.9; p < 0.001) during infusion with baclofen 5-33 micrograms/kg/24 hours (median 19 micrograms/kg/24 hours). The infusion catheter tip was placed at levels Th1-Th12 (median Th7.5). Peroral baclofen was reduced from an average of 5.0 to 0.44 mg/kg/24 hours, tizanidine from 0.4 to 0.1 mg/kg/24 hours, and dantrolene from 4.0 to 0.4 mg/kg/24 hours. After initial adjustments successively increased dosages of average 0.46 microgram/kg/month were needed to maintain the same level of efficacy. In questionnaires parents or guardians rated less spasticity in lower extremities in 15 out of 19 patients, and less pain in 13 out of 19 patients. CONCLUSION: Continuous intrathecal baclofen was effective in treating severe spasticity and dystonia of cerebral origin with major effect on muscles of the lower extremities, pelvis, and back and in particular opisthotonus was relieved. Efficacy on upper extremities was far less pronounced.