The expanding clinical and genetic spectrum of DYNC1H1-related disorders.

Intracellular trafficking involves an intricate machinery of motor complexes including the dynein complex to shuttle cargo for autophagolysosomal degradation. Deficiency in dynein axonemal chains as well as cytoplasmic light and intermediate chains have been linked with ciliary dyskinesia and skeletal dysplasia. The cytoplasmic dynein 1 heavy chain protein (DYNC1H1) serves as a core complex for retrograde trafficking in neuronal axons. Dominant pathogenic variants in DYNC1H1 have been previously implicated in peripheral neuromuscular disorders (NMD) and neurodevelopmental disorders (NDD). As heavy-chain dynein is ubiquitously expressed, the apparent selectivity of heavy-chain dyneinopathy for motor neuronal phenotypes remains currently unaccounted for. Here, we aimed to evaluate the full DYNC1H1-related clinical, molecular and imaging spectrum, including multisystem features and novel phenotypes presenting throughout life. We identified 47 cases from 43 families with pathogenic heterozygous variants in DYNC1H1 (aged 0-59 years) and collected phenotypic data via a comprehensive standardized survey and clinical follow-up appointments. Most patients presented with divergent and previously unrecognized neurological and multisystem features, leading to significant delays in genetic testing and establishing the correct diagnosis. Neurological phenotypes include novel autonomic features, previously rarely described behavioral disorders, movement disorders, and periventricular lesions. Sensory neuropathy was identified in nine patients (median age of onset 10.6 years), of which five were only diagnosed after the second decade of life, and three had a progressive age-dependent sensory neuropathy. Novel multisystem features included primary immunodeficiency, bilateral sensorineural hearing loss, organ anomalies, and skeletal manifestations, resembling the phenotypic spectrum of other dyneinopathies. We also identified an age-dependent biphasic disease course with developmental regression in the first decade and, following a period of stability, neurodegenerative progression after the second decade of life. Of note, we observed several cases in whom neurodegeneration appeared to be prompted by intercurrent systemic infections with double-stranded DNA viruses (Herpesviridae) or single-stranded RNA viruses (Ross-River fever, SARS-CoV-2). Moreover, the disease course appeared to be exacerbated by viral infections regardless of age and/or severity of NDD manifestations, indicating a role of dynein in anti-viral immunity and neuronal health. In summary, our findings expand the clinical, imaging, and molecular spectrum of pathogenic DYNC1H1 variants beyond motor neuropathy disorders and suggest a life-long continuum and age-related progression due to deficient intracellular trafficking. This study will facilitate early diagnosis and improve counselling and health surveillance of affected patients.

Olfactory function after mild traumatic brain injury in children-a longitudinal case control study.

The prevalence of posttraumatic olfactory dysfunction in children after mild traumatic brain injury ranges from 3 to 58%, with potential factors influencing this variation, including traumatic brain injury severity and assessment methods. This prospective longitudinal study examines the association between mild traumatic brain injury and olfactory dysfunction in children. Seventy-five pediatric patients with mild traumatic brain injury and an age-matched healthy control group were enrolled. Olfactory function was assessed using the Sniffin' Sticks battery, which focuses on olfactory threshold and odor identification. The study found that children with mild traumatic brain injury had impaired olfactory function compared with healthy controls, particularly in olfactory threshold scores. The prevalence of olfactory dysfunction in the patient group was 33% and persisted for 1 yr. No significant association was found between traumatic brain injury symptoms (e.g. amnesia, loss of consciousness) and olfactory dysfunction. The study highlights the importance of assessing olfactory function in children after mild traumatic brain injury, given its potential impact on daily life. Although most olfactory dysfunction appears transient, long-term follow-up is essential to fully understand the recovery process. The findings add valuable insights to the limited literature on this topic and urge the inclusion of olfactory assessments in the management of pediatric mild traumatic brain injury.

[Gender-specific results of the Dresden children and adolescents headache program DreKiP]. / Geschlechtsspezifische Ergebnisse des Dresdner Kinder- und Jugendkopfschmerzprogrammes DreKiP.

BACKGROUND: Girls and women are more frequently affected by headache than boys and men. The influence of gender on the effectiveness of headache therapies has so far been hardly investigated. We examined gender differences in the outpatient multimodal Dresden Child and Adolescent Headache Program DreKiP. METHODS: We treated 140 patients with primary headache in a 15-hour structured group program. At baseline (T0) and six (T1) and twelve months (T2) after the end of the program, data on headache-related limitation of daily activities (PedMIDAS) as well as headache frequency, intensity, and pain-related disability (P-PDI) were collected. Retrospectively, these data were analyzed separately for girls and boys. RESULTS: For 91 patients (9-19 years, median = 15; 71.4 % female) data were available for at least two measurement time points. Girls showed significantly higher headache frequency than boys at all time points (median headache days/last three months at T0: ♀ 43, ♂ 20; T1: ♀ 32, ♂ 12; T2: ♀ 28, ♂ 9) as well as numerically higher headache-related limitation of daily life. There were significant effects over time with a decrease in headache frequency (F (2.88) = 5.862; p = 0.004) and improvement in daily functioning (F (2.92) = 5.340; p = 0.006). There was no gender-specific treatment response. DISCUSSION: The DreKiP therapy shows effects in girls and boys with primary headache. Higher headache frequencies and everyday life restrictions in girls may have hormonal but also psychosocial causes and should be addressed in educational measures.

Feedback-Based Learning of Timing in Attention-Deficit/Hyperactivity Disorder and Neurofibromatosis Type 1.

OBJECTIVE: Patients with Neurofibromatosis Type 1 (NF1) frequently display symptoms resembling those of Attention Deficit/Hyperactivity Disorder (ADHD). Importantly, these disorders are characterised by distinct changes in the dopaminergic system, which plays an important role in timing performance and feedback-based adjustments in timing performance. In a transdiagnostic approach, we examine how far NF1 and ADHD show distinct or comparable profiles of timing performance and feedback-based adjustments in timing. METHOD: We examined time estimation and learning processes in healthy control children (HC), children with ADHD with predominantly inattentive symptoms and those with NF1 using a feedback-based time estimation paradigm. RESULTS: Healthy controls consistently responded closer to the correct time window than both patient groups, were less variable in their reaction times and displayed intact learning-based adjustments across time. The patient groups did not differ from each other regarding the number of in-time responses. In ADHD patients, the performance was rather unstable across time. No performance changes could be observed in patients with NF1 across the entire task. CONCLUSIONS: Children with ADHD and NF1 differ in feedback learning-based adjustments of time estimation processes. ADHD is characterised by behavioural fluctuations during the learning process. These are likely to be associated with inefficiencies in the dopaminergic system. NF1 is characterised by impairments of feedback learning which could be due to various neurotransmitter alterations occurring in addition to deficits in dopamine synthesis. Results show that despite the strong overlap in clinical phenotype and neuropsychological deficits between NF1 and ADHD, the underlying cognitive mechanisms are different.

Effect of Different Corticosteroid Dosing Regimens on Clinical Outcomes in Boys With Duchenne Muscular Dystrophy: A Randomized Clinical Trial.

Importance: Corticosteroids improve strength and function in boys with Duchenne muscular dystrophy. However, there is uncertainty regarding the optimum regimen and dosage. Objective: To compare efficacy and adverse effects of the 3 most frequently prescribed corticosteroid regimens in boys with Duchenne muscular dystrophy. Design, Setting, and Participants: Double-blind, parallel-group randomized clinical trial including 196 boys aged 4 to 7 years with Duchenne muscular dystrophy who had not previously been treated with corticosteroids; enrollment occurred between January 30, 2013, and September 17, 2016, at 32 clinic sites in 5 countries. The boys were assessed for 3 years (last participant visit on October 16, 2019). Interventions: Participants were randomized to daily prednisone (0.75 mg/kg) (n = 65), daily deflazacort (0.90 mg/kg) (n = 65), or intermittent prednisone (0.75 mg/kg for 10 days on and then 10 days off) (n = 66). Main Outcomes and Measures: The global primary outcome comprised 3 end points: rise from the floor velocity (in rise/seconds), forced vital capacity (in liters), and participant or parent global satisfaction with treatment measured by the Treatment Satisfaction Questionnaire for Medication (TSQM; score range, 0 to 100), each averaged across all study visits after baseline. Pairwise group comparisons used a Bonferroni-adjusted significance level of .017. Results: Among the 196 boys randomized (mean age, 5.8 years [SD, 1.0 years]), 164 (84%) completed the trial. Both daily prednisone and daily deflazacort were more effective than intermittent prednisone for the primary outcome (P < .001 for daily prednisone vs intermittent prednisone using a global test; P = .017 for daily deflazacort vs intermittent prednisone using a global test) and the daily regimens did not differ significantly (P = .38 for daily prednisone vs daily deflazacort using a global test). The between-group differences were principally attributable to rise from the floor velocity (0.06 rise/s [98.3% CI, 0.03 to 0.08 rise/s] for daily prednisone vs intermittent prednisone [P = .003]; 0.06 rise/s [98.3% CI, 0.03 to 0.09 rise/s] for daily deflazacort vs intermittent prednisone [P = .017]; and -0.004 rise/s [98.3% CI, -0.03 to 0.02 rise/s] for daily prednisone vs daily deflazacort [P = .75]). The pairwise comparisons for forced vital capacity and TSQM global satisfaction subscale score were not statistically significant. The most common adverse events were abnormal behavior (22 [34%] in the daily prednisone group, 25 [38%] in the daily deflazacort group, and 24 [36%] in the intermittent prednisone group), upper respiratory tract infection (24 [37%], 19 [29%], and 24 [36%], respectively), and vomiting (19 [29%], 17 [26%], and 15 [23%]). Conclusions and Relevance: Among patients with Duchenne muscular dystrophy, treatment with daily prednisone or daily deflazacort, compared with intermittent prednisone alternating 10 days on and 10 days off, resulted in significant improvement over 3 years in a composite outcome comprising measures of motor function, pulmonary function, and satisfaction with treatment; there was no significant difference between the 2 daily corticosteroid regimens. The findings support the use of a daily corticosteroid regimen over the intermittent prednisone regimen tested in this study as initial treatment for boys with Duchenne muscular dystrophy. Trial Registration: ClinicalTrials.gov Identifier: NCT01603407.

Functional improvement in children and adolescents with primary headache after an interdisciplinary multimodal therapy program: the DreKiP study.

BACKGROUND: More than 2/3 of children and adolescents in Germany regularly suffer from headaches. Headache-related limitations in everyday life, school drop-out and educational impairment are common. Structured therapy programs for young headache patients are widely missing. METHODS: One hundred eleven patients with frequent migraine and/or tension type headache were treated in a 15 hour group program in afternoons, parallel with school, parents received 7 hours of therapy. At the beginning of the program (T0), 6 (T1) and 12 months (T2) after completion, data on headache related disability (PedMidas), headache frequency, intensity, and pediatric pain disability score (PPDI) were prospectively collected to investigate the effects of the therapy. RESULTS: Seventy-five patients (9-19 years, median = 14; 66.7% female) and their parents provided patient reported outcome measures showing at T1 (65 patients) and T2 (47 patients) reduced headache frequency (last 3 months headache days median T0: 30 days; T1: 18 days, reduction of median 12 days since T0; T2: 13 days, reduction of median 17 days since T0). Linear mixed models revealed significant reduction (T0/T1 p = 0,002; T0/T2 p = 0,001). Reduced headache disability has been reported at T1 and T2 (PedMidas median T0 = 30, T1 = 15, T2 = 7; p < 0,001, p < 0,001 respectively). Follow up data of a subgroup of patients 24 months after the treatment point to sustainable effects. CONCLUSIONS: The interdisciplinary multimodal headache therapy program DreKiP reduces headache frequency and headache related disability significantly 6-12 months following its completion. TRIAL REGISTRATION: DRKS00027523, retrospectively registered.

The clinical-phenotype continuum in DYNC1H1-related disorders-genomic profiling and proposal for a novel classification.

Mutations in the cytoplasmic dynein 1 heavy chain gene (DYNC1H1) have been identified in rare neuromuscular (NMD) and neurodevelopmental (NDD) disorders such as spinal muscular atrophy with lower extremity dominance (SMALED) and autosomal dominant mental retardation syndrome 13 (MRD13). Phenotypes and genotypes of ten pediatric patients with pathogenic DYNC1H1 variants were analyzed in a multi-center study. Data mining of large-scale genomic variant databases was used to investigate domain-specific vulnerability and conservation of DYNC1H1. We identified ten patients with nine novel mutations in the DYNC1H1 gene. These patients exhibit a broad spectrum of clinical findings, suggesting an overlapping disease manifestation with intermixed phenotypes ranging from neuropathy (peripheral nervous system, PNS) to severe intellectual disability (central nervous system, CNS). Genomic profiling of healthy and patient variant datasets underlines the domain-specific effects of genetic variation in DYNC1H1, specifically on toleration towards missense variants in the linker domain. A retrospective analysis of all published mutations revealed domain-specific genotype-phenotype correlations, i.e., mutations in the dimerization domain with reductions in lower limb strength in DYNC1H1-NMD and motor domain with cerebral malformations in DYNC1H1-NDD. We highlight that the current classification into distinct disease entities does not sufficiently reflect the clinical disease manifestation that clinicians face in the diagnostic work-up of DYNC1H1-related disorders. We propose a novel clinical classification for DYNC1H1-related disorders encompassing a spectrum from DYNC1H1-NMD with an exclusive PNS phenotype to DYNC1H1-NDD with concomitant CNS involvement.

Just Expect It: Compound Heterozygous Variants of POMT1 in a Consanguineous Family-The Role of Next Generation Sequencing in Neuromuscular Disorders.

Muscular dystrophy-dystroglycanopathies (MDDG) are a group of genetically heterogeneous autosomal recessive disorders characterized by hypoglycosylation of α-dystroglycan. Here, we report on two female patients from a consanguineous Lebanese family that presented in early infancy with generalized muscle hypotonia and primary microcephaly. Brain magnetic resonance imaging (MRI) showed different degrees of hypoplasia of the cerebellar vermis and hypoplasia of corpus callosum. Muscle biopsy analyses revealed a muscular dystrophy with reduced expression of α-dystroglycan and merosin in immunoblot analyses. Homozygosity mapping failed to elucidate the causal mutation due to the accepted notion that, in consanguineous families, homozygote mutations cause disease. However, by applying whole exome sequencing, we identified a novel compound heterozygous POMT1 mutation that segregates with the phenotype and is in line with the clinical presentation. This underscores that a less expected compound heterozygous instead of homozygous mutation in a consanguineous marriage results in a recessive disorder and highlights the growing role of next generation sequencing in neuromuscular disorder diagnostics.

[Recommendations for gene therapy of spinal muscular atrophy with onasemnogene abeparvovec-AVXS-101 : Consensus paper of the German representatives of the Society for Pediatric Neurology (GNP) and the German treatment centers with collaboration of the medical scientific advisory board of the German Society for Muscular Diseases (DGM)]. / Handlungsempfehlungen zur Gentherapie der spinalen Muskelatrophie mit Onasemnogene Abeparvovec ­ AVXS-101 : Konsensuspapier der deutschen Vertretung der Gesellschaft für Neuropädiatrie (GNP) und der deutschen Behandlungszentren unter Mitwirkung des Medizinisch-Wissenschaftlichen Beirates der Deutschen Gesellschaft für Muskelkranke (DGM) e. V.

BACKGROUND: Spinal muscular atrophy (SMA) is a severe, life-limiting neurodegenerative disease. A disease-modifying and approved therapy with nusinersen has been available in Germany since July 2017. Gene therapies offer another promising treatment option through a once in a lifetime administration. In May 2019 a gene replacement therapy for the treatment of SMA was approved for the first time by the U.S. Food and Drug Administration (FDA). An application for approval in Europe has been submitted and is currently pending. OBJECTIVE: This consensus paper was compiled at the invitation of the German Society for Muscular Diseases (DGM) with the participation of all potential German neuromuscular treatment centers, the German section of the Society for Pediatric Neurology (GNP) and with the involvement of the medical scientific advisory board of the DGM. The aim was to define and establish the necessary prerequisites for a safe and successful application of the new gene replacement therapy in clinical practice. CONCLUSION: Gene replacement therapy with onasemnogene abeparvovec has the potential to significantly influence the course of SMA. Long-term data on sustainability of effects and possible adverse effects of gene replacement therapy are not yet available. The application of this innovative therapy must be carried out in specialized and appropriately qualified treatment centers under strict safety conditions. This article makes suggestions for the necessary framework conditions and gives recommendations for a systematic pretreatment and posttreatment assessment schedule under gene therapy. The effectiveness and safety of the therapy should be systematically documented in an industry-independent and disease-specific register.

The prevalence of headache in German pupils of different ages and school types.

BACKGROUND/OBJECTIVE: Headache in pupils is underestimated and has a negative impact on learning and life. The aim of this study was to investigate headache prevalence and its collateral effects, in pupils of different ages and school types in a German city. METHODS: Anonymized questionnaires were distributed to 5419 pupils attending primary and secondary schools. Demographics, headache frequency, analgesic use, school absence and, for secondary school children, data on lifestyle were collected. RESULTS: The questionnaire was returned by 2706 children (49%), 1362 (50.3%) girls, 1344 (49.7%) boys. Of these, 36.6% indicated a frequency of 1, and 31.5% a frequency of ≥ 2 headache days per month within the last 3 months. Headache prevalence increased with school grade, age and secondary school type: 63.6%, 67.2% and 79.5% for primary school children, pupils attending 8-year and pupils attending 6-year secondary schools, respectively. With secondary school level I certificates, pupils are prepared for general professional training in 6 years. Secondary school level II results, after 8 years of training, in university entrance level II certificates, which are the precondition for university studies. Girls reported significantly more headache than boys (73% vs. 63.1%). A significant relationship has been observed between headache frequency and school absence and between headache intensity and headache frequency. Of pupils with headache at least twice a month, 48.1% reported analgesic intake. Ibuprofen (49.1%) and paracetamol (32.8%) were the most frequently used analgesics. Of those pupils with headache ≥ 2 days/month, 68.3% did not have a specific headache diagnosis. Concomitant diseases and regular drug intake, analgesic intake for another reason than headache, caffeine consumption and lack of participation in sports were positively correlated with headache. CONCLUSIONS: The majority of pupils suffer from headache at least once a month. Since frequent headache results in educational and social limitations, pupils at risk should be identified and referred to headache education programs. Efforts are needed to improve the management of juvenile headache patients.

Influence of chronic diseases on the olfactory function in children.

The association between smell impairment and chronic diseases has been reported in some studies in adults. Such information is not available for chronic diseases in children. The aim of this study was to examine olfactory function of children with chronic diseases such as diabetes mellitus type 1, hypothyroidism, and bronchial asthma in combination with allergic rhinitis in comparison to healthy controls. The data were obtained from n = 205 participants (104 boys, 101 girls) between the age of 6 and 17 years. Seventy-eight of the participants were healthy controls, n = 43 had diabetes mellitus type 1, n = 50 suffer from allergic rhinitis or bronchial asthma, and 34 presented a reduced function of their thyroid in medical history. All participants underwent olfactory testing including olfactory threshold using "Sniffin' Sticks" and odor identification using the "U-Sniff" test. In addition, a depression inventory and cognitive testing using the Ravens Progressive Matrices was performed. No significant difference in olfactory function was observed for any of the chronic diseases in children in comparison to healthy controls. Further analysis showed a trend in significance for a subpopulation of children with bronchial asthma and comorbidities performed worse on the olfactory threshold test compared to patients with bronchial asthma without comorbidities. Pediatric patients suffering from chronic diseases scored higher on the depression inventory compared to healthy controls.Conclusion: In conclusion, this study demonstrates that the influence of chronic diseases (bronchial asthma, diabetes mellitus type 1 and hypothyroidism) on olfactory function in childhood, if any, seems to be insignificant. This is partly in contrast to adult patients. Further research should be conducted in a subgroup of patients with bronchial asthma, allergic rhinitis, and atopic dermatitis or other comorbidities to better understand the association of allergic diathesis and olfactory function and the putative pathogenesis of olfactory dysfunction. What is known: • The association between smell impairment and chronic diseases has been reported in some studies in adults. • Such information is not available for chronic diseases in children. What is new: • The influence of chronic diseases (bronchial asthma, diabetes mellitus type 1, and hypothyroidism) on olfactory function in childhood, if any, seems to be insignificant. • In patients with bronchial asthma and allergic rhinitis, only a subgroup of patients with additional comorbidity (atopic dermatitis) showed a tendency to a reduced sense of smell.

Acquired Olfactory Dysfunction in Children and Adolescents: A Systematic Review of the Literature.

Olfactory function can be influenced by many factors and olfactory dysfunction is associated with several diseases. But even considering this, the causes of acquired olfactory dysfunction in children are not well understood. This review was conducted to gain an overview of the etiologies of acquired olfactory dysfunction in a pediatric population. Studies were identified using a predefined literature search, including studies if patients were ≤18 years of age and results of psychophysical olfactory testing were reported. A total of 44 articles met the inclusion criteria for this review and were included in the qualitative analysis. The influence of 6 disease groups on olfactory function in children was observed (otorhinolaryngology, traumatic brain injury, oncology, psychiatric diseases, environmental factors, and other diseases). The current literature is convincing that diseases in the otorhinolaryngology group and traumatic brain injury can lead to acquired olfactory dysfunction, whereas according to the current literature, the role of other influencing factors such as most psychiatric disorders remains uncertain. A number of diseases and circumstances affect olfactory function in children and may cause acquired olfactory dysfunction in this age group. Nevertheless, more research is needed to better understand the causes of acquired olfactory dysfunction in children. Future research should have the goal of early diagnosis and, if possible, early treatment of the condition to prevent a negative impact of olfactory dysfunction on children and adolescents.

Novel VPS33B mutation in a patient with autosomal recessive keratoderma-ichthyosis-deafness syndrome.

Autosomal recessive keratoderma-ichthyosis-deafness (ARKID) syndrome is a rare multisystem disorder caused by biallelic mutations in VPS33B; only three patients have been reported to date. ARKID syndrome is allelic to arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome (MIM #208085), a severe disorder with early lethality whose phenotypic characteristics also include ichthyosis, hearing loss, severe failure to thrive, platelet dysfunction and osteopenia. We report on an 11-year-old male patient with ARKID syndrome and compound heterozygous VPS33B mutations, one of which [c.1440delG; p.(Arg481Glyfs*11)] was novel. Clinical features of this patient included ichthyosis, palmoplantar keratosis, hearing loss, intellectual disability, unilateral hip dislocation, microcephaly and short stature. He also had copper hepatopathy and exocrine pancreatic insufficiency, features that have so far been associated with neither ARKID nor ARC syndrome. The patient broadens the clinical and molecular spectrum of ARKID syndrome and contributes to genotype-phenotype associations of this rare disorder.

Childhood primary large vessel CNS vasculitis: single-centre experience and review of the literature.

Ischaemic brain injuries are rare conditions in the paediatric age group. Main causes include non-arteriosclerotic arteriopathies, which in childhood usually result from primary vasculitis of large or small vessels and lead to impaired perfusion and subsequent ischaemic brain lesions. In accordance with the nomenclature of systemic forms, CNS vasculitis is subdivided into groups, based on the size of affected vessels: angiography-positive primary angiitis of medium-sized and large vessels (pPACNS), and angiography-negative angiitis of small vessels (svPACNS). We report the clinical presentation, diagnostic approach, and therapy of four children with progressive pPACNS. Patients were treated with high-dose corticosteroids and anticoagulation with unfractionated heparin in the acute phase, followed by immune modulatory treatment with mycophenolate mofetil (MMF) and dual antiplatelet therapy with acetylsalicylic acid and clopidogrel. In this manuscript, we illustrate the experience gained in our hospital, resulting in significantly faster diagnosis and treatment initiation, and discuss the applied immune modulating treatment regimen in the context of the literature. Based on our observations, we conclude that immune modulating therapy with initial high-dose corticosteroids, followed by steroid-sparing maintenance treatment with MMF, may be safe and effective in childhood progressive pPACNS.

Novel Mutation in the DKC1 Gene: Neonatal Hoyeraal-Hreidarsson Syndrome As a Rare Differential Diagnosis in Pontocerebellar Hypoplasia, Primary Microcephaly, and Progressive Bone Marrow Failure.

Primary microcephaly and severe developmental delay are complex but unspecific signs pointing to various genetic or acquired diseases. A concomitant finding of hematological failure may lead to the differential diagnosis of rare genetic diseases such as chromosome breakage disorders or diseases associated with telomere dysfunction. X-linked Hoyeraal-Hreidarsson syndrome (HHS) is a rare heterogenic disorder characterized by severe neurological impairment and progressive bone marrow failure. The latter represents the main cause of mortality, usually in early childhood. We report on the clinical course of an infant with HHS due to a novel mutation in the DKC1 gene and the particular finding of pontocerebellar hypoplasia.

Dysferlinopathy in Switzerland: clinical phenotypes and potential founder effects.

BACKGROUND: Dysferlin is reduced in patients with limb girdle muscular dystrophy type 2B, Miyoshi myopathy, distal anterior compartment myopathy, and in certain Ethnic clusters. METHODS: We evaluated clinical and genetic patient data from three different Swiss Neuromuscular Centers. RESULTS: Thirteen patients from 6 non-related families were included. Age of onset was 18.8 ± 4.3 years. In all patients, diallelic disease-causing mutations were identified in the DYSF gene. Nine patients from 3 non-related families from Central Switzerland carried the identical homozygous mutation, c.3031 + 2 T>C. A possible founder effect was confirmed by haplotype analysis. Three patients from two different families carried the heterozygous mutation, c.1064_1065delAA. Two novel mutations were identified (c.2869 C>T (p.Gln957Stop), c.5928 G>A (p.Trp1976Stop)). CONCLUSIONS: Our study confirms the phenotypic heterogeneity associated with DYSF mutations. Two mutations (c.3031 + 2 T>C, c.1064_1065delAA) appear common in Switzerland. Haplotype analysis performed on one case (c. 3031 + 2 T>C) suggested a possible founder effect.

A five year-old child with clear cell petro-clival meningioma: case report with clinical and histopathological long-term follow-up.

BACKGROUND: Only a few cases have been previously published about clear cell meningiomas in children, the majority of them in the location of the spine. We describe an unusual case of clear cell meningioma occurring at the petro-clival region in a 5-year-old child. We further seek to determine the impact of several growth factors as well as the AKT1 mutation on the tumor growth pattern. CASE PRESENTATION: A five-year-old girl was presented with a one-week history of cephalgia, ataxia, and left sided torticollis. Magnetic resonance imaging (MRI) revealed a dumbbell-shaped homogeneously petro-clival gadolinium-enhancing mass. A staged operative approach was chosen, and a complete removal of the tumor was achieved. Due to recurrent tumor progression, the child underwent several tumor surgeries and two cranial radiations. None of the treatments were able to stop tumor progression. Consequently, the child died at the age of 14 after further extensive intracranial and extracranial tumor progression. The initial histological examination revealed a clear cell meningioma WHO grade II with an MIB-1 labeling index of <1%, which gradually increased with every recurrence up to 10% by the last progression at the age of 13 years. Analogically, an increasing overexpression of epidermal growth factor receptor (EGFR), the platelet-derived growth factor receptor (PDGFR), and the vascular endothelial growth factor receptor (VEGFR) was observed with each recurrence. The AKT1 (E17K) mutation in the tumor was not detectable in all investigated specimens. CONCLUSION: Pediatric clear cell meningiomas WHO grade II are very rare. Our data demonstrate the progressive overexpression of EGF-, PDGF-, and VEGF-receptors in each recurrence, providing one of these receptors as targeted therapy in such cases. Further evaluation of these growth factors in clear cell meningioma is required to establish the optimal treatment of these aggressive tumors.

Hexosamine biosynthetic pathway mutations cause neuromuscular transmission defect.

Neuromuscular junctions (NMJs) are synapses that transmit impulses from motor neurons to skeletal muscle fibers leading to muscle contraction. Study of hereditary disorders of neuromuscular transmission, termed congenital myasthenic syndromes (CMS), has helped elucidate fundamental processes influencing development and function of the nerve-muscle synapse. Using genetic linkage, we find 18 different biallelic mutations in the gene encoding glutamine-fructose-6-phosphate transaminase 1 (GFPT1) in 13 unrelated families with an autosomal recessive CMS. Consistent with these data, downregulation of the GFPT1 ortholog gfpt1 in zebrafish embryos altered muscle fiber morphology and impaired neuromuscular junction development. GFPT1 is the key enzyme of the hexosamine pathway yielding the amino sugar UDP-N-acetylglucosamine, an essential substrate for protein glycosylation. Our findings provide further impetus to study the glycobiology of NMJ and synapses in general.