Effect of nusinersen on motor, respiratory and bulbar function in early-onset spinal muscular atrophy.

5q-associated spinal muscular atrophy is a rare neuromuscular disorder with the leading symptom of a proximal muscle weakness. Three different drugs have been approved by the European Medicines Agency and Food and Drug Administration for the treatment of spinal muscular atrophy patients, however, long-term experience is still scarce. In contrast to clinical trial data with restricted patient populations and short observation periods, we report here real-world evidence on a broad spectrum of patients with early-onset spinal muscular atrophy treated with nusinersen focusing on effects regarding motor milestones, and respiratory and bulbar insufficiency during the first years of treatment. Within the SMArtCARE registry, all patients under treatment with nusinersen who never had the ability to sit independently before the start of treatment were identified for data analysis. The primary outcome of this analysis was the change in motor function evaluated with the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders and motor milestones considering World Health Organization criteria. Further, we evaluated data on the need for ventilator support and tube feeding, and mortality. In total, 143 patients with early-onset spinal muscular atrophy were included in the data analysis with a follow-up period of up to 38 months. We observed major improvements in motor function evaluated with the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders. Improvements were greater in children >2 years of age at start of treatment than in older children. 24.5% of children gained the ability to sit independently. Major improvements were observed during the first 14 months of treatment. The need for intermittent ventilator support and tube feeding increased despite treatment with nusinersen. Our findings confirm the increasing real-world evidence that treatment with nusinersen has a dramatic influence on disease progression and survival in patients with early-onset spinal muscular atrophy. Major improvements in motor function are seen in children younger than 2 years at the start of treatment. Bulbar and respiratory function needs to be closely monitored, as these functions do not improve equivalent to motor function.

Association between Tubulointerstitial Nephritis and Uveitis Syndrome and Small-Vessel CNS Vasculitis: A Case of Polyautoimmunity.

INTRODUCTION: We report a case study of two male pediatric patients presenting with anterior uveitis and elevated renal function parameters. Both were diagnosed with tubulointerstitial nephritis and uveitis syndrome and subsequently developed diffuse cerebral symptoms such as headache, fatigue, and diziness. METHODS: Magnetic resonance images (MRIs) of the brain showed T2-hyperintense lesions with and without gadolinium enhancement leading to brain biopsy and diagnosis of small-vessel central nervous system (CNS) vasculitis in both cases. Both patients were treated according to BrainWorks small-vessel vasculitis protocol and symptoms vanished over the course of treatment. Follow-up MRIs up to 12 months after initiation of therapy showed no signs of recurrence indicating a monophasic disease. CONCLUSION: Small-vessel CNS vasculitis can occur simultaneously to other autoimmune diseases (ADs) in the scope of polyautoimmunity. As clinical findings of CNS vasculitis are often unspecific, neurological symptoms in nonneurological ADs should be adressed thoroughly. Under suspicion of small-vessel CNS vasculitis brain biopsy is still the gold standard and only secure way of definitive diagnosis.

A Recurrent Gain-of-Function Mutation in CLCN6, Encoding the ClC-6 Cl-/H+-Exchanger, Causes Early-Onset Neurodegeneration.

Dysfunction of the endolysosomal system is often associated with neurodegenerative disease because postmitotic neurons are particularly reliant on the elimination of intracellular aggregates. Adequate function of endosomes and lysosomes requires finely tuned luminal ion homeostasis and transmembrane ion fluxes. Endolysosomal CLC Cl-/H+ exchangers function as electric shunts for proton pumping and in luminal Cl- accumulation. We now report three unrelated children with severe neurodegenerative disease, who carry the same de novo c.1658A>G (p.Tyr553Cys) mutation in CLCN6, encoding the late endosomal Cl-/H+-exchanger ClC-6. Whereas Clcn6-/- mice have only mild neuronal lysosomal storage abnormalities, the affected individuals displayed severe developmental delay with pronounced generalized hypotonia, respiratory insufficiency, and variable neurodegeneration and diffusion restriction in cerebral peduncles, midbrain, and/or brainstem in MRI scans. The p.Tyr553Cys amino acid substitution strongly slowed ClC-6 gating and increased current amplitudes, particularly at the acidic pH of late endosomes. Transfection of ClC-6Tyr553Cys, but not ClC-6WT, generated giant LAMP1-positive vacuoles that were poorly acidified. Their generation strictly required ClC-6 ion transport, as shown by transport-deficient double mutants, and depended on Cl-/H+ exchange, as revealed by combination with the uncoupling p.Glu200Ala substitution. Transfection of either ClC-6Tyr553Cys/Glu200Ala or ClC-6Glu200Ala generated slightly enlarged vesicles, suggesting that p.Glu200Ala, previously associated with infantile spasms and microcephaly, is also pathogenic. Bafilomycin treatment abrogated vacuole generation, indicating that H+-driven Cl- accumulation osmotically drives vesicle enlargement. Our work establishes mutations in CLCN6 associated with neurological diseases, whose spectrum of clinical features depends on the differential impact of the allele on ClC-6 function.

A homozygous missense variant in CACNB4 encoding the auxiliary calcium channel beta4 subunit causes a severe neurodevelopmental disorder and impairs channel and non-channel functions.

P/Q-type channels are the principal presynaptic calcium channels in brain functioning in neurotransmitter release. They are composed of the pore-forming CaV2.1 α1 subunit and the auxiliary α2δ-2 and ß4 subunits. ß4 is encoded by CACNB4, and its multiple splice variants serve isoform-specific functions as channel subunits and transcriptional regulators in the nucleus. In two siblings with intellectual disability, psychomotor retardation, blindness, epilepsy, movement disorder and cerebellar atrophy we identified rare homozygous variants in the genes LTBP1, EMILIN1, CACNB4, MINAR1, DHX38 and MYO15 by whole-exome sequencing. In silico tools, animal model, clinical, and genetic data suggest the p.(Leu126Pro) CACNB4 variant to be likely pathogenic. To investigate the functional consequences of the CACNB4 variant, we introduced the corresponding mutation L125P into rat ß4b cDNA. Heterologously expressed wild-type ß4b associated with GFP-CaV1.2 and accumulated in presynaptic boutons of cultured hippocampal neurons. In contrast, the ß4b-L125P mutant failed to incorporate into calcium channel complexes and to cluster presynaptically. When co-expressed with CaV2.1 in tsA201 cells, ß4b and ß4b-L125P augmented the calcium current amplitudes, however, ß4b-L125P failed to stably complex with α1 subunits. These results indicate that p.Leu125Pro disrupts the stable association of ß4b with native calcium channel complexes, whereas membrane incorporation, modulation of current density and activation properties of heterologously expressed channels remained intact. Wildtype ß4b was specifically targeted to the nuclei of quiescent excitatory cells. Importantly, the p.Leu125Pro mutation abolished nuclear targeting of ß4b in cultured myotubes and hippocampal neurons. While binding of ß4b to the known interaction partner PPP2R5D (B56δ) was not affected by the mutation, complex formation between ß4b-L125P and the neuronal TRAF2 and NCK interacting kinase (TNIK) seemed to be disturbed. In summary, our data suggest that the homozygous CACNB4 p.(Leu126Pro) variant underlies the severe neurological phenotype in the two siblings, most likely by impairing both channel and non-channel functions of ß4b.

Flexible endoscopic evaluation of swallowing in children with type 1 spinal muscular atrophy.

PURPOSE: This study aimed to report on implementing flexible endoscopic evaluation of swallowing (FEES) in infants and toddlers with type 1 spinal muscular atrophy (SMA). In addition, a comparison of FEES results and clinical scores was carried out. METHODS: A prospective pilot study was conducted including ten symptomatic children with SMA type 1 (two SMN2 copies). They started treatment with one of the three currently approved therapies for SMA at a median age of 3.8 months (range 0.7-8.9). FEES was performed according to a standard protocol using Penetration-Aspiration Scale (PAS) and Murray Secretion Scale as a primary outcome. The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) for motor function, Neuromuscular Disease Swallowing Status Scale (NdSSS), Oral and Swallowing Abilities Tool (OrSAT), and single clinical swallowing-related parameters were also assessed. RESULTS: Distinct swallowing disorders were already evident in eight children at inclusion. The most common findings from FEES were pharyngeal secretion pooling, penetration, and aspiration of saliva and food as well as delayed initiation of swallowing. Despite an average increase in motor function, no comparable improvement was found in swallowing function. None of the surveyed clinical scores showed a significant dependence on PAS in a mixed linear model. CONCLUSIONS: Valuable information regarding the status of dysphagia can be gathered endoscopically, particularly concerning secretion management and when oral intake is limited. Currently available clinical tools for children with type 1 may represent a change in nutritional status but are not yet mature enough to conclude swallowing ability. Further development is still required.

Autosomal dominantly inherited myopathy likely caused by the TNNT1 variant p.(Asp65Ala).

Nemaline myopathies (NEMs) are genetically and clinically heterogenous. Biallelic or monoallelic variants in TNNT1, encoding slow skeletal troponin T1 (TnT1), cause NEM. We report a 2-year-old patient and his mother carrying the heterozygous TNNT1 variant c.194A>C/p.(Asp65Ala) that occurred de novo in the mother. Both had muscle hypotrophy and muscle weakness. Muscle pathology in the proband's mother revealed slow twitch type 1 fiber hypotrophy and fast twitch type 2 fiber hypertrophy that was confirmed by a reduced ratio of slow skeletal myosin to fast skeletal myosin type 2a. Reverse transcription polymerase chain reaction and immunoblotting data demonstrated increased levels of high-molecular-weight TnT1 isoforms in skeletal muscle of the proband's mother that were also observed in some controls. In an overexpression system, complex formation of TnT1-D65A with tropomyosin 3 (TPM3) was enhanced. The previously reported TnT1-E104V and TnT1-L96P mutants showed reduced or no co-immunoprecipitation with TPM3. Our studies support pathogenicity of the TNNT1 p.(Asp65Ala) variant.

Paralog Studies Augment Gene Discovery: DDX and DHX Genes.

Members of a paralogous gene family in which variation in one gene is known to cause disease are eight times more likely to also be associated with human disease. Recent studies have elucidated DHX30 and DDX3X as genes for which pathogenic variant alleles are involved in neurodevelopmental disorders. We hypothesized that variants in paralogous genes encoding members of the DExD/H-box RNA helicase superfamily might also underlie developmental delay and/or intellectual disability (DD and/or ID) disease phenotypes. Here we describe 15 unrelated individuals who have DD and/or ID, central nervous system (CNS) dysfunction, vertebral anomalies, and dysmorphic features and were found to have probably damaging variants in DExD/H-box RNA helicase genes. In addition, these individuals exhibit a variety of other tissue and organ system involvement including ocular, outer ear, hearing, cardiac, and kidney tissues. Five individuals with homozygous (one), compound-heterozygous (two), or de novo (two) missense variants in DHX37 were identified by exome sequencing. We identified ten total individuals with missense variants in three other DDX/DHX paralogs: DHX16 (four individuals), DDX54 (three individuals), and DHX34 (three individuals). Most identified variants are rare, predicted to be damaging, and occur at conserved amino acid residues. Taken together, these 15 individuals implicate the DExD/H-box helicases in both dominantly and recessively inherited neurodevelopmental phenotypes and highlight the potential for more than one disease mechanism underlying these disorders.

Dominant KPNA3 Mutations Cause Infantile-Onset Hereditary Spastic Paraplegia.

OBJECTIVE: Hereditary spastic paraplegia (HSP) is a highly heterogeneous neurologic disorder characterized by lower-extremity spasticity. Here, we set out to determine the genetic basis of an autosomal dominant, pure, and infantile-onset form of HSP in a cohort of 8 patients with a uniform clinical presentation. METHODS: Trio whole-exome sequencing was used in 5 index patients with infantile-onset pure HSP to determine the genetic cause of disease. The functional impact of identified genetic variants was verified using bioinformatics and complementary cellular and biochemical assays. RESULTS: Distinct heterozygous KPNA3 missense variants were found to segregate with the clinical phenotype in 8 patients; in 4 of them KPNA3 variants had occurred de novo. Mutant karyopherin-α3 proteins exhibited a variable pattern of altered expression level, subcellular distribution, and protein interaction. INTERPRETATION: Our genetic findings implicate heterozygous variants in KPNA3 as a novel cause for autosomal dominant, early-onset, and pure HSP. Mutant karyopherin-α3 proteins display varying deficits in molecular and cellular functions, thus, for the first time, implicating dysfunctional nucleocytoplasmic shuttling as a novel pathomechanism causing HSP. ANN NEUROL 2021;90:738-750.

Health-Related Quality of Life and mental health of families with children and adolescents affected by rare diseases and high disease burden: the perspective of affected children and their siblings.

BACKGROUND: Advances in genetic and pharmaceutical technology and pediatric care have enabled treatment options for an increasing number of rare diseases in affected children. However, as current treatment options are primarily of palliative nature, the Health-Related Quality of Life (HRQoL) and mental health of this impaired population and their siblings are of increasing importance. Among children and adolescents with rare diseases, those who are technology-dependent carry a high disease burden and are selected as the target population in our study. In a cross-sectional observational design, the children's HRQoL was assessed with the DISABKIDS (DCGM-37) as well as KIDSCREEN-27, while mental health was assessed with the Strengths and Difficulties Questionnaire (SDQ) by both the affected children, their parents, and siblings. RESULTS: Results of the study sample were compared to normative data. Affected children scored significantly lower than the norm on almost all HRQoL subscales as reported by parent and child. From the parental perspective, more mental health subscales were significantly impaired compared to the child's perspective. Siblings showed no impairment in HRQoL as well as significantly fewer behavioral problems and higher prosocial behavior regarding their mental health compared to the norm. CONCLUSION: Children and adolescents with rare diseases seem particularly impaired in social and emotional aspects of HRQoL and mental health. Interventions may focus primarily on promoting social skills, fostering prosocial behavior and peer relationships.

Evaluation of putative CSF biomarkers in paediatric spinal muscular atrophy (SMA) patients before and during treatment with nusinersen.

Spinal muscular atrophy (SMA) is a genetic neurodegenerative disorder leading to immobilization and premature death. Currently, three alternative therapeutic options are available. Therefore, biomarkers that might reflect or predict the clinical course of the individual patient with treatment are of great potential use. Currently, the antisense oligonucleotide nusinersen is the prevalent and longest validated therapy for SMA. We analysed CSF candidate biomarkers for degenerative CNS processes (namely phosphorylated heavy chain (pNf-H), light-chain neurofilaments (NfL), total tau protein (T-Tau), neurogranin, ß-secretase BACE-1 and alpha-synuclein) in 193 CSF samples of 44 paediatric SMA types 1, 2 and 3 patients before and under nusinersen treatment and related them to standardized clinical outcome scores in a single-centre pilot study. pNf-H and NfL correlated with disease severity and activity, emphasizing their relevance as marker of neuronal loss and clinical outcome. T-Tau was significantly correlated with motor function scores in SMA type 1 making it an interesting marker for treatment response. Additionally, baseline T-Tau levels were elevated in most SMA patients possibly reflecting the extension of neuronal degeneration in paediatric-onset SMA. Further investigations of these CSF proteins might be beneficial for paediatric SMA subtypes and treatment modalities as an indicator for clinical outcome and should be analysed in larger cohorts.

New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics.

PURPOSE: A few de novo missense variants in the cytoplasmic FMRP-interacting protein 2 (CYFIP2) gene have recently been described as a novel cause of severe intellectual disability, seizures, and hypotonia in 18 individuals, with p.Arg87 substitutions in the majority. METHODS: We assembled data from 19 newly identified and all 18 previously published individuals with CYFIP2 variants. By structural modeling and investigation of WAVE-regulatory complex (WRC)-mediated actin polymerization in six patient fibroblast lines we assessed the impact of CYFIP2 variants on the WRC. RESULTS: Sixteen of 19 individuals harbor two previously described and 11 novel (likely) disease-associated missense variants. We report p.Asp724 as second mutational hotspot (4/19 cases). Genotype-phenotype correlation confirms a consistently severe phenotype in p.Arg87 patients but a more variable phenotype in p.Asp724 and other substitutions. Three individuals with milder phenotypes carry putative loss-of-function variants, which remain of unclear pathogenicity. Structural modeling predicted missense variants to disturb interactions within the WRC or impair CYFIP2 stability. Consistent with its role in WRC-mediated actin polymerization we substantiate aberrant regulation of the actin cytoskeleton in patient fibroblasts. CONCLUSION: Our study expands the clinical and molecular spectrum of CYFIP2-related neurodevelopmental disorder and provides evidence for aberrant WRC-mediated actin dynamics as contributing cellular pathomechanism.

Prevalence and clinical prediction of mitochondrial disorders in a large neuropediatric cohort.

Neurological symptoms are frequent and often a leading feature of childhood-onset mitochondrial disorders (MD) but the exact incidence of MD in unselected neuropediatric patients is unknown. Their early detection is desirable due to a potentially rapid clinical decline and the availability of management options. In 491 children with neurological symptoms, a comprehensive diagnostic work-up including exome sequencing was performed. The success rate in terms of a molecular genetic diagnosis within our cohort was 51%. Disease-causing variants in a mitochondria-associated gene were detected in 12% of solved cases. In order to facilitate the clinical identification of MDs within neuropediatric cohorts, we have created an easy-to-use bedside-tool, the MDC-NP. In our cohort, the MDC-NP predicted disease conditions related to MDs with a sensitivity of 0.83, and a specificity of 0.96.

Clinical and Magnetic Resonance Imaging Outcome Predictors in Pediatric Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

OBJECTIVE: To evaluate disease symptoms, and clinical and magnetic resonance imaging (MRI) findings and to perform longitudinal volumetric MRI analyses in a European multicenter cohort of pediatric anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) patients. METHODS: We studied 38 children with NMDARE (median age = 12.9 years, range =1-18) and a total of 82 MRI scans for volumetric MRI analyses compared to matched healthy controls. Mixed-effect models and brain volume z scores were applied to estimate longitudinal brain volume development. Ordinal logistic regression and ordinal mixed models were used to predict disease outcome and severity. RESULTS: Initial MRI scans showed abnormal findings in 15 of 38 (39.5%) patients, mostly white matter T2/fluid-attenuated inversion recovery hyperintensities. Volumetric MRI analyses revealed reductions of whole brain and gray matter as well as hippocampal and basal ganglia volumes in NMDARE children. Longitudinal mixed-effect models and z score transformation showed failure of age-expected brain growth in patients. Importantly, patients with abnormal MRI findings at onset were more likely to have poor outcome (Pediatric Cerebral Performance Category score > 1, incidence rate ratio = 3.50, 95% confidence interval [CI] = 1.31-9.31, p = 0.012) compared to patients with normal MRI. Ordinal logistic regression models corrected for time from onset confirmed abnormal MRI at onset (odds ratio [OR] = 9.90, 95% CI = 2.51-17.28, p = 0.009), a presentation with sensorimotor deficits (OR = 13.71, 95% CI = 2.68-24.73, p = 0.015), and a treatment delay > 4 weeks (OR = 5.15, 95% CI = 0.47-9.82, p = 0.031) as independent predictors of poor clinical outcome. INTERPRETATION: Children with NMDARE exhibit significant brain volume loss and failure of age-expected brain growth. Abnormal MRI findings, a clinical presentation with sensorimotor deficits, and a treatment delay > 4 weeks are associated with worse clinical outcome. These characteristics represent promising prognostic biomarkers in pediatric NMDARE. ANN NEUROL 2020 ANN NEUROL 2020;88:148-159.

Intrathecal Administration of Nusinersen in Pediatric SMA Patients with and without Spine Deformities: Experiences and Challenges over 3 Years in a Single Center.

Spinal muscular atrophy (SMA) is a rare neurodegenerative disease leading to progressive muscular atrophy, respiratory failure, and premature death. Secondary thorax and spine deformities are frequent. In July 2017, the antisense oligonucleotide nusinersen (Spinraza) was approved for the recurrent lifelong intrathecal treatment of SMA in Europe. Lumbar punctures are challenging especially in SMA patients with severe spine deformities and after spine surgery. In the light of alternative SMA therapies that are available or are expected to be available soon and which are administered orally or via one-time infusion, an appraisal of the established therapy is significant. Discussion about which therapy is the best for each individual patient will have to include not only the safety and efficacy of data but also the application form and its burden for the patient and the health care system. Therefore, we analyzed our 3-year experiences and challenges with 478 lumbar puncture procedures in 61 pediatric SMA patients with and without spine deformities or instrumentation.

De Novo Variants in GRIA4 Lead to Intellectual Disability with or without Seizures and Gait Abnormalities.

Using trio whole-exome sequencing, we have identified de novo heterozygous pathogenic variants in GRIA4 in five unrelated individuals with intellectual disability and other symptoms. GRIA4 encodes an AMPA receptor subunit known as GluR4, which is found on excitatory glutamatergic synapses and is important for learning and memory. Four of the variants are located in the highly conserved SYTANLAAF motif in the transmembrane protein M3, and the fifth is in an extra-cellular domain. Molecular modeling of the altered protein showed that three of the variants in the SYTANLAAF motif orient toward the center of the pore region and most likely lead to disturbance of the gating mechanism. The fourth variant in the SYTANLAAF motif most likely results in reduced permeability. The variant in the extracellular domain potentially interferes with the binding between the monomers. On the basis of clinical information and genetic results, and the fact that other subunits of the AMPA receptor have already been associated with neurodevelopmental disorders, we suggest that pathogenic de novo variants in GRIA4 lead to intellectual disability with or without seizures, gait abnormalities, problems of social behavior, and other variable features.

Mutations in EXTL3 Cause Neuro-immuno-skeletal Dysplasia Syndrome.

EXTL3 regulates the biosynthesis of heparan sulfate (HS), important for both skeletal development and hematopoiesis, through the formation of HS proteoglycans (HSPGs). By whole-exome sequencing, we identified homozygous missense mutations c.1382C>T, c.1537C>T, c.1970A>G, and c.2008T>G in EXTL3 in nine affected individuals from five unrelated families. Notably, we found the identical homozygous missense mutation c.1382C>T (p.Pro461Leu) in four affected individuals from two unrelated families. Affected individuals presented with variable skeletal abnormalities and neurodevelopmental defects. Severe combined immunodeficiency (SCID) with a complete absence of T cells was observed in three families. EXTL3 was most abundant in hematopoietic stem cells and early progenitor T cells, which is in line with a SCID phenotype at the level of early T cell development in the thymus. To provide further support for the hypothesis that mutations in EXTL3 cause a neuro-immuno-skeletal dysplasia syndrome, and to gain insight into the pathogenesis of the disorder, we analyzed the localization of EXTL3 in fibroblasts derived from affected individuals and determined glycosaminoglycan concentrations in these cells as well as in urine and blood. We observed abnormal glycosaminoglycan concentrations and increased concentrations of the non-sulfated chondroitin disaccharide D0a0 and the disaccharide D0a4 in serum and urine of all analyzed affected individuals. In summary, we show that biallelic mutations in EXTL3 disturb glycosaminoglycan synthesis and thus lead to a recognizable syndrome characterized by variable expression of skeletal, neurological, and immunological abnormalities.

Nine newly identified individuals refine the phenotype associated with MYT1L mutations.

Both point mutations and deletions of the MYT1L gene as well as microdeletions of chromosome band 2p25.3 including MYT1L are associated with intellectual disability, obesity, and behavioral problems. Thus, MYT1L is assumed to be the-at least mainly-causative gene in the 2p25.3 deletion syndrome. Here, we present comprehensive descriptions of nine novel individuals bearing MYT1L mutations; most of them single nucleotide variants (SNVs). This increases the number of known individuals with causative deletions or SNVs of MYT1L to 51. Since eight of the nine novel patients bear mutations affecting MYT1L only, the total number of such individuals now nearly equals the number of individuals with larger microdeletions affecting additional genes, allowing for a comprehensive phenotypic comparison of these two patient groups. For example, 55% of the individuals with mutations affecting MYT1L only were overweight or obese as compared to 86% of the individuals with larger microdeletions. A similar trend was observed regarding short stature with 5 versus 35%, respectively. However, these differences were nominally significant only after correction for multiple testing, further supporting the hypothesis that MYT1L haploinsufficiency is central to the 2p25.3 deletion phenotype. Most importantly, the large number of individuals with MYT1L mutations presented and reviewed here allowed for the delineation of a more comprehensive clinical picture. Seizures, postnatal short stature, macrocephaly, and microcephaly could be shown to be over-represented among individuals with MYT1L mutations.

The Clinical Picture of a Bilateral Perisylvian Syndrome as the Initial Symptom of Mega-Corpus-Callosum Syndrome due to a MAST1-Gene Mutation.

Congenital bilateral perisylvian syndrome (CBPS) is a rare neurological disorder associated with typical clinical and imaging features such as bilateral symmetrical polymicrogyria, either exclusively or mainly affecting the perisylvian region of the brain. We present a girl with the typical clinical picture of a CBPS and a complex migration disorder, predominantly presenting as bilateral symmetrical polymicrogyria associated with corpus callosum hyperplasia, ventricular dilation, and pontine hypoplasia. At the age of 6 months, the girl showed a profound global developmental delay, seizures refractory to treatment, and severe oromotor dysfunction. Exome analysis revealed a de novo mutation in microtubule-associated serine/threonine kinase 1 (MAST1). Recently, mutations in this gene were described in six patients with a cortical migration disorder named mega-corpus-callosum syndrome with cerebellar hypoplasia. Although all patients present the clinical and imaging features of CBPS, a clear assignment between CBPS and MAST1 mutations has not been reported yet.

The impact of long-term ventilator-use on health-related quality of life and the mental health of children with neuromuscular diseases and their families: need for a revised perspective?

BACKGROUND: Life extension by medical interventions and health-related quality of life (HRQOL) are sometimes conflicting aspects of medical care. Long-term ventilation in children with neuromuscular disease is a well-established life-extending procedure and often at the center of this conflict. HRQOL and the mental health of affected children and their families become even more important in respect to emerging therapies in neuromuscular diseases with longer life-expectancy of treated patients and considerable costs of medical treatment. METHODS: We performed a questionnaire survey in a total of forty-three families of children with neuromuscular disease treated in the University Medical Center Hamburg-Eppendorf and the Children's Hospital Altona. We evaluated self- and proxy-reported HRQOL and mental health outcomes of affected children and their parents using validated and age-appropriate instruments. RESULTS: Compared to normative data, children with neuromuscular diseases and their families experienced a lower HRQOL and mental health. However, there was no additional negative influence on the overall HRQOL by ventilator use. CONCLUSIONS: As ventilator use was not responsible for the reduction of HRQOL and mental health our data contributes an important aspect to the discussion about life-prolonging procedures, in particular mechanical ventilation, in severly disabled patients.

[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.