Abstract
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.
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
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 ...β4 subunits. β4 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 β4b cDNA. Heterologously expressed wild-type β4b associated with GFP-CaV1.2 and accumulated in presynaptic boutons of cultured hippocampal neurons. In contrast, the β4b-L125P mutant failed to incorporate into calcium channel complexes and to cluster presynaptically. When co-expressed with CaV2.1 in tsA201 cells, β4b and β4b-L125P augmented the calcium current amplitudes, however, β4b-L125P failed to stably complex with α1 subunits. These results indicate that p.Leu125Pro disrupts the stable association of β4b with native calcium channel complexes, whereas membrane incorporation, modulation of current density and activation properties of heterologously expressed channels remained intact. Wildtype β4b was specifically targeted to the nuclei of quiescent excitatory cells. Importantly, the p.Leu125Pro mutation abolished nuclear targeting of β4b in cultured myotubes and hippocampal neurons. While binding of β4b to the known interaction partner PPP2R5D (B56δ) was not affected by the mutation, complex formation between β4b-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 β4b.
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.
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. Keywords: Health-Related Quality of Life, Mental health, Technologically dependent, Siblings
5q spinal muscular atrophy (SMA) is a disabling and life-limiting neuromuscular disease. In recent years, novel therapies have shown to improve clinical outcomes. Yet, the absence of reliable ...biomarkers renders clinical assessment and prognosis of possibly already affected newborns with a positive newborn screening result for SMA imprecise and difficult. Therapeutic decisions and stratification of individualized therapies remain challenging, especially in symptomatic children. The aim of this proof-of-concept and feasibility study was to explore the value of .sup.1H-nuclear magnetic resonance (NMR)-based metabolic profiling in identifying non-invasive diagnostic and prognostic urinary fingerprints in children and adolescents with SMA. Urine samples were collected from 29 treatment-naïve SMA patients (5 pre-symptomatic, 9 SMA 1, 8 SMA 2, 7 SMA 3), 18 patients with Duchenne muscular dystrophy (DMD) and 444 healthy controls. Using machine-learning algorithms, we propose a set of prediction models built on urinary fingerprints that showed potential diagnostic value in discriminating SMA patients from controls and DMD, as well as predictive properties in separating between SMA types, allowing predictions about phenotypic severity. Interestingly, preliminary results of the prediction models suggest additional value in determining biochemical onset of disease in pre-symptomatic infants with SMA identified by genetic newborn screening and furthermore as potential therapeutic monitoring tool. This study provides preliminary evidence for the use of .sup.1H-NMR-based urinary metabolic profiling as diagnostic and prognostic biomarker in spinal muscular atrophy.
Background
Spinal muscular atrophy (SMA) is a genetic neurodegenerative disease leading to muscular weakness and premature death. Three therapeutic options are currently available including gene ...replacement therapy (GRT), which is potentially cardiotoxic. High-sensitive cardiac troponin I (hs-cTnI) is widely used to monitor potential cardiac contraindications or side effects of GRT, but reference data in healthy newborns are limited and lacking in neonates with SMA. The aim of this study is to determine the range of pre-therapeutic hs-cTnI concentrations in neonates with SMA and to provide guidance for the assessment of these values.
Methods
Hs-cTnI levels, genetic and clinical data of 30 newborns (age range 2–26 days) with SMA were retrospectively collected from 6 German neuromuscular centers. In addition, hs-cTnI levels were measured in 16 neonates without SMA.
Results
The median hs-cTnI concentration in neonates with SMA was 39.5 ng/L (range: 4–1205). In 16 newborns with SMA, hs-cTnI levels were above the test-specific upper reference limit (URL). Exploratory statistical analysis revealed no relevant correlation between hs-cTnI levels and gender, gestational age, mode of delivery, SMN2 copy number, symptoms of SMA or abnormal cardiac findings.
Discussion
Our results suggest higher hs-cTnI plasma levels in newborns with and without SMA compared to assay-specific reference values generated in adults. Given the wide range of hs-cTnI values in neonates with SMA, hs-cTnI levels must be determined before treatment in each patient and post-treatment elevations should be interpreted in the context of the course rather than as individual values.
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, β‐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.
PDF
