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BackgroundTuberous Sclerosis Complex (TSC) is a rare multisystem disorder. In 2012 diagnostic criteria for TSC were revised. However, data on the incidence of TSC are limited.MethodsProspective, national surveillance study in Germany over a 2-year-period (03/2015–02/2017) using current revised criteria for TSC. Patients up to the age of 18 years with a new diagnosis of definite or possible TSC (clinical and/or genetic) were included. The aims of this study were 1) to generate up-to-date data on the incidence of definite or possible TSC, 2) to assess age at first diagnosis, and 3) to compare these data with previous epidemiologic data.ResultsIn total, 86 patients met inclusion criteria (definite or possible TSC) with a median age at diagnosis of 6 months (range: 5 months before birth – 197 months of age). Among patients identified with features of TSC, 73.3% met criteria for definite diagnosis (median age: 7 months) and 26.7% met criteria for a possible diagnosis (median age: 3 months). 55.8% of patients were male. When excluding prenatally diagnosed patients, median age at diagnosis was 11 months with a range of 0 to 197 months. The 3 most common clinical features at diagnosis of TSC were central nervous system involvement in 73.3% patients (of these 95.2% experienced seizures), cutaneous involvement in 58.1% patients (with the most common lesion being hypomelanotic macules in 92%) and cardiac rhabdomyoma in half of the patients. Cardiac rhabdomyoma were detected by prenatal ultrasonography in 22.1% of patients. The presence of cardiac rhabdomyoma was associated with cardiac arrhythmias in 25.6% (about 13% of all diagnosed patients) in our cohort. The overall prevalence of seizure disorders was 69.8%. The annual incidence rate of TSC is estimated at a minimum of 1:17.785 live births. However correcting for underreporting, the estimated incidence rate of definite or possible TSC is approximately 1:6.760–1:13.520 live births in Germany.ConclusionsThis is the first study that assessed prospectively the incidence rate of TSC in children and adolescents using the updated diagnostic criteria of 2012. This prospective surveillance study demonstrates a low age at first diagnosis (median: 6 months), likely due to antenatal detection of cardiac rhabdomyoma. Early diagnosis bears the potential for implementing effective therapies at an earlier stage.Electronic supplementary materialThe online version of this article (10.1186/s13023-018-0870-y) contains supplementary material, which is available to authorized users.

About 15% of Duchenne muscular dystrophy (DMD) cases are caused by point mutations leading to premature stop codons and disrupted synthesis of the dystrophin protein. Stop codon read-through therapy is available with the drug Ataluren (Translarna® by PTC Therapeutics). Following positive results in ambulatory nmDMD (non-sense mutation Duchenne muscular dystrophy) patients, Ataluren received conditional approval in ambulant nmDMD patients by the EMA in 2014. However, there are limited data on non-ambulatory nmDMD patients treated with Ataluren. Here, we report our experience in four non-ambulatory nmDMD patients. Routine investigations included cardiac function, pulmonary function tests and muscle strength. We compared changes in left ventricular fractional shorting, forced volume vital capacity and BMI from two defined time periods (18–26-month period prior to and after Ataluren start). Mean age at loss of ambulation was 10.1 ± 0.5 years, mean age when initiating Ataluren treatment 14.1 ± 1.4 years. Serial echocardiography, pulmonary lung function tests, and assessment of muscle strength indicated mild attenuation of disease progression after initiation of Ataluren treatment. A possible side effect of Ataluren was a reduction in BMI. There were no adverse clinical effects or relevant abnormalities in routine laboratory values. We conclude that Ataluren appears to mildly ameliorate the clinical course in our patients with a good safety profile. However, larger clinical trials are required to assess the role of Ataluren and its long-term impact on disease progression in non-ambulant nmDMD patients.

Aim: To provide data on the inadequate use of emergency medical transports services (EMTS) in children and underlying contributing factors.Methods: This was a prospective single-center cohort study (01/2017-12/2017) performed at the Saarland University Children's Hospital, Homburg, Germany. Patients ≤20 years of age transported by EMTS for suspected acute illness/trauma were included and proportion of inadequate/adequate EMTS use, underlying contributing factors, and additional costs were analyzed.Results: Three hundred seventy-nine patients (mean age: 9.0 ± 6.3 years; 55.7% male, 44.3% female) were included in this study. The three most common reasons for EMTS use were: central nervous system (30.6%), respiratory system affection (14.0%), and traumas (13.2%). ETMS use was categorized as inadequate depending on physician's experience: senior physician (58.8%), pediatrician (54.9%), resident (52.7%). All three physicians considered 127 (33.5%) cases to be medically indicated for transportation by EMTS, and 177 (46.7%) to be medically not indicated. The following parameters were significantly associated with inadequate EMTS use: non-acute onset of symptoms (OR 2.5), parental perception as non-life-threatening (OR 1.7), and subsequent out-patient treatment (OR 4.0). Conversely, transport by an emergency physician (OR 3.5) and first time parental EMTS call (OR 1.7) were associated with adequate use of EMTS. Moreover, a significant relation existed between maternal, respectively, paternal educational status and inadequate EMTS use (each p = 0.01). Using multiple logistic regression analysis, non-acute onset of symptoms (OR 2.2) was associated with inadequate use of EMTS while first time parental EMTS call (OR 1.8), transport by an emergency physician (OR 3.3), and need for in-patient treatment (OR 4.0) were associated with adequate use of EMTS.Conclusion: A substantial number of pediatric EMTS is medically not indicated. Possibly, specific measures including multifaceted educational efforts may be helpful in reducing unnecessary EMTS use.

Tuberous sclerosis complex (TSC) is a genetic multisystem disorder with prominent skin involvement including facial angiofibromas that often appear in early childhood. Here we report the case of a 12-year-old girl with widespread disfiguring facial angiofibromas that were successfully treated with topical rapamycin, a mTOR inhibitor. A sustained remission of skin lesions was documented in detail over a 3-year follow-up. This case highlights the fact that topical rapamycin is a useful option in treating TSC-associated skin lesions. Especially in medically complex patients topical treatment may lessen the need for surgical interventions, reducing the risks of surgery, its adverse effects and permanent scarring. However, there is no standard dose or formulation at present. Topical rapamycin appears safe, but long-term maintenance therapy is necessary to prevent facial lesions from regrowth.

Background and purpose The therapeutic landscape of spinal muscular atrophy (SMA) has changed dramatically during the past 4 years, but treatment responses differ remarkably between individuals, and therapeutic decision‐making remains challenging, underlining the persistent need for validated biomarkers. Methods We applied untargeted proteomic analyses to determine biomarkers in cerebrospinal fluid (CSF) samples of SMA patients under treatment with nusinersen. Identified candidate proteins were validated in CSF samples of SMA patients by Western blot and enzyme‐linked immunosorbent assay. Furthermore, levels of peripheral neurofilament heavy and light chain were determined. Results Untargeted proteomic analysis of CSF samples of three SMA type 1 patients revealed the lysosomal protease cathepsin D as a candidate biomarker. Subsequent validation analysis in a larger cohort of 31 pediatric SMA patients (type 1, n = 12; type 2, n = 9; type 3, n = 6; presymptomatically treated, n = 4; age = 0–16 years) revealed a significant decline of cathepsin D levels in SMA patients aged ≥2 months at the start of treatment. Although evident in all older age categories, this decline was only significant in the group of patients who showed a positive motor response. Moreover, downregulation of cathepsin D was evident in muscle biopsies of SMA patients. Conclusions We identified a decline of cathepsin D levels in CSF samples of SMA patients under nusinersen treatment that was more pronounced in the group of "treatment responders" than in "nonresponders." We believe that our results indicate a suitability of cathepsin D levels as a possible biomarker in SMA also in older patients, in combination with analysis of peripheral neurofilament light chain in adolescents or alone in adult patients.

Neuromuscular disorders (NMDs) of Childhood onset are a genetically heterogeneous group of diseases affecting the anterior horn cell, the peripheral nerve, the neuromuscular junction, or the muscle. For many decades, treatment of NMDs has been exclusively symptomatic. But this has changed fundamentally in recent years due to the development of new drugs attempting either to ameliorate secondary pathophysiologic consequences or to modify the underlying genetic defect itself. While the effects on the course of disease are still modest in some NMDs (e.g., Duchenne muscular dystrophy), new therapies have substantially prolonged life expectancy and improved motor function in others (e.g., spinal muscular atrophy and infantile onset Pompe disease). This review summarizes recently approved medicaments and provides an outlook for new therapies that are on the horizon in this field.

5q-associated spinal muscular atrophy (SMA) is a rare neuromuscular disorder with the leading symptom of a proximal muscle weakness. Three different drugs have been approved by EMA and FDA for the treatment of SMA patients, however long-term experience is still scarce. In contrast to clinical trial data with restricted patient populations and short observation periods, we here report real-world evidence on a broad spectrum of patients with early-onset SMA 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 start of treatment were identified for data analysis. Primary outcome of this analysis was the change in motor function evaluated with the CHOP INTEND score and motor milestones considering WHO criteria. Further, we evaluated data on the need for ventilator support and tube feeding, and mortality. In total, 143 patients with early-onset SMA 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 CHOP INTEND score. Improvements were greater in children less than two 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 SMA. Major improvements in motor function are seen in children younger than two years at start of treatment. Bulbar and respiratory function needs to be closely monitored, as these functions do not improve equivalent to motor function.