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Spinal muscular atrophy (SMA) is an autosomal recessive disorder causing progressive proximal muscular, respiratory, and bulbar weakness. We present outcome data on motor function, ventilation, nutrition, and language development of SMA patients treated with nusinersen in Switzerland. This multicenter, observational study included 44 patients. At treatment initiation, after 2 months and then every 4 months we assessed motor function with the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP–INTEND), Hammersmith Functional Motor Scale expanded (HFMSE) and 6-Minute Walk Test (6MWT). At treatment initiation, patients were 0.1–44.6 years old, treatment duration ranged from 6 to 41 months. All 11 SMA type 1 children achieved higher CHOP-INTEND scores at the last assessment compared to treatment initiation, 4 acquired stable sitting. Six type 1 children were

The natural history of patients with spinal muscular atrophy (SMA) has changed due to advances in standard care and development of targeted treatments. Nusinersen was the first drug approved for the treatment of all SMA patients. The transfer of clinical trial data into a real-life environment is challenging, especially regarding the advice of patients and families to what extent they can expect a benefit from the novel treatment. We report the results of a modified Delphi consensus process among child neurologists from Germany, Austria and Switzerland about the indication or continuation of nusinersen treatment in children with SMA type 1 based on different clinical case scenarios.

In Switzerland, complementary medicine (CM) is officially recognised within the healthcare system and mainly practised in an integrative manner, in conjunction with conventional medicine. As in other countries, there is high demand for and use of CM with children. However, there has so far been no research into the attitude towards, training in and offer of CM among paediatricians in Switzerland. Our study addresses this gap by investigating these topics with an online survey of paediatricians in Switzerland.METHODS: We conducted a national online survey using a 19-item, self- reporting questionnaire among all ordinary and junior members of the Swiss Society of Paediatrics (SSP). A comparison of the study sample with the population of all paediatricians registered with the Swiss Medical Association (FMH) allowed an assessment of the survey’s representativeness. The data analysis was performed on the overall group level as well as for predefined subgroups (e.g. sex, age, language, workplace and professional experience).RESULTS: 1890 paediatricians were approached and 640, from all parts of Switzerland, responded to the survey (response rate 34%). Two thirds of respondents were female, were aged between 35 and 55 years, trained as paediatric generalist and worked in a practice. Apart from young paediatricians in training, the study sample was representative of all Swiss paediatricians. 23% had attended training in CM, most frequently in phytotherapy, homeopathy, acupuncture/traditional Chinese medicine (TCM) and anthroposophic medicine. 65% were interested in CM courses and training. 16% provide CM services to their patients and almost all paediatricians (97%) are asked by patients/parents about CM therapies. More than half of the responding paediatricians use CM for themselves or their families. 42% were willing to contribute to paediatric CM research.CONCLUSIONS: In a representative sample of paediatricians in Switzerland, their personal attitude towards CM is positive, emphasised by great interest in CM training, a willingness to contribute to CM research and a high rate of paediatricians who use CM for themselves and their families. In contrast, the percentage of paediatricians offering CM is currently rather low despite strong demand for CM for children. This study provides key pointers for the future development of complementary and integrative medicine for children in Switzerland.

Objective: To determine whether patients with pyridoxine-responsive seizures but normal biomarkers for antiquitin deficiency and normal sequencing of the ALDH7A1 gene may have PNPO mutations. Methods: We sequenced the PNPO gene in 31 patients who fulfilled the above-mentioned criteria. Results: We were able to identify 11 patients carrying 3 novel mutations of the PNPO gene. In 6 families, a homozygous missense mutation p.Arg225His in exon 7 was identified, while 1 family was compound heterozygous for a novel missense mutation p.Arg141Cys in exon 5 and a deletion c.279_290del in exon 3. Pathogenicity of the respective mutations was proven by absence in 100 control alleles and expression studies in CHO-K1 cell lines. The response to pyridoxine was prompt in 4, delayed in 2, on EEG only in 2, and initially absent in another 2 patients. Two unrelated patients homozygous for the p.Arg225His mutation experienced status epilepticus when switched to pyridoxal 5′-phosphate (PLP). Conclusions: This study challenges the paradigm of exclusive PLP responsiveness in patients with pyridoxal 5′-phosphate oxidase deficiency and underlines the importance of consecutive testing of pyridoxine and PLP in neonates with antiepileptic drug–resistant seizures. Patients with pyridoxine response but normal biomarkers for antiquitin deficiency should undergo PNPO mutation analysis.

OBJECTIVE: Short-chain enoyl-CoA hydratase (ECHS1) is a multifunctional mitochondrial matrix enzyme that is involved in the oxidation of fatty acids and essential amino acids such as valine. Here, we describe the broad phenotypic spectrum and pathobiochemistry of individuals with autosomal-recessive ECHS1 deficiency. METHODS: Using exome sequencing, we identified ten unrelated individuals carrying compound heterozygous or homozygous mutations in ECHS1. Functional investigations in patient-derived fibroblast cell lines included immunoblotting, enzyme activity measurement, and a palmitate loading assay. RESULTS: Patients showed a heterogeneous phenotype with disease onset in the first year of life and course ranging from neonatal death to survival into adulthood. The most prominent clinical features were encephalopathy (10/10), deafness (9/9), epilepsy (6/9), optic atrophy (6/10), and cardiomyopathy (4/10). Serum lactate was elevated and brain magnetic resonance imaging showed white matter changes or a Leigh-like pattern resembling disorders of mitochondrial energy metabolism. Analysis of patients' fibroblast cell lines (6/10) provided further evidence for the pathogenicity of the respective mutations by showing reduced ECHS1 protein levels and reduced 2-enoyl-CoA hydratase activity. While serum acylcarnitine profiles were largely normal, invitro palmitate loading of patient fibroblasts revealed increased butyrylcarnitine, unmasking the functional defect in mitochondrial β-oxidation of short-chain fatty acids. Urinary excretion of 2-methyl-2,3-dihydroxybutyrate - a potential derivative of acryloyl-CoA in the valine catabolic pathway - was significantly increased, indicating impaired valine oxidation. INTERPRETATION: In conclusion, we define the phenotypic spectrum of a new syndrome caused by ECHS1 deficiency. We speculate that both the β-oxidation defect and the block in l-valine metabolism, with accumulation of toxic methacrylyl-CoA and acryloyl-CoA, contribute to the disorder that may be amenable to metabolic treatment approaches.

We describe a 3.5-year-old female with Alpers disease with a POLG genotype of p.A467T/p.G848S and with a lethal outcome. Laboratory investigation revealed elevated CSF neopterin, IL-6, IL-8, IFN-gamma, reduced CSF 5-methyltetrahydrofolate (5MTHF), and increased serum as well as CSF folate receptor blocking autoantibodies. Treatment with oral Leucovorine (5-formyl-tetrahydrofolate) was initiated at 0.25mg/kg bid, and later increased to 4mg/kg bid. Under treatment CSF levels of 5MTHF, seizure frequency and communicative abilities improved. Over a time span of 17months, CSF levels of IL-6 and IFN-gamma decreased, levels of folate receptor blocking autoantibodies continued to raise, whereas CSF IL-8 remained elevated 1500-fold above normal. The child died without apparent stress at the age of 5.5years. Alpers disease, a neurodegenerative disease usually presents in the first years of life as a progressive encephalopathy with multifocal myoclonic seizures, developmental regression, cortical blindness and early death. The underlying genetic defect has been attributed to mutations of the catalytic subunit of the mitochondrial DNA polymerase-gamma leading to an organ-specific mitochondrial DNA depletion syndrome with reduced activity of respiratory chain enzyme complexes in the brain and the liver. A curative therapy is not available. This case report of Alpers disease provides new insights into the pathophysiology of Alpers disease, where mitochondrial dysfunction in conjunction with inflammatory cytokines and blocking folate receptor autoantibodies may lead to a secondary cerebral folate deficiency syndrome. The treatment of the latter provides relief to the patient without stopping the underlying disease.