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Aicardi Goutieres syndrome (AGS) is an autosomal recessive disorder characterized by severe pre- and postnatal occurring neurological symptoms, e.g. spasticity, dystonia and psychomotoric retardation, abnormalities in cerebrospinal fluid and specific alterations in neuroimaging, e.g. calcification of basal ganglia, white matter degeneration and brain atrophy(1). Successively, disease-causing mutations within genes involved in nucleic acid metabolism (TREX1, RNASEH2A/B/C, SAMHD1, ADAR1), or signaling (IFIH1) were identified.

Nusinersen is the first disease-modifying therapy for spinal muscular atrophy (SMA), but there are few data on potential long-term endocrinological and metabolic systemic effects of this novel treatment as well as metabolic alterations in SMA itself. In this retrospective and multicentric study, we analyzed anthropometric, endocrinological, and motor function data of 81 pediatric and adult patients with SMA1 to 3 undergoing treatment with nusinersen. In 39 patients (51%), we observed a slight increase in body mass index (BMI) centiles under treatment with nusinersen, especially in patients with SMA2 and in pediatric patients between 3.1 and 12 years. A correlation to the SMN2 copy number or motor function was not found. Additionally, length centiles decreased significantly under treatment. The results of longitudinal endocrinological assessments were interpreted as not clinically significant in most patients; in three patients, the signs of an altered glucose metabolism were present. Our study indicates a putative effect of treatment with nusinersen on BMI, which might be due to a conjoint effect of weight gain and reduction of height velocity, without evidence of correlation to increased muscle function. Further studies need to address specific effects of targeted therapies such as nusinersen or onasemnogene abeparvovec on body composition including fat and muscle mass.

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.

Background Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by muscle weakness and muscle atrophy. Nusinersen acts as a splicing modifier and has recently been approved for intrathecal treatment of SMA. Objective Prior to approval, nusinersen was provided to patients with SMA type 1 in Germany within an Expanded Access Program (EAP). In contrast to previous clinical trials, children of different age groups and different stages of the disease were treated with nusinersen. Methods We conducted a prospective, longitudinal data collection of patients treated with nusinersen within the EAP in seven neuromuscular centers in Germany. Standardized assessments including CHOP-INTEND and HINE-2 motor milestones were performed at baseline and 60 and 180 days after start of treatment. Results Data from 61 SMA type 1 patients (mean age 21.08 months, range 1-93) were available for analysis. After six months of treatment, 47 children (77.0%) improved by ≥4 points in CHOP INTEND score. Mean change in CHOP INTEND score was 9.0±8.0 points. Nineteen patients (31.1%) improved by ≥2 points in HINE-2 motor milestones. Regression analysis revealed age at onset of treatment as major determinant of change in CHOP INTEND from baseline. Conclusion When analyzing a broad spectrum of SMA type 1 patients, many children showed an improvement of motor function after six months of treatment with nusinersen, which is generally not expected within the natural course of the disease. Long-term observation and follow-up of patients with later onset types of SMA are crucial to understand the clinical impact of treatment with nusinersen.

Background Monogenic Interferonopathies are a rare group of inflammatory diseases that are difficult to diagnose in the onset phase given the lack of well-defined disease-markers.1A correlation with interferon-stimulated genes (ISG) has been reported for SIGLEC1 (syn. CD169), in systemic lupus erythematodes (SLE).2 Furthermore, expression of SIGLEC1 on monocytes is the second highest ISG in SLE.3 Objectives To study the relevance of SIGLEC1 as a putative diagnostic marker for early detection of interferonopathies. Methods Clinical data, classical inflammatory markers, blood count values and genetic information were obtained from the medical files of eight patients with genetically confirmed monogenic interferonopathies. SIGLEC1 expression was measured by flow cytometry with a highly standardized quantitative assay with a reference range in healthy controls less than 2500 SIGLEC1 molecules/monocyte. Additionally, transcriptional level of SIGLEC1, IFI44L, IFI27, ISG15 and RSAD2 as type I Interferon stimulated genes were assessed by real-time PCR. Results All eight patients with interferonopathies carried mutations in the genes TREX-1 (n=3), IFIH-1 (n=2), SAMDH1 (n=2) and RNASE2HB (n=1). Mean age of patients was 12 years (range 6 months to 49 years). Six of eight patients showed neurological symptoms consistent with Aicardi-Goutieres-Syndrome presenting developmental delay and microcephaly. Five patients showed abnormalities on cranial MRI including periventricular calcifications and corpus callosum thinning. Two patients were diagnosed with Singleton-Merten-Syndrome presenting abnormal ossification of extremities and dental anomalies. One patient with homozygous TREX1 mutation presented with postnatal glaucoma, microcephaly, sensorimotor polyneuropathia and recurrent fever with persistent chilblain lesions. All patients had elevated SIGLEC1 levels (mean molecules/monocyte +/- SD: 10272 +/- 3746) without high levels of standard inflammatory markers. In six patients, elevated SIGLEC1 expression showed dysregulation of the type 1 interferon pathway prior to genetic testing. The relative expression (ΔCt) of all ISG’s was significantly elevated in comparison to healthy controls (SIGLEC1 p= 0,0167, ISG15 p=0,0015, RSAD2 p=0,0067, IFIL44 p=0,0001, IFI27 p=0,0056). Conclusion We report high expression of SIGLEC1 in monogenic interferonopathies like Aicardi-Goutieres-Syndrome. Therefore, SIGLEC1 qualifies as an easy accessible and cheap diagnostic marker to screen patients with suspected interferonopathy. References [1] Crow, Y.J., Type I interferonopathies: mendelian type I interferon up-regulation. Curr Opin Immunol, 2015. 32: p. 7-12. [2] Rose, T., et al., Are interferon-related biomarkers advantageous for monitoring disease activity in systemic lupus erythematosus? A longitudinal benchmark study. Rheumatology (Oxford), 2017. 56(9): p. 1618-1626. [3] Biesen, R., et al., Sialic acid-binding Ig-like lectin 1 expression in inflammatory and resident monocytes is a potential biomarker for monitoring disease activity and success of therapy in systemic lupus erythematosus. Arthritis Rheum, 2008. 58(4): p. 1136-45. Disclosure of Interests Banu Orak: None declared, Marc Nikolaus: None declared, Ellen Knierim: None declared, Angela Kaindl: None declared, Manuela Theophil: None declared, Axel Panzer: None declared, Barbara Zieba: None declared, Frederic Ebstein: None declared, Elke Kruger: None declared, Nadine Unterwalder: None declared, Christian Meisel: None declared, Tilmann Kallinich Grant/research support from: Novartis, Speakers bureau: Sobi, Roche, Novartis, CLB

BACKGROUND: Infantile spasms constitute a severe form of epileptic encephalopathy. In the International Collaborative Infantile Spasms Study (ICISS), we showed that combining vigabatrin with hormonal therapy was more effective than hormonal therapy alone at stopping spasms between days 14 and 42 of treatment. In this planned follow-up, we aimed to assess whether combination therapy was associated with improved developmental and epilepsy outcomes at 18 months of age.METHODS: In ICISS, a multicentre, open-label, randomised controlled trial, infants were enrolled from 102 hospitals (three in Australia, 11 in Germany, two in New Zealand, three in Switzerland, and 83 in the UK). Eligible infants had a clinical diagnosis of infantile spasms and a hypsarrhythmic (or similar) electroencephalogram (EEG) no more than 7 days before enrolment. Participants were randomly assigned (1:1) by a secure website to receive hormonal therapy with vigabatrin or hormonal therapy alone. If parents consented, there was an additional randomisation (1:1) of type of hormonal therapy used (prednisolone or tetracosactide depot). Block randomisation was stratified for hormonal treatment and risk of developmental impairment. Parents and clinicians were not masked to therapy, but investigators assessing epilepsy and developmental outcomes at 18 months were masked to treatment allocation. Minimum doses were oral prednisolone 10 mg four times a day or intramuscular tetracosactide depot 0·5 mg (40 IU) on alternate days with or without oral vigabatrin 100 mg/kg per day. The primary outcome at 18 months was development as assessed by the Vineland Adaptive Behaviour Scales (VABS) composite score. Secondary outcomes were the presence or absence of epileptic seizures or infantile spasms in the previous 28 days, as recorded by parents and carers, and the use of any anti-epileptic treatment (including ketogenic diet) in the previous 28 days. Analysis was by intention to treat. The trial is registered with the ISRCTN registry, number 54363174, and EudraCT, number 2006-000788-27.FINDINGS: Between March 7, 2007, and May 22, 2014, 766 infants were screened and, of those, 377 were randomly assigned to hormonal therapy with vigabatrin (n=186) or hormonal therapy alone (n=191). 362 infants were assessed for developmental and epilepsy outcomes at 18 months, 181 in each treatment group. Mean VABS scores did not differ significantly between the combination therapy group and the hormonal therapy alone group (73·9 [SE 1·3] vs 72·7 [1·4], difference -1·2 [95% CI -4·9 to 2·6], p=0·55). Presence of epilepsy at the assessment at age 18 months was similar in both treatment groups (54 [30·0%] of 180 infants who received combination therapy vs 52 [29·2%] of 178 who received hormonal therapy alone; difference 0·8% [95% CI -8·8 to 10·4], p=0·90). Presence of spasms was also similar in both treatment groups (27 [15·0%] of 180 infants on combination therapy vs 28 [15·7%] of 178 on hormonal therapy alone; difference 0·7% [95% CI -6·9 to 8·3], p=0·85). At the 18-month assessment, 158 (44·1%) of 358 infants were on some form of anti-epileptic treatment. Initial control of spasms between days 14 and 42 of treatment was associated with higher mean VABS scores at 18 months (79·1 [SE 1·2] vs 63·2 [1·1], difference 15·9 [95% CI 12·4 to 19·5], pINTERPRETATION: Combination therapy did not result in improved developmental or epilepsy outcomes at 18 months. However, early clinical response to treatment was associated with improved developmental and epilepsy outcomes at 18 months. Longer lead-time to treatment was associated with poorer outcomes. Rapid diagnosis and effective treatment of infantile spasms could therefore improve outcomes.FUNDING: The Castang Foundation, Bath Unit for Research in Paediatrics, National Institute of Health Research, the Royal United Hospitals Bath NHS Foundation Trust, BRONNER-BENDER Stiftung/Gernsbach, University Children's Hospital Zurich.