# Differential Expression of Interferon-Alpha Protein Provides Clues to Tissue Specificity Across Type I Interferonopathies

Lorenzo Lodi, Isabelle Melki, Vincent Bondet, Luis Seabra, Gillian I. Rice, Edwin Carter, Alice Lepelley, Maria José Martin-Niclós, Buthaina Al Adba, Brigitte Bader-Meunier, et al.

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## To cite this version:

Lorenzo Lodi, Isabelle Melki, Vincent Bondet, Luis Seabra, Gillian I. Rice, et al. Differential Expression of Interferon-Alpha Protein Provides Clues to Tissue Specificity Across Type I Interferonopathies. Journal of Clinical Immunology, 2021, 41 (3), pp.603-609. 10.1007/s10875-020-00952-x. pasteur-03236262

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# Differential Expression of Interferon-Alpha Protein Provides Clues to Tissue Specificity Across Type I Interferonopathies

Lorenzo Lodi¹,² · Isabelle Melki¹,³,⁴ · Vincent Bondet⁵ · Luis Seabra¹ · Gillian I. Rice⁶ · Edwin Carter⁷ · Alice Lepelley¹ · Maria José Martin-Niclós¹ · Buthaina Al Adba⁸ · Brigitte Bader-Meunier⁴ · Magalie Barth⁹ · Thomas Blauwblomme¹⁰ · Christine Bodemer¹¹ · Odile Boespflug-Tanguy¹² · Russel C. Dale¹³ · Isabelle Desguerre¹⁴ · Camille Ducrocq³ · Fabienne Dulieu¹⁵ · Cécile Dumaine³ · Pierre Ellul¹⁶,¹⁷ · Alice Hadchouel¹⁸ · Véronique Hentgen¹⁹ · Miguel Hié²⁰ · Marie Hully¹⁴ · Eric Jeziorski²¹ · Romain Lévy⁴ · Fanny Mochel²²,²³ · Simona Orcesi²⁴,²⁵ · Sandrine Passemard¹² · Marie Pouletty³ · Pierre Quartier⁴ · Florence Renaldo²⁶ · Rainer Seidl²⁷ · Jay Shetty²⁸ · Bénédicte Neven⁴ · Stéphane Blanche⁴ · Darragh Duffy⁵ · Yanick J. Crow¹,⁷ · Marie-Louise Frémond¹,⁴ ID

Received: 23 October 2020 / Accepted: 22 December 2020 / Published online: 7 January 2021
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature 2021

## Abstract

Whilst upregulation of type I interferon (IFN) signaling is common across the type I interferonopathies (T1Is), central nervous system (CNS) involvement varies between these disorders, the basis of which remains unclear. We collected cerebrospinal fluid (CSF) and serum from patients with Aicardi-Goutières syndrome (AGS), STING-associated vasculopathy with onset in infancy (SAVI), presumed monogenic T1Is (pT1I), childhood systemic lupus erythematosus with neuropsychiatric features (nSLE), non-IFN-related autoinflammation (AI) and non-inflammatory hydrocephalus (as controls). We measured IFN-alpha protein using digital ELISA. Eighty-two and 63 measurements were recorded respectively in CSF and serum of 42 patients and 6 controls. In an intergroup comparison (taking one sample per individual), median CSF IFN-alpha levels were elevated in AGS, SAVI, pT1I, and nSLE compared to AI and controls, with levels highest in AGS compared to all other groups. In AGS, CSF IFN-alpha concentrations were higher than in paired serum samples. In contrast, serum IFN was consistently higher compared to CSF levels in SAVI, pT1I, and nSLE. Whilst IFN-alpha is present in the CSF and serum of all IFN-related diseases studied here, our data suggest the primary sites of IFN production in the monogenic T1I AGS and SAVI are, respectively, the CNS and the periphery. These results inform the diagnosis of, and future therapeutic approaches to, monogenic and multifactorial T1Is.

**Keywords** Interferon · cerebrospinal fluid · Aicardi-Goutières syndrome · STING-associated vasculopathy with onset in infancy · systemic lupus erythematosus

## Introduction

Beyond their function in mediating an antiviral state, type I interferons (IFN) play an important role in the pathogenesis of several human diseases [1]. In 2011, the term type I interferonopathy (T1I) was coined to define a novel set of Mendelian inborn errors [2], the neuroinflammatory disorder

Aicardi-Goutières syndrome (AGS) being the first identified [3]. Since that time, there has been the expansion of this grouping [4] including STING-associated vasculopathy with onset in infancy (SAVI), proteasome-associated autoinflammatory syndromes (PRAAS), and COPA syndrome. By definition, these monogenic disorders share the common feature of upregulated type I IFN signaling, which is considered central to disease pathogenesis (i.e. not merely representing a biomarker). Furthermore, enhanced type I IFN is also observed in several multifactorial disorders, including systemic lupus erythematosus (SLE) and dermatomyositis (DM) [5]. Although some features are shared across certain of these phenotypes (for example intracranial calcification (ICC) and vasculitic-like skin involvement), phenotypic differences are also notable (for example severe pulmonary

<footnote>☒ Yanick J. Crow
yanickcrow@mac.com</footnote>

<footnote>Marie-Louise Frémond
marie-louise.fremond@aphp.fr</footnote>
disease is common in SAVI, COPA syndrome and DM, but only very rarely reported in AGS). The basis of such differential tissue involvement remains unclear.

Central nervous system (CNS) disease is a prominent feature of certain T1Is, with ICC serving as an important diagnostic indicator of enhanced IFN activity in the cerebrospinal fluid (CSF) [6]. However, the direct quantification of IFN in the CSF, and the periphery, has proven challenging, with a single-molecule array (Simoa) ultra-sensitive digital ELISA to measure IFN-alpha (IFNα) described only recently [7].

Here, we quantified IFNα in the CSF and blood of the known T1Is AGS and SAVI, presumed monogenic T1Is (pT1I) and a multifactorial IFN-related disorder, SLE with neuropsychiatric features (nSLE), comparing these data with samples from children with non-IFN-related autoinflammation (AI) and non-inflammatory hydrocephalus (as controls). In doing so, we hoped to determine if differential tissue expression of type I IFN might explain some of the phenotypic diversity between these diseases.

# Methods

## Patient Cohort

We retrospectively identified all patients referred to our laboratory between December 2014 and December 2019 for the evaluation of CSF IFNα protein levels. Six controls with non-inflammatory hydrocephalus were also included in the study. We recorded the concentration of IFNα in the CSF and in paired (or temporally closely related—range 1–4 days) samples of serum or plasma, using a pan-IFNα subtype antibody on a digital

ELISA (single-molecule array: Simoa) platform [7], as well as the expression of IFN-stimulated genes (ISGs) [8] where available. Patients included were subsequently assigned to one of the five disease groups: AGS, SAVI, pT1I, nSLE, and AI. See Supplementary Methods for additional details.

## Statistical Analysis

Analyses were performed with PRISM software (v6 for Macintosh, GraphPad Inc.) as indicated in the figure legends. A *p* value less than 0.05 was considered significant.

## Results

### Composition of the Study Groups

We collected 93 CSF samples from 59 individuals, comprising 53 patients and 6 controls. We excluded 11 patients not fulfilling inclusion criteria. Thus, 82 CSF samples deriving from 42 patients and 6 controls were included in our analyses (Figure S1 and Table 1). Sixty-three serum or plasma samples and 39 ISG scores were recorded in peripheral blood, taken concomitantly or within four days of CSF sampling.

The AGS group included 13 patients from 12 families with a median age of 4.8 (range 0.1–38.1) years and a molecularly confirmed diagnosis due to mutations in one of four AGS-related genes (*RNASEH2B* [9] *n* = 6, *ADAR1* [10] *n* = 3, *IFIH1* [11] *n* = 2, *TREX1* [12] *n* = 2), and comprised 33 CSF samples (Table S2 and S3). Four SAVI patients (7 CSF samples) carried a previously

<table><caption>**Table 1** Number of patients, samples and median IFNα protein concentration in the CSF according to phenotype</caption><thead><tr><th>Phenotype</th><th>Patient numbers</th><th>Sex ratio M:F</th><th>Age at first sampling in y (median; IQR)</th><th>Sample numbers</th><th>Samples per patient (median; range)</th><th>IFNα CSF fg/ml (median; IQR)</th></tr></thead><tbody><tr><td>AGS</td><td>13</td><td>6:7</td><td>10.80 (1.4–15.1)</td><td>33</td><td>3 (1–4)</td><td>765.71 (122.83–4407–.19)</td></tr><tr><td>SAVI</td><td>4</td><td>3:1</td><td>6.20 (1.4–14.6)</td><td>7</td><td>1 (1–4)</td><td>49.92 (28.26–61.04)</td></tr><tr><td>pT1I</td><td>5</td><td>2:3</td><td>15.75 (10.7–16.9)</td><td>8</td><td>1 (1–3)</td><td>77.23 (23.17–153.5–9)</td></tr><tr><td>nSLE</td><td>14</td><td>3:11</td><td>15.15 (13.3–16.1)</td><td>22</td><td>1 (1–4)</td><td>25.52 (8.81–295.15)</td></tr><tr><td>AI</td><td>6</td><td>2:4</td><td>9.50 (5.4–13.4)</td><td>6</td><td>1</td><td>1.28 (0.93–2.16)</td></tr><tr><td>Controls</td><td>6</td><td>2:4</td><td>3.06 (0.1–12.4)</td><td>6</td><td>1</td><td>0.64 (0.64–1.74)</td></tr></tbody></table>

AGS, Aicardi-Goutières syndrome; AI, autoinflammatory disorder (non-interferon mediated); CSF, cerebrospinal fluid; F, female; IFNα, interferon α; IQR, interquartile range; M, male; nSLE, systemic lupus erythematosus with neuropsychiatric features; pT1I, presumed monogenic type I interferonopathy; SAVI, STING-associated vasculopathy with onset in infancy; y, years
**Fig. 1** Concentration of CSF IFNα in patient cohorts and IFNα levels in the CSF of patients with AGS according to age. **a** IFNα protein concentration assessed by Simoa in the first cerebrospinal fluid (CSF) sample recorded for controls (n = 6) and patients with AGS (n = 13), SAVI (n = 4), pT1I (n = 5), nSLE (n = 14), and AI (n = 6). Comparison among groups was performed with the one-way ANOVA test (Kruskal–Wallis) and Dunn’s multiple comparison testing (*p* < 0.05, **p** < 0.01, ***p* < 0.001, ****p < 0.0001). Red horizontal bars indicate median levels. **b** IFNα protein concentration assessed by Simoa in the first cerebrospinal fluid (CSF) sample recorded in AGS patients (n = 13). Values are plotted by age. AGS, Aicardi-Goutières syndrome; AI, classical autoinflammatory disorder non-interferon mediated; CSF, cerebrospinal fluid; IFNα, interferon-alpha; nSLE, systemic lupus erythematosus with neuropsychiatric features; pT1I, presumed monogenic type I interferonopathy; SAVI, STING-associated vasculopathy with onset in infancy

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reported mutation in *STING*1 [13, 14] (Table S2). Among the five pT1I patients (8 CSF samples), only one had a mutation identified (in *BLM* [15]), with one of the six AI patients (6 CSF samples) harboring a recognized mutation in *NLRC4* [16, 17]. The nSLE group constituted fourteen patients (22 CSF samples). Six control individuals with non-inflammatory hydrocephalus had a median age at sampling of 3.1 years (Table S4). Detailed demographic, clinical, genotypic, and treatment data are provided in Tables S2, S4, and S5.

## Comparison of CSF IFNα Levels Within and Between Study Groups

Median levels of CSF IFNα per group, with number of patients and samples, are detailed in Table 1. To avoid any bias due to multiple sampling of an individual patient, a total of 42

CSF samples from 42 patients were considered in the comparison analysis, with only the first sample recorded for each patient included. The median IFNα level in the CSF of 6 controls was 0.64 fg/ml (interquartile range [IQR]: 0.64–1.74) (Fig. 1a and Table S4).

IFNα concentration was elevated in the CSF of AGS patients (median: 347.1 fg/ml, IQR: 104–3295) compared to controls (0.64 fg/ml, IQR: 0.64–1.74, *p* < 0.0001) and the AI group (1.28 fg/ml, IQR: 0.93–2.16, *p* = 0.0002) (Fig. 1a). The highest concentrations of IFNα were recorded in CSF taken from the youngest AGS patients (Fig. 1b and Table S2). CSF IFNα levels in patients with SAVI, pT1I, and nSLE were also higher than in controls and the AI group, albeit considerably lower than in AGS patients (medians: 28.34 fg/ml, IQR: 7.79–59.11; 60.16 fg/ml, IQR: 7.21–121.8; 35.46 fg/ml, IQR: 6.16–557.4, respectively) (Fig. 1a and Table S2).
<figure><img src="image_6.png" /><figcaption>**Fig. 2** Comparison of IFNα levels in the CSF and blood of interferon-related disorders. a IFNα protein concentration assessed by Simoa in the CSF compared with IFNα concentration in serum/plasma of temporally matched samples in the different IFN-related disorders (AGS (n = 29 pairs), pT1I (n = 7 pairs), and nSLE (n = 18 pairs)). Comparison between groups was performed using Wilcoxon matched-pairs signed-rank test (*p* < 0.05, **p** < 0.01, ****p < 0.0001). Median levels are indicated by red horizontal bars. No temporally concomitant dosage of IFNα in the CSF and blood was available for the SAVI group. However, a comparison of CSF samples with all serum samples from patients with SAVI is shown in c. b IFNα protein concentration assessed by Simoa in temporally matched pairs of CSF and serum/plasma from patients with AGS. Red lines indicate the only four sample pairs in AGS patients demonstrating a higher IFNα protein concentration in the serum than in</figcaption></figure>

the CSF. Dotted lines denote the only two sample pairs in nSLE patients demonstrating a higher IFNα protein concentration in the CSF than in the serum. c IFNα protein concentration assessed by Simoa in the CSF of patients with SAVI compared with IFNα concentration in serum/plasma of all samples available including serial results from the same patient (CSF n = 7, blood n = 13). Comparison between groups was performed using the Mann–Whitney test (****p < 0.0001). Median levels are indicated by red horizontal bars. AGS, Aicardi-Goutières syndrome; AI, classical autoinflammatory disorder non-interferon mediated; CSF, cerebrospinal fluid; IFNα, interferon-alpha; nSLE, systemic lupus erythematosus with neuropsychiatric features; pT1I, presumed monogenic type I interferonopathy; SAVI, STING-associated vasculopathy with onset in infancy

## Comparison of IFNα Levels in CSF and Blood

Contemporaneous or temporally closely related measurements of IFNα in the blood were available for 29 of 33 CSF samples in the AGS cohort (Table S2). Among all 33 CSF samples recorded in AGS, 19 were collected whilst the patient was under treatment

with JAK inhibitors, high-dose steroids, immunoadsorption, or other immunomodulating drugs (Table S2). We recorded similarly raised levels of IFNα in the CSF and blood of patients receiving treatment compared to those who were not being treated (Figure S2). Thus, analyzing all CSF-blood sample pairs available in AGS patients (n = 29), we observed that IFNα

<figure><img src="image_7.png" /></figure>
protein median levels were significantly higher in the CSF than in the blood (551.8 fg/ml, IQR: 104.1–3189 versus 153.6 fg/ml; IQR 38.99–622.0; *p* = 0.0028) (Fig. 2a). Three AGS patients, all with SLE-like features at the time of sampling, demonstrated a higher IFNα level in the blood than in the CSF (AGS1537, AGS2461 [18] and AGS2577) (Fig. 2b and Tables S2 and S5). To avoid bias due to multiple sampling of an individual AGS patient, we also performed an analysis using only the first matched sample available (n = 12 pairs) and observed similar results (Figure S3).

In contrast to AGS, in the nSLE and pT11 patients, we recorded significantly lower concentrations of IFNα protein in CSF compared to blood (Fig. 2a and 2b, and Table S2). No temporally concomitant dosage of IFNα in the CSF and blood was available for the SAVI group. However, comparing all CSF and serum samples from patients with SAVI, the median blood IFNα level was markedly higher than in CSF (Fig. 2c). In the AI group, low or normal IFNα levels were recorded in both compartments (Table S2).

## Discussion

Whilst a link between IFN and AGS was made more than thirty years ago [6], the cells producing the IFN detectable in the CSF of AGS patients remains to be determined. Although leakage of IFN from the blood into CSF across the blood-brain barrier is possible, primary intrathecal production of IFN is supported by a previous assessment of IFN activity in CSF and serum [6, 8]. Murine models of AGS do not recapitulate the human neurolog- ical phenotype. However, using human inducible pluripotent stem cells, Thomas et al. demonstrated a contribution of TREX1-deficient astrocytes to IFN secretion in response to ex-tranuclear DNA accumulation [19]. Our data support the idea that the CNS represents a primary site of IFN production in AGS.

In contrast, the periphery is apparently the major site of IFN production in SAVI, where systemic involvement is prominent [13, 20] and neurological features have been reported in only one individual [21]. Of interest, ICC is observed in SAVI [22], con- sistent with our recording of IFNα in the CSF of affected pa- tients. Such differences likely reflect tissue specificity in the ex- pression, or biological redundancy, of the mutated gene. Endogenous self-nucleic acids are presumed to trigger the ob- served IFN response in AGS [4, 19, 23, 24] so that it is possible that their generation is more pronounced in the CNS than in peripheral tissues. Other explanations might also pertain, such as differential endosomal compartmentalization and signaling of IFN [25]. Consistent with previous studies [6, 8], we observed that CSF IFNα protein levels were highest in younger patients with AGS and appeared to decrease with age, mirroring the natural history of the ‘classical’ AGS phenotype [26]. This point should be considered when assessing the effect of anti-IFN ther- apy initiated very early on in the disease process.

Our observations indicate disease-specific tissue/cellular involvement in different T1Is. In this regard, we previously suggested that monocytes and plasmacytoid dendritic cells (DCs) represent a source of IFNα in SAVI patients [7], whilst no circulating cells in healthy individuals and other patient groups (specifically, SLE and AGS) produced IFNα [7]. Another study showed that IFN transcription occurs mainly in DCs and monocytes in SAVI patients, whereas in PRAAS monocytes alone express IFN during disease flares [27]. It should be noted that we focus exclusively on IFNα in this study. Whilst previous reports have indicated that the antiviral activity in the CSF and serum of patients with AGS can be neutralized by antibodies against IFNα and not IFNβ [6], the possibility that other type I interferons play a pathogenic role should be kept in mind.

Summarising, for the first time, we document levels of CSF IFNα protein in patients with AGS, and in a cohort of pediat- ric patients with monogenic and multifactorial T1Is, suggest- ing that the primary site of IFN production relates to disease pathogenesis and differential tissue expression.

**Supplementary Information** The online version contains supplementary material available at https://doi.org/10.1007/s10875-020-00952-x.

**Acknowledgments** We thank ImmunoQure AG for sharing antibodies used in the IFNα assay. The authors would like also to thank the data science platform of Imagine Institute (DrWareHouse).

**Contributors** L.L., I.M., Y.J.C., and M.L.F. designed the study. L.L. and I.M. collected clinical data. V.B., L.S., G.I.R., E.C., A.L., and M.J.M.M. performed the experiments and analyzed data. I.M., B.A.A., B.B.M., M.B., T.B., C.B., O.B.T., R.C.D., I.D., C.Duc, F.D., C.Dum, P.E., A.H., V.H., M.Hi, M.Hu, E.J., R.L., F.M., S.O., S.P., M.P., P.Q., F.R., R.S., J.S., B.N., S.B., Y.J.C., and M.L.F. participated in patient evalua- tion and provided resources. L.L. and M.L.F. performed statistical anal- yses. L.L. and M.L.F. wrote the paper. L.L., I.M., V.B., A.L., B.A.A., B.B.M., R.C.D., C.Dum, P.E., F.M., J.S., B.N., S.B., D.D., Y.J.C., and M.L.F. reviewed and edited the manuscript. Y.J.C. and M.L.F. supervised the study. All authors have read the final approval of the version published.

**Funding** Y.J.C. acknowledges the European Research Council (GA309449 and 786142-E-T1IFNs) and a state subsidy managed by the National Research Agency (France) under the ‘Investments for the Future’ programme bearing the reference ANR-10-IAHU-01. The project was supported by MSDAVENIR (Devo-Decode Project). Y.J.C. and D.D. acknowledge the Agence Nationale de la Recherche (grant CE17001002).

## Compliance with Ethical Standards

**Conflict of Interest** The authors declare that they have no conflict of interest.

**Ethics Approval** The study was approved by the Comité de protection des personnes Ile de France II and the French advisory committee on data processing in medical research (ID-RCB: 2014-A01017-40).
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Affiliations

Lorenzo Lodi¹,² · Isabelle Melki¹,³,⁴ · Vincent Bondet⁵ · Luis Seabra¹ · Gillian I. Rice⁶ · Edwin Carter⁷ · Alice Lepelley¹ · Maria José Martin-Niclós¹ · Buthaina Al Adba⁸ · Brigitte Bader-Meunier⁴ · Magalie Barth⁹ · Thomas Blauwblomme¹⁰ · Christine Bodemer¹¹ · Odile Boespflug-Tanguy¹² · Russel C. Dale¹³ · Isabelle Desguerre¹⁴ · Camille Ducrocq³ · Fabienne Dulieu¹⁵ · Cécile Dumaine³ · Pierre Ellul¹⁶,¹⁷ · Alice Hadchouel¹⁸ · Véronique Hentgen¹⁹ · Miguel Hié²⁰ · Marie Hully¹⁴ · Eric Jeziorski²¹ · Romain Lévy⁴ · Fanny Mochel²²,²³ · Simona Orcesi²⁴,²⁵ · Sandrine Passemard¹² · Marie Pouletty³ · Pierre Quartier⁴ · Florence Renaldo²⁶ · Rainer Seidl²⁷ · Jay Shetty²⁸ · Bénédicte Neven⁴ · Stéphane Blanche⁴ · Darragh Duffy⁵ · Yanick J. Crow¹,⁷ · Marie-Louise Frémond¹,⁴ ID

¹ Université de Paris, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, 24 boulevard du Montparnasse, 75015 Paris, France

² Department of Health Sciences, University of Florence - Meyer Children's University Hospital, Florence, Italy

³ General Paediatrics- Infectious Diseases and Internal Medicine Department, Robert-Debré Hospital, AP-HP, Nord - Université de Paris, Paris, France

⁴ Paediatric Haematology-Immunology and Rheumatology Unit, Necker Hospital, AP-HP, Centre - Université de Paris, Paris, France

5 Translational Immunology Lab, Institut Pasteur, Paris, France

⁶ School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, Division of Evolution and Genomic Sciences, University of Manchester, Manchester, UK

7 Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, The University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK

8 Department of Paediatric Rheumatology, Sidra Medicine, Doha, Qatar

9 UMR CNRS 6015-INSERM U1083, MitoVasc Institute, University of Angers, Angers, France

10 Paediatric Neurosurgery Unit, Necker Hospital, AP-HP, Centre Université de Paris, Paris, France

11 Paediatric Dermatology Department, Necker Hospital, AP-HP, Centre Université de Paris, Paris, France

12 Paediatric Neurology Department, Robert-Debré Hospital, AP-HP, Nord – Université de Paris, Paris, France

13 Kids Neuroscience Centre, The Children’s Hospital at Westmead, University of Sydney, Westmead, NSW, Australia

14 Paediatric Neurology Department, Necker Hospital, AP-HP, Centre Université de Paris, Paris, France

15 Paediatrics Department, Nice Hospitals, CHU LENVAL, Nice, France

16 Department of Child and Adolescent Psychiatry, Robert-Debré Hospital, AP-HP, Nord – Université de Paris, Paris, France

17 INSERM, Immunology-Immunopathology-Immunotherapy (i3), Sorbonne Université, Paris, France

18 Paediatric Pulmonology Department, Necker Hospital, AP-HP, Centre Université de Paris, Paris, France

19 Paediatrics Department, Versailles Hospital, Le Chesnay, France

20 French National Referral Center for Systemic Lupus Erythematosus, Antiphospholipid Antibody Syndrome and Other Autoimmune Disorders, Service de Médecine Interne 2, Institut E3M, Inserm UMRS, Centre d'Immunologie et des Maladies Infectieuses, Pitié-Salpêtrière Hospital, AP-HP, Sorbonne Université, Paris, France

21 Paediatrics Department, Centre Hospitalier Universitaire de Montpellier, Montpellier, France

22 National Reference Center for Neurometabolic Diseases, Pitié-Salpêtrière Hospital, AP-HP, Sorbonne Université, Paris, France

23 Institut du Cerveau et de la Moelle épinière, INSERM U 1127, Sorbonne Université, Paris, France

24 Child Neurology and Psychiatry Unit IRCCS Mondino Foundation, Pavia, Italy

25 Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy

26 Paediatric Neurology Department, Trousseau Hospital, AP-HP, Sorbonne Université, Paris, France

27 Department of Paediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria

28 Department of Paediatric Neurosciences, Royal Hospital for Sick Children, Sciennes Road, Edinburgh, UK