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Gael Nicolas - One of the best experts on this subject based on the ideXlab platform.
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distinct functional classes of pdgfrb pathogenic variants in primary familial Brain Calcification
Human Molecular Genetics, 2021Co-Authors: Sandrine Lenglez, Gael Nicolas, Ariane Sablon, Gilles Fenelon, Anne Boland, Jeanfrancois Deleuze, Claire Boutoleaubretonniere, Jeanbaptiste DemoulinAbstract:Platelet-derived growth factor receptor beta (PDGFRB) is one of the genes associated with primary familial Brain Calcification (PFBC), an inherited neurological disease (OMIM:173410). Genetic analysis of patients and families revealed at least 13 PDGFRB heterozygous missense variants, including two novel ones described in the present report. Limited experimental data published on five of these variants had suggested that they decrease the receptor activity. No functional information was available on the impact of variants located within the receptor extracellular domains. Here, we performed a comprehensive molecular analysis of PDGFRB variants linked to PFBC. Mutated receptors were transfected in various cell lines to monitor receptor expression, signaling, mitogenic activity, and ligand binding. Four mutants caused a complete loss of tyrosine kinase activity in multiple assays. One of the novel variants, p.Pro154Ser, decreased the receptor expression and abolished binding of platelet-derived growth factor (PDGF-BB). Others showed a partial loss of function related to reduced expression or signaling. Combining clinical, genetic and molecular data, we consider nine variants as pathogenic or likely pathogenic, three as benign or likely benign and one as a variant of unknown significance. We discuss the possible relationship between the variant residual activity, incomplete penetrance, Brain Calcification and neurological symptoms. In conclusion, we identified distinct molecular mechanisms whereby PDGFRB variants may result in a receptor loss of function. This work will facilitate genetic counselling in PFBC.
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characterization of xpr1 slc53a1 variants located outside of the spx domain in patients with primary familial Brain Calcification
Scientific Reports, 2019Co-Authors: Uriel Lopezsanchez, Gael Nicolas, Anne-claire Richard, David Maltete, Mahmoud Charif, Xavier Ayrignac, Cyril Goizet, Jawida Touhami, Gilles Labesse, Jeanluc BattiniAbstract:Primary familial Brain Calcification (PFBC) is a rare neurological disease characterized by deposits of calcium phosphate in the basal ganglia and other regions of the Brain. Pathogenic variants in the XPR1/SLC53A1 gene, which encodes the only known inorganic phosphate exporter, cause an autosomal dominant form of PFBC. These variants are typically located in the SPX N-terminal domain of the protein. Here, we characterize three XPR1 variants outside of SPX in three PFBC patients with an apparently sporadic presentation: c.1375C > T p.(R459C), c.1855A > G p.(N619D) and c.1886T > G p.(I629S), with the latter identified as the first XPR1/SLC53A1 de novo mutation to occur in a PFBC proband. When tested in an in vitro physiological complementation assay, the three XPR1 variants were impaired in phosphate export function, although they were normally expressed at the cell surface and could serve as functional receptors for retrovirus entry. Moreover, peripheral blood cells from the p.N619D patient could be assayed ex vivo and displayed significantly impaired phosphate export. Our results establish for the first time the clinical and molecular characteristics of XPR1 variants located outside the SPX domain and assert a direct link between these variants, deficient phosphate export, and PFBC. Moreover, we unveiled new structural features in XPR1 C-terminal domain that play a role in phosphate export and disease.
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Brain Calcification process and phenotypes according to age and sex: Lessons from SLC20A2, PDGFB, and PDGFRB mutation carriers
American journal of medical genetics. Part B Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics, 2015Co-Authors: Gael Nicolas, Andrea Legati, R R Lemos, Giovanni Coppola, David Wallon, Camille Charbonnier, Anne-claire Richard, Olivier Guillin, Daniel H. Geschwind, Thierry FrebourgAbstract:Primary Familial Brain Calcification (PFBC) is a dominantly inherited cerebral microvascular calcifying disorder with diverse neuropsychiatric expression. Three causative genes have been identified: SLC20A2, PDGFRB and, recently, PDGFB, whose associated phenotype has not yet been extensively studied. We included in the largest published case series of genetically confirmed PFBC, 19 PDGFB (including three new mutations), 24 SLC20A2 (including 4 new mutations), and 14 PDGFRB mutation carriers, from two countries (France and Brazil). We studied clinical features and applied our visual rating scale on all 49 available CT scans. Among the symptomatic mutation carriers (33/57, 58%), the three most frequently observed categories of clinical features were psychiatric signs (72.7%, 76.5%, and 80% for PDGFB, SLC20A2, and PDGFRB, respectively), movement disorders (45.5%, 76.5%, and 40%), and cognitive impairment (54.6%, 64.7%, and 40%). The median age of clinical onset was 31 years, 25% had an early onset (before 18) and 25% a later onset (after 53). Patients with an early clinical onset exhibited mostly isolated psychiatric or cognitive signs, while patients with a later onset exhibited mostly movement disorders, especially in association with other clinical features. CT scans rating allowed identifying four patterns of Calcification. The total Calcification score was best predicted by the combined effects of gene (SLC20A2 > PDGFB > PDGFRB mutations), sex (male), and (increasing) age, defining three risk classes, which correlated with the four patterns of Calcification. These Calcification patterns could reflect the natural history of the calcifying process, with distinct risk classes characterized by different age at onset or rate of progression.
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mutations in xpr1 cause primary familial Brain Calcification associated with altered phosphate export
Nature Genetics, 2015Co-Authors: Andrea Legati, Donatella Giovannini, Gael Nicolas, Uriel Lopezsanchez, Beatriz Quintans, João Ricardo Mendes De Oliveira, Renee L. Sears, Eliana Marisa RamosAbstract:Primary familial Brain Calcification (PFBC) is a neurological disease characterized by calcium phosphate deposits in the basal ganglia and other Brain regions and has thus far been associated with SLC20A2, PDGFB or PDGFRB mutations. We identified in multiple families with PFBC mutations in XPR1, a gene encoding a retroviral receptor with phosphate export function. These mutations alter phosphate export, implicating XPR1 and phosphate homeostasis in PFBC.
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a de novo nonsense pdgfb mutation causing idiopathic basal ganglia Calcification with laryngeal dystonia
European Journal of Human Genetics, 2014Co-Authors: Gael Nicolas, Agnes Jacquin, Christel Thauvinrobinet, Anne Roveletlecrux, Olivier Rouaud, Cyril Pottier, Mariehelene Aubriotlorton, Stephane RousseauAbstract:Idiopathic basal ganglia Calcification (IBGC) is characterized by Brain Calcification and a wide variety of neurologic and psychiatric symptoms. In families with autosomal dominant inheritance, three causative genes have been identified: SLC20A2, PDGFRB, and, very recently, PDGFB. Whereas in clinical practice sporadic presentation of IBGC is frequent, well-documented reports of true sporadic occurrence are rare. We report the case of a 20-year-old woman who presented laryngeal dystonia revealing IBGC. Her healthy parents' CT scans were both normal. We identified in the proband a new nonsense mutation in exon 4 of PDGFB, c.439C>T (p.Gln147*), which was absent from the parents' DNA. This mutation may result in a loss-of-function of PDGF-B, which has been shown to cause IBGC in humans and to disrupt the blood-Brain barrier in mice, resulting in Brain Calcification. The c.439C>T mutation is located between two previously reported nonsense mutations, c.433C>T (p.Gln145*) and c.445C>T (p.Arg149*), on a region that could be a hot spot for de novo mutations. We present the first full demonstration of the de novo occurrence of an IBGC-causative mutation in a sporadic case.
Kailash P. Bhatia - One of the best experts on this subject based on the ideXlab platform.
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deconstructing fahr s disease syndrome of Brain Calcification in the era of new genes
Parkinsonism & Related Disorders, 2017Co-Authors: Amit Batla, Xin You Tai, Lucia Schottlaender, Roberto Erro, Bettina Balint, Kailash P. BhatiaAbstract:Abstract Introduction There are now a number genes, known to be associated with familial primary Brain Calcification (PFBC), causing the so called ‘Fahr's’ disease or syndrome. These are SCL20A2 , PDGFB, PDGFRB and XPR1 . In this systematic review, we analyse the clinical and radiological features reported in genetically confirmed cases with PFBC. We have additionally reviewed pseudohypoparathyroidism which is a close differential diagnosis of PFBC in clinical presentation and is also genetically determined. Methods We performed a Medline search, from 1st Jan 2012 through to 7th November 2016, for publications with confirmed mutations of SCL20A2 , PDGFB, PDGFRB, and XPR1 and found twenty papers with 137 eligible cases. A second search was done for publications of cases with Pseudohypoparathyroidism or pseudopseudohypoparathyroidism, and found 18 publications with 20 eligible cases. Results SLC20A2 was the most common gene involved with 75 out of 137 cases included with PFBC (55%) followed by PDGFB (31%) and PDGFRB (11%). Statistically significant correlation was found between the presence of parkinsonism with SLC20A2 mutations, headache in PDGFB and generalised tonic-clonic seizures in patients with pseudohypoparathyroidism. Conclusion We combine statistical analysis and clinical inference to suggest a diagnostic algorithm based on the observations in this study to help with investigation of a patient with neurological features and Brain Calcification.
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Deconstructing Fahr's disease/syndrome of Brain Calcification in the era of new genes.
Parkinsonism & Related Disorders, 2016Co-Authors: Amit Batla, Xin You Tai, Lucia Schottlaender, Roberto Erro, Bettina Balint, Kailash P. BhatiaAbstract:Abstract Introduction There are now a number genes, known to be associated with familial primary Brain Calcification (PFBC), causing the so called ‘Fahr's’ disease or syndrome. These are SCL20A2 , PDGFB, PDGFRB and XPR1 . In this systematic review, we analyse the clinical and radiological features reported in genetically confirmed cases with PFBC. We have additionally reviewed pseudohypoparathyroidism which is a close differential diagnosis of PFBC in clinical presentation and is also genetically determined. Methods We performed a Medline search, from 1st Jan 2012 through to 7th November 2016, for publications with confirmed mutations of SCL20A2 , PDGFB, PDGFRB, and XPR1 and found twenty papers with 137 eligible cases. A second search was done for publications of cases with Pseudohypoparathyroidism or pseudopseudohypoparathyroidism, and found 18 publications with 20 eligible cases. Results SLC20A2 was the most common gene involved with 75 out of 137 cases included with PFBC (55%) followed by PDGFB (31%) and PDGFRB (11%). Statistically significant correlation was found between the presence of parkinsonism with SLC20A2 mutations, headache in PDGFB and generalised tonic-clonic seizures in patients with pseudohypoparathyroidism. Conclusion We combine statistical analysis and clinical inference to suggest a diagnostic algorithm based on the observations in this study to help with investigation of a patient with neurological features and Brain Calcification.
Andrea Legati - One of the best experts on this subject based on the ideXlab platform.
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Primary Brain Calcification: an international study reporting novel variants and associated phenotypes
European Journal of Human Genetics, 2018Co-Authors: Eliana Marisa Ramos, Andrea Legati, Luca Magistrelli, Miryam Carecchio, Roberta Lemos, Joana Ferreira, Renee Louise Sears, Sandy Chan Hsu, Celeste Panteghini, Ettore SalsanoAbstract:Primary familial Brain Calcification (PFBC) is a rare cerebral microvascular calcifying disorder with a wide spectrum of motor, cognitive, and neuropsychiatric symptoms. It is typically inherited as an autosomal-dominant trait with four causative genes identified so far: SLC20A2, PDGFRB, PDGFB, and XPR1. Our study aimed at screening the coding regions of these genes in a series of 177 unrelated probands that fulfilled the diagnostic criteria for primary Brain Calcification regardless of their family history. Sequence variants were classified as pathogenic, likely pathogenic, or of uncertain significance (VUS), based on the ACMG-AMP recommendations. We identified 45 probands (25.4%) carrying either pathogenic or likely pathogenic variants (n = 34, 19.2%) or VUS (n = 11, 6.2%). SLC20A2 provided the highest contribution (16.9%), followed by XPR1 and PDGFB (3.4% each), and PDGFRB (1.7%). A total of 81.5% of carriers were symptomatic and the most recurrent symptoms were parkinsonism, cognitive impairment, and psychiatric disturbances (52.3%, 40.9%, and 38.6% of symptomatic individuals, respectively), with a wide range of age at onset (from childhood to 81 years). While the pathogenic and likely pathogenic variants identified in this study can be used for genetic counseling, the VUS will require additional evidence, such as recurrence in unrelated patients, in order to be classified as pathogenic.
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Brain Calcification process and phenotypes according to age and sex: Lessons from SLC20A2, PDGFB, and PDGFRB mutation carriers
American journal of medical genetics. Part B Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics, 2015Co-Authors: Gael Nicolas, Andrea Legati, R R Lemos, Giovanni Coppola, David Wallon, Camille Charbonnier, Anne-claire Richard, Olivier Guillin, Daniel H. Geschwind, Thierry FrebourgAbstract:Primary Familial Brain Calcification (PFBC) is a dominantly inherited cerebral microvascular calcifying disorder with diverse neuropsychiatric expression. Three causative genes have been identified: SLC20A2, PDGFRB and, recently, PDGFB, whose associated phenotype has not yet been extensively studied. We included in the largest published case series of genetically confirmed PFBC, 19 PDGFB (including three new mutations), 24 SLC20A2 (including 4 new mutations), and 14 PDGFRB mutation carriers, from two countries (France and Brazil). We studied clinical features and applied our visual rating scale on all 49 available CT scans. Among the symptomatic mutation carriers (33/57, 58%), the three most frequently observed categories of clinical features were psychiatric signs (72.7%, 76.5%, and 80% for PDGFB, SLC20A2, and PDGFRB, respectively), movement disorders (45.5%, 76.5%, and 40%), and cognitive impairment (54.6%, 64.7%, and 40%). The median age of clinical onset was 31 years, 25% had an early onset (before 18) and 25% a later onset (after 53). Patients with an early clinical onset exhibited mostly isolated psychiatric or cognitive signs, while patients with a later onset exhibited mostly movement disorders, especially in association with other clinical features. CT scans rating allowed identifying four patterns of Calcification. The total Calcification score was best predicted by the combined effects of gene (SLC20A2 > PDGFB > PDGFRB mutations), sex (male), and (increasing) age, defining three risk classes, which correlated with the four patterns of Calcification. These Calcification patterns could reflect the natural history of the calcifying process, with distinct risk classes characterized by different age at onset or rate of progression.
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mutations in xpr1 cause primary familial Brain Calcification associated with altered phosphate export
Nature Genetics, 2015Co-Authors: Andrea Legati, Donatella Giovannini, Gael Nicolas, Uriel Lopezsanchez, Beatriz Quintans, João Ricardo Mendes De Oliveira, Renee L. Sears, Eliana Marisa RamosAbstract:Primary familial Brain Calcification (PFBC) is a neurological disease characterized by calcium phosphate deposits in the basal ganglia and other Brain regions and has thus far been associated with SLC20A2, PDGFB or PDGFRB mutations. We identified in multiple families with PFBC mutations in XPR1, a gene encoding a retroviral receptor with phosphate export function. These mutations alter phosphate export, implicating XPR1 and phosphate homeostasis in PFBC.
Dennis W Dickson - One of the best experts on this subject based on the ideXlab platform.
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ossified blood vessels in primary familial Brain Calcification elicit a neurotoxic astrocyte response
Brain, 2019Co-Authors: Yvette Zarb, Ulrike Weberstadlbauer, Daniel Kirschenbaum, Diana Rita Kindler, Juliet Richetto, Daniel Keller, Rosa V Rademakers, Dennis W Dickson, Andreas Pasch, Tatiana ByzovaAbstract:Brain Calcifications are commonly detected in aged individuals and accompany numerous Brain diseases, but their functional importance is not understood. In cases of primary familial Brain Calcification, an autosomally inherited neuropsychiatric disorder, the presence of bilateral Brain Calcifications in the absence of secondary causes of Brain Calcification is a diagnostic criterion. To date, mutations in five genes including solute carrier 20 member 2 (SLC20A2), xenotropic and polytropic retrovirus receptor 1 (XPR1), myogenesis regulating glycosidase (MYORG), platelet-derived growth factor B (PDGFB) and platelet-derived growth factor receptor β (PDGFRB), are considered causal. Previously, we have reported that mutations in PDGFB in humans are associated with primary familial Brain Calcification, and mice hypomorphic for PDGFB (Pdgfbret/ret) present with Brain vessel Calcifications in the deep regions of the Brain that increase with age, mimicking the pathology observed in human mutation carriers. In this study, we characterize the cellular environment surrounding Calcifications in Pdgfbret/ret animals and show that cells around vessel-associated Calcifications express markers for osteoblasts, osteoclasts and osteocytes, and that bone matrix proteins are present in vessel-associated Calcifications. Additionally, we also demonstrate the osteogenic environment around Brain Calcifications in genetically confirmed primary familial Brain Calcification cases. We show that Calcifications cause oxidative stress in astrocytes and evoke expression of neurotoxic astrocyte markers. Similar to previously reported human primary familial Brain Calcification cases, we describe high interindividual variation in Calcification load in Pdgfbret/ret animals, as assessed by ex vivo and in vivo quantification of Calcifications. We also report that serum of Pdgfbret/ret animals does not differ in Calcification propensity from control animals and that vessel Calcification occurs only in the Brains of Pdgfbret/ret animals. Notably, ossification of vessels and astrocytic neurotoxic response is associated with specific behavioural and cognitive alterations, some of which are associated with primary familial Brain Calcification in a subset of patients.
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Clinical presentation of a patient with SLC20A2 and THAP1 deletions: differential diagnosis of oromandibular dystonia.
Parkinsonism & related disorders, 2015Co-Authors: Shinsuke Fujioka, Dennis W Dickson, Rosa Rademakers, Audrey Strongosky, Anhar Hassan, Zbigniew K WszolekAbstract:Oromandibular dystonia is a rare, focal dystonia that is characterized by forceful contractions of the face, jaw, and/or tongue [1]. These contractions cause difficulty with the opening and closing of the mouth, which leads to mastication impairment and speech problems. Idiopathic basal ganglia Calcification (IBGC) is a rare, autosomal-dominant disease that is accompanied by abnormal calcium deposition in the Brain [2]. IBGC is clinically characterized by dystonia, parkinsonism, tremor, ataxia, dementia, psychosis, and seizures [2]. IBGC is classified into five subgroups, IBGC1 - IBGC5, and this classification is based on causative genes/loci. Wang and colleagues [3] identified SLC20A2 mutations as a genetic cause of IBGC3. We recently discovered SLC20A2 and THAP1 deletions in a familial form of basal ganglia Calcification in which dystonia was the most predominant clinical manifestation [4, 5]. We provide a video presentation of a previously reported case from this previously described family (patient III-3 in the previous report [5]) [6]. We also include a summary of the clinical features associated with the type of oromandibular dystonia that arises from known genetic causes (Table). Table 1 Neurogenetic disorders that have been associated with oromandibular dystonia A right-handed man developed abnormal movements of his trunk and arms at the age of 26 years. His initial symptoms were writer’s cramp and involuntary posturing of his shoulders and trunk; these symptoms were more prominent on his right-side. His symptoms remained stable until he was 50-years-old, which was when he developed progressive dysarthria with speech-induced involuntary jaw opening, mild short-term memory loss, and gait impairment. His family history was notable for dystonia, chorea, and postural tremor. A Brain CT showed Calcifications in the occipital cortex, subcortical white matter, basal ganglia, thalamus, and the cerebellum. The esupp video shows the patient during two examinations; one was conducted when he was 77-years-old, and the other was conducted when he was 80-years-old.. The patient provided written consent before filming. The video displays that the patient had speech-induced jaw opening dystonia, severe dysarthria, chorea, right shoulder postural dystonia, and writer’s cramp. His gait deteriorated between his first and second examinations. He eventually developed severe cognitive impairment and behavioral problems. He died at the age of 85 years. An autopsy identified patchy, multifocal Calcifications in the periventricular regions, basal ganglia, anterior thalamus, visual cortex, and the cerebellum. Genetic testing revealed that the patient carried SLC20A2 and THAP1 deletions [4]. To date, eighteen genetic disorders with known causative gene mutations have been reported to be associated with oromandibular dystonia (Table. Of these, only neurodegeneration with Brain iron accumulation 1 (NBIA1) is known to cause Calcification in the Brain. NBIA1 is caused by PANK2 mutations and is clinically characterized by dystonia, dysarthria, pyramidal signs, cognitive impairment, pigmentary retinopathy, dysphagia, chorea, psychiatric symptoms, developmental delay, oculomotor abnormalities, and parkinsonism. Typical symptomatic disease onset for NBIA1 usually occurs before the age of 10 years. However, a minority of patients exhibit atypical clinical features, such as a later symptomatic disease onset (between 15–40 years), prominent speech problems, psychiatric symptoms, and a more gradual disease progression. Calcifications in the Brains of NBIA1 patients generally can be observed in the basal ganglia. Our patient and his family [5,6] can be clinically distinguished from NBIA1 patients based on the more extensive distribution of Brain Calcification in their Brains. Currently,, no patients carrying SLC20A2 mutations have been reported to present with oromandibular dystonia [3]. However, oromandibular dystonia is one of the prominent features of patients with THAP1 mutations. The oromandibular dystonia seen in this case and in that of others previously reported [5,6] could presumably be caused solely by a mutation in the THAP1 gene. Additional functional studies to confirm this hypothesis are warranted. Genetic testing, especially for THAP1, should be considered in individuals that have extensive basal ganglia Calcifications and a family history of dystonia.
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genetic screening and functional characterization of pdgfrb mutations associated with basal ganglia Calcification of unknown etiology
Human Mutation, 2014Co-Authors: Monica Sanchezcontreras, Dennis W Dickson, Matthew C Baker, Nicole A Finch, Alexandra M Nicholson, Aleksandra Wojtas, Zbigniew K Wszolek, Owen A Ross, Rosa RademakersAbstract:Three causal genes for idiopathic basal ganglia Calcification (IBGC) have been identified. Most recently, mutations in PDGFRB, encoding a member of the platelet-derived growth factor receptor family type β, and PDGFB, encoding PDGF-B, the specific ligand of PDGFRβ, were found implicating the PDGF-B/PDGFRβ pathway in abnormal Brain Calcification. In this study, we aimed to identify and study mutations in PDGFRB and PDGFB in a series of 26 patients from the Mayo Clinic Florida Brain Bank with moderate to severe basal ganglia Calcification (BCG) of unknown etiology. No mutations in PDGFB were found. However, we identified one mutation in PDGFRB, p.R695C located in the tyrosine kinase domain, in one BGC patient. We further studied the function of p.R695C mutant PDGFRβ and two previously reported mutants, p.L658P and p.R987W PDGFRβ in cell culture. We show that, in response to PDGF-BB stimulation, the p.L658P mutation completely suppresses PDGFRβ autophosphorylation, whereas the p.R695C mutation results in partial loss of autophosphorylation. For the p.R987W mutation, our data suggest a different mechanism involving reduced protein levels. These genetic and functional studies provide the first insight into the pathogenic mechanisms associated with PDGFRB mutations and provide further support for a pathogenic role of PDGFRB mutations in BGC.
Laura Andreoli - One of the best experts on this subject based on the ideXlab platform.
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sine causa tetraparesis a pilot study on its possible relationship with interferon signature analysis and aicardi goutieres syndrome related genes analysis
Medicine, 2018Co-Authors: Jessica Galli, Francesco Gavazzi, Micaela De Simone, Silvia Giliani, Jessica Garau, Marialuisa Valente, Donatella Vairo, Marco Cattalini, Marzia Mortilla, Laura AndreoliAbstract:Tetraparesis is usually due to cerebral palsy (CP), inborn errors of metabolism, neurogenetic disorders and spinal cord lesions. However, literature data reported that about 10% of children with tetraparesis show a negative/non-specific neuroradiological findings without a specific etiological cause. Aicardi Goutieres Syndrome (AGS) is a genetic encephalopathy that may cause tetraparesis. Interferon signature is a reliable biomarker for AGS and could be performed in sine-causa tetraparesis. The aim of the study was to examine the type I interferon signature and AGS related-genes in children with sine causa tetraparesis, to look for misdiagnosed AGS. A secondary aim was to determine which aspects of the patient history, clinical picture and Brain imaging best characterize tetraparesis due to an interferonopathy. Seven out of 78 patients affected by tetraparesis, characterized by unremarkable pre-peri-postnatal history and normal/non-specific Brain magnetic resonance imaging (MRI) were selected and underwent anamnestic data collection, clinical examination, Brain imaging review, peripheral blood interferon signature and AGS-related genes analysis. At our evaluation time (mean age of 11.9 years), all the 7 patients showed spastic-dystonic tetraparesis. At clinical onset Brain MRI was normal in 4 and with non-specific abnormalities in 3; at follow-up 3 patients presented with new white-matter lesions, associated with Brain Calcification in 1 case. Interferon signature was elevated in one subject who presented also a mutation of the IFIH1 gene. AGS should be considered in sine-causa tetraparesis. Core features of interferonopathy-related tetraparesis are: onset during first year of life, psychomotor regression with tetraparesis evolution, Brain white-matter lesions with late Calcifications. A positive interferon signature may be a helpful marker to select patients with spastic tetraparesis who should undergo genetic analysis for AGS.