Publications by authors named "Stefano Sotgiu"

67 Publications

Seizures associated with selective serotonin reuptake inhibitors: A case of pharmacologically induced epileptic myoclonia.

Seizure 2021 Apr 1;88:75-77. Epub 2021 Apr 1.

Center for Diagnosis and Care of Paediatric Epilepsy, University Hospital of Sassari, Viale San Pietro, 43/B, 07100 Sassari, Italy; Unit of Child Neuropsychiatry, University Hospital of Sassari, Viale San Pietro, 43/B, 07100 Sassari, Italy.

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http://dx.doi.org/10.1016/j.seizure.2021.03.031DOI Listing
April 2021

Immune regulation of neurodevelopment at the mother-foetus interface: the case of autism.

Clin Transl Immunology 2020 13;9(11):e1211. Epub 2020 Nov 13.

Unit of Child Neuropsychiatry Department of Medical Surgical and Experimental Sciences University of Sassari Sassari Italy.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder defined by deficits in social communication and stereotypical behaviours. ASD's aetiology remains mostly unclear, because of a complex interaction between genetic and environmental factors. Recently, a strong consensus has developed around ASD's immune-mediated pathophysiology, which is the subject of this review. For many years, neuroimmunological studies tried to understand ASD as a prototypical antibody- or cell-mediated disease. Other findings indicated the importance of autoimmune mechanisms such as familial and individual autoimmunity, adaptive immune abnormalities and the influence of infections during gestation. However, recent studies have challenged the idea that autism may be a classical autoimmune disease. Modern neurodevelopmental immunology shows the double-edged nature of many immune effectors, which can be either beneficial or detrimental depending on tissue homeostasis, stressors, neurodevelopmental stage, inherited and gene mutations and other variables. Nowadays, mother-child interactions in the prenatal environment appear to be crucial for the occurrence of ASD. Studies of animal maternal-foetal immune interaction are being fruitfully carried out using different combinations of type and timing of infection, of maternal immune response and foetal vulnerability and of resilience factors to hostile events. The derailed neuroimmune crosstalk through the placenta initiates and maintains a chronic foetal neuroglial activation, eventually causing the alteration of neurogenesis, migration, synapse formation and pruning. The importance of pregnancy can also allow early immune interventions, which can significantly reduce the increasing risk of ASD and its heavy social burden.
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http://dx.doi.org/10.1002/cti2.1211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662086PMC
November 2020

Juvenile Chronic Inflammatory Demyelinating Polyneuropathy Epidemiology in Sardinia, Insular Italy.

Neuropediatrics 2021 02 27;52(1):56-61. Epub 2020 Oct 27.

Neuromuscular Disease and Neuroimmunology Service, Humanitas Clinical and Research Institute, Milan, Italy.

Background: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare and disabling immunomediated radiculoneuropathy. Its worldwide epidemiology is heterogeneous and, in adults, CIDP prevalence varies from 0.6 to 9 cases per 100,000 population. Juvenile CIDP (jCIDP) is even rarer, with age-specific prevalence rates varying from 0.23 to 1.26 owing to different diagnostic criteria (American Academy of Neurology [AAN] and European Federation of Neurological Societies/Peripheral Nerve Society [EFNS/PNS]), different age grouping or, genuine differences.

Objectives: We assessed jCIDP incidence and prevalence in Sardinia, an area at very-high risk for autoimmune diseases, using comparable methods.

Design: The study area was the northern Sardinia, insular Italy, with 491,571 inhabitants and a pediatric population (0-18 years) of 79,086 individuals.

Results: On prevalence day (December 31, 2019) the total crude, age-specific prevalence rate were 6.32 per 100,000 according with AAN criteria, 7.58 per 100,000 population with European Neuromuscular Center (ENMC) criteria, and 8.85 per 100,000 population with both 2006 and 2010 EFNS/PNS criteria. Crude mean incidence rate were 0.42 per 100,000 per year with AAN criteria, 0.50 per 100,000 per year with ENMC criteria, and 0.59 per 100,000 per year using 2006 and 2010 EFNS/PNS criteria. Of the eight patients, six had typical CIDP, one had multifocal-acquired demyelinating sensory and motor neuropathy (MADSAM), and one chronic immune sensory polyradiculopathy (CISP). Patient's disability was generally mild. Clinical course was progressive, monophasic, or relapsing.

Conclusion: jCIDP prevalence and incidence rates in Sardinia were criteria-dependent, the lowest obtained when using AAN criteria, the highest using the EFNS/PNS. Nonetheless, even with the exclusion of the "possible" category, by using comparable methodology, prevalence rates in Sardinia are considerably higher than the range reported in all previous jCIDP studies.
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http://dx.doi.org/10.1055/s-0040-1715626DOI Listing
February 2021

Paroxysmal rhythmic pelvic movements: an unusual paediatric presentation of Chiari I malformation with syringomyelia.

Childs Nerv Syst 2020 Dec 1;36(12):2901-2903. Epub 2020 Oct 1.

Unit of Child Neuropsychiatry, University Hospital of Sassari, Sassari, Italy.

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http://dx.doi.org/10.1007/s00381-020-04904-zDOI Listing
December 2020

Chronic immune sensory polyradiculopathy (CISP): First juvenile case description.

Neurol Sci 2021 Jan 10;42(1):333-336. Epub 2020 Jul 10.

Humanitas Clinical and Research Institute, Milan, Italy.

In its typical presentation, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) occurs more often in old males as a progressive/recurrent motor and sensory nerve dysfunction with tendon areflexia. However, CIDP has also atypical clinical presentations, including pure sensory neuropathies, among which chronic immune sensory polyradiculopathy (CISP) accounts for only 0.5% of all CIDP, with no juvenile cases reported as yet. A 17-year-old girl presented for a progressive sensory ataxia and hands clumsiness. Diffuse tendon areflexia and hypokinaesthesia were observed. Motor and sensory nerve conduction studies were normal. F-waves were normal in median nerves and elongated in tibial nerves. H-reflex and somatosensory evoked potentials (SSEP) were absent. CSF normal cellularity with hyperproteinorrachia was found. Paraneoplastic, metabolic, and paraproteinemic neuropathies were excluded. A diagnosis of CISP has been made based on the presence of pure sensory symptoms in a polyneuropathic distribution, normal peripheral nerve conduction studies, and two supportive criteria (SSEP and CSF). Our paper describes the first CISP case in the pediatric age. We confirm SSEP and CSF as useful complementary tests for this diagnosis also at this age and suggest that clinicians should consider CISP in the spectrum of sporadic sensory ataxias of the pediatric age. We also suggest that in the presence of normal F-wave and peripheral motor nerve conduction, an absent H-reflex can further substantiate SSEPs in the diagnosis of CISP. Intravenous immunoglobulins were rapidly effective and safe.
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http://dx.doi.org/10.1007/s10072-020-04588-yDOI Listing
January 2021

Vitamin D Receptor Polymorphisms Associated with Autism Spectrum Disorder.

Autism Res 2020 05 21;13(5):680-690. Epub 2020 Feb 21.

IRCCS Fondazione Don Carlo Gnocchi, Milan, Italy.

Vitamin D is endowed with a number of biological properties, including down-regulation of inflammation, and might contribute to the pathogenesis of autism spectrum disorders (ASD). Vitamin D binds to the vitamin D Receptor (VDR); the biological activity of the ensuing complex depends on VDR FokI, BsmI, ApaI, and TaqI gene polymorphisms. We evaluated such Single Nucletoide Polymorphismsm (SNPs) in a cohort of 100 Italian families with ASD children. FokI genotype distribution was skewed in ASD children compared with their healthy sibs (P = 0.03 2 df) and to a group of 170 Italian healthy women (HC) (P = 0.04 2 df). FokI genotype and allelic distribution skewing were also observed in mothers of ASD children compared to HC (P = 0.04 2 df). Both Transmission Disequilibrium Test for single loci and haplotype analysis distribution revealed a major FokI (C) allele-mediated protective effect, which was more frequently transmitted (73%) than not transmitted to healthy sibs (P = 0.02). A protective FokI-, BsmI-, ApaI-, and TaqI (CCAG) haplotype was more frequently carried by healthy sibs than by ASD children (P = 1 × 10 ; OR: 0.1, 95% CI: 0.03-0.4) too. Finally, a strong gene-dose association of FokI (T) allele with both higher Childhood Autism Rating Scale score (P = 0.01) and, particularly, with hyperactivity behavior (P = 0.006) emerged in ASD children. Because the protein produced by the FokI (T) allele is transcriptionally less active than that produced by the FokI (C) allele, the reduced biological activity of the vitamin D/VDR complex prevalent in ASD could favor ASD- and maternal immune activation- associated inflammation. Vitamin D supplementation might be useful in preventative and rehabilitation protocols for ASD. Autism Res 2020, 13: 680-690. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Vitamin D deficiency and Vitamin D receptor (VDR) polymorphisms are associated with structural and functional brain abnormalities and behavioral disorders. We analyzed the association of VDR gene polymorphisms in a cohort of 100 Italian families with ASD children. A strong correlation between one of the VDR polymorphisms and hyperactivity behavior was evidenced in ASD children. In healthy mothers, the same VDR polymorphism was also correlated with an increased risk of giving birth to children with ASD.
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http://dx.doi.org/10.1002/aur.2279DOI Listing
May 2020

Hashimoto encephalopathy in the 21st century.

Neurology 2020 01 27;94(2):e217-e224. Epub 2019 Dec 27.

From the Neuroimmunology Program (S.M., L.S., H.A., T.A., A.S., J.D., F.G.), Institut d'Investigació Biomèdica August Pi i Sunyer, Barcelona, Spain; Department of Medical, Surgical and Experimental Medicine (S.M., S.S.), University of Sassari, Italy; Service of Neurology (D.E., A.S.), Hospital Clinic, and Pediatric Neuroimmunology Unit (T.A.), Neurology Department, Sant Joan de Déu Children's Hospital, University of Barcelona, Spain; Neurology Division (M.S.), Hospital das Clínicas, São Paulo University, Brazil; Department of Neurology (T.I.), Kitasato University School of Medicine, Sagamihara; Division of Neurology (M.H.), Department of Medicine, Nihon University School of Medicine, Tokyo, Japan; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; and Institució Catalana de Recerca i Estudis Avançats (J.D.), Barcelona, Spain.

Objective: To report the presenting syndromes and to determine whether pretreatment criteria of Hashimoto encephalopathy (HE) predict response to steroids.

Methods: We assessed symptoms and steroid responsiveness in 24 patients with pretreatment criteria of HE, including (1) subacute onset of cognitive impairment, psychiatric symptoms, or seizures; (2) euthyroid status or mild hypothyroidism; (3) serum thyroid peroxidase antibodies (TPOAb) >200 IU/mL; (4) absent neuronal antibodies in serum/CSF; and (5) no other etiologies. Additional studies included determination of TPOAb (>200 IU/mL) in 74 patients with criteria of possible autoimmune encephalitis (AE) without neuronal antibodies and 205 patients with different neuroimmunologic diseases, psychosis, or new-onset refractory status epilepticus (NORSE). Serum antibodies to the amino (ΝΗ2)-terminal of α-enolase (NH2-α-enolaseAb) were examined in the indicated 24 patients and 13 controls.

Results: The 24 patients (14 women) with suspected HE had a median age of 48 years (range 8-79 years). Four syndromes were identified: psychiatric (7, 29%), encephalopathy (7, 29%), NORSE-like (6, 25%), and limbic encephalitis (4, 17%). Only 6 of 19 (31.6%) patients completely responded to steroids. The frequency of TPOAb in the 74 patients with possible AE (6 of 74, 8.1%) was similar to that of the 205 controls (17 of 205, 8.2%; = 0.84). NH2-α-enolaseAb were identified in 1 of 24 suspected HE cases and 1 of 13 controls.

Conclusion: Current pretreatment criteria of HE do not predict steroid responsiveness. The detection of TPOAb across all control groups reveals their poor disease-specificity. NH2-α-enolaseAb did not help in the diagnosis of HE. These findings imply a redefinition of HE that requires a systematic exclusion of antibody-mediated encephalitis.
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http://dx.doi.org/10.1212/WNL.0000000000008785DOI Listing
January 2020

Anti-GAD epileptic encephalopathy in a toddler with Parry-Romberg syndrome.

Neurol Sci 2020 Mar 11;41(3):705-708. Epub 2019 Dec 11.

Department of Paediatrics, Institute Giannina Gaslini, Genoa, Italy.

Parry-Romberg syndrome (PRS) is a progressive facial hemiatrophy often associated with severe epilepsy. Although an immune-mediated vasculitic pathogenesis is widely assumed, no CNS-specific autoantibody has been described so far. A 2-year-old boy was admitted for a status epilepticus preceded by fever, restlessness, insomnia, and left facial rash. Cerebrospinal fluid was positive for glutamic acid decarboxylase (GAD)-antibodies. Brain MRI revealed FLAIR hyperintensities on left mediotemporal areas. He was successfully treated with intravenous methylprednisolone. One month later, seizures and facial rash reappeared and steroids were satisfactorily repeated. However, left hemifacial rash reappeared 5 months later, slowly followed by sclerotic skin lesions on frontal scalp and hemifacial sub-atrophy, leading to a diagnosis of PRS. Three years later, and despite chronic immunosuppression, new MRI lesions on left white matter are seen and left hemifacial atrophy has progressed. For the first time, we describe GAD autoantibodies in a PRS patient with epileptic encephalopathy. Epileptic syndromes with GAD autoantibodies are frequently described though with a questionable pathogenic significance. Given the clinical and MRI similarities of PRS with both Morphea and Rasmussen's encephalitis, we suggest that, in our patient, the initial facial skin vasculitis spread into CNS vessels through perforating arteries, inducing neuronal MHC-class I presentation of GAD epitopes, ultimately causing CD8-mediated neuronal cytotoxicity and the epileptic encephalopathy. GAD autoantibodies might represent the missing pathophysiological link between PRS and neuropsychiatric manifestations.
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http://dx.doi.org/10.1007/s10072-019-04187-6DOI Listing
March 2020

VARS2-linked mitochondrial encephalopathy: two case reports enlarging the clinical phenotype.

BMC Med Genet 2019 05 7;20(1):77. Epub 2019 May 7.

Unit of Child Neuropsychiatry Residency Program, University Hospital of Sassari, Viale San Pietro 43/B, I-07100, Sassari, Italy.

Background: Mitochondrial respiratory chain consists of five complexes encoded by nuclear and mitochondrial genomes. Mitochondrial aminoacyl-tRNA synthetases are key enzymes in the synthesis of such complexes. Bi-allelic variants of VARS2, a nuclear gene encoding for valyl-tRNA (Val-tRNA) synthetase, are associated to several forms of mitochondrial encephalopathies or cardiomyoencephalopathies. Among these, the rare homozygous c.1100C > T (p.Thr367Ile) mutation variably presents with progressive developmental delay, axial hypotonia, limbs spasticity, drug-resistant epilepsy leading, in some cases, to premature death. Yet only six cases, of which three are siblings, harbouring this homozygous mutation have been described worldwide.

Case Presentation: Hereby, we report two additional cases of two non-related young girls from Sardinia, born from non-consanguineous and healthy parents, carrying the aforesaid homozygous VARS2 variant. At onset both the patients presented with worsening psychomotor delay, muscle hypotonia and brisk tendon reflexes. Standard genetic tests were normal, as well as metabolic investigations. Brain MRI showed unspecific progressive abnormalities, such as corpus callosum hypoplasia (patient A) and cerebellar atrophy (patient A and B). Diagnosis was reached by adopting massive parallel next generation sequencing. Notably clinical phenotype of the first patient appears to be milder compared to previous known cases. The second patient eventually developed refractory epilepsy and currently presents with severe global impairment. Because no specific treatment is available as yet, both patients are treated with supporting antioxidant compounds along with symptomatic therapies.

Conclusions: Given the paucity of clinical data about this very rare mitochondrial encephalopathy, our report might contribute to broaden the phenotypic spectrum of the disorder. Moreover, noteworthy, three out of five pedigrees so far described belong to the Northern Sardinia ethnicity.
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http://dx.doi.org/10.1186/s12881-019-0798-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505124PMC
May 2019

Exploring by whole exome sequencing patients with initial diagnosis of Rubinstein-Taybi syndrome: the interconnections of epigenetic machinery disorders.

Hum Genet 2019 Mar 26;138(3):257-269. Epub 2019 Feb 26.

Genetica Medica, Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy.

Rubinstein-Taybi syndrome (RSTS) is an autosomal-dominant neurodevelopmental disease affecting 1:125,000 newborns characterized by intellectual disability, growth retardation, facial dysmorphisms and skeletal abnormalities. RSTS is caused by mutations in genes encoding for writers of the epigenetic machinery: CREBBP (~ 60%) or its homologous EP300 (~ 10%). No causative mutation is identified in up to 30% of patients. We performed whole-exome sequencing (WES) on eight RSTS-like individuals who had normal high-resolution array CGH testing and were CREBBP- and EP300-mutation -negative, to identify the molecular cause. In four cases, we identified putatively causal variants in three genes (ASXL1, KMT2D and KMT2A) encoding members of the epigenetic machinery known to be associated with the Bohring-Opitz, Kabuki and Wiedemann-Steiner syndromes. Each variant is novel, de novo, fulfills the ACMG criteria and is predicted to result in loss-of-function leading to haploinsufficiency of the epi-gene. In two of the remaining cases, homozygous/compound heterozygous variants in XYLT2 and PLCB4 genes, respectively, associated with spondyloocular and auriculocondylar 2 syndromes and in the latter an additional candidate variant in XRN2, a gene yet unrelated to any disease, were detected, but their pathogenicity remains uncertain. These results underscore the broad clinical spectrum of Mendelian disorders of the epigenetic apparatus and the high rate of WES disclosure of the genetic basis in cases which may pose a challenge for phenotype encompassing distinct syndromes. The overlapping features of distinct intellectual disability syndromes reflect common pathogenic molecular mechanisms affecting the complex regulation of balance between open and closed chromatin.
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http://dx.doi.org/10.1007/s00439-019-01985-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736609PMC
March 2019

HLA-G allelic distribution in Sardinian children with Autism spectrum disorders: A replication study.

Brain Behav Immun 2019 07 11;79:314-318. Epub 2019 Feb 11.

IRCCS Fondazione Don Carlo Gnocchi, Milano, Italy; Pathophysiology and Transplantation, University of Milano, Milano, Italy.

Recent results show that in mainland Italian children with Autism spectrum disorder (ASD), HLA-G coding alleles distribution is skewed and an association between HLA-G*01:05N and ASD is present. Herein, in an independent cohort of Sardinian ASD (sASD) children and their relatives, we verify whether HLA-G allele association with ASD could be confirmed in this genetically peculiar insular population. One hundred children with a diagnosis of ASD, born in Sardinia and of Sardinian descent, 91 of their mothers, and 40 of their healthy siblings were enrolled. DNA sequencing analysis of HLA-G exon 2, 3 and 4 was used to obtain HLA-G allelic frequencies. Alleles distribution was compared with that of continental ASD children and with a control group of Caucasoid couples of multiparous women and their partners from Brazil and Denmark. Skewing of HLA-G allele distribution was replicated in sASD children; in particular, the HLA-G*01:03 allele, associated with reduced fetal tolerogenicity and development of myeloid leukemia, was more common in both ASD groups compared to controls (p = 1 × 10; OR:3.5, 95%CI: 1.8-6.8). However, given the lack of data on HLA-G*01:03 allelic distribution among Sardinian healthy subjects, we cannot exclude a population effect. These data confirm an association of HLA-G locus with ASD development, particularly with those alleles linked to a lower expression of tolerogenic HLA-G protein, thus warranting further studies on HLA-G polymorphism distribution in different ASD populations.
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http://dx.doi.org/10.1016/j.bbi.2019.02.003DOI Listing
July 2019

Confirmation of a new phenotype in an individual with a variant in the last part of exon 30 of CREBBP.

Am J Med Genet A 2019 04 8;179(4):634-638. Epub 2019 Feb 8.

Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche (CNR), Monserrato (CA), Italy.

We report here a novel de novo missense variant affecting the last amino acid of exon 30 of CREBBP [NM_004380, c.5170G>A; p.(Glu1724Lys)] in a 17-year-old boy presenting mild intellectual disability and dysmorphisms but not resembling the phenotype of classical Rubinstein-Taybi syndrome. The patient showed a marked overweight from early infancy on and had cortical heterotopias. Recently, 22 individuals have been reported with missense mutations in the last part of exon 30 and the beginning of exon 31 of CREBBP, showing this new phenotype. This additional case further delineates the genotype-phenotype correlations within the molecular and phenotypic spectrum of variants in CREBBP and EP300.
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http://dx.doi.org/10.1002/ajmg.a.61052DOI Listing
April 2019

Clinical and Neurobehavioral Features of Three Novel Kabuki Syndrome Patients with Mosaic KMT2D Mutations and a Review of Literature.

Int J Mol Sci 2017 Dec 28;19(1). Epub 2017 Dec 28.

Division of Medical Genetics, IRCSS Casa Sollievo della Sofferenza Hospital, viale Cappuccini, 71013 San Giovanni Rotondo, Italy.

Kabuki syndrome (KS) is a rare disorder characterized by multiple congenital anomalies and variable intellectual disability caused by mutations in and , two interacting chromatin modifier responsible respectively for 56-75% and 5-8% of the cases. To date, three KS patients with mosaic deletions in blood lymphocytes have been described. We report on three additional subjects displaying gene mosaics including one in which a single nucleotide change results in a new frameshift mutation (p.L1199HfsX7), and two with already-known nonsense mutations (p.R4484X and p.R5021X). Consistent with previously published cases, mosaic mutations may result in mild KS facial dysmorphisms and clinical and neurobehavioral features, suggesting that these characteristics could represent the handles for genetic testing of individuals with slight KS-like traits.
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http://dx.doi.org/10.3390/ijms19010082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796032PMC
December 2017

HLA-G coding region polymorphism is skewed in autistic spectrum disorders.

Brain Behav Immun 2018 Jan 18;67:308-313. Epub 2017 Sep 18.

Don C. Gnocchi Foundation IRCCS, Milano, Italy; Department of Pathophysiology and Transplantation, University of Milano, Milano, Italy.

Different isoforms of HLA-G protein are endowed with a differential ability to induce allogenic tolerance during pregnancy. As prenatal immune activation is suggested to play a role in the onset of autistic spectrum disorders (ASD), we evaluated HLA G*01:01-*01:06 allelic polymorphism in a cohort of Italian children affected by ASD (N=111) their mothers (N=81), and their healthy siblings (N=39). DNA sequencing analysis of HLA-G exon 2, 3 and 4 was used to obtain HLA-G allelic frequencies; alleles distribution was compared with that of two control groups of Caucasoid couples of multiparous women and their partners from Brazil and Denmark. HLA-G distribution was significantly different in ASD children compared to both control groups (Brazilian p=1×10; Danish p=1×10). Since HLA-G distribution was similar in the two control groups, their data were pooled. Results indicated that HLA-G*01:01 was significantly less frequent (p=1×10; OR:0.5, 95%CI: 0.3-0.7) whereas HLA-G*01:05N was significantly more frequent (p=2×10; OR:7.3, 95%CI: 2.4-26.6) in ASD children compared to combined controls. Finally, no clear pattern emerged when HLA-G allelic distribution was analyzed in healthy sibs. Notably, HLA-G allelic distribution found in ASD mothers was similar to that observed in the control subgroup of women with recurrent miscarriages, whilst it was significantly different compared to women without miscarriages (p=6×10 df=12). Since HLA-G*01:01 is associated with the elicitation of KIR-mediated tolerogenic responses and HLA-G*01:05N correlates with NK cells activation, results herein indicate that an immune activating milieu during pregnancy is more likely observed in association with the development of ASD, similarly to what occurs in women with recurrent miscarriages.
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http://dx.doi.org/10.1016/j.bbi.2017.09.007DOI Listing
January 2018

HLA-G∗14bp Insertion and the KIR2DS1-HLAC2 Complex Impact on Behavioral Impairment in Children with Autism Spectrum Disorders.

Neuroscience 2018 02 13;370:163-169. Epub 2017 Jun 13.

Don C. Gnocchi Foundation IRCCS, Milano, Italy; Department of Pathophysiology and Transplantation, University of Milano, Milano, Italy.

Activating KIR-HLA-C ligand complexes and HLA-G∗14bp insertion/deletion (+/-) polymorphism were associated to Autism Spectrum Disorders (ASD) and were suggested to correlate with inflammation during fetal development. We evaluated whether HLA-G∗14bp(+/-) and KIR-HLA-C complexes are associated with cognitive and behavioral scores and EEG profile in 119 ASD children (58 from Sardinia, 61 from Peninsular Italy). KIR2DS1-C2; KIR2DS2-C1; KIR2DL1-C2; KIR2DL2-C1; KIR2DL3-C1 and HLA-G∗14bp(+/-) were molecularly genotyped by Single Specific Primer PCR and gel electrophoresis. Univariate linear model analysis adjusted for age, gender and provenience showed statistically higher scores of Childhood Autism Rating Scale (CARS) and Autistic Core Behavior in KIR2DS1-C2+/HLA-G∗14bp+ASD children (43.7±1.5, p=0.03; 3.3±0.1, p=0.03, respectively). These results suggested a synergistic polygenic association of KIR2DS1-HLAC2+/HLA-G∗14bp+ pattern with behavioral impairment in ASD children.
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http://dx.doi.org/10.1016/j.neuroscience.2017.06.012DOI Listing
February 2018

Epidemiology of multiple sclerosis in the pediatric population of Sardinia, Italy.

Eur J Pediatr 2016 Jan 10;175(1):19-29. Epub 2015 Jul 10.

Department of Clinical and Experimental Medicine, Section of Child Neuropsychiatry, University of Sassari, Sassari, Italy.

Unlabelled: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Several authors report MS affecting not only young adults but also children and adolescents. Sardinia is one of the regions at the highest risk for MS worldwide in the adult population; to date, no definite data exist on the pediatric population. The aim of this study was to estimate the incidence and prevalence of pediatric MS (pMS) in northern Sardinia. Patients with diagnosis of optic neuritis, myelitis, acute disseminated encephalomyelitis (ADEM), demyelinating disorders, MS, or clinically isolated syndrome (CIS) according to McDonald criteria were enrolled, when disease onset occurred within the range of 0-18 years. From January 1, 2001 to December 31, 2012, 21 cases of pMS and 5 cases of CIS were found in northern Sardinia. The annual mean pMS incidence was 2.85 cases per 100,000 pediatric population, and the annual mean CIS incidence was 0.68 cases per 100,000 pediatric population. The pMS and CIS prevalence computed on 31 December 2012 was 26.92 and 6.41 per 100,000 pediatric population, respectively.

Conclusion: Our pMS data among Sardinians corroborate the epidemiological scenario described in the adult population being the incidence estimates significantly higher than those reported elsewhere.

What Is Known: Sardinia is one of the regions at the highest risk for MS worldwide in the adult population. To date, no definite data exist on the pediatric population.

What Is New: The pediatric MS incidence in Sardinia is estimated to be significantly higher than those reported elsewhere. The pediatric MS prevalence in Sardinia is among the highest values worldwide.
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http://dx.doi.org/10.1007/s00431-015-2588-3DOI Listing
January 2016

Neurotoxicity and synaptic plasticity impairment of N-acetylglucosamine polymers: implications for Alzheimer's disease.

Neurobiol Aging 2015 May 6;36(5):1780-91. Epub 2015 Jan 6.

Section of Neurology, Department of Neurological and Movement Sciences, University of Verona, Verona, Italy. Electronic address:

We assessed whether polymers of N-acetylglucosamine (GlcNAc) have any pathogenetic role in Alzheimer's disease (AD). First, by using specific dyes, we found deposits of polymers of GlcNAc in sporadic but not in familial AD. We found that neurons and microglia exposed to GlcNAc and uridine diphosphate (UDP)-GlcNAc are able to form GlcNAc polymers, which display a significant neurotoxicity in vitro. Moreover, the exposure of organotypic hippocampal cultures to the same compounds led to synaptic impairment with decreased levels of syntaxin and synaptophysin. In addition, acute hippocampal slices treated with GlcNAc/UDP-GlcNAc showed a clear reduction of long-term potentiation of excitatory synapses. Finally, we demonstrated that microglial cells are able to phagocytose chitin particles and, when exposed to GlcNAc/UDP-GlcNAc, show cellular activation and intracellular deposition of GlcNAc polymers that are eventually released in the extracellular space. Taken together, our results indicate that both microglia and neurons produce GlcNAc polymers, which trigger neurotoxicity both directly and through microglia activation. GlcNAc polymer-driven neurotoxicity offers novel pathogenic insights in sporadic AD and new therapeutic options.
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http://dx.doi.org/10.1016/j.neurobiolaging.2014.12.033DOI Listing
May 2015

MxA mRNA quantification and disability progression in interferon beta-treated multiple sclerosis patients.

PLoS One 2014 14;9(4):e94794. Epub 2014 Apr 14.

Multiple Sclerosis Center, Spedali Civili of Brescia, Brescia, Italy.

Even though anti-interferon beta (IFNβ) antibodies are the main determinants of IFNβ bioactivity loss and Myxovirus-resistance protein A (MxA) is the most established marker of IFNβ biological activity in IFNβ-treated multiple sclerosis patients, their usefulness in the routine clinical practice is still debated. Therefore, 118 multiple sclerosis patients naïve for treatment were enrolled for a 3-year longitudinal observational study mimicking the conditions of a real-world setting. In order to evaluate the kinetics of bioactivity loss in blood samples obtained every 6 months after therapy initiation, MxA and interferon receptor isoform/subunit mRNA were quantified by real-time PCR, anti-IFNβ binding antibodies were detected by radioimmunoprecipitation, and neutralizing antibodies by cytopathic effect inhibition assay. Clinical measures of disease activity and disability progression were also obtained at all time points. We found that, at the individual-patient level, the response to IFNβ therapy was extremely heterogeneous, including patients with stable or transitory, early or late loss of IFNβ bioactivity, and patients with samples lacking MxA mRNA induction in spite of absence of antibodies. No interferon receptor isoform alterations that could explain these findings were found. At the group level, none of these biological features correlated with the measures of clinical disease activity or progression. However, when MxA mRNA was evaluated not at the single time point as a dichotomic marker (induced vs. non-induced), but as the mean of its values measured over the 6-to-24 month period, the increasing average MxA predicted a decreasing risk of short-term disability progression, independently from the presence of relapses. Therefore, a more bioactive treatment, even if unable to suppress relapses, reduces their severity by an amount that is proportional to MxA levels. Together with its feasibility in the routine laboratory setting, these data warrant the quantification of MxA mRNA as a primary tool for a routine monitoring of IFNβ therapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0094794PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3986392PMC
May 2015

Molecular analysis, pathogenic mechanisms, and readthrough therapy on a large cohort of Kabuki syndrome patients.

Hum Mutat 2014 Jul 9;35(7):841-50. Epub 2014 Apr 9.

Medical Genetics Unit, IRCCS Casa Sollievo Della Sofferenza Hospital, San Giovanni Rotondo, Italy.

Kabuki syndrome (KS) is a multiple congenital anomalies syndrome characterized by characteristic facial features and varying degrees of mental retardation, caused by mutations in KMT2D/MLL2 and KDM6A/UTX genes. In this study, we performed a mutational screening on 303 Kabuki patients by direct sequencing, MLPA, and quantitative PCR identifying 133 KMT2D, 62 never described before, and four KDM6A mutations, three of them are novel. We found that a number of KMT2D truncating mutations result in mRNA degradation through the nonsense-mediated mRNA decay, contributing to protein haploinsufficiency. Furthermore, we demonstrated that the reduction of KMT2D protein level in patients' lymphoblastoid and skin fibroblast cell lines carrying KMT2D-truncating mutations affects the expression levels of known KMT2D target genes. Finally, we hypothesized that the KS patients may benefit from a readthrough therapy to restore physiological levels of KMT2D and KDM6A proteins. To assess this, we performed a proof-of-principle study on 14 KMT2D and two KDM6A nonsense mutations using specific compounds that mediate translational readthrough and thereby stimulate the re-expression of full-length functional proteins. Our experimental data showed that both KMT2D and KDM6A nonsense mutations displayed high levels of readthrough in response to gentamicin treatment, paving the way to further studies aimed at eventually treating some Kabuki patients with readthrough inducers.
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http://dx.doi.org/10.1002/humu.22547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234006PMC
July 2014

Role of SH levels and markers of immune response in the stroke.

Dis Markers 2013 20;35(3):141-7. Epub 2013 Aug 20.

Center for Integrated Research, Department of Laboratory Medicine and Microbiology, Campus Bio-Medico, University of Rome, Italy.

Background: Sulfhydryl groups (SH) are considered a key factor in redox sensitive reaction of plasma, and their modification could be considered an expression of abnormal generation of oxygen free radicals.

Methods: Fifty consecutive patients with acute brain stroke were enclosed in this study. The plasma concentrations of SH groups were correlated to cytokines (IL-1b, IL-6, IL-8, TNF- α ), plasma chitotriosidase (Chit), metalloprotease (MMP2-9), intercellular adhesion molecule-1 (ICAM-1).

Results: The results demonstrated a significant reduction of SH groups within 24 hours from the onset of an acute ischemic stroke, a reduction of plasma IL-1b, IL-6, and IL-8, and an increase of Chit and TNF- α in relation to the stroke severity.

Conclusion: The observation of an intense microenvironment activation that follows the stroke and the correlation between SH levels and markers of immune response suggest that, especially in stroke, is necessary to maintain the redox function to prevent the brain damage. The reduced SH levels represent an attempt to neutralize the abnormal generation of free radicals. Since the reperfusion of brain after ischemic event represents a severe oxidative stress, which must be corrected by regeneration of redox sensitive function, pharmacological intervention could be beneficial in this setting.
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http://dx.doi.org/10.1155/2013/246205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3774977PMC
June 2014

Activating KIR molecules and their cognate ligands prevail in children with a diagnosis of ASD and in their mothers.

Brain Behav Immun 2014 Feb 11;36:54-60. Epub 2013 Oct 11.

Don C. Gnocchi Foundation, IRCCS, Milano, Italy; Department of Pathophysiology and Transplantation, University of Milano, Milano, Italy.

The activity of natural killer (NK) cells is modulated by the interaction between killer-cell immune globulin-like receptor (KIR) proteins and their cognate HLA ligands; activated NK cells produce inflammatory cytokines and mediate innate immune responses. Activating KIR/HLA complexes (aKIR/HLA) were recently suggested to prevail in children with autism spectrum disorders (ASD), a neurodevelopmental syndrome characterized by brain and behavioral abnormalities and associated with a degree of inflammation. We verified whether such findings could be confirmed by analyzing two sample cohorts of Sardinian and continental Italian ASD children and their mothers. Results showed that aKIR/HLA are increased whereas inhibitory KIR/HLA complexes are reduced in ASD children; notably this skewing was even more significant in their mothers. KIR and HLA molecules are expressed by placental cells and by the trophoblast and their interactions result in immune activation and influence fetal, as well as central nervous system development and plasticity. Data herein suggest that in utero KIR/HLA immune interactions favor immune activation in ASD; this may play a role in the pathogenesis of the disease.
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http://dx.doi.org/10.1016/j.bbi.2013.10.006DOI Listing
February 2014

Natalizumab inhibits the expression of human endogenous retroviruses of the W family in multiple sclerosis patients: a longitudinal cohort study.

Mult Scler 2014 Feb 22;20(2):174-82. Epub 2013 Jul 22.

Department of Clinical and Experimental Medicine, University of Sassari, Italy.

Background: Several viruses were reported as co-factors triggering the pathogenesis of multiple sclerosis (MS), including the endogenous retroviruses of the HERV-W family, that were also proposed as biomarkers of disease progression and therapy outcome.

Objective: The objective of this article is to clarify whether in MS patients treatment with natalizumab has effects on MSRV/syncytin-1/HERV-W expression and the possible relationship with disease outcome.

Methods: Peripheral blood mononuclear cells were collected from 22 patients with relapsing-remitting disease, at entry and after three, six and 12 months of treatment with natalizumab. The cell subpopulations and the expression of MSRVenv/syncytin-1/HERV-Wenv were analyzed by flow cytometry and by discriminatory env-specific RT-PCR assays.

Results: By flow cytometry the relative amounts of T, NK and monocyte subpopulations were shown to remain fairly constant. A relative increase of B lymphocytes was observed at three to six months (p = 0.033). The MSRVenv and syncitin-1 transcripts were reduced at six to 12 months of therapy (p = 0.0001). Accordingly, at month 12, the plasma-membrane levels of the HERV-Wenv protein were reduced (p = 0.0001). B cells, NK and monocytes but not T cells expressed the HERV-Wenv protein. None of the patients relapsed during therapy.

Conclusion: Effective therapy with natalizumab downregulates MSRV/syncytin-1/HERV-W expression.
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http://dx.doi.org/10.1177/1352458513494957DOI Listing
February 2014

Protein-protein interaction analysis highlights additional loci of interest for multiple sclerosis.

PLoS One 2012 18;7(10):e46730. Epub 2012 Oct 18.

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

Genetic factors play an important role in determining the risk of multiple sclerosis (MS). The strongest genetic association in MS is located within the major histocompatibility complex class II region (MHC), but more than 50 MS loci of modest effect located outside the MHC have now been identified. However, the relative candidate genes that underlie these associations and their functions are largely unknown. We conducted a protein-protein interaction (PPI) analysis of gene products coded in loci recently reported to be MS associated at the genome-wide significance level and in loci suggestive of MS association. Our aim was to identify which suggestive regions are more likely to be truly associated, which genes are mostly implicated in the PPI network and their expression profile. From three recent independent association studies, SNPs were considered and divided into significant and suggestive depending on the strength of the statistical association. Using the Disease Association Protein-Protein Link Evaluator tool we found that direct interactions among genetic products were significantly higher than expected by chance when considering both significant regions alone (p<0.0002) and significant plus suggestive (p<0.007). The number of genes involved in the network was 43. Of these, 23 were located within suggestive regions and many of them directly interacted with proteins coded within significant regions. These included genes such as SYK, IL-6, CSF2RB, FCLR3, EIF4EBP2 and CHST12. Using the gene portal BioGPS, we tested the expression of these genes in 24 different tissues and found the highest values among immune-related cells as compared to non-immune tissues (p<0.001). A gene ontology analysis confirmed the immune-related functions of these genes. In conclusion, loci currently suggestive of MS association interact with and have similar expression profiles and function as those significantly associated, highlighting the fact that more common variants remain to be found to be associated to MS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0046730PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475710PMC
April 2013

Expression and activation by Epstein Barr virus of human endogenous retroviruses-W in blood cells and astrocytes: inference for multiple sclerosis.

PLoS One 2012 27;7(9):e44991. Epub 2012 Sep 27.

Department of Biomedical Sciences and Centre of Excellence for Biotechnology Development and Biodiversity Research, University of Sassari, Sassari, Italy.

Background: Proposed co-factors triggering the pathogenesis of multiple sclerosis (MS) are the Epstein Barr virus (EBV), and the potentially neuropathogenic MSRV (MS-associated retrovirus) and syncytin-1, of the W family of human endogenous retroviruses.

Methodology/principal Findings: In search of links, the expression of HERV-W/MSRV/syncytin-1, with/without exposure to EBV or to EBV glycoprotein350 (EBVgp350), was studied on peripheral blood mononuclear cells (PBMC) from healthy volunteers and MS patients, and on astrocytes, by discriminatory env-specific RT-PCR assays, and by flow cytometry. Basal expression of HERV-W/MSRV/syncytin-1 occurs in astrocytes and in monocytes, NK, and B, but not in T cells. This uneven expression is amplified in untreated MS patients, and dramatically reduced during therapy. In astrocytes, EBVgp350 stimulates the expression of HERV-W/MSRV/syncytin-1, with requirement of the NF-κB pathway. In EBVgp350-treated PBMC, MSRVenv and syncytin-1 transcription is activated in B cells and monocytes, but not in T cells, nor in the highly expressing NK cells. The latter cells, but not the T cells, are activated by proinflammatory cytokines.

Conclusions/significance: In vitro EBV activates the potentially immunopathogenic and neuropathogenic HERV-W/MSRV/syncytin-1, in cells deriving from blood and brain. In vivo, pathogenic outcomes would depend on abnormal situations, as in late EBV primary infection, that is often symptomatic, or/and in the presence of particular host genetic backgrounds. In the blood, HERV-Wenv activation might induce immunopathogenic phenomena linked to its superantigenic properties. In the brain, toxic mechanisms against oligodendrocytes could be established, inducing inflammation, demyelination and axonal damage. Local stimulation by proinflammatory cytokines and other factors might activate further HERV-Ws, contributing to the neuropathogenity. In MS pathogenesis, a possible model could include EBV as initial trigger of future MS, years later, and HERV-W/MSRV/syncytin-1 as actual contributor to MS pathogenicity, in striking parallelism with disease behaviour.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0044991PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3459916PMC
February 2013

Human endogenous retrovirus type W envelope expression in blood and brain cells provides new insights into multiple sclerosis disease.

Mult Scler 2012 Dec 28;18(12):1721-36. Epub 2012 Mar 28.

GeNeuro, Geneva, Switzerland.

Background: The envelope protein from multiple sclerosis (MS) associated retroviral element (MSRV), a member of the Human Endogenous Retroviral family 'W' (HERV-W), induces dysimmunity and inflammation.

Objective: The objective of this study was to confirm and specify the association between HERV-W/MSRV envelope (Env) expression and MS.

Methods: 103 MS, 199 healthy controls (HC) and controls with other neurological diseases (28), chronic infections (30) or autoimmunity (30) were analysed with an immunoassay detecting Env in serum. Env RNA or DNA copy numbers in peripheral blood mononuclear cells (PBMC) were determined by a quantitative polymerase chain reaction (PCR). Env was detected by immunohistology in the brains of patients with MS with three specific monoclonals.

Results: Env antigen was detected in a serum of 73% of patients with MS with similar prevalence in all clinical forms, and not in chronic infection, systemic lupus, most other neurological diseases and healthy donors (p<0.01). Cases with chronic inflammatory demyelinating polyneuropathy (5/8) and rare HC (4/103) were positive. RNA expression in PBMC and DNA copy numbers were significantly elevated in patients with MS versus HC (p<0.001). In patients with MS, DNA copy numbers were significantly increased in chronic progressive MS (secondary progressive MS vs relapsing-remitting MS (RRMS) p<0.001; primary progressive MS vs RRMS -<0.02). Env protein was evidenced in macrophages within MS brain lesions with particular concentrations around vascular elements.

Conclusion: The association between MS disease and the MSRV-type HERV-W element now appears quite strong, as evidenced ex-vivo from serum and PBMC with post-mortem confirmation in brain lesions. Chronic progressive MS, RRMS and clinically isolated syndrome show different ELISA (Enzyme-Linked Immunosorbent Assay) and/or PCR profiles suggestive of an increase with disease evolution, and amplicon sequencing confirms the association with particular HERV-W elements.
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http://dx.doi.org/10.1177/1352458512441381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3573672PMC
December 2012

Cytoskeletal proteins in the cerebrospinal fluid as biomarker of multiple sclerosis.

Neurol Sci 2013 Feb 24;34(2):181-6. Epub 2012 Feb 24.

Dipartimento di Scienze Biomediche, Università di Sassari, viale San Pietro 43/B, 07100 Sassari, Italy.

The axonal cytoskeleton is a finely organized system, essential for maintaining the integrity of the axon. Axonal degeneration is implicated in the pathogenesis of unremitting disability of multiple sclerosis (MS). Purpose of this study is to evaluate levels of cytoskeletal proteins such as neurofilament light protein (NFL), glial fibrillary acidic protein (GFAP), and β-tubulin (β-Tub) isoforms II and III in the cerebrospinal fluid (CSF) of MS patients and their correlation with MS clinical indices. CSF levels of cytoskeletal proteins were determined in 51 patients: 33 with MS and 18 with other neurological diseases (OND). NFL, GFAP and β-Tub II proteins were significantly higher (p < 0.0001) in MS than in OND group; no significant difference (p > 0.05) was found between MS and OND with regard to β-Tub III. Interestingly, levels of β-Tub III and NFL were higher in progressive than in remitting MS forms; on the contrary, higher levels of β-Tub II and GFAP were found in remitting MS forms. However, with the exception of β-Tub III, all proteins tend to decrease their CSF levels concomitantly with the increasing disability (EDSS) score. Overall, our results might indicate β-Tub II as a potential candidate for diagnostic and β-Tub III as a possible prognostic biomarker of MS. Therefore, further analyses are legitimated and desirable.
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http://dx.doi.org/10.1007/s10072-012-0974-4DOI Listing
February 2013

SNAP-25 single nucleotide polymorphisms are associated with hyperactivity in autism spectrum disorders.

Pharmacol Res 2011 Sep 8;64(3):283-8. Epub 2011 Apr 8.

Don C. Gnocchi Foundation ONLUS, P. le Morandi 6, 20121 Milano, Italy.

Synaptosomal-associated protein of 25kD (SNAP-25), a protein participating in the regulation of synaptic vesicle exocytosis and in calcium homeostasis, was recently involved in neuropsychiatric conditions. Because alterations affecting the homeostasis of calcium are described in patients affected by autism spectrum disorders (ASD) we investigated a possible involvement of SNAP-25 in ASD by evaluating five SNAP-25 gene polymorphisms in a cohort of 67 ASD children. Data analyzed in relationship with clinical outcomes and compared to those of 205 healthy sex-matched children did not reveal significant differences. Further analyses nevertheless showed the presence of highly significant associations of the rs363043 (CT) genotype, localized in the intron 1 region that affects the transcription factor binding sites of the SNAP-25 gene, with both increasing CARS (p=0.001) and hyperactivity scores (p=0.006). The finding that polymorphisms of the SNAP-25 gene, a gene involved in neurotransmission and regulation of calcium homeostasis, are associated with the degree of hyperactivity in children with ASD, reinforces the hypothesis that alterations of these mechanisms play a pivotal role in the events leading to ASD-associated behavioral impairment. Modulation of these processes could result in novel therapeutic strategies.
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http://dx.doi.org/10.1016/j.phrs.2011.03.015DOI Listing
September 2011

HLA polymorphisms in Italian children with autism spectrum disorders: results of a family based linkage study.

J Neuroimmunol 2011 Jan 17;230(1-2):135-42. Epub 2010 Nov 17.

Laboratory of Molecular Medicine and Biotechnologies, Don C Gnocchi Foundation IRCCS, S Maria Nascente, Milan, Italy.

To verify correlations between HLA and autism spectrum disorders (ASD) we studied 61 Italian families with an ASD child; results showed such correlation in 65% of cases. Case-control and TDT analysis of intrafamilial transmission of SNPs, Msats, and HLA markers surrounding the α and β blocks, indicated significant positive associations for MOGc*131 and D6S2239*105 alleles in ASD, and a negative association of MIB *332 allele in healthy siblings. Polymorphism haplotype analysis demonstrated that two haplotypes comprising the TNF-238(G)-TNF-308(G)-MIB*332-HLA-B*38-HLA-Cw*12 and the D6S265*218-HLA-A*23-MOGc*131-rs2857766(G) alleles are more frequently transmitted to ASD. MOGc and MIB loci are linked with ASD in Italian patients.
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http://dx.doi.org/10.1016/j.jneuroim.2010.10.019DOI Listing
January 2011