The intellectual disability is found in approximately 2-3% of the population in a mild-to-moderate form and 0.5-1% in a moderate-to-severe form. The mutations on the chromosome X are responsible for both syndromic and non-syndromic intellectual disability. In the syndromic forms behavioral disorders, autism and/or seizures are frequent

Antona, V.

Consiglio, V.

CORSELLO, Giovanni

Graziano, L.

Lauricella, S.

PICCIONE, Maria

Salzano, E.

VECCHIO, Davide

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X-LINKED INTELLECTUAL DISABILITYPICCIONE MARIA, VINCENZO ANTONA, LUCIANO GRAZIANO, VALERIA CONSIGLIO1, EMANUELA SALZANO, DAVIDE VECCHIO,LAURICELLA SALVATRICE ANTONIA2, GIOVANNI CORSELLODipartimento di Scienze per la Promozione della Salute e Materno Infantile, Università degli Studi di Palermo - 1CRR Malattie RareAOOR Villa Sofia-Cervello Palermo - 2Laboratorio di Citogenetica Medica AOOR Villa Sofia-Cervello PalermoIntroductionThe intellectual disability is found in approxi-mately 2–3% of the population in a mild-to-moder-ate form and 0.5-1% a moderate-to-severe form(1).The etiology can be different (unknown andenvironmental causes(2), chromosomal anomalies(3-6),genetic mutations(7), prenatally, perinatally, or post-natally causes etc.) and a careful anamnesis is nec-essary for a correct diagnosis.When in a single family are more males withintellectual disability in pedigree of three genera-tions, we suppose that it is caused by X-linkedpathology, even if the clinical diagnosis of intellec-tual disability X-linked (XLID) is usually a diagno-sis of exclusion of other causes of developmentaldelay in male.Intellectual disability is more common in themale rather than in the female population, due tomutations on the X chromosome(8-10). XLID is generally divided into syndromicforms, in which intellectual disability is only one ofa large set of symptoms, and non-syndromic forms,in which intellectual disability is the only manifes-tation of the pathology(1). The syndromic forms are prevalent, and aboutone half of XLID patients also manifest autismand/or seizures. To date, more than 150 XLID syn-dromes have been characterized and 102 XLIDgenes have been identified, accounting for 81 ofthese syndromes(8).The XLID genes encode for proteins that arehighly expressed in the brain, especially in the hip-pocampus, a region that plays a key role in learningand memory.We report the data for three X-linked syn-dromes with intellectual disability.Fragile X syndromeFragile X syndrome is a rare genetic diseaseassociated with typical dysmorphism and mild tosevere intellectual deficit that may be associatedwith behavioral disorders.The clinical phenotype is variable. Prevalenceis estimated at approximately 1/2,500 (prevalenceof the full mutation allele) to 1/4,000 (prevalence ofsymptomatic cases)(11) for both genders.The majority of males with Fragile X syn-drome reveal significant intellectual disability (for-Acta Medica Mediterranea, 2013, 29: 77ABSTRACTThe intellectual disability is found in approximately 2–3% of the population in a mild-to-moderate form and 0.5–1% in amoderate-to-severe form. The mutations on the chromosome X are responsible for both syndromic and non-syndromic intellectualdisability. In the syndromic forms behavioral disorders, autism and/or seizures are frequent.Key words: intellectual disability X-linked, syndromic forms, dysmorphic features.Received August 21, 2013; Accepted Septemper 20, 201378 Piccione Maria, Vincenzo Antona et Almerly referred to as “mental retardation”).Disabilities in Fragile X syndrome include a rangefrom moderate learning disabilities to more severeintellectual ones. In males, the disease occurs dur-ing childhood with delayed developmental mile-stones (motor and/or language delay)(12,13). In malesand in 50% of females, intellectual disorders asso-ciated with behavioral problems and/or dysmorphicfeatures appear. Behavioral characteristics caninclude attention deficit / hyperactivity disorder(ADD/ADHD), autism and autistic behaviors,social anxiety, hand-biting and/or flapping, pooreye contact, sensory disorders and increased riskfor aggression(14-16). Mood disorders, anxiety andaggressive behavior can be present(17). In females,intellectual and behavioral disorders are mild (emo-tional and learning problems). Physical featuresmay include large ears, long face, soft skin andlarge testicles (called “macroorchidism”) in post-pubertal males. Connective tissue problems mayinclude ear infections(18), flat feet, high-archedpalate, double-jointed fingers and hyper-flexiblejoints. Fragile X is caused by a “full” mutation inthe fragile X mental retardation 1 (FMR1) gene,which creates a protein called “fragile X mentalretardation protein” (FMRP). Nearly all cases offragile X syndrome are caused by a mutation inwhich a DNA segment, known as the CGG tripletrepeat, is expanded within the FMR1 gene.Normally, this DNA segment is repeated from 5 toabout 40 times. In people with fragile X syndrome,however, the CGG segment is repeated more than200 times. The abnormally expanded CGG segmentturns off (silences) the FMR1gene, which preventsthe gene from producing FMRP. Loss or a shortage(deficiency) of this protein disrupts nervous systemfunctions and leads to the signs and symptoms offragile X syndrome(19). Premutations are associatedwith phenotypes distinct from Fragile X syndromeincluding a risk of premature ovarian insufficiencyin women, and the fragile X-associated tremor/atax-ia syndrome. In some rare cases, Fragile X syn-drome was shown to result from intragenic FMR1point mutations rather than expansion of a CGGrepeat. One function of the FMRP protein in thebrain is to put the brakes on another protein in thebrain, called “metabotropic glutamate receptor 5”(MGluR5). MGluR5 tells theneuronsto growden-drites, which are long, narrow parts that allow themto attach to other neurons. When the dendrites arethe right size and shape, FMRP makes MGluR5 tellthe neurons to stop. When FMRP is missing, thedendrites grow wild and uncontrolled. Fragile Xsyndrome is an X-linked dominant disorder withreduced penetrance in females. Genetic counselingshould be offered to families of an affected individ-ual in order to explain the mode of inheritance ofthe mutations (there is a 50% recurrence risk in pre-mutated females). Prenatal diagnosis is possible onsamples of chorionic villi or amniotic fluid. Mostpatients with fragile X syndrome generally have anormal life span.New targeted treatments for Fragile X syn-drome (mGluR5 antagonists, GABA A and B ago-nists, minocycline) are now being studied.Alpha thalassemia - X-linked intellectual deficitsyndromeX-linked alpha thalassemia mental retardation(ATR-X) syndrome is a rare, inherited conditioncharacterized by severe intellectual disability, char-acteristic facial features, genital abnormalities andalpha thalassemia(20-22).Female carriers are usually physically andintellectually normal. The phenotype is usually characterized by dis-tinctive craniofacial features, genital anomalies,severe developmental delays, hypotonia, intellectu-al disability, and mild-to-moderate anemia sec-ondary to alpha-thalassemia associated with spas-ticity or seizures, and growth retardation with mid-face hypoplasia and skeletal abnormalities and gas-tro-esophageal reflux that may cause death(23).Craniofacial abnormalities include microcephaly,telecanthus or ocular hypertelorism, small nose,tented upper lip, and prominent or everted lower lipwith coarsening of the facial features over time.This syndrome is X-linked recessive andresults from mutations in the ATRX gene, whichencodes an ATP-dependent chromatin-remodeler.This disease results in severe disability and short-ened lifespan. The best way to diagnose this condi-tion is to identify a gene mutation in the affectedindividual through molecular genetic testing of theATRX gene. Genetic counseling can be offered tofamilies. Rett syndromeRett syndrome is a genetic disorder that affectsapproximately 1 in 12,000 females (it is rarelyseenin males). Rett syndrome primarily affects females,making it one of the most common genetic causesof severe intellectual disability in females. It causes severe physical and mental disabilitythat begins in early childhood.The changes typically appear in the first 6-18months of the infant’s life. These include:• a general slowness in development; • floppiness; • difficulty in feeding; • abnormal hand movements (such as repeat-edly making wringing, clapping or washingmotions with the hands); • less interest in social contact and eye con-tact;  • not very interested in toys;  • walking awkwardly and poor co-ordinationof trunk and limbs. The “rapid destructive stage”, usually beginsbetween the ages of one and four and may last forweeks or months.The children will gradually orsuddenly start to develop severe problems withcommunication, language, learning, co-ordinationand other brain functions(24-26). Despite the identification of mutations in theX-linked gene methyl CpG-binding protein 2(MECP2) in the majority of Rett syndrome patients,the etiology remains unclear. More recently muta-tions in two other genes, cyclin-dependent kinaselike 5 (CDKL5) and Netrin G1, have been identi-fied in patients with a clinical phenotype thatstrongly overlaps with Rett syndrome. Lifeexpectancies are not well studied, although survivalat least until the mid-20s is likely. The average lifeexpectancy of a girl with Rett syndrome may bemid-40s. Death is often related to seizure, aspira-tion pneumonia and malnutrition(27,28).ConclusionManagement of XLID is symptom-based andrequires a multidisciplinary approach, which shouldbe combined with speech therapy, sensory integra-tion occupational therapy, individualized education-al plans, and behavioral interventions. Geneticcounseling and prenatal diagnosis can be offered tofamilies. diabetic patients independently of HT andheart failure. Prospective studies with a largercohort are now needed to observe the effects of CT-1 treatment in a diabetic population.References1) Bassani S, Zapata J, Gerosa L, Moretto E, MurruL, Passafaro M. The Neurobiology of X-LinkedIntellectual Disability Neuroscientist.Neuroscientist. 2013 Oct; 19(5): 541-52.2) Piro E, Piccione M, Marrone G, Giuffrè M,Corsello G. Dyke-Davidoff-Masson syndrome:case report of fetal unilateral ventriculomegalyand hyplastic left middle cerebral artery. Ital. JPediatr 2013; 14; 39(1): 32.3) Busè M, Giuffrè M, Martines M, Piro E, PiccioneM, Corsello G.16p11.2 Microdeletion/microdupli-cation syndrome: further characterization of acritical region for neuropsychiatric development.Acta Medica Mediterranea, 2013, 29: 241-246.4) Piro E, Busè M, Sciarrabone GM, Antona V,Martines M, Ballacchino A, Piccione M, CorselloG. Copy number variations in the etiology ofautism spectrum disorders. Acta MedicaMediterranea, 2013, 29: 337-342.5) Piro E, Martines M, Ballacchino A, Busè M,Graziano F, Salzano M, Consiglio V, Antona V,Corsello G. Copy number variations in the etiolo-gy of epilepsy. Acta Medica Mediterranea, 2013,29: 317-320.6) Graziano F, Antona V, Martines M, BallacchinoA, Consiglio V, Piro E, Corsello G. Type andcounter-type from specific chromosomal regions.Acta Medica Mediterranea, 2013, 29: 333-336.7) Piro E, Antona V, Consiglio V, Ballacchino A,Graziano F, Giuffrè M, Alongi A, Vecchio D,Corsello G. Microcephaly a clinical-geneticapproach. Acta Medica Mediterranea 2013, 29:327-331.8) Raymond FL. X linked mental retardation: aclini-cal guide. J Med Genet 2006; 43: 193-200.9) des Portes V. X-linked mental deficiency. HandbClin Neurol. 2013; 111: 297-306.10) Guillén-Navarro E, Glóver-López G. Monogeniccauses of X-linked mental retardation. RevNeurol. 2006 Jan 7; 42Suppl 1:S45-911) Coffee B, Keith K, Albizua I, Malone T, MowreyJ, Sherman SL and others Incidence of fragile Xsyndrome by newborn screening for methylatedFMR1 DNA. Am J Hum Genet 2009, 85: 503-14.12) Finestack LH, Abbeduto L. Expressive languageprofiles of verbally expressive adolescents andyoung adults with Down syndrome or fragile Xsyndrome. J Speech Lang Hear Res. 2010 Oct;53(5): 1334-48. 13) McDuffie A, Kover S, Abbeduto L, Lewis P,Brown T. Profiles of receptive and expressive lan-guage abilities in boys with comorbid fragile Xsyndrome and autism. Am J Intellect Dev Disabil.2012 Jan; 117(1): 18-32. X-linked Intellectual Disability 7914) Kover ST, Abbeduto L. Expressive language inmale adolescents with fragile X syndrome withand without comorbid autism. J Intellect DisabilRes. 2010 Mar; 54(3): 246-65.15) Martines F, Martines E, Mucia M, Sciacca V,Salvago P. Prelingual sensorineural hearing lossand infants at risk: Western Sicily report. Int JPediatr Otorhinolaryngol 2013; 77(4): 513-8. 16) Salvago P, Martines E, Martines F. Prevalenceand risk factors for sensorineural hearing loss:Western Sicily overview. Eur ArchOtorhinolaryngol 2013. doi: 10.1007/s00405-013-2379-2.17) Cook D, Nuro E, Murai KK. Increasing ourunderstanding of human cognition through thestudy of Fragile X Syndrome. Dev Neurobiol.2013 May 31. doi: 10.1002/dneu.22096. 18) Martines F, Bentivegna D, Maira E, Sciacca V.,Martines E. Risk factors for otitis media with effu-sion: Case-control study in Sicilian schoolchild-ren. Int J Pediatr Otorhinolaryngol 2011; 75: 754-759.19) Tabolacci E, Neri G. Epigenetic modifications ofthe FMR1 gene. Methods Mol Biol. 2013; 1010:141-53.20) Stromme P, Mangelsdorf ME, Shaw MA, LowerKM, Lewis SM, Bruyere H, et al. Mutations inthe humanortholog of Aristaless cause X-linkedmental retardation and epilepsy. Nat Genet 2002;30(4): 441-5.21) Iwase S, Xiang B, Ghosh S, Ren T, Lewis PW,Cochrane JC, et al. ATRX ADD domain links anatypical histone methylation recognition mecha-nism to human mental-retardation syndrome. NatStruct Mol Biol. 2011 Jun 12; 18(7): 769-76.22) Thienpont B, de Ravel T, Van Esch H, VanSchoubroeck D, Moerman P, Vermeesch JR, et al.Partial duplications of the ATRX gene cause theATR-X syndrome. Eur J Hum Genet. 2007 Oct;15(10): 1094-7.23) Gibbons R. Alphathalassaemia-mental retarda-tion, X linked. Orphanet J Rare Dis. 2006 May4;1: 15.24) Bahi-Buisson N. Genetically determinedencephalopathy: Rett syndrome. Handb ClinNeurol. 2013; 111: 281-6.25) Dolce A, Ben-Zeev B, Naidu S, Kossoff EH. Rettsyndrome and epilepsy: an update for child neu-rologists. Pediatr Neurol. 2013 May; 48(5): 337-45.26) Bao X, Downs J, Wong K, Williams S, LeonardH. Using a large international sample to investi-gate epilepsy in Rett syndrome. Dev Med ChildNeurol. 2013 Jun; 55(6): 553-8.27) Mari F, Azimonti S, Bertani I, Bolognese F,Colombo E, Caselli R, et al. CDKL5 belongs tothe same molecular pathway of MeCP2 and it isresponsible for the early-onset seizure variant ofRett syndrome. Hum Mol Genet 2005, 14: 1935-46.28) Ricciardi S, Ungaro F, Hambrock M, RademacherN, Stefanelli G, Brambilla D, et al. CDKL5ensures excitatory synapse stability by reinforcingNGL-1-PSD95 interaction in the postsynapticcompartment and is impaired in patient iPSC-derived neurons. Nat Cell Biol 2012, 14: 911-23.________Request reprints from:DR. PICCIONE MARIA(Italy)80 Piccione Maria, Vincenzo Antona et Al

X-linked intellectual disability

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X-linked intellectual disability

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