Brandeis NBIO 146A - Rett Syndrome: A Prototypical Neurodevelopmental Disorder

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118 THE NEUROSCIENTIST Neuroscience Curricula for UndergraduatesCopyright © 2004 Sage PublicationsISSN 1073-8584IntroductionPsychosocial development occurs along a well-definedtrajectory in which specific milestones are realized atdefined intervals. During development, two abnormali-ties can occur: developmental delay (i.e., the failure tomeet milestones within a normal time frame) or devel-opmental regression (i.e., the loss of previously acquiredmilestones). The latter is an ominous symptom of anunderlying progressive neurological abnormality. Recentgenetic and molecular advances have provided insightinto a cause of developmental regression in girls: Rettsyndrome.Andreas Rett, an Austrian physician, originallydescribed Rett syndrome in 1966 when he observed twogirls with a similar abnormality in his waiting room(Rett 1966). The condition was generally unrecognizeduntil Hagberg and others (1983) described a series of 35European girls with Rett syndrome. Subsequent researchfound the prevalence of Rett syndrome to range from1:10,000 to 1:22,000 (Percy 2002).Classic Rett syndrome is a clinical diagnosis based ondefined criteria (Hagberg and others 1985). Girls withRett syndrome are born after a normal pregnancy anduneventful delivery and have apparently normal devel-opment throughout the first 6 months of life. The headsize is normal at birth, but a subsequent deceleration ofhead growth occurs after 2 to 4 months of life, ultimate-ly resulting in an acquired microcephaly. Replacementof purposeful hand use with stereotyped movementsoccurs after 6 months of life. The hand stereotypies con-sist of midline hand wringing, clapping, and handmouthing. Autistic features such as social withdrawaland impaired language are noted. A characteristic gaitapraxia is prevalent, often curtailing or, in some cases,eliminating ambulation.Clinical variants of Rett syndrome that do not com-pletely meet the accepted diagnostic criteria have beendescribed (Hagberg and Skjeldal 1994). At the severeend of the spectrum of atypical Rett variants are patientswithout a period of normal development, known as con-genital variants of Rett syndrome. In contrast, mildforms exist that are known as forme fruste, or “worndown,” variants. The preserved speech variant (PSV) isan interesting variant with particular unique characteris-tics, such as obesity and preserved head size (Zappellaand others 1998).Although girls with Rett syndrome are small for theirages, their brains are disproportionately small (Armstrongand others 1999). This small brain and grey matter atro-phy led initially to the belief that Rett syndrome was aneurodegenerative condition of childhood, but the lackof progressive atrophy as the girls aged argued against adegenerative process. Neuropathological analysis ofbrains indicates no gross developmental abnormalitiesand no neuronal degeneration but rather small, closelyRett Syndrome: A PrototypicalNeurodevelopmental DisorderJEFFREY L. NEUL and HUDA Y. ZOGHBIRett syndrome, one of the leading causes of mental retardation and developmental regression in girls, isthe first pervasive developmental disorder with a known genetic cause. The majority of cases of sporadicRett syndrome are caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2).MeCP2 binds methylated DNA and likely regulates gene expression and chromatin structure.Genotype/phenotype analysis revealed that the phenotypic spectrum of MECP2 mutations in humans isbroader than initially suspected: Mutations have been discovered in Rett syndrome variants, mentallyretarded males, and autistic children. A variety of in vivo and in vitro models has been developed that allowanalysis of MeCP2 function and pathogenic studies of Rett syndrome. Because the neuropathology ofRett syndrome shares certain features with other neurodevelopmental disorders, a common pathogenicprocess may underlie these disorders. Thus, Rett syndrome is a prototype for the genetic, molecular, andneurobiologicalanalysis of neurodevelopmental disorders. NEUROSCIENTIST 10(2):118–128, 2004. DOI:10.1177/1073858403260995KEY WORDS MeCP2, MBD, Synapse, Autism, AngelmanWe thank Steven Maricich and Dawna Armstrong for useful commentson the manuscript.Department of Pediatrics, Baylor College of Medicine, Houston(JLN); Departments of Pediatrics, Molecular and Human Genetics,Neurology, and Neuroscience and the Howard Hughes MedicalInstitute, Baylor College of Medicine, Houston (HYZ). Address correspondence to: Huda Y. Zoghbi, Department ofMolecular and Human Genetics, Baylor College of Medicine, OneBaylor Plaza, Room T807, MS #225, Houston, TX 77030 (e-mail:[email protected]).REVIEW ■Volume 10, Number 2, 2004 THE NEUROSCIENTIST 119packed neurons with reduced dendritic spines and arbors(Armstrong and others 1995).Molecular Basis of Rett SyndromeThe genetic identification of the chromosomal regioninvolved in Rett syndrome was initially hampered by therelative lack of familial Rett syndrome cases, which pre-vented a standard genetic linkage analysis. However, thesyndrome is generally only found in girls; thus, it wasassumed to be an X-linked dominant trait that causedfetal demise in males (Hagberg and others 1983). Thesmall number of familial cases allowed exclusion map-ping of the X chromosome, which narrowed the regionto Xq27-qter (see references in Shahbazian and Zoghbi2002). Candidate transcripts in the region were analyzedfor variations, and ultimately mutations in methyl-CpG-binding protein 2 (MECP2), located at Xq28, were iden-tified in Rett patients (Amir and others 1999). Furthersupporting the role of MECP2 in Rett syndrome was thediscovery that MECP2 mutations were found in 80% ofsporadic, classic Rett syndrome cases (Shahbazian andZoghbi 2001). In these sporadic cases, most mutationsarise from the parental germline and often occur at CpGmutational hotspots by deamination of methylated cyto-sine, which creates C-T transitions. Nearly 70% of themutations in Rett syndrome arise from C-T transitions ateight CpG dinucleotides (Lee and others 2001).MeCP2 and Other Methyl-CpG-bindingDomain (MBD) ProteinsMeCP2 is the first protein identified that defines a fam-ily of methyl-CpG-binding proteins. Other identifiedmembers include methyl-CpG-binding proteins 1–4(MBD1–4), all of which share an MBD (Hendrich andBird 1998). MeCP2 contains three functionally defineddomains: an amino-terminal MBD (Lewis and others1992; Nan and others 1993), a transcriptional


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Brandeis NBIO 146A - Rett Syndrome: A Prototypical Neurodevelopmental Disorder

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