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Rett Syndrome Exploring the Autism Link

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Rett Syndrome Exploring the Autism Link NEUROLOGICAL REVIEW Rett Syndrome Exploring the Autism Link Alan K. Percy, MD he presence of autism in individuals with neurodevelopmental disorders, whether tran- sient as in Rett syndrome (RTT) or enduring as in fragile X syndrome or Down syn- drome, suggests the possibility of common neurobiologic mechanisms whose eluci- dation could fundamentally advance our understanding. This review explores the Tcommonalities and differences between autism and RTT at clinical and molecular levels with re- spect to current status and challenges for each, highlights recent findings from the Rare Disease Network Natural History study on RTT, and summarizes the broad range of phenotypes resulting from mutations in the methyl-CpG-binding protein 2 gene (MECP2), which is responsible for RTT in 95% of individuals with the disorder. For RTT, animal models have been critical resources for advancing pathobiologic discovery and promise to be important test beds for evaluating new thera- pies. Fundamental understanding of autism based on unique genetic mechanism(s) must await similar advances. Arch Neurol. 2011;68(8):985-989 Rett syndrome (RTT) is a neurodevelop- tact, language, and finger skills; and sub- mental disorder, predominantly affect- sequent improvement in social contact and ing females, resulting from mutations in eye gaze by age 5. Effective interaction per- the methyl-CpG-binding protein 2 gene sists throughout life, yet motor functions (MECP2) (OMIM 312750) located at Xq28 gradually slow in adulthood. in at least 95% of individuals meeting clini- Autism is a complex neurodevelopmen- cal criteria for the disorder.1-5 Rett syn- tal disorder involving poor communication drome is characterized by profound cog- and socialization and a limited repertoire of nitive impairment, poor communication behaviors and interests.6 Unlike RTT and a skills, stereotypic hand movements, and growing number of other gene-based neu- pervasive growth failure beginning be- rodevelopmental disorders discussed here, tween ages 6 and 18 months after a pe- mutations in a gene or specific set of genes riod of apparently normal development in- have not been identified in nonsyndromic cluding acquisition of fine motor skills and autism.Thediagnosisofautismhasbeencon- language. During the regression period, firmed in several neurodevelopmental dis- fine motor skills, effective eye contact, and orders including fragile X syndrome, Down communication are lost. Features of au- syndrome, Angelman syndrome (AS), tism, including limited eye contact and Prader-Willi syndrome, Smith-Magenis syn- poor socialization or interaction, along drome, Williams syndrome, neurofibroma- with inconsolable crying or irritability, oc- tosis type 1, tuberous sclerosis, Sanfilippo cur at this time. Typically, autistic fea- syndrome, phenylketonuria, adenylosucci- tures are transient, lasting from weeks to natelyasedeficiency,andSmith-Lemli-Opitz many months. By school age, intense eye syndrome. Specifically, up to 60% of indi- gaze and interaction with others return, viduals with fragile X syndrome and up to yet language does not. As such, individu- 7% of those with Down syndrome may have als with RTT demonstrate a rather pre- autism. The diagnosis of autism in some, but dictable temporal profile: apparently nor- not all, individuals with these disorders, mal early development; arrest of whether transient as in RTT or enduring as developmental progress at 6 to 18 months in fragile X syndrome or Down syndrome, followed by frank regression of social con- suggests the possibility of common neuro- biologic mechanisms whose elucidation Author Affiliation: Civitan International Research Center, University of Alabama could fundamentally advance our under- at Birmingham. standing. However, concern has been raised ARCH NEUROL / VOL 68 (NO. 8), AUG 2011 WWW.ARCHNEUROL.COM 985 ©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Table 1. Comparative Features of Autism and Rett Syndrome Characteristic Autism Rett Syndrome Regression Some Universal Eye gaze Poor Good, except during regression period Socialization Poor Good, except during regression period Head circumference Infants: large; Postnatal deceleration adults: normal Hand skills Generally good Poor to absent Gait Good Dyspraxic/none Periodic breathing Uncommon Common as to whether individuals with neurodevelopmental disor- has a predicted binding site in the MECP2 promoter re- ders demonstrating severe or profound cognitive impair- gion, and the MECP2 family of methyl-binding proteins ment can be assigned an autism diagnosis.6 binds the EGR2 enhancer region. In this review, the phenotypic variability and molecu- Angelman syndrome, due principally to 15q11-q13 de- lar complexities associated with MECP2 gene abnormali- letions, represents another potentially important link with ties and the clinical and molecular convergence be- autism and RTT. Mutations in ubiquitin protein ligase tween RTT and autism are explored. E3A (UBE3A/E6AP) (OMIM *601623), a gene con- tained within this deletion, result in AS. Expression of ␤ ␥ RTT AND AUTISM UBE3A/E6AP and the 3 subunit of -aminobutyric acidA receptors located within the deleted region (GABRB3) Clinical Considerations (OMIM ϩ137192) reduced in Mecp2-deficient mice and in the brains of humans with RTT, AS, or autism.8 Rett syndrome and autism are regarded as neurodevelop- mental disorders characterized clinically by apparently FUNCTIONAL ROLE OF MECP2 normal early development, failure of normal developmen- tal progress, and absence of progressive deterioration; neu- Methyl-CpG-binding protein 2, a member of the methyl- robiologic characteristics include fundamental failure of binding protein family, is capable of transcriptional regu- normalneuronalmaturationandabsenceofprogressiveneu- lation. However, specific gene targets are not defined fully.9 ronal or glial pathologic changes. As such, these disorders Methyl-CpG-binding protein 2 is ubiquitous in mam- are potentially reversible. Autism and RTT share many com- malian tissues and is highly expressed in the brain, func- mon features, but clear differences exist (Table 1). Autism tioning in the development and maintenance of neu- occurs predominantly in males, is associated at least initially rons. During brain development, MECP2 appears in a with accelerated rate of head growth, lacks a specific genetic caudal-rostral gradient, with cortical neurons being the basis, and has a greater incidence than RTT (1:100 births last to express. In the early prenatal period, forebrain ex- vs 1:10 000 female births), which occurs mainly in females pression is limited to Cajal-Retzius neurons. Recent evi- and is associated with postnatal deceleration in the rate of dence9 suggests that MECP2, initially proposed as a tran- head growth and MECP2 mutations. scriptional repressor, participates in upregulation or A clear understanding of the relationship between au- downregulation of many genes. tism and RTT is lacking. Does brain function differ in autism and RTT? Are similar brain regions affected, and BRAIN MORPHOLOGIC do these change over time? Innovative technologies such CHARACTERISTICS IN RTT as functional magnetic resonance imaging should be able to provide important insights into such questions. In the human brain, morphologic characteristics of RTT include reduced volume, particularly of the fronto- Molecular Convergence temporal lobes and caudate, reduced brain weight, and re- duced or absent melanin pigmentation, notably in sub- A potential molecular convergence exists for autism and stantia nigra.10 At the microscopic level, cortical neurons RTT involving MECP2 and early growth response gene-2 are small and demonstrate simplified dendrites with re- (EGR2) (OMIM *129010), an activity-dependent imme- duced and immature dendritic spines.10 No evidence of rec- diate-early gene.7 EGR2, the only member of the EGR fam- ognizable disease progression, especially neuronal loss, is ily restricted to central nervous system neurons, encodes evident in RTT. This pattern appears to be a common theme a DNA-binding zinc finger protein important for cerebral among other neurodevelopmental disorders. Autism is as- development and synaptic plasticity. Expression of EGR2 sociated with increased packing density, decreased cell size, and MECP2 increase coordinately in mouse and human and increased spine density; Down syndrome with re- cortex; regulation of EGR2 and MECP2 is disrupted in au- duced dendritic branches and spines after early infancy; AS tism and RTT; MECP2 expression is decreased in the cor- with reduced dendritic branches and immature spines; and tex of people with autism; and EGR2 expression is de- fragile X syndrome with immature spines. These common- creased in the cortex of individuals with autism or RTT, alities suggest a convergence of molecular mechanisms un- as well as in the cortex of an Mecp2 knockout mouse. EGR2 derlying their pathobiologic characteristics. ARCH NEUROL / VOL 68 (NO. 8), AUG 2011 WWW.ARCHNEUROL.COM 986 ©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 A 14 † 2 µm ∗ 12 10 8 Control (eYEP) R106W 6 4 2 Spine Density, spines/10 µm Spine Density, 0 Control R106W T158M Wild-type Wild-type MECP2 T158M (eYEP) MECP2 14 B Non-MR, age 3 Non-MR, age 35 12 10 † 8 6 RTT, age 5 RTT, age 21 4 Spine Density, spines/10 µm Spine Density, 2 0 Non-MR Control RTT Figure. Pyramidal neuron dendritic spines from rat hippocampal slice cultures
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