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MECP2 Disorders

, MSc, M Phil and , MBBS, PhD, FRACP, FFSc, FRCPA, FAHMS.

Author Information

Initial Posting: ; Last Update: September 19, 2019.

Estimated reading time: 29 minutes

Summary

Clinical characteristics.

The spectrum of MECP2-related phenotypes in females ranges from classic Rett syndrome to variant Rett syndrome with a broader clinical phenotype (either milder or more severe than classic Rett syndrome) to mild learning disabilities; the spectrum in males ranges from severe neonatal encephalopathy to pyramidal signs, parkinsonism, and macroorchidism (PPM-X) syndrome to severe syndromic/nonsyndromic intellectual disability.

  • Females: Classic Rett syndrome, a progressive neurodevelopmental disorder primarily affecting girls, is characterized by apparently normal psychomotor development during the first six to 18 months of life, followed by a short period of developmental stagnation, then rapid regression in language and motor skills, followed by long-term stability. During the phase of rapid regression, repetitive, stereotypic hand movements replace purposeful hand use. Additional findings include fits of screaming and inconsolable crying, autistic features, panic-like attacks, bruxism, episodic apnea and/or hyperpnea, gait ataxia and apraxia, tremors, seizures, and acquired microcephaly.
  • Males: Severe neonatal-onset encephalopathy, the most common phenotype in affected males, is characterized by a relentless clinical course that follows a metabolic-degenerative type of pattern, abnormal tone, involuntary movements, severe seizures, and breathing abnormalities. Death often occurs before age two years.

Diagnosis/testing.

The diagnosis of a MECP2 disorder is established by molecular genetic testing in a female proband with suggestive findings and a heterozygous MECP2 pathogenic variant, and in a male proband with suggestive findings and a hemizygous MECP2 pathogenic variant.

Management.

Treatment of manifestations: Treatment is mainly symptomatic and focuses on optimizing the individual's abilities using a multidisciplinary approach that should also include psychosocial support for family members. Risperidone may help in treating agitation; melatonin can ameliorate sleep disturbances. Treatment of seizures, constipation, gastroesophageal reflux, scoliosis, prolonged QTc, and spasticity as per standard care.

Surveillance: Periodic evaluation by the multidisciplinary team; regular assessment of QTc for evidence of prolongation; regular assessment for scoliosis.

Agents/circumstances to avoid: Drugs known to prolong the QT interval.

Genetic counseling.

MECP2 disorders are inherited in an X-linked manner. More than 99% are simplex cases (i.e., a single occurrence in a family), resulting from a de novo pathogenic variant or possibly from inheritance of the pathogenic variant from a parent who has germline mosaicism. Rarely, a MECP2 variant may be inherited from a heterozygous mother in whom favorable skewing of X-chromosome inactivation results in minimal to no clinical findings. When the mother is a known heterozygote, the risk to her offspring of inheriting the MECP2 variant is 50%. When the pathogenic MECP2 variant has been identified in the family, heterozygote testing for at-risk female relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic diagnosis are possible. Because of the possibility of parental germline mosaicism, it is appropriate to offer prenatal diagnosis to couples who have had a child with a MECP2 disorder regardless of whether the MECP2 pathogenic variant has been detected in a parent.

GeneReview Scope

MECP2 Disorders: Included Phenotypes 1, 2
Females
  • MECP2 classic Rett syndrome
  • Variant Rett syndrome
  • Mild learning disabilities
Males
  • MECP2-related severe neonatal encephalopathy
  • Pyramidal signs, parkinsonism, and macroorchidism (PPM-X) syndrome
  • Syndromic/nonsyndromic intellectual disability
1.

For other genetic causes of these phenotypes see Differential Diagnosis.

2.

Note: The allelic disorder MECP2 duplication syndrome is not included in this GeneReview. See Genetically Related Disorders.

Diagnosis

Note: Duplication of MECP2 (ranging from 0.3 to 4 Mb and larger) is associated with the allelic disorder MECP2 duplication syndrome and is not addressed in this GeneReview.

Suggestive Findings in Females

A MECP2 disorder should be suspected/considered in females with the following clinical findings suggestive of MECP2 classic Rett syndrome or variant Rett syndrome (based on clinical diagnostic criteria published by Neul et al [2010] [full text] prior to the widespread availability of molecular genetic testing), or mild learning disabilities.

Clinical findings of MECP2 classic Rett syndrome and variant Rett syndrome

  • Most distinguishing finding: A period of regression (range: ages 1-4 years) followed by recovery or stabilization (range: ages 2-10 years; mean: age 5 years)
  • Main findings
    • Partial or complete loss of acquired purposeful hand skills
    • Partial or complete loss of acquired spoken language or language skill (e.g., babble)
    • Gait abnormalities: impaired (dyspraxic) or absence of ability
    • Stereotypic hand movements including hand wringing/squeezing, clapping/tapping, mouthing, and washing/rubbing automatisms
  • Supportive findings
    • Breathing disturbances when awake
    • Bruxism when awake
    • Impaired sleep pattern
    • Abnormal muscle tone
    • Peripheral vasomotor disturbances
    • Scoliosis/kyphosis
    • Growth retardation
    • Small, cold hands and feet
    • Inappropriate laughing/screaming spells
    • Diminished response to pain
    • Intense eye communication - "eye pointing"
  • Exclusionary findings
    • Brain injury secondary to peri- or postnatal trauma, neurometabolic disease, or severe infection that causes neurologic problems
    • Grossly abnormal psychomotor development in the first six months of life, with early milestones not being met

Clinical findings of MECP2 mild learning disability. Typically mild and non-progressive. Note: Typically, females with mild learning disability are identified through molecular genetic testing following diagnosis of a first-degree relative (e.g., a more significantly affected brother or sister).

Suggestive Findings in Males

MECP2 disorders should be considered in a male with severe neonatal encephalopathy; pyramidal signs, parkinsonism, and macroorchidism (PPM-X) syndrome; or syndromic/nonsyndromic intellectual disability.

Clinical findings of MECP2 severe neonatal encephalopathy

  • Microcephaly
  • Relentless clinical course that follows a metabolic-degenerative type of pattern
  • Abnormal tone
  • Involuntary movements
  • Severe seizures
  • Breathing abnormalities (including central hypoventilation or respiratory insufficiency)

Clinical findings of MECP2 severe intellectual disability (including PPM-X syndrome)

  • Moderate-to-severe intellectual disability
  • Resting tremor
  • Slowness of movements
  • Ataxia
  • PPM-X syndrome: pyramidal signs, parkinsonism, and macroorchidism
  • No seizures or microcephaly
  • Usually normal brain MRI, EEG, EMG, and nerve conduction velocity studies

Establishing the Diagnosis

Female proband. The diagnosis of a MECP2 disorder is usually established in a female proband with suggestive findings and a heterozygous pathogenic variant in MECP2 identified by molecular genetic testing (see Table 1).

Male proband. The diagnosis of a MECP2 disorder is established in a male proband with suggestive findings and a hemizygous pathogenic variant in MECP2 identified by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (either single-gene or multigene panel) or comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of MECP2 disorders is broad, females with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas females and males with a phenotype indistinguishable from many other inherited disorders with intellectual disability and/or neonatal encephalopathy are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the clinical findings suggest the diagnosis of a MECP2 disorder, molecular genetic testing approaches can include use of single-gene testing or a multigene panel:

  • Single-gene testing. Sequence analysis of MECP2 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. Note: Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
  • Various multigene panels such as Rett/Angelman syndrome panels and more comprehensive childhood-onset epilepsy panels that include MECP2 and other genes of interest (see Differential Diagnosis) are most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype overlaps with many other inherited disorders characterized by intellectual disability and/or neonatal encephalopathy, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is another option. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in MECP2 Disorders

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
MECP2Sequence analysis 3, 490%-95% 5
Gene-targeted deletion/duplication analysis 65%-10% 7, 8
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.

5.
6.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by Hardwick et al [2007]) may not be detected by these methods.

7.

The sizes of many reported disease-associated deletions are at the upper limits of detection by sequence analysis and the lower limits of detection by gene-targeted deletion/duplication analysis; therefore, the proportion of pathogenic variants detected by either method depends on the methods used by a laboratory.

8.

Clinical Characteristics

Clinical Description

In females the spectrum of MECP2-related phenotypes ranges from classic Rett syndrome, to variant Rett syndrome (either milder or more severe than classic Rett syndrome), to mild learning disabilities. In males the spectrum ranges from severe neonatal encephalopathy, to pyramidal signs, parkinsonism, and macroorchidism (PPM-X) syndrome, to severe syndromic/nonsyndromic intellectual disability.

MECP2 Disorders in Females

Table 2.

Features of MECP2 Disorders in Females

PhenotypeFeature% of Persons with Feature
MECP2 classic Rett syndromeRegression followed by recovery or stabilization99%
Deceleration of head growth80%
Gait abnormalities99%
Seizures60%-80%
Hand stereotypies & loss of purposeful hand skills100% 1
Absence of speech; high-pitched crying99%
Cold extremities99%
Irregular breathing99%
Variant Rett syndromeRegression followed by recovery or stabilization99%
Gait abnormalities80%-99%
Sleep disturbences80%-99%
seizures6%-80%
Hand stereotypies & loss of purposeful hand skills97.3%
Breathing irregularities80%-99%
Agitation80%-99%
1.

Stallworth et al [2019]; 44% showed different patterns including hand wringing, washing, clapping, and tapping.

MECP2 classic Rett syndrome. Most individuals with classic Rett syndrome are female; however, males meeting the clinical criteria for classic Rett syndrome who have a 47,XXY karyotype [Hoffbuhr et al 2001, Leonard et al 2001, Schwartzman et al 2001] and postzygotic MECP2 variants resulting in somatic mosaicism have been described [Clayton-Smith et al 2000, Topçu et al 2002].

Although early development is reportedly normal in children with classic Rett syndrome, parents – in retrospect – often identify subtle differences compared to unaffected sibs. Most (but not all) affected children have acquired microcephaly; stereotypic hand movements and breathing irregularities are seen in the majority.

Variant Rett syndrome. Females with variant Rett syndrome exhibit a broader spectrum of clinical features than those observed in classic Rett syndrome. At the more severe end of the spectrum, development is delayed from very early infancy; congenital hypotonia and infantile spasms are also seen. At the milder end of the spectrum, regression is less dramatic and intellectual disability is much less severe; some speech may be preserved.

Mild learning disabilities. In rare instances, females with a pathogenic MECP2 variant may only exhibit mild learning disabilities or some autistic features, presumably as a consequence of favorable skewing of X-chromosome inactivation. When there is no regression phase and no characteristic hand stereotypes, the clinical course differs from that of classic and variant Rett syndrome.

MECP2 Disorders in Males

Table 3.

Features of MECP2 Disorders in Males

PhenotypeFeature% of Persons with Feature
PresentAbsentNot
reported
MECP2-related
severe neonatal
encephalopathy 1
Normal birth parameters71%29%
Head growth deceleration / microcephaly94%5.8%
Hypotonia &/or feeding difficulties in infancy82.4%17.6%
Hypertonia of extremities52.9%11.8%35.3%
Movement disorder, e.g., myoclonus, tremors, & dystonia58.8%17.7%23.5%
Mild cerebral atrophy18%35%47%
Polymicrogyria5.9%23.5%70.6%
Poor head control35%12%53%
Seizures58.8%17.7%23.5%
Severe development delay82.4%17.6%
Irregular breathing / sleep apnea47.1%29.4%23.5%
Gastroesophageal reflux35.3%64.7%
EEG abnormality88.2%5.9%5.9%
Pyramidal signs,
parkinsonism, and
macroorchidism
(PPM-X syndrome) 2
Psychosis67.6%10.8%21.6%
Pyramidal signs46%2.7%51.3%
Macroorchidism19%81%
Intellectual disability50%50%
Parkinsonism2.7%97.3%
Progressive spasticity67.6%32.4%
Delayed development54%46%
Speech difficulties50%50%
Seizures2.7%
Bilateral juvenile cataract2.7%
Scoliosis or kyphosis10.8%
Large ears8.1%
Movement disorders32.4%
Apraxia2.7%36%
Seizures8.1%91.9%
Dysmorphic features5.4%94.6%
Syndromic/
nonsyndromic
intellectual
disability 3
Severe intellectual disability90%10%
Gait abnormalities57%7%36%
Facial dysmorphism10%3%87%
Behavioral problems40%3%57%
Autistic-like behavior3%53%44%
Seizures20%30%50%
Poor/absent language skills47%17%36%
Hypotonia23%77%
Microcephaly13%23%64%
History of regression17%27%56%
Spasticity33%17%50%
Sleep disturbances13%10%77%

Severe neonatal-onset encephalopathy is characterized by a relentless clinical course that follows a metabolic-degenerative type of pattern, abnormal tone, involuntary movements, severe seizures, and breathing abnormalities (including central hypoventilation or respiratory insufficiency) [Wan et al 1999, Villard et al 2000, Zeev et al 2002, Kankirawatana et al 2006]. Often, males with a severe neonatal encephalopathy die before age two years [Schanen et al 1998, Wan et al 1999].

The severe encephalopathy phenotype appears to be rare in females [Lugtenberg et al 2009].

X-linked ID and PPM-X syndrome. PPM-X syndrome, caused by the p.(Ala140Val) MECP2 variant in males, is characterized by moderate-to-severe intellectual disability. Most have spasticity that may be progressive; some may have extrapyramidal movements. Episodic psychosis is seen in many but not all. Most affected males also have macroorchidism. Microcephaly is variable. See also Genotype-Phenotype Correlations.

Genotype-Phenotype Correlations

Genotype-phenotype correlations are inconsistent, due in part to the pattern of X-chromosome inactivation (XCI); females who have a MECP2 pathogenic variant and favorably skewed XCI may have mild or no manifestations [Wan et al 1999, Amir et al 2000, Cheadle et al 2000, Huppke et al 2000, Weaving et al 2003, Chae et al 2004, Schanen et al 2004,Charman et al 2005].

MECP2 pathogenic variants with some residual function that are associated with milder phenotypes include the following:

Prevalence

The worldwide prevalence is 1:10,000-1:23,000 female births [Ellaway et al 1999, Armstrong et al 2010]. Reports of incidence are limited; available estimates range from 0.43-0.71:10,000 for females in France [Bienvenu et al 2006] to 0.586:10,000 for females in Serbia [Sarajlija et al 2015] and 1.09:10,000 for females in Australia [Laurvick et al 2006].

Differential Diagnosis

Table 4.

Disorders to Consider in the Differential Diagnosis of MECP2 Disorders

Differential
Diagnosis
Disorder
Gene(s) / Genetic MechanismMOIClinical Features of Differential Diagnosis Disorder
Overlapping w/MECP2 DisordersDistinguishing from MECP2 Disorders
Angelman syndromeDeficient expression or function of maternally inherited UBE3A alleleSee footnote 1ID, severe speech impairment, gait ataxia &/or tremulousness of the limbs; microcephaly & seizures common; DD 1st noted at age ~6 mosIn classic Rett syndrome DD is not overtly evident in the 1st 6 mos.
Early infantile epileptic encephalopathy (OMIM 300672)CDKL5XLIn females: early-onset severe seizures w/poor cognitive development; facial gestalt, cortical visual impairment;
In males: severe-profound ID & early-onset intractable seizures 2
Very early-onset seizures, facial dysmorphism, & cortical visual impairment are not generally seen in classic Rett syndrome.
Rett syndrome, congenital variant (OMIM 613454)FOXG1ADShort normal period of development before onset of regression leading to severe ID, DD, postnatal microcephaly, agenesis of the corpus callosum, seizures, dyskinesia, & hypotonia 3Except for microcephaly, structural abnormalities are not usually seen on brain MRI.

AD = autosomal dominant; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked

1.

The risk to sibs of a proband depends on the genetic mechanism leading to the loss of UBE3A function: typically less than 1% risk for probands with a deletion or uniparental disomy (UPD), and as high as 50% for probands with an imprinting defect or a pathogenic variant of UBE3A.

2.
3.

Overlapping features and a similar facial appearance between individuals with FOXG1 pathogenic variants has led to the suggestion that these individuals should be regarded as having FOXG1 syndrome rather than a variant of Rett syndrome [Kortüm et al 2011].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a MECP2 disorder, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

Recommended Evaluations Following Initial Diagnosis in Individuals with a MECP2 Disorder

System/ConcernEvaluationComment
ConstitutionalMeasurement of height, weight, & head circumference
NeurologicNeurologic evaluationTo incl brain MRI; consider EEG / video monitoring if seizures are a concern.
DevelopmentDevelopmental assessment
  • Motor, adaptive, cognitive, & speech/language evaluation
  • Evaluation for early intervention / special education
Psychiatric/
Behavioral
Neuropsychiatric evaluationIn individuals age >12 mos: screening for behavior problems incl sleep disturbances, ADHD, anxiety, &/or traits suggestive of ASD
MusculoskeletalOrthopedics, physical medicine & rehabilitation, PT, OT evaluationTo incl assessment of:
  • Gross motor & fine motor skills
  • Scoliosis
  • Mobility & activities of daily living & need for adaptive devices
  • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Gastrointestinal/
Feeding
Gastroenterology / nutrition / feeding team evaluationTo incl:
  • Evaluation of aspiration risk & nutritional status
  • History of constipation & GERD
Consider need for gastric tube placement.
RespiratoryOvernight sleep studies
  • Analysis for abnormalities of breathing regularity
  • Noninvasive assessment of pulmonary gas exchange
Sleep disorderBreathing monitoring using portable polygraphic screening devicesTo assess occurrence of apnea & hypopnea
CardiovascularCardiac evaluationTo assess for prolonged QTc
OsteopeniaBone densitometryTo assess for osteopenia
EyesOphthalmologic evaluationTo assess for reduced vision, abnormal ocular movement, strabismus
HearingAudiology evaluationAssess for hearing loss
ENT/Mouth
Genitourinary
IntegumentHistory & examinationReduced perfusion of hands & feet (possible autonomic abnormalities)
Miscellaneous/
Other
Consultation w/clinical geneticist &/or genetic counselorTo incl genetic counseling
Family supports/resourcesAssess:
  • Use of community or online resources, e.g., Parent to Parent
  • Need for social work involvement for parental support
  • Need for home nursing referral

ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GERD=gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy

Treatment of Manifestations

Treatment needs to be individualized following an assessment of the affected individual's clinical problems and needs.

Management is symptomatic and focuses on optimizing the individual's abilities using a multidisciplinary approach with input from a pediatric or adult specialist physician, dietician, occupational therapist, speech therapist, music therapist, dentist, and other medical subspecialists as needed.

Table 6.

Treatment of Manifestations in Individuals with a MECP2 Disorder

Manifestation/
Concern
TreatmentConsiderations/Other
DD/IDSee Developmental Delay / Intellectual Disability Management Issues.
EpilepsyStandardized treatment w/AEDs by an experienced neurologist
  • Many AEDs may be effective; no one AED has been demonstrated effective specifically for this disorder.
  • Education of parents/caregivers 1
Psychiatric/
Behavioral
Risperidone (low dose) or selective serotonin uptake inhibitors have been somewhat successful in treating agitation.
MusculoskeletalScoliosisAs per guidelines 2
Poor weight
gain / failure
to thrive
Feeding therapy; gastrostomy tube placement may be required for persistent feeding issuesLow threshold for clinical feeding evaluation &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia; nutritional guidelines are available. 3
SpasticityOrthopedics / physical medicine & rehabilitation / PT / OT incl stretching to help avoid contractures & fallsConsider need for positioning & mobility devices, disability parking placard.
Sleep disorderMelatonin can ameliorate sleep disturbances.Chloral hydrate, hydroxyzine, or diphenhydramine may be used w/melatonin.
Abnormal vision &/or strabismusStandard treatment(s) as recommended by ophthalmologistCommunity vision services through early intervention or school district
Central visual impairmentNo specific treatment; early intervention to help stimulate visual development
HearingHearing aids may be helpful as per otolaryngologistCommunity hearing services through early intervention or school district
Gastrointestinal
  • Constipation: stool softeners, prokinetics, osmotic agents, or laxatives as needed
  • GERD: anti-reflux agents, smaller & thickened feedings, & positioning
CardiovascularTreatment for prolonged QTcUnder care of pediatric cardiologist
OsteopeniaBaseline densitometry; optimization of physical activity & calcium & vitamin D levelsGuidelines for management of bone health are available. 4
Family/
Community
  • Ensure appropriate social work involvement to connect families w/local resources, respite, & support
  • Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies
  • Ongoing assessment for need of palliative care involvement &/or home nursing
  • Consider involvement in adaptive sports or Special Olympics.

AED = antiepileptic drug; DD = developmental delay; GERD = gastroesophageal reflux disease; ID = intellectual disability

1.

Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.

2.
3.
4.

Developmental Disability / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life. Some issues to consider:

  • Individualized education plan (IEP) services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine if any changes are needed.
    • As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
    • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.

Motor Dysfunction

Gross motor dysfunction

  • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
  • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
  • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox®, anti-parkinsonian medications, or orthopedic procedures.

Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.

Oral motor dysfunction should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically by an occupational or speech therapist) is recommended to improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary.

Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech and in many cases can improve it.

Social/Behavioral Concerns

Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.

Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary.

Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.

Surveillance

Many of the clinical features in females with atypical Rett syndrome (Table 2) evolve with age and hence should be reassessed every six to 12 months.

Table 7.

Recommended Surveillance for Individuals with a MECP2 Disorder

System/ConcernEvaluationFrequency
FeedingMeasurement of growth parametersAt each multidisciplinary
clinic visit;
minimum annually
Evaluation of nutritional status & safety of oral intake
GastrointestinalMonitor for constipation.
RespiratoryMonitor for evidence of aspiration, respiratory insufficiency.
NeurologicMonitor those w/seizures as clinically indicated.
Assess for new manifestations, e.g., seizures, changes in tone, movement disorders.
DevelopmentMonitor developmental progress & educational needs.
Speech & languageMonitor communication skills.
Psychiatric/
Behavioral
Behavioral assessment for anxiety, attention, & aggressive or self-injurious behavior
MusculoskeletalPhysical medicine, OT/PT assessment of mobility, self-help skills
Monitor scoliosis.
CardiovascularMonitor for prolonged QTc.
RespiratoryApnea/hyperventilation
Miscellaneous/
Other
Assess family need for social work support (e.g., palliative/respite care, home nursing; other local resources) & care coordination.

Agents/Circumstances to Avoid

Because individuals with MECP2 disorders are at increased risk for life-threatening arrhythmias associated with a prolonged QT interval, avoidance of drugs known to prolong the QT interval, including the following, is recommended:

  • Prokinetic agents (e.g., cisapride)
  • Antipsychotics (e.g., thioridazine), tricyclic antidepressants (e.g., imipramine)
  • Antiarrhythmics (e.g., quinidine, sotolol, amiodarone)
  • Anesthetic agents (e.g., thiopental, succinylcholine)
  • Antibiotics (e.g., erythromycin, ketoconazole)

Click here (pdf) for a more extensive list of drugs to avoid.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

A number of clinical trials are currently under way, including observational studies, studies focused on improvement of language and communication skills, and drug trials.

For details see www.rettsyndrome.org.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

MECP2 disorders are inherited in an X-linked manner.

Risk to Family Members

Parents of a proband

Sibs of a proband. The risk to sibs depends on the genetic status of the parents:

Offspring of a proband

  • Each child of a female proband with a MECP2 disorder has a 50% chance of inheriting the MECP2 pathogenic variant. Females with more severe MECP2 disorders do not reproduce; mildly affected females have reproduced.
  • Males with a MECP2 disorder are not known to reproduce.

Other family members. The risk to other family members depends on the genetic status of the proband's mother: if the mother is affected or has a pathogenic MECP2 variant, her family members may be at risk.

Related Genetic Counseling Issues

First-degree female relatives. Once the pathogenic MECP2 variant has been identified in a proband, it is appropriate to offer testing to all first-degree female relatives regardless of their clinical status. Apparently unaffected sisters of a female proband with a MECP2 disorder may be heterozygous for the MECP2 variant present in their sister but have few to no manifestations because of skewed X-chromosome inactivation. Genetic counseling should address this possibility as clinically unaffected sisters may be at risk of transmitting the pathogenic MECP2 variant to their children.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are mildly affected or are at risk of having a pathogenic MECP2 variant.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the MECP2 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible. Males with a MECP2 variant who survive infancy will most likely have severe intellectual disability. The phenotype in a female with a MECP2 variant is difficult to predict and can range from apparently normal to severely affected.

Note: Because parental germline mosaicism for a MECP2 pathogenic variant has been reported in multiple families, it is appropriate to offer prenatal testing to the parents of a child with a MECP2 disorder whether or not the MECP2 pathogenic variant has been identified in the leukocyte DNA of either parent.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • International Rett Syndrome Foundation (IRSF)
    4600 Devitt Drive
    Cincinnati OH 45246
    Phone: 800-818-7388 (toll-free); 513-874-3020
    Fax: 513-874-2520
  • My46 Trait Profile
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
  • Rett New Zealand
    PO Box 28 049
    Wellington
    New Zealand
    Phone: 04 475 9265
    Email: rett.info@nzord.org.nz
  • Rett Syndrome Europe
  • Medical Home Portal
    The Parents & Families section of the Medical Home Portal provides information and resources to help families learn how to better care for a child with chronic and complex conditions and to become more effective partners in their child’s care.
    Department of Pediatrics University of Utah
    P.O. Box 581289
    Salt Lake City UT 84158
    Phone: 801-213-3920
    Email: info@medicalhomeportal.org
  • Rett Syndrome Research Trust
    67 Under Cliff Road
    Trumbull CT 06611
    Phone: 203-445-0041
    Email: info@rsrt.org
  • Rett UK
    Langham House West
    Mill Street
    Luton LU1 2NA
    United Kingdom
    Phone: 01582 798 910
    Email: info@rettuk.org
  • Australian Rett Syndrome Study / InterRett Registry
    Telethon Institute for Child Health Research
    PO Box 855
    West Perth 6872
    Australia
    Phone: +61 8 9489 7790; +61 419 956 946
    Fax: +61 8 9489 7700
    Email: rett@ichr.uwa.edu.au

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

MECP2 Disorders: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for MECP2 Disorders (View All in OMIM)

300005METHYL-CpG-BINDING PROTEIN 2; MECP2
300055MENTAL RETARDATION, X-LINKED, SYNDROMIC 13; MRXS13
300496AUTISM, SUSCEPTIBILITY TO, X-LINKED 3; AUTSX3
300673ENCEPHALOPATHY, NEONATAL SEVERE, DUE TO MECP2 MUTATIONS
312750RETT SYNDROME; RTT

Molecular Pathogenesis

Loss of the protein MeCP2 leads to epigenetic aberrations of chromatin, suggesting that MeCP2 deficiency could lead to loss of imprinting, thereby contributing to the pathogenesis of Rett syndrome [Horike et al 2005, Kaufmann et al 2005, Makedonski et al 2005].

The nuclear MeCP2 protein functional domains include:

It has also been shown that MeCP2 plays a role in gene splicing [Young et al 2005] and in long-range chromatin remodeling [Horike et al 2005], and may be a transcriptional activator [Chahrour et al 2008].

Mechanism of disease causation. Most pathogenic MECP2 variants occur de novo. It has been suggested that pathogenic variants result in loss of protein function; some functional studies show that pathogenic MECP2 variants affect the MBD or TRD domains of the abnormal protein, depending on the location of the variant [Kudo et al 2001, Kudo et al 2002, Kudo et al 2003].

MECP2-specific laboratory technical considerations. Two transcripts have been described:

  • NM_001110792.1: encodes MECP2_e1, includes exons 1, 3, and 4 but not exon 2 (498 amino acids)
  • NM_004992.3, encodes MECP2_e2, includes exons 2, 3, and 4 but not exon 1 (486 amino acids)

Although the isoforms are nearly identical, use of two alternative start codons creates alternative N-termini. The e1 transcript is much more highly expressed in brain than the e2 transcript [Kriaucionis & Bird 2004, Mnatzakanian et al 2004].Of note:

The majority of pathogenic variants occur in the region encoding the methyl binding domain (MBD, exons 3 and 4; amino acids 90-174 of the MeCP2 e2 isoform), affecting the ability of the MeCP2 protein to bind to target DNA. A number of highly recurrent nonsense variants are found in the transcriptional repression domain (TRD, exon 4; amino acids 219-322 of the MeCP2 e2 isoform) and beyond the TRD, a large number of frameshift variants delete the C-terminal end of the protein (3' end of exon 4).

Table 8.

Notable MECP2 Pathogenic Variants

Reference SequencesDNA Nucleotide ChangePredicted Protein ChangeComment [Reference]
NM_004492​.3
NP_004983​.1
c.473C>Tp.(Thr158Met)Common, recurrent pathogenic variants [Miltenberger-Miltenyi & Laccone 2003, Archer et al 2006, Philippe et al 2006]
c.502C>Tp.(Arg168Ter)
c.763C>Tp.(Arg255Ter)
c.808C>Tp.(Arg270Ter)
c.916C>Tp.(Arg306Cys)
c.397C>Tp.(Arg133Cys)Milder phenotype in females is consistent w/in vitro functional studies showing that DNA binding is not impaired [Leonard et al 2003, Sheikh et al 2016].
c.419C>Tp.(Ala140Val)Non-classic, variant Rett syndrome, observed in familial cases w/affected males [Dotti et al 2002, Klauck et al 2002, Gomot et al 2003, Venkateswaran et al 2014, Lambert et al 2016, Sheikh et al 2016]; heterozygous females may have mild ID & impaired speech acquistion [Klauck et al 2002, Lambert et al 2016].
c.925C>Tp.(Arg309Trp)Observed in females & males w/ID & some features of a MECP2 disorder, but not classic or variant Rett syndrome [Campos et al 2007, Schönewolf-Greulich et al 2016]

ID = intellectual disability

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

References

Published Guidelines / Consensus Statements

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Chapter Notes

Author History

Vicky L Brandt; Baylor College of Medicine (2000-2004)
John Christodoulou, MBBS, PhD, FRACP, FRCPA, FHGSA (2006-present)
Gladys Ho, MSc; Children's Hospital at Westmead, Sydney (2009-2019)
Simranpreet Kaur, MSci, MPhil (2019-present)
Huda Y Zoghbi, MD; Baylor College of Medicine (2004-2006)

Revision History

  • 19 September 2019 (bp) Comprehensive update posted live
  • 28 June 2012 (me) Comprehensive update posted live
  • 2 April 2009 (me) Comprehensive update posted live
  • 25 January 2008 (cd) Revision: MECP2 duplication syndrome added to Genetically Related Disorders
  • 15 August 2006 (me) Comprehensive update posted live
  • 11 February 2004 (me) Comprehensive update posted live
  • 3 October 2001 (me) Review posted live
  • September 2000 (vb) Original submission
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