Rett Syndrome, Classic or Atypical - MECP2 Disorders

  • Diagnosis
  • Algorithms
  • Screening
  • Background
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

  • Confirm clinical diagnosis of Rett syndrome or an MECP2-related disorder
  • Determine the cause of severe neonatal encephalopathy or intellectual disability in males
  • Rule out an MECP2 mutation in families with X-linked developmental delay
    • Target testing for parents who have a child with an MECP2 mutation to help define recurrence risk
  • Rule out an MECP2 mutation in individuals with clinical features of Angelman syndrome and who lack a molecular abnormality involving 15q11.2-13

Laboratory Testing

  • Testing for Rett is complex and testing choices should be discussed with a genetics counselor
  • MECP2 gene analysis
    • MECP2 full gene analysis – detects 95% of pathogenic mutations
    • MECP2 sequencing and deletion/duplication analysis by MLPA
  • CGH or X-chromosome – only detects large deletions or duplications
  • Testing for less common mutations
    • CDKL5 gene analysis
      • Confirm clinical diagnosis of a CDKL5-related disorder in individuals with
        • Infantile seizures
        • X-linked infantile spasm syndrome (ISSX)
        • MECP2-negative atypical Rett syndrome
        • Autism
        • Intellectual disability with seizure disorder
    • ART gene analysis
    • FOXG1 gene analysis

Differential Diagnosis

  • Angelman syndrome
  • Autism
  • Cerebral palsy
  • Inborn errors of metabolism (in males with congenital encephalopathy)
  • Developmental delay
  • Prenatal diagnosis should be offered to all couples who have a child with an identified MECP2 mutation – germline mosaicism cannot be excluded

MECP2 disorders in females include classic and atypical Rett syndrome and, rarely, learning disabilities and neuropsychiatric phenotype due to MECP2 duplications. MECP2 disorders in males include congenital encephalopathy, atypical Rett syndrome, developmental delay, and MECP2 duplication syndrome.

Epidemiology

  • Prevalence – 1/10,000-15,000 female births
  • Age – early childhood
  • Sex – M<F

Inheritance

  • X-linked dominant with almost 100% penetrance
  • Most MECP2 alterations are de novo; however, MECP2 duplications can be maternally inherited
  • Gene duplications are rare
    •  ~100 cases have been reported – <5% were cytogenetically visible
  • MECP2 deletions or nonsense mutations are generally associated with a more severe phenotype than missense mutations
  • MECP2 mutations are variably expressed based on sex and pattern of X-chromosome activation (in females)

Pathophysiology

  • Deficit in bioaminergic metabolism
  • Probable abnormal development of the cortex in infancy
  • Autonomic system and associated brainstem dysregulation

Clinical Presentation

  • Clinical severity influenced by patient’s sex, specific MECP2 mutation, and pattern of X inactivation (in females)
  • Classic Rett syndrome
    • Typically seen in affected females
    • Males with a 47,XXY karyotype and an MECP2 mutation or males with somatic MECP2 mutations may also present with classic Rett syndrome
    • Apparently normal prenatal and perinatal history
    • Normal growth and development until 6-18 months, followed by rapid neurodevelopmental regression
    • Normal head circumference at birth with postnatal head growth deceleration
    • Purposeful hand movements replaced with repetitive stereotyped hand movements
    • Loss of acquired speech
    • Non-ambulatory or gait ataxia
    • Social withdrawal or autistic features
    • Associated findings include seizures (in up to 90%), abnormal EEG, breathing irregularities, sleep disturbances, bruxism, scoliosis
  • Mild to severe developmental delay
    • Possible phenotype in males or females
    • Females with mild phenotypes may have highly skewed X-chromosome inactivation
  • MECP2 duplication syndrome
    • Severity among affected males usually consistent within families; however, phenotypic variability may occur in 40-60% cases
      • Infantile hypotonia, mostly truncal/axial and facial
      • Developmental delay (severe)
      • Absence of speech (84%)
      • Recurrent respiratory infections (80%)
      • Seizures (50%)
      • Progressive spasticity
      • Lack of ambulation
      • Genital or digital abnormalities
      • Progressive cerebellar degeneration
      • Autism
    • Female carriers may manifest neuropsychiatric symptoms despite ~100% favorably skewed X inactivation in peripheral blood
  • CDKL5 mutations
    • Associated with infantile spasms or atypical Rett syndrome
    • X-linked dominant – most cases are due to de novo mutations
    • Heterozygous females commonly present with infantile spasms or epileptic seizures within the first six months of life, a later intractable epileptic seizure disorder, intellectual disability, hypotonia, and limited developmental progression
    • Hemizygous males may present with early-onset intractable epilepsy, severe encephalopathy, and profound mental retardation, although less severe phenotypes have been reported
    • Variable clinical phenotypes associated with CDKL5 mutations
      • Skewed x-inactivation patterns in females may help explain phenotypic variability
      • ISSX
        • Also known as West syndrome
        • Severe infantile spasms
        • Intellectual disability
        • Lack of developmental progression
        • Hypsarrhythmia
      • Hanefeld variant (atypical Rett in females)
        • Early onset epileptic seizures
        • Infantile spasms and Rett-like features
  • ART gene mutations
    • Associated with variable phenotypes
    • May include developmental delay, early onset intractable seizures, lissencephaly or other brain malformations, generalized dystonia, and ambiguous genitalia
    • X-linked – typically males are severely affected while females may be unaffected or have milder phenotypes
  • FOXG1 gene mutations
    • Most often associated with a congenital form of Rett syndrome
    • Autosomal dominant inheritance
    • Heterozygous individuals with Rett-like features (congenital encephalopathy, postnatal microcephaly, and complex movement disorders) may lack the early normal period of development typically seen in classic Rett syndrome

Treatment

  • Mainly supportive
  • Seizure control may require drug therapy
  • Pharmacological therapies may reduce agitation, hyperventilation, or sleep dysfunction
  • Restraints may be considered to prevent self-injurious behavior and reduce agitation
  • Assessment of feeding and digestive issues – constipation and reflux are common
  • Bracing or surgical intervention for scoliosis
  • Avoid use of drugs associated with prolongation of QT interval effects (eg, prokinetic agents, antipsychotics, antiarrhythmics, anesthetic agents)
Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Rett Syndrome (MECP2), Full Gene Sequencing 0051378
Method: Polymerase Chain Reaction/Sequencing

Recommended Use 

Confirm clinical diagnosis of Rett syndrome or MECP2-related disorder

Determine cause of severe neonatal encephalopathy or intellectual disability in males

Rule out MECP2 variant in individuals with clinical features of Angelman syndrome who lack a molecular abnormality involving 15q11.2-13 

Acceptable first-tier diagnostic test for females with a phenotype of classic or atypical Rett syndrome; preferred test is MECP2 sequencing and deletion/duplication

​Consultation with a genetic counselor is recommended to plan the optimal MECP2 genetic testing sequence

May be useful for females with

  • Nonspecific intellectual disability
  • Autism
  • Clinically suspected but molecularly unconfirmed Angelman syndrome

May be useful for males with

  • Unexplained neonatal encephalopathy
  • Nonspecific intellectual disability
  • Phenotype of Rett syndrome (classical or atypical)
  • Manic-depressive psychosis, pyramidal signs, Parkinsonian, and macro-orchidism (PPM-X syndrome)
  • Clinically suspected but molecularly unconfirmed Angelman syndrome

Clinical sensitivity

  • Classic Rett syndrome – ~80%
  • Atypical Rett – ~40%
Limitations 

Deep intronic variants and large deletions/duplications will not be identified

Rare diagnostic errors can occur due to primer site variants

Rett Syndrome (MECP2), Sequencing and Deletion/Duplication 0051614
Method: Sequencing/Multiplex Ligation-dependent Probe Amplification

Recommended Use 

Confirm clinical diagnosis of Rett syndrome or MECP2-related disorder

Determine cause of severe neonatal encephalopathy or intellectual disability in males

Rule out MECP2 variant in individuals with clinical features of Angelman syndrome and who lack a molecular abnormality involving 15q11.2-13

Preferred initial test for females with a phenotype of classic or atypical Rett syndrome

Detects up to 95% of MECP2 pathogenic variants

Consultation with a genetic counselor is recommended to plan the optimal MECP2 genetic testing sequence

Consider for females with

  • Classic or atypical Rett syndrome
  • Nonspecific intellectual disability
  • Autism
  • Clinically suspected, but molecularly unconfirmed, Angelman syndrome
  • Suspicion for classic or atypical Rett syndrome remains despite negative MECP2 sequencing result

Consider for males with

  • Unexplained neonatal encephalopathy
  • Nonspecific intellectual disability
  • Phenotype of Rett syndrome (classic or atypical)
  • Manic-depressive psychosis, pyramidal signs, Parkinsonian and macroorchidism (PPM-X syndrome)
  • Clinically suspected, but molecularly unconfirmed, Angelman syndrome
  • Suspected MECP2 duplication syndrome

Clinical sensitivity –

  • Classic Rett syndrome
    • Sequencing – ~80%
    • Deletions/duplications – ~8-10%
  • Atypical Rett
    • Sequencing – ~40%
    • Deletions/duplications – ~3%
Limitations 

Breakpoints of large deletions/duplications will not be determined; deep intronic variants will not be detected

Rare diagnostic errors can occur due to primer or probe site variants

CDKL5-Related Disorders (CDKL5) Sequencing and Deletion/Duplication 2004935
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Recommended Use 

Preferred initial test to confirm clinical diagnosis of a CDKL5-related disorder in individuals with

  • Infantile seizures
  • X-linked infantile spasm syndrome (ISSX)
  • MECP2-negative atypical Rett syndrome
  • Autism
  • Intellectual disability with seizure disorder

Clinical sensitivity – for sequencing combined with deletion/duplication; dependent on phenotype;  ~17% for females with early-onset seizures

Consultation with a genetic counselor is recommended

Limitations 

Diagnostic errors can occur due to rare sequence variations

Not determined or evaluated – deep intronic mutations, regulatory region mutations, breakpoints of large deletions/duplications

Familial Mutation, Targeted Sequencing 2001961
Method: Polymerase Chain Reaction/Sequencing

Recommended Use 

Useful when a pathogenic familial variant identifiable by sequencing is known

Consultation with a genetic counselor is recommended

General References

Christodoulou J, Ho G. MECP2-Related Disorders. In: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews, University of Washington, 1993-2015. Seattle, WA [Last updated Jun 2012; Accessed: Nov 2015]

Echenne B, Roubertie A, Lugtenberg D, Kleefstra T, Hamel BC, Van Bokhoven H, Lacombe D, Philippe C, Jonveaux P, de Brouwer AP. Neurologic aspects of MECP2 gene duplication in male patients. Pediatr Neurol. 2009; 41(3): 187-91. PubMed

Mencarelli MA, Spanhol-Rosseto A, Artuso R, Rondinella D, De Filippis R, Bahi-Buisson N, Nectoux J, Rubinsztajn R, Bienvenu T, Moncla A, Chabrol B, Villard L, Krumina Z, Armstrong J, Roche A, Pineda M, Gak E, Mari F, Ariani F, Renieri A. Novel FOXG1 mutations associated with the congenital variant of Rett syndrome. J Med Genet. 2010; 47(1): 49-53. PubMed

Philippe C, Amsallem D, Francannet C, Lambert L, Saunier A, Verneau F, Jonveaux P. Phenotypic variability in Rett syndrome associated with FOXG1 mutations in females. J Med Genet. 2010; 47(1): 59-65. PubMed

Sanmann JN, Schaefer B, Buehler BA, Sanger WG. Algorithmic approach for methyl-CpG binding protein 2 (MECP2) gene testing in patients with neurodevelopmental disabilities. J Child Neurol. 2012; 27(3): 346-54. PubMed

Shoubridge C, Fullston T, Gécz J. ARX spectrum disorders: making inroads into the molecular pathology. Hum Mutat. 2010; 31(8): 889-900. PubMed

Medical Reviewers

Bayrak-Toydemir, Pinar, MD, PhD, Medical Director, Molecular Genetics and Genomics at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

Krautscheid, Patti, MS, LCGC, Genetic Counselor, Molecular Genetics and Special Genetics Laboratories at ARUP Laboratories

Last Update: May 2017