Rett Syndrome, Classic or Atypical - MECP2 Disorders

Diagnosis

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 – 80% clinical sensitivity
    • MECP2 deletion and duplication analysis by MLPA – clinical sensitivity up to 95%
  • 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

Screening

  • Prenatal diagnosis should be offered to all couples who have a child with an identified MECP2 mutation – germline mosaicism cannot be excluded

Clinical Background

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)

Indications for Laboratory Testing

  • 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
Test Name and Number Recommended Use Limitations Follow Up
Rett Syndrome (MECP2), Sequencing and Deletion/Duplication 0051614
Method: Sequencing/Multiplex Ligation-dependent Probe Amplification

Diagnose atypical or classic Rett syndrome

Components include MECP2 sequencing and duplication/deletion analysis by MLPA

Clinical sensitivity up to 95%

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

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

Counseling and informed consent are recommended for genetic testing

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

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

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

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

Rare diagnostic errors can occur due to primer site mutations

Clinical sensitivity up to 80%

Counseling and informed consent are recommended for genetic testing

Rett Syndrome (MECP2), Deletion and Duplication 0051618
Method: Multiplex Ligation-dependent Probe Amplification

May be useful in females when suspicion for classical or atypical Rett syndrome remains despite negative MECP2 sequencing result

May be useful  in males with

  • Severe developmental delay/intellectual disability and a history of recurrent infections, swallowing dysfunction, hypotonia, spasticity, limited speech, and limited ambulation
  • Intellectual disability with a family history suggestive of X-linked inheritance

Deletion/duplication breakpoints will not be determined; deep intronic mutations, single base pair substitutions and small deletions/duplications will not be detected

Rare diagnostic errors can occur due to probe site mutations

Clinical sensitivity up to 15%

Counseling and informed consent are recommended for genetic testing

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

Useful when a familial mutation identifiable by sequencing is known

Rare diagnostic errors can occur due to primer site mutations

Counseling and informed consent are recommended for genetic testing

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

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 – 17% for females with early-onset seizures

Large deletions/duplications of exon 3 will not be detected; deletion/duplication breakpoints will not be determined; deep intronic mutations will not be detected

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

Counseling and informed consent are recommended for genetic testing

Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
CDKL5-Related Disorders (CDKL5) Sequencing 2004931
Method: Polymerase Chain Reaction/Sequencing

Acceptable initial test in evaluation of CDKL5-related disorder

CDKL5-Related Disorders (CDKL5) Deletion/Duplication 2004927
Method: Polymerase Chain Reaction/Multiplex Ligation-dependent Probe Amplification

Use if mutation not detected with sequencing in cases of suspected CDKL5-related disorders