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Disease Categories > Genetic Disease

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Rett Syndrome - MECP2 Disorders

MECP2 disorders in females include classic and atypical Rett syndrome, and learning disabilities. In males, MECP2 disorders include congenital encephalopathy, atypical Rett syndrome, mental retardation, and MECP2 duplication syndrome.

Epidemiology

Prevalence – 1/10,000
Age – presentation in early childhood
Sex – F>M

Inheritance

X-linked dominant with almost 100% penetrance
Most MECP2 sequence changes or deletions are de novo; however, MECP2 duplications are maternally inherited
The majority (~80%) of MECP2 mutations are sequence variants, up to 15% are deletions, gene duplications are rare and detectable by routine cytogenetic analysis in approximately 5% of cases
MECP2 deletions or nonsense mutations are generally associated with a more severe phenotype than missense mutations
MECP2 mutations are variably expressed based on sex
- Females – usually classic Rett, but atypical Rett or mild learning disabilities may result due to skewed X chromosome inactivation
- Males – clinical presentations can include severe congenital encephalopathy, atypical Rett, mild to severe mental retardation or MECP2 duplication syndrome
  - Males with XXY karyotype, or somatic MECP2 mutations may present with classic Rett
  - MECP2 duplication syndrome
    - Affected males; female carriers are unaffected due to skewed X inactivation
    - Severity is usually consistent within families but interfamilial variability may occur

Pathophysiology

Probable abnormal development of the cortex in infancy
Dysregulation of the autonomic system and associated brainstem dysregulation

Clinical Presentation

Classic Rett
- Apparently normal prenatal and perinatal history
- Normal growth and development until 6-18 months of age 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 (occur in up to 90%), abnormal EEG, breathing irregularities, sleep disturbances, bruxism and scoliosis
Atypical Rett
- Rett-like features that do not completely meet clinical criteria
MECP2 duplication syndrome
- Infantile hypotonia
- Severe mental retardation
- Absence of speech
- Progressive spasticity
- Recurrent respiratory infections (75%)
- Seizures (50%)
Congenital encephalopathy
Mild to severe mental retardation
- Carrier females may have mild cognitive symptoms due to skewed X chromosome inactivation
- Clinical severity may be related to the specific mutation, its location within MECP2 and pattern of X inactivation

Diagnosis

Based on clinical criteria
Confirmed by the identification of an MECP2 mutation
- MECP2 gene sequencing – 80% clinical sensitivity
- MECP2 duplication/deletion analysis – clinical sensitivity up to 15%
- CGH array – detection of deletions or duplications only
Targeted testing should be offered to parents who have a child with an MECP2 mutation to help define recurrence risk
Prenatal diagnosis of subsequent pregnancies of a couple who has a child with an identified MECP2 mutation should be offered (germline mosaicism cannot be excluded)

Differential Diagnosis

Angelman syndrome
Autism
Cerebral palsy
Inborn errors of metabolism (in males with congenital encephalopathy)
Mental retardation

Treatment

Mainly supportive
Seizure control may require drug therapy
Pharmacological therapies to reduce agitation, hyperventilation or sleep dysfunction may be used
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 (prokinetic agents, antipsychotics, antiarrhythmics, anesthetic agents, etc.)

Test Name and Number	Recommended Use	Limitations	Follow Up
Rett Syndrome (MECP2), Full Gene Analysis 0051614 Method: Full Gene Sequencing/Multiplex Ligation 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 cannot be determined; deep intronic mutations will not be detected; rare mutations in primer and probe annealing sites may decrease analytic sensitivity	Counseling and informed consent are recommended for genetic testing
Rett Syndrome (MECP2), Deletion and Duplication 0051618 Method: Multiplex Ligation Probe Amplification	Order for females with classic Rett syndrome negative by MECP2 sequencing or males with a phenotype suggestive of an MECP2 copy number variation Clinical sensitivity up to 15%	Deletion/duplication breakpoints cannot be determined; deep intronic mutations, single base pair substitutions and small deletions/duplications will not be detected	Counseling and informed consent are recommended for genetic testing
Rett Syndrome (MECP2), Full Gene Sequencing 0051378 Method: Polymerase Chain Reaction/Sequencing	Diagnose atypical or classic Rett syndrome. Clinical sensitivity up to 80%	Deep intronic mutations and large deletions/duplications will not be identified; analytical sensitivity may be compromised by rare primer site mutations	Counseling and informed consent are recommended for genetic testing

Rett Syndrome - MECP2 Disorders

Indications for Ordering