Classic or Atypical Rett Syndrome - MECP2 Disorders

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

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Clinical Overview

Diagnosis

Indications for Testing

Clinical diagnosis of Rett syndrome or an MECP2-related disorder – confirmatory testing
Severe neonatal encephalopathy or intellectual disability in male – testing to determine cause
Familial X-linked developmental delay – testing to rule out an MECP2 variant
- In parents of a child with an MECP2 variant – targeted testing to help define recurrence risk
Clinical features of Angelman syndrome, but no molecular abnormality involving 15q11.2-13 – testing to rule out an MECP2 variant

Laboratory Testing

Testing for Rett is complex; testing choices should be discussed with a genetic counselor
MECP2 gene analysis
- MECP2 full gene analysis – detects 95% of pathogenic variants
- MECP2 sequencing and deletion/duplication analysis by multiplex ligation-dependent probe amplification (MLPA)
Comparative genomic hybridization (CGH) or X-chromosome – only detects large deletions or duplications
Testing for less common variants
- 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 variant; germline mosaicism cannot be excluded.

Background

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, and <5% were cytogenetically visible
MECP2 deletions or nonsense variants are generally associated with a more severe phenotype than are missense variants
MECP2 variants are variably expressed based on sex and pattern of X-chromosome activation (in females)

Pathophysiology

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

Clinical Presentation

Clinical severity influenced by patient’s sex, specific MECP2 variant, and pattern of X inactivation (in females)
Classic Rett syndrome
- Typically seen in affected females
- Males with a 47,XXY karyotype and an MECP2 variant or males with somatic MECP2 variants 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
- Nonambulatory or gait ataxia
- Social withdrawal or autistic features
- Associated findings include seizures (in up to 90%), abnormal electroencephalogram (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-chromosome inactivation in peripheral blood
CDKL5 variants
- Associated with infantile spasms or atypical Rett syndrome
- X-linked dominant – most cases are due to de novo variants
- Heterozygous females commonly present with infantile spasms or epileptic seizures within the first 6 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 variants
  - 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 variants
- 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, whereas females may be unaffected or have milder phenotypes
FOXG1 gene variants
- 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)

ARUP Lab Tests

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
Phenotype of Rett syndrome (classical or atypical)
Manic-depressive psychosis, pyramidal signs, Parkinsonian, and macroorchidism (PPM-X syndrome)
Clinically suspected, but molecularly unconfirmed, Angelman syndrome

Limitations

Deep intronic variants, regulatory region variants, and breakpoints of large deletions/duplications will not be detected

Diagnostic errors can occur due to rare sequence variations

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 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

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
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

Limitations

Deep intronic variants, regulatory region variants, and breakpoints of large deletions/duplications will not be detected

Diagnostic errors can occur due to rare sequence variations

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
ISSX
MECP2-negative atypical Rett syndrome
Autism
Intellectual disability with seizure disorder

Consultation with a genetic counselor is recommended

Limitations

Diagnostic errors can occur due to rare sequence variations

Deep intronic variants, regulatory region variants, and breakpoints of large deletions/duplications will not be detected

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

Medical Experts

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

References

Guidelines

Pini G, Bigoni S, Congiu L, Romanelli AM, Scusa MF, Di Marco P, Benincasa A, Morescalchi P, Ferlini A, Bianchi F, Tropea D, Zappella M. Rett syndrome: a wide clinical and autonomic picture. Orphanet J Rare Dis. 2016; 11(1): 132. PubMed

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: May 2018]

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

Testing Algorithms

Testing for Genetic Syndromes Related to Developmental Delay (DD), Intellectual Disability (ID), and Autism Spectrum Disorder (ASD)

Read more about Testing for Genetic Syndromes Related to Developmental Delay (DD), Intellectual Disability (ID), and Autism Spectrum Disorder (ASD)

Content Review:

April 2018

Last Update: December 2018

Classic or Atypical Rett Syndrome - MECP2 Disorders

Diagnosis

Indications for Testing

Laboratory Testing

Differential Diagnosis

Screening

Background

Epidemiology

Inheritance

Pathophysiology

Clinical Presentation

Treatment

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

Testing for Genetic Syndromes Related to Developmental Delay (DD), Intellectual Disability (ID), and Autism Spectrum Disorder (ASD)

ARUP Laboratories

ARUP Websites

ARUP Consult


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Classic or Atypical Rett Syndrome - MECP2 Disorders

Diagnosis

Indications for Testing

Laboratory Testing

Differential Diagnosis

Screening

Background

Epidemiology

Inheritance

Pathophysiology

Clinical Presentation

Treatment

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

Testing for Genetic Syndromes Related to Developmental Delay (DD), Intellectual Disability (ID), and Autism Spectrum Disorder (ASD)

ARUP Laboratories

ARUP Websites

ARUP Consult