Clinical Guidance

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

• . The phenotype is syndromic (PPM-X) intellectual disability in males and very mild cognitive impairment in females [, , , , , ].

• . The phenotype is less severe than classic Rett syndrome in females; this variant can be present in affected males .

• is found in females and males with intellectual disability and some features of MECP2 disorders, but not classic or variant Rett syndrome .

Source: GeneReviews — "MECP2 Disorders"

Diagnostic Criteria

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 [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

Source: GeneReviews — "MECP2 Disorders"

Differential Diagnosis

Table 4. MECP2 Disorders: Differential Diagnosis

Management Guidelines

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

Source: GeneReviews — "MECP2 Disorders"

Clinical Guidance

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)

See CredibleMeds® (free registration required) for a more extensive list of drugs to avoid.

Source: GeneReviews — "MECP2 Disorders"

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.

Source: GeneReviews — "MECP2 Disorders"

Surveillance Guidelines

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

Table 7.

MECP2 Disorders: Recommended Surveillance

System/Concern | Evaluation | Frequency

Feeding

| • Measurement of growth parameters

• Eval of nutritional status safety of oral intake

| At each multidisciplinaryclinic visit;at least annually

Gastrointestinal

| Monitor for constipation.

Respiratory

| Monitor for evidence of aspiration, respiratory insufficiency.

Neurologic

| • Monitor those w/seizures as clinically indicated.

• Assess for new manifestations, e.g., seizures, changes in tone, movement disorders.

Development

| Monitor developmental progress educational needs.

Speech language

| Monitor communication skills.

Psychiatric/

Behavioral

| Behavioral assessment for anxiety, attention, aggressive or self-injurious behavior

Musculoskeletal

| • Physical medicine, OT/PT assessment of mobility, self-help skills

• Monitor scoliosis.

Cardiovascular

| Monitor for prolonged QTc.

Respiratory

| Apnea/hyperventilation

Miscellaneous/

Other

| Assess family need for social work support (e.g., palliative/respite care, home nursing; other local resources) care coordination.

OT = occupational therapy; PT = physical therapy

Source: GeneReviews — "MECP2 Disorders"