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DESCRIPTIONRett syndrome (RTT), a neurodevelopmental disorder, is usually caused by mutations in the MECP2 gene. Genetic testing is available to determine whether a pathogenic mutation exists in a patient with clinical features of Rett syndrome, or in a patient’s family member.
There is wide variability in the rate of progression and severity of the disease. In addition to the classical form of RTT, there are a number of recognized atypical variants. Variants of RTT may appear with a severe or a milder form. The severe variant has no normal developmental period; individuals with a milder phenotype experience less dramatic regression and milder expression of the characteristics of classical RTT.
The diagnosis of RTT remains a clinical one, using diagnostic clinical criteria that have been established for the diagnosis of classic and variant Rett syndrome.
Treatment of Rett Syndrome
Pharmacological approaches to managing problems associated with RTT include melatonin for sleep disturbances and several agents for the control of breathing disturbances; seizures; and stereotypic movements. RTT patients have an increased risk of life-threatening arrhythmias associated with a prolonged QT interval, and avoidance of a number of drugs is recommended, including prokinetic agents, antipsychotics, tricyclic antidepressants, antiarrhythmics, anesthetic agents and certain antibiotics.
Genetics of Rett Syndrome
As the spectrum of clinical phenotypes is broad, to facilitate genotype-phenotype correlation analyses, the International Rett Syndrome Association has established a locus-specific MECP2 variation database (RettBASE) and a phenotype database (InterRett).
Approximately 99.5% of cases of RTT are sporadic, resulting from a de novo mutation, which arise almost exclusively on the paternally derived X chromosome. The remaining 0.5% of cases are familial and usually explained by germline mosaicism or favorably skewed X-chromosome inactivation in the carrier mother that results in her being unaffected or only slightly affected (mild intellectual disability). In the case of a carrier mother, the recurrence risk of RTT is 50%. If a mutation is not identified in leukocytes of the mother, the risk to a sibling of the proband is below 0.5% (since germline mosaicism in either parent cannot be excluded).
The identification of a mutation in MECP2 does not necessarily equate to a diagnosis of RTT. Rare cases of MECP2 mutations have also been reported in other clinical phenotypes, including individuals with an Angelman-like picture, nonsyndromic X-linked intellectual disability, PPM-X syndrome (an X-linked genetic disorder characterized by psychotic disorders [most commonly bipolar disorder], parkinsonism, and intellectual disability), autism and neonatal encephalopathy.
A proportion of patients with a clinical diagnosis of RTT do not appear to have mutations in the MECP2 gene. Two other genes, CDKL5 and FOXG1, have been shown to be associated with atypical variants.
No FDA-cleared genotyping tests were found. Thus, genotyping is offered as a laboratory-developed test. Clinical laboratories may develop and validate tests in-house (“home-brew”) and market them as a laboratory service; such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). The laboratory offering the service must be licensed by CLIA for high-complexity testing.
POLICYMutation testing for Rett syndrome may be considered medically necessary to confirm a diagnosis of Rett syndrome in a female child with developmental delay and signs/symptoms of Rett syndrome, but when there is uncertainty in the clinical diagnosis.
All other indications for mutation testing for Rett syndrome, including prenatal screening and testing of family members, are considered investigational.
POLICY EXCEPTIONSFederal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.
POLICY GUIDELINESInvestigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY11/15/2012: Approved by Medical Policy Advisory Committee.
11/15/2013: Policy reviewed; no changes.
10/20/2014: Policy reviewed; description updated regarding genetics of Rett Syndrome. Policy statement unchanged.
SOURCE(S)Blue Cross Blue Shield Association policy # 2.04.81
This may not be a comprehensive list of procedure codes applicable to this policy.
The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.