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DESCRIPTIONRett syndrome (RTT), a neurodevelopmental disorder, is usually caused by mutations in the MECP2 (methyl-CpG-binding protein 2) 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
Pharmacologic 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.
In a mouse model of RTT, genetic manipulation of mutated MECP2 has demonstrated reversibility of the genetic defect.
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.
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). Genetic testing for Rett syndrome is available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.
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, when a definitive diagnosis cannot be made without genetic testing.
All other indications for mutation testing for Rett syndrome, including carrier testing (preconception or prenatal), and testing of asymptomatic family members to determine future risk of disease, 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.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual’s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.
Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Nervous/Mental Conditions, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:
A. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and
B. appropriate with regard to standards of good medical practice; and
C. not solely for the convenience of the Member, his or her Provider; and
D. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.
For the definition of Medically Necessary, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
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.
08/18/2015: Medical policy revised to add ICD-10 codes.
02/15/2016: Policy description updated regarding treatment of Rett Syndrome and testing. Policy statements updated for clarification. Medically necessary statement updated to change "but when there is uncertainty in the clinical diagnosis" to "when a definitive diagnosis cannot be made without genetic testing." Investigational statement updated to change "prenatal screening" to "carrier testing (preconception or prenatal)." It previously stated: All other indications for mutation testing for Rett syndrome, including prenatal screening and testing of family members, are considered investigational. Policy guidelines updated regarding genetic counseling and to add medically necessary and investigational definitions.
06/07/2016: Policy number A.2.04.81 added.
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.
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