BlueCross and BlueShield of Montana Medical Policy/Codes
NOTCH3 Genotyping for Diagnosis of CADASIL
Chapter: Medicine: Tests
Current Effective Date: October 25, 2013
Original Effective Date: March 18, 2012
Publish Date: October 25, 2013
Revised Dates: November 09, 2012; September 25, 2013
Description

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an uncommon, autosomal dominant disease. It is the most common cause of hereditary stroke and hereditary vascular dementia in adults. The CADASIL syndrome is an adult-onset, disabling systemic condition, characterized by migraine with aura, recurrent lacunar strokes, progressive cognitive impairment, and psychiatric disorders. The overall prevalence of the disease is unknown in the general population.

The clinical presentation of CADASIL is variable, and may be confused with multiple sclerosis, Alzheimer dementia, and Binswanger disease. The specific clinical signs and symptoms, along with family history and brain magnetic resonance imaging (MRI) findings, are extremely important in determining the diagnosis of CADASIL. When the differential diagnosis includes CADASIL, various other tests are available for diagnosis:

  • Immunohistochemistry assay of a skin biopsy sample, using a monoclonal antibody with reactivity against the extracellular domain of the NOTCH3 receptor. Positive immunostaining reveals the accumulation of NOTCH3 protein in the walls of small blood vessels. (1) Lesnick Oberstein et al. (2003) estimated sensitivity and specificity at 85-90% and 95-100%, respectively, for 2 observers of the test results in a population of patients and controls correlated with clinical, genetic and MRI parameters. (2)
  • Detection of granular osmiophilic material (GOM) in the same skin biopsy sample by electron microscopy. The major component of GOM is the ectodomain of the NOTCH3 gene product. (3) GOM accumulates directly in vascular smooth muscle cells and, when present, is considered a hallmark of the disease. (4) However, GOM may not be present in all biopsy samples. Sensitivity has been reported as low as 45% and 57%, but specificity is generally near or at 100%. (5-7)
  • Genetic testing, by direct sequencing of selected exons or of exons 2-24 of the NOTCH3 gene (see Rationale).
  • Examination of brain tissue for the presence of GOM. GOM was originally described as limited to brain vessels. (8) Examination of brain biopsy or autopsy after death was an early gold standard for diagnosis. In some cases, peripheral staining for GOM has been absent even though positive results were seen in brain vessels.

Mutations in NOTCH3 have been identified as the underlying cause of CADASIL. In almost all cases, the mutations lead to loss or gain of a cysteine residue that could lead to increased reactivity of the NOTCH3 protein, resulting in ligand-binding and toxic effects. (9)

The NOTCH3 gene is found on chromosome 19p13.2-p13.1 and encodes the third discovered human homologue of the Drosophila melanogaster type I membrane protein NOTCH. The NOTCH3 protein consists of 2,321 amino acids primarily expressed in vascular smooth muscle cells and plays an important role in the control of vascular transduction. It has an extracellular ligand-binding domain of 34 epidermal growth factor-like repeats, traverses the membrane once, and has an intracellular domain required for signal transduction. (10)

Mutations in the NOTCH3 gene have been differentiated into those that are causative of the CADASIL syndrome and those that are of uncertain significance. Causative mutations affect conserved cysteine residues within 34 epidermal growth factor (EGF)-like repeat domains in the extracellular portion of the NOTCH3 protein. (10, 11) More than 150 causative mutations have been reported in at least 500 pedigrees. NOTCH3 has 33 exons, but all CADASIL mutations reported to date have occurred in exons 2–24, which encode the 34 EGF-like repeats, with strong clustering in exons 3 and 4, which encode EGFR 2–5 (>40% of mutations in >70% of families occur in these exons). (12)

Regulatory Status

There are no manufactured test kits for detecting NOTCH3 gene mutations; therefore, this testing has not been reviewed by the U.S. Food and Drug Administration (FDA). Rather, NOTCH3 gene sequencing is a laboratory-developed test, offered by clinical laboratories licensed under Clinical Laboratory improvement Act (CLIA) for high-complexity testing.

Policy

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Investigational

Blue Cross and Blue Shield of Montana (BCBSMT) considers NOTCH3 testing for the diagnosis of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) experimental, investigational and unproven.

Rationale

Literature Review

Literature that describes the analytic validity, clinical validity, and clinical utility of NOTCH3 testing was sought. No relevant primary data on analytic validity were identified. The test is generally done by gene sequencing analysis, which is expected to have high analytic validity when performed under optimal conditions.

Clinical validity

Several retrospective and prospective studies have examined the association between NOTCH3 genes and CADASIL, as shown in the following table. These have been divided into 2 categories: Part 1, diagnostic studies, in which the patients enrolled were suspected but not confirmed to have CADASIL; and Part 2, clinical validity studies, in which the patients had already been diagnosed with the disease by some method other than genetic testing. The diagnostic studies are more likely to represent the target population in which the test would be used.

Table. Studies of the association of NOTCH3 with CADASIL diagnosis; results of published studies supporting NOTCH3 genotyping test claims.

Study

 

Patients Evaluated

 

NOTCH3 Exons Evaluated

Results

 

Part 1 Diagnostic Studies

Diagnostic Yield

Specificity

Mosca et al. 2011(9)  

Patients: 140 patients with clinical suspicion of CADASIL (Italian and Chinese).
 

 
Patient Selection: History of premature strokes; migraine with aura; vascular dementia; suggestive MRI findings; a consistent family history; or a combination of the above criteria.  

Direct sequencing of exons 2-8, 10, 14, 19, 20, and 22.  

Patients:

14 patients with causative mutations located in 10 different exons. 126 patients free of pathogenic mutations.
 

Family Members:

Analysis of 15 additional family members identified 11 of the same causative mutations.  

NR 

Lee et al. 2009 (13)  

Patients: 39 patients with suspected CADASIL (China). 100 healthy elderly controls 80 years or older.
 

 
Patient Selection: Suggestive MRI findings and at least one of the following: young age at onset, cognitive decline, psychiatric disorders, or consistent family history.  

Direct sequencing of exons 2-23.  

Patients: 9 different point mutations identified in 21/39 patients.
 

 
Family members: No data for additional family members  

100%
 

 
No mutations found in 100 healthy elderly controls. 

Markus et al. 2002 (7)  

Patients: 83 patients with suspected CADASIL (UK).
 

 
Patient Selection: Patients were younger than 60 years of age with recurrent lacunar stroke with leukoaraiosis on neuroimaging. Migraine, psychiatric disorders, or dementia could occur but were not essential.  

Direct sequencing of exons 3-4; SSCP of exons 2, 5-23.  

Patients: 15 different point mutations identified in 48 families with a total of 116 symptomatic patients, 73% in exon 4, 8% in exon 3, and 6% in exons 5 and 6.
 

 
Family Members: No data for additional family patients  

NR 

Part 2 Clinical Validity Studies

Sensitivity

Specificity

Peters et al. 2005(14)  

Patients: 125 unrelated patients diagnosed with CADASIL.
 

 
Patient Diagnosis/Selection: Skin biopsy-proven CADASIL pts referred between 1994 and 2003 (German).  

Bidirectional sequencing of all exons.  

Sensitivity: 96%
 

 
Patients: 54 distinct mutations in 120 (96.0%) of the 125 patients. In 5 patients (4.0%), no mutation was identified.
 

 
Family Members: No data for additional family patients 
 

NR 

Tikka et al. 2009(15)  

Patients: 131 patients from 28 families diagnosed with CADASIL (Finnish, Swedish, and French).
 

 
Patient Diagnosis/Selection: EM examination of skin biopsy was performed; 26 asymptomatic controls from CADASIL families  

Direct sequencing of exons 2-24.  

Sensitivity: 100%
 

 
Patients: 131 CADASIL patients were mutation positive.
 

 
Family Members: No data for additional family patients.
 

 
No mutation reporting per family or per unrelated individual.  

100%
 

 
No mutations were found in the 26 negative controls. 

Dotti et al. 2005 (16)  

Patients: 28 unrelated, consecutively diagnosed patients with CADASIL (Italian).
 

 
Patient Diagnosis/Selection: Patients were diagnosed via clinical and MRI.  

DHPLC, followed by confirmatory sequencing of identified mutations.  

Sensitivity: 100%.
 

 
Patients: All 28 patients had mutations.  

NR 

Joutel et al. 1997(17)  

Patients: 50 unrelated patients with a clinical suspicion of CADASIL and 100 healthy controls.
 

 

Patient Diagnosis/Selection:

History of recurrent strokes, migraine with aura, vascular dementia, or a combination; brain MRI with suggestive findings; and a consistent familial history.  

SSCP or heteroduplex analysis of all exons, followed by confirmatory sequencing of identified mutations.  

Sensitivity: 90%
 

 
Patients: 45 of 50 CADASIL patients had mutations, .  

100%
 

 
No mutations were found in 100 healthy controls.

SSCP, single-stranded conformational polymorphism; EM, electron microscope; DHPLC, denaturing high-performance liquid chromatography; NR, not reported

The results of the clinical validity studies demonstrate that a NOTCH3 mutation is found in a high percentage of patients with a clinical diagnosis of CADASIL, with studies reporting a clinical sensitivity of 90-100%. Limited data on specificity is from testing small numbers of healthy controls, and no false positive NOTCH3 mutations have been reported in these populations. The diagnostic yield studies report a variable diagnostic yield, ranging from 10-54%. These lower numbers likely reflect testing in heterogeneous populations that include patients with other disorders.

Clinical utility

There is no clinical treatment for CADASIL. Supportive care in the form of practical help, emotional support, and counseling are appropriate for affected individuals and their families. (10) Three studies were found that addressed treatment efficacy in CADASIL as follows.

A double-blind, placebo controlled trial that evaluated the efficacy and safety of donepezil hydrochloride (HCl) in individuals with CADASIL was conducted. The study resulted in donepezil HCl having no effect on the primary cognitive endpoint, the V-ADAS-cog score (vascular Alzheimer’s Disease assessment scale cognitive subscale) in patients with CADASIL who had cognitive impairment. (18)

Another study evaluated the efficacy and tolerance of a 24-week treatment with 250 mg/d acetazolamide (ACZ), which could be chronically implemented to improve cerebral hemodynamics in CADASIL patients (n=16). Treatment with ACZ resulted in a significant increase of mean blood flow velocity (MFV) in the middle cerebral artery (MCA) compared with MFV in the MCA at rest before treatment (57.68±12.7 cm/s versus 67.12±9.4 cm/s; P=0.001). During the treatment period, none of the subjects developed new neurologic symptoms, and the original symptoms in these patients, such as headaches and dizziness, were relieved. (19)

A third study evaluated the use of HMG-CoA-reductase-inhibitors (statins) in 24 CADASIL subjects treated with atorvastatin for 8 weeks. Treatment was started with 40 mg, followed by a dosage increase to 80 mg after 4 weeks. Transcranial Doppler sonography measuring MFV in the MCA was performed at baseline and at the end of the treatment period. There was no significant treatment effect on MFV (p=0.5) or cerebral vasoreactivity, as assessed by hypercapnia (p=0.5) and intravenous L-arginine (p=0.4) in the overall cohort. However, an inverse correlation was found between vasoreactivity at baseline and changes of both CO2- and L-arginine-induced vasomotor response (both p<0.05). Short-term treatment with atorvastatin resulted in no significant improvement of hemodynamic parameters in the overall cohort of CADASIL subjects. (20)

Family Members. 

It has been suggested that asymptomatic family members follow the guidelines for presymptomatic testing for Huntington’s disease. Genetic counseling is recommended to discuss the impact of positive or negative test results, followed by molecular testing if desired. (4)

Prenatal Screening.

A novel case was reported involving a potential father diagnosed with CADASIL and genotyped with a disease-causing mutation, c.459C>T (R153C) in exon 4 of the NOTCH3 gene. (21) A preimplantation genetic diagnosis (PGD) protocol was designed to identify the father’s mutation. Standard prenatal diagnosis procedures were employed to confirm the PGD results. One blastomere was removed at day 3 from each of 8 embryos. Detection of the c.459C>T NOTCH3 mutation, coupled to informative polymorphic markers, unambiguously identified 3 unaffected embryos. Blastocyst transfer resulted in a singleton pregnancy, and subsequent prenatal diagnosis confirmed that the fetus was disease-free. (21)

Practice Guidelines and Position Statements

No technology assessments or meta-analyses relating to CADASIL genetic testing were found.

The European Federation of Neurological Societies guideline on the molecular diagnosis of channelopathies, epilepsies, migraine, stroke, and dementias notes that most NOTCH3 mutations occur within exons 3 and 4 and suggests direct sequencing of these 2 exons if clinical suspicion is high. (22)

An online keyword search on ‘CADASIL’ in the full texts of the American Academy of Neurology guidelines returned no direct guidelines on CADASIL diagnosis or management.

Ongoing Clinical Trials

No ongoing clinical trials were found at the online site: Clinicaltrials.gov (search strategy = CADASIL) relating to genetic testing for diagnosis.

Summary

NOTCH3 mutations are found to be the cause of CADASIL in the majority of patients with the syndrome. The diagnostic accuracy of NOTCH3 cannot be determined with certainty due to the lack of a true gold standard for diagnosis of CADASIL. However, a high percentage of patients in whom CADASIL is diagnosed by clinical methods will have a NOTCH3 mutation on genetic testing. Conversely, NOTCH3 mutations are not commonly found in unaffected individuals.

Testing with NOTCH3 has uncertain clinical utility. The diagnosis of CADASIL can often be made by a combination of clinical presentation, MRI findings, and skin biopsy findings. In such cases, NOTCH3 testing is not necessary for diagnosis. In other cases, the diagnosis cannot be made on the basis of clinical presentation, MRI, and skin biopsy results. In these cases, NOTCH3 testing may be useful in confirming or excluding the diagnosis of CADASIL.

However, there is no effective treatment for CADASIL, so that establishing a definitive diagnosis of CADASIL will not change management. Knowledge of the presence of a NOTCH3 mutation may lead to changes in lifestyle decisions for the affected individual, for example in the areas of reproduction and employment. Therefore, testing of an index case for NOTCH3 can assist in predictive testing for family members, since it can then be determined if family members have inherited the same NOTCH3 mutation present in the index case. The impact of these changes in decision making on health outcomes is uncertain. As a result, NOTCH3 mutation testing for the diagnosis of CADASIL is considered experimental, investigational and unproven.

Coding

Disclaimer for coding information on Medical Policies           

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.           

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.           

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

Rationale for Benefit Administration
 
ICD-9 Codes

Experimental, investigational and unproven for all diagnoses.

ICD-10 Codes

Experimental, investigational and unproven for all diagnoses.

Procedural Codes: [Deleted 1/2013: 83891, 83898, 83904, 83909, 83912]
References
  1. Joutel A, Favrole P, Labauge P et al. Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis. Lancet 2001; 358(9298):2049-51.
  2. Lesnik Oberstein SA, van Duinen SG, van den Boom R et al. Evaluation of diagnostic NOTCH3 immunostaining in CADASIL. Acta Neuropathol 2003; 106(2):107-11.
  3. Ishiko A, Shimizu A, Nagata E et al. Notch3 ectodomain is a major component of granular osmiophilic material (GOM) in CADASIL. Acta Neuropathol 2006; 112(3):333-9.
  4. del Rio-Espinola A, Mendioroz M, Domingues-Montanari S et al. CADASIL management or what to do when there is little one can do. Expert Rev Neurother 2009; 9(2):197-210.
  5. Malandrini A, Gaudiano C, Gambelli S et al. Diagnostic value of ultrastructural skin biopsy studies in CADASIL. Neurology 2007; 68(17):1430-2.
  6. Brulin P, Godfraind C, Leteurtre E et al. Morphometric analysis of ultrastructural vascular changes in CADASIL: analysis of 50 skin biopsy specimens and pathogenic implications. Acta Neuropathol 2002; 104(3):241-8.
  7. Markus HS, Martin RJ, Simpson MA et al. Diagnostic strategies in CADASIL. Neurology 2002; 59(8):1134-8.
  8. Rubio A, Rifkin D, Powers JM et al. Phenotypic variability of CADASIL and novel morphologic findings. Acta Neuropathol 1997; 94(3):247-54.
  9. Mosca L, Marazzi R, Ciccone A et al. NOTCH3 gene mutations in subjects clinically suspected of CADASIL. J. Neurol. Sci. 2011; 307(1-2):144-8.
  10. Lesnik Oberstein SAJ, Boon EMJ, Dichgans M. CADASIL. In: Pagon RA, Bird TD, Dolan CR, Stephens K, eds. GeneReviews . Seattle WA: University of Washington, Seattle; 1993.
  11. Donahue CP, Kosik KS. Distribution pattern of Notch3 mutations suggests a gain-of-function mechanism for CADASIL. Genomics 2004; 83(1):59-65.
  12. Chabriat H, Joutel A, Dichgans M et al. Cadasil. Lancet Neurol 2009; 8(7):643-53.
  13. Lee YC, Liu CS, Chang MH et al. Population-specific spectrum of NOTCH3 mutations, MRI features and founder effect of CADASIL in Chinese. J. Neurol. 2009; 256(2):249-55.
  14. Peters N, Opherk C, Bergmann T et al. Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies. Arch. Neurol. 2005; 62(7):1091-4.
  15. Tikka S, Mykkanen K, Ruchoux MM et al. Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients. Brain 2009; 132(Pt 4):933-9.
  16. Dotti MT, Federico A, Mazzei R et al. The spectrum of Notch3 mutations in 28 Italian CADASIL families. J. Neurol. Neurosurg. Psychiatry 2005; 76(5):736-8.
  17. Joutel A, Vahedi K, Corpechot C et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet 1997; 350(9090):1511-5.
  18. Dichgans M, Markus HS, Salloway S et al. Donepezil in patients with subcortical vascular cognitive impairment: a randomised double-blind trial in CADASIL. Lancet Neurol 2008; 7(4):310-8.
  19. Huang L, Yang Q, Zhang L et al. Acetazolamide improves cerebral hemodynamics in CADASIL. J. Neurol. Sci. 2010; 292(1-2):77-80.
  20. Peters N, Freilinger T, Opherk C et al. Effects of short term atorvastatin treatment on cerebral hemodynamics in CADASIL. J. Neurol. Sci. 2007; 260(1-2):100-5.
  21. Konialis C, Hagnefelt B, Kokkali G et al. Pregnancy following preimplantation genetic diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Prenat. Diagn. 2007; 27(11):1079-83.
  22. Burgunder JM, Finsterer J, Szolnoki Z et al. EFNS guidelines on the molecular diagnosis of channelopathies, epilepsies, migraine, stroke, and dementias. Eur. J. Neurol. 2010; 17(5):641-8.
  23. NOTCH3 Genotyping for Diagnosis of CADASIL. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (September 2011) Medicine 2.04.75.
History
January 2012 New Policy for BCBSMT: Policy created with literature search through September 2011, considered investigational.
November 2012 Policy updated with literature review, reference 8 added. Policy statement unchanged.
October 2013 Policy formatting and language revised.  Policy statement unchanged.
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NOTCH3 Genotyping for Diagnosis of CADASIL