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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. 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.
• 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. 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%.
• Genetic testing, by direct sequencing of selected exons or of exons 2-24 of the NOTCH3 gene.
• Examination of brain tissue for the presence of GOM. GOM was originally described as limited to brain vessels. 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.

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.

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). 

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

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

11/28/2012: Policy reviewed; no changes.

01/14/2013:  Added the following new 2013 CPT code to the Code Reference section: 81479.

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