Coverage Policy Manual
Policy #: 2007016
Category: Laboratory
Initiated: September 2007
Last Review: June 2018
  Genetic Test: Amyotrophic Lateral Sclerosis

Description:
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that involves deterioration of both the upper motor neurons (UMNs) and the lower motor neurons (LMNs), and which eventually progresses to fatal paralysis, typically within 3 to 5 years of onset.
 
There are many different types of ALS; these types are distinguished by their signs and symptoms and their genetic cause or lack of clear genetic association. Most people with ALS have a form of the condition that is described as sporadic, which means it occurs in people with no apparent history of the disorder in their family. People with sporadic ALS usually first develop features of the condition in their late fifties or early sixties. A small proportion of people with ALS, estimated at 5 to 10 percent, have a family history of the condition. The signs and symptoms of familial ALS (FALS) typically first appear in one's late forties or early fifties. Rarely, people with familial ALS develop symptoms in childhood or their teenage years. These individuals have a form of the disorder known as juvenile ALS.
Mutations in several genes, including the C9orf72, SOD1, TARDBP, FUS, ANG, ALS2, SETX, and VAPB genes, cause familial ALS and contribute to the development of sporadic ALS. Mutations in the C9orf72 gene are responsible for 30 to 40 percent of familial ALS in the United States and Europe. Worldwide, SOD1 gene mutations cause about 20 percent of familial ALS, TARDBP gene mutations account for about 5 percent, FUS gene mutations cause about 5 percent, and ANG gene mutations account for around 1 percent. The other genes that have been associated with familial ALS each account for a small proportion of cases. It is estimated that 60 percent of individuals with familial ALS have an identified genetic mutation. The cause of the condition in the remaining individuals remains unknown.
 
Various laboratories provide genetic testing for ALS, primarily for SOD1 or angiogenin (ANG) sequence variants using polymerase chain reaction (PCR) amplification and direct sequencing. PCR-based single-strand conformation polymorphism (SSCP) analysis is also used to identify susceptibility variants for ALS.
 
Coding
 
There are CPT codes to more specifically report several of the gene mutations associated with FALS.
 
CPT code 81403 includes:
ANG (angiogenin, ribonuclease, RNase A family, 5) (eg, amyotrophic lateral sclerosis), full gene sequence
 
CPT code 81404 includes:
SOD1 (superoxide dismutase 1, soluble) (eg, amyotrophic lateral sclerosis), full gene sequence
 
CPT code 81405 includes:
TARDBP (TAR DNA binding protein) (eg, amyotrophic lateral sclerosis), full gene sequence
 
CPT code 81406 includes:
FUS (fused in sarcoma) (amyotrophic lateral sclerosis), full gene sequence
SETX (senataxin) (eg, ataxia), full gene sequence
 
CPT 81479 would be used to report testing for ALS2, C90rf72 and VAPB gene mutations.
 
HCPCS S3800 (Genetic testing for amyotrophic lateral sclerosis) was introduced into HCPCS as an active code on 1 Jul 2007.
 
 

Policy/
Coverage:
Genetic testing for amyotrophic lateral sclerosis does not meet primary coverage criteria and is not covered.

Primary Coverage Criteria requires an intervention must be proven to be effective. If there is a lack of scientific evidence regarding a new intervention, or if the available scientific evidence is in conflict or the subject of continuing debate, the new intervention shall be deemed “not effective”.  

For contracts without primary coverage criteria, genetic testing for amyotrophic lateral sclerosis is considered investigational and is not covered.  Investigational services are an exclusion in the member benefit certificate.

Rationale:
In this instance the diagnosis of ALS can be made with other findings and does not require genetic testing to confirm the diagnosis or determine treatment.  By Tanaka et al:  "Although more than 130 years have gone by since the first description in 1869 by Jean-Martin Charcot, the mechanism underlying the characteristic selective motor neuron degeneration in amyotrophic lateral sclerosis (ALS) has remained elusive. Modest advances in this research field have been achieved by the identification of copper/zinc superoxide dismutase 1 (SOD1) as one of the causative genes for rare familial ALS (FALS) and by the development and analysis of mutant SOD1 transgenic mouse models. However, in sporadic ALS (SALS) with many more patients, causative or critical genes situated upstream of the disease pathway have not yet been elucidated and no available disease models have been established. To approach genes causative or critical for ALS, gene expression profiling in tissues primarily affected by the disease has represented an attractive research strategy. We have been working on screening these genes employing and combining several new technologies such as cDNA microarray, molecular indexing, and laser capture microdissection. Many of the resultant genes are of intense interest and may provide a powerful tool for determining the molecular mechanisms of ALS. However, we have barely arrived at the starting point and are confronting an enormous number of genes whose roles remain undetermined. Challenging tasks lie ahead of us such as identifying which genes are really causative for ALS and developing a disease model of SALS with due consideration for the expression changes in those genes."
 
The prevalence of ALS is relatively low and more than 90% of ALS patients show no familial trait. Up to 3% of ALS patients with no family history of the disease have SOD1 mutations.  Of the 5%-10% of ALS patients with a familial trait only 20%-30% of the cases are associated with a mutation in the copper/zinc superoxide dismutase 1 gene (SOD1).  Failure to detect a SOD1 mutation does not rule out familial ALS.
 
2011 Update
 
Clinical Utility:
The clinical utility of a direct diagnostic test for the detection of a mutation of the  SOD1 gene to confirm a diagnosis of Amyotrophic Lateral Sclerosis does not rise to the level of usefulness required at this time.
 
New York State Validation Program:
Currently there is no evidence that testing for a mutation of the SOD1 gene in Amyotrophic Lateral Sclerosis has been validated by the New York State Validation program.
 
Clinical Appropriateness:
The SOD1 mutation genetic testing is not deemed appropriate for patients in which a clinical diagnosis of Amyotrophic Lateral Sclerosis has been made, except for the purposes of genetic counseling for family members and sub typing of the mutation.
 
EGAPP:
SOD1 mutation testing has not been evaluated by EGAPP. It has not been identified as a topic of interest, and it is not currently on the list of tests to be evaluated in the future.
 
Gene Reviews:
Gene mutation testing has been evaluated by Gene Reviews and is recognized as a legitimate testing modality for confirmation of the diagnosis of ALS. It is currently on the Gene Reviews website with a full explanation of the testing process and the current laboratories that perform these molecular diagnostic tests. Tests for several different gene mutations are available; however, the SOD1 mutation is, by far the most common mutation found. The information gained from testing for these mutations is used purely for defining a subtype of the mutation and for genetic counseling.
 
American College of Medical Genetics:
Gene mutation testing for the SOD1 gene is not currently listed on the website for the American College of Medical Genetics.
 
BCBSA MPRM Policy:
BCBSA MPRM currently has no policy on SOD1 gene mutation testing for Amyotrophic Lateral Sclerosis.
 
Hayes Inc Assessment:
Hayes Inc Assessment states that gene mutation testing for Amyotrophic Lateral Sclerosis has a C rating for the SOD1 gene and a D rating for other, less common gene mutations known to be associated with ALS.
 
2012 Update
A literature review was conducted using the MEDLINE database through May 2012.  There was no new literature identified that would prompt a change in the coverage statement.
 
2013 Update
A literature search was conducted through May 2013.  There was no new information identified that would prompt a change in the coverage statement.  There remains a lack of scientific evidence regarding the clinical utility of genetic testing in the diagnosis and treatment of ALS.
 
No specific therapy for patients with SOD1 gene mutations have been approved (Anderson, 2012). Clinical trials on drugs targeting SOD1 are currently underway and are discussed below. Miller and colleagues recently published results of a first-in-man, phase 1, placebo-controlled trial assessing the safety, tolerability and pharmacokinetics of an intrathecal administration of ISIS 333611 in patients with SOD1-related familial ALS (Miller, 2013).
 
The EFNS Task Force published an update of the 2005 EFNS guidelines on the clinical management of ALS (Andersen, 2012). The task force gives recommendations which result in either an A, B or C recommendation depending on the level of evidence.  No recommendations were given based on A, B, or C level of evidence. Recommendations where there is a lack of evidence but a consensus of opinion, are noted as “Good Clinical Practice Points (GCPP)”. The following recommendations were stated as GCPP.
 
    • “Clinical DNA analysis for gene mutation should only be performed in cases with a known family history of ALS, and in sporadic ALS cases with the characteristic phenotype of the recessive D90A mutation (GCPP)”.
    • Clinical DNA analysis for gene mutations should not be performed in cases with sporadic ALS with a typical classical ALS phenotype (GCPP).
 
The following ongoing clinical trials were identified on the clinicaltrials.gov website:
 
NCT00706147- Phase 2/3 randomized, placebo-controlled trial to assess the efficacy, safety and tolerability of arimoclomol in SOD1 positive familial ALS.  This study is sponsored by the University of Miami in collaboration with the ALS Association, FDA Office of Orphan Products Development and Massachusetts General Hospital. The study is currently recruiting and has an estimated completion date of December 2013.
 
NCT01083667- Phase 1/2 open-label study to assess the safety, tolerability and effect on SOD1 levels by pyrimethamine in patients with familial ALS. The study is sponsored by Weill Medical College of Cornell Univeristy in collaboration with the Muscular Dystrophy Association. The study has an estimated completion date of May 2013.
 
The results of the literature search do not prompt a change in the coverage statement. Further evidence is needed regarding the clinical utility of genetic testing in the diagnosis and management of ALS.
 
2014 Update
A literature search was conducted through May 2014.  There was no new information identified that would prompt a change in the coverage statement.
 
2015 Update
A literature search was conducted through May 2015. There was no new information that would prompt a change in the coverage statement. At present, there is no published scientific evidence supporting the clinical utility of genetic testing for amyotrophic lateral sclerosis.  There is no FDA approved medications for patients with SOD1 or other gene mutations. Clinical trials are ongoing on the use of arimoclomol and pyrimethamine in patients with SOD1 mutations (Clinicaltrials.gov, 2015).
 
Other gene mutations identified with familial amyotrophic lateral sclerosis include C9orf72, SOD1, TARDBP, FUS, ANG, ALS2, SETX, and VAPB. The literature search did not identify any specific therapy for patients with these gene mutations.
  
2017 Update
A literature search conducted through May 2017 did not reveal any new information that would prompt a change in the coverage statement.
 
2018 Update
A literature search conducted through May 2018 did not reveal any new information that would prompt a change in the coverage statement.
 

CPT/HCPCS:
81403MOLECULAR PATHOLOGY PROCEDURE LEVEL 4
81404MOLECULAR PATHOLOGY PROCEDURE LEVEL 5
81405MOLECULAR PATHOLOGY PROCEDURE LEVEL 6
81406MOLECULAR PATHOLOGY PROCEDURE LEVEL 7
81479Unlisted molecular pathology procedure
S3800Genetic testing for amyotrophic lateral sclerosis (ALS)

References: Andersen PM, Abrahams S, Borasio GD, et al.(2012) EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS)-revised report of an EFNS task force. European Journal of Neurology 2012, 19:360-375.

Battistini S, Giannini F, et al.(2005) SOD1 mutations in amyotrophic lateral sclerosis. Results from a multicenter Italian study. J Neurol, 2005; 252:782-8.

Clinicaltrials.gov. Accessed at www.clinicaltrials.gov. Last accessed June 15, 2015.

Clinicaltrials.gov. Accessed at www.clinicaltrials.gov. Last accessed June 17, 2013.

Dellefave L, Siddique T.(2007) Amyotrophic lateral sclerosis overview. http://www.geneclinics.org/profiles.

Genetics Home Reference.(2015) Amyotrophic Lateral Sclerosis. http://ghr.nlm.nih.gov/condition/amyotrophic-lateral-sclerosis. Last accessed June 2015.

Gonzalez de Aguilar JL, Echaniz-Laguna A, et al.(2007) Amyotrophic lateral sclerosis: all roads lead to Rome. J Neurochem, 2007; 101:1153-60.

Gros-Louis F, Gaspar C, Rouleau GA.(2006) Genetics of familial and sporadic amyotrhophic lateral sclerosis. Biochimica Biophysica Acta, 2006; 1762:956-72.

Miller TM, Pestronk A, David W, et al.(2013) An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomized, first-in-man study. Lancet neurol. 2013 My;12(5):435-42.

Tanaka F, Niwa JI, et al.(2006) Gene expression profiling toward understanding of ALS pathogenesis. Ann N Y Acad Sci, 2006; 1086:1-10.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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