Clinical Policy Title: Genetic testing for maple syrup urine disease

Transcription

1 Clinical Policy Title: Genetic testing for maple syrup urine disease Clinical Policy Number: Effective Date: June 1, 2018 Initial Review Date: April 10, 2018 Most Recent Review Date: May 1, 2018 Next Review Date: May 2019 Related policies: Policy contains: Maple syrup urine disease. Branched-chain ketoaciduria. Genetic testing. Mutation. CP# CP# CP# CP# CP# CP# CP# CP# Genetic testing for autism spectrum disorders Genetic testing for cytochrome p450 polymorphisms Genetic testing for rare diseases Genetic testing for prostate cancer prognosis Genetic testing in neurology Genetic testing in sensorineural hearing loss Maternal genetic testing Genetic testing for breast and ovarian cancer ABOUT THIS POLICY: Select Health of South Carolina has developed clinical policies to assist with making coverage determinations. Select Health of South Carolina s clinical policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services (CMS), state regulatory agencies, the American Medical Association (AMA), medical specialty professional societies, and peerreviewed professional literature. These clinical policies along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including any state- or plan-specific definition of medically necessary, and the specific facts of the particular situation are considered by Select Health of South Carolina when making coverage determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws and/or regulatory requirements, the plan benefits and/or state and federal laws and/or regulatory requirements shall control. Select Health of South Carolina s clinical policies are for informational purposes only and not intended as medical advice or to direct treatment. Physicians and other health care providers are solely responsible for the treatment decisions for their patients. Select Health of South Carolina s clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, Select Health of South Carolina will update its clinical policies as necessary. Select Health of South Carolina s clinical policies are not guarantees of payment. Coverage policy Select Health of South Carolina considers genetic testing for screening and diagnosis of maple syrup urine disease (branched-chain ketoaciduria) to be clinically proven and, therefore, medically necessary when the following criteria are met (ACOG, 2017; De Castro-Hamoy, 2017; Kuhl, 2017; Wilson, 2016; Couce, 2015; Miryounesi, 2015; Herber, 2015; Moorthie, 2014; Raske, 2014; Hawkes, 2014): There is a family history of an affected sibling with the condition. OR 1

2 There is known ethnic risk of inheriting the condition (e.g., Ashkenazi Jewish, Amish, or Mennonite ancestry). AND The test is ordered and interpreted by a trained professional. The result of the test will directly impact management of the patient and/or guardian. The test is an analytically and clinically valid test (i.e., supported by peer-reviewed published research). Women with positive screening test results are offered further counseling and testing. Limitations: Molecular testing is appropriate in patients with maple syrup urine disease to confirm the diagnosis, to provide additional information about prognosis, to provide the basis for in-depth genetic counseling for the family, and to provide the basis for prenatal testing. Carrier testing for at-risk relatives requires prior identification of the pathogenic variants of maple syrup urine disease in the family. Prenatal diagnosis and preimplantation genetic diagnosis for at-risk pregnancies require prior identification of the pathogenic variants in the family. Repeat uses of genetic testing for diagnosis and screening of maple syrup urine disease are not medically necessary. Alternative covered services: Routine patient evaluation and management by a network health care provider, including invasive prenatal diagnostic tests with amniocentesis or chorionic villus sampling. Background Maple syrup urine disease (branched-chain ketoaciduria) is a rare autosomal recessive genetic condition with an estimated prevalence of 1:185,000 live births (Adam, 2018; Moorthie, 2014). It is manifested biochemically as failed ketoacid decarboxylation of the branched-chain amino acids leucine, isoleucine, and valine. At conception, each sibling of an affected individual has a 25 percent chance of being affected, a 50 percent chance of being unaffected and a carrier, and a 25 percent chance of being unaffected and not a carrier. 2

3 Classic maple syrup urine disease is caused by known mutations in the BCKDHA, BCKDHB, and DBT genes at the 19q13.2, 6q14.1, and 1p21.2 loci, respectively. These genes encode proteins essential for breaking down branched-chain amino acids, although multiple less-widely attributed gene mutations may also be in play (Adam, 2018; Su, 2017; Couce, 2015; Miryounesi, 2015). Individuals with intermediate maple syrup urine disease have a partial enzyme deficiency that only manifests intermittently; these individuals can experience severe metabolic intoxication and encephalopathy during periods of sufficient catabolic stress and protein breakdown. The failure to execute the cellular metabolic step of branched-chain ketoacid dehydrogenation results in high levels of leucine, isoleucine, valine, and their corresponding α-ketoacids in the serum, urine, and cerebrospinal fluid. The disease earned its name by the characteristic and distinctive sweet odor from the excessive ketones in the urine of the affected individual. Other clinical features of the disease include failure to thrive, lethargy, developmental delay, and neurological impairment. If left untreated, maple syrup urine disease can lead to vomiting, coma, and death. In a number of states, screening of all newborns for maple syrup urine disease (and other inherited disorders) is mandatory at birth (Save Babies Through Screening Foundation 2018). Newborn screening programs typically employ tandem mass spectrometry performed between 24 and 48 hours of age to detect maple syrup urine disease. This technique measures whole blood combined leucine-isoleucine concentration and its ratio to other amino acids such as alanine and phenylalanine. It can be determined if newborns who are from a family with previously affected siblings and/or have high ethnic risk (e.g., individuals of Ashkenazi Jewish ancestry) who have not been tested prenatally are affected by molecular genetic testing of umbilical cord blood if the family-specific pathogenic alleles have been identified by prior testing of parents or an affected sib. A commonly used next generation sequencing testing panel, the Pan-Ethnic Carrier Screen: Gene Sequencing Panel (EGL Genetic Diagnostics, Tucker GA), tests for a total of 136 conditions including maple syrup urine disease. Searches Select Health of South Carolina searched PubMed and the databases of: UK National Health Services Centre for Reviews and Dissemination. Agency for Healthcare Research and Quality s National Guideline Clearinghouse and other evidence-based practice centers. The Centers for Medicare & Medicaid Services (CMS). We conducted searches on February 9, Search terms were: maple syrup urine disease, genetic testing, and branched-chain ketoaciduria." We included: 3

4 Systematic reviews, which pool results from multiple studies to achieve larger sample sizes and greater precision of effect estimation than in smaller primary studies. Systematic reviews use predetermined transparent methods to minimize bias, effectively treating the review as a scientific endeavor, and are thus rated highest in evidence-grading hierarchies. Guidelines based on systematic reviews. Economic analyses, such as cost-effectiveness, and benefit or utility studies (but not simple cost studies), reporting both costs and outcomes sometimes referred to as efficiency studies which also rank near the top of evidence hierarchies. Findings The American College of Obstetricians and Gynecologists (ACOG) offers direction in its Committee Opinion (ACOG, 2017) concerning carrier screening for genetic conditions, including uncommon conditions, in the Ashkenazi Jewish population. Among the disease entities identified by ACOG that should be considered in this cohort for individual testing is maple syrup urine disease. The Society of Obstetricians and Gynaecologists of Canada (SOGC) and Canadian College of Medical Geneticists (CCMG) have issued an opinion for reproductive genetic carrier screening (Wilson, 2016). The SOGC-CCMG joint committee recommends that Ashkenazi Jewish carrier screening be offered when a positive family pedigree is elicited for one of the conditions known to be present at an increased frequency in this population (associated carrier frequencies are listed): Bloom syndrome 1/104; Fanconi anemia group C 1/89; Niemann-Pick type A 1/90; mucolipidosis type IV 1/ ; Gaucher disease 1/18; glycogen storage disease type 1a 1/64; familial hyperinsulinism 1/68; maple syrup urine disease 1/97; dihydrolipoamide hydrogenase deficiency 1/107; CF 1/28; Usher syndrome 1/120; nemaline myopathy 1/168; Joubert syndrome 1/92; and Walker-Warburg syndrome 1/150. Strauss (2012) established in a community clinic setting that maple syrup urine disease affects about one per 400 Amish and Mennonite infants. Relying on genetic testing, the group managed Mennonite maple syrup urine disease in 68 patients longitudinally from the newborn period. Half of them were targeted diagnoses because of a positive family history or carrier testing, diagnosed between 12 and 24 hours of birth and managed as outpatients. The remainder were diagnosed by newborn screening and hospitalized for an average of five days. A community project through the University of Wisconsin Biochemical Genetics Clinic and the Wisconsin Newborn Screening Program successfully provided testing of a high-risk population (n=80) for maple syrup urine disease and propionic acidemia to identify members of the population at risk for having children with these conditions (Kuhl, 2017). The intervention conducted targeted variant analysis of the common pathogenic variants in this population using blood spot testing kits offered to health care providers. Diagnosis was confirmed for three adults with propionic acidemia and one couple was identified as being at risk for having a child with propionic acidemia. Genetic counseling was provided to those identified and follow-up diagnostic testing was completed for the at-risk couple's children; none 4

5 were found to be affected. Though no cases of maple syrup urine disease were found, the authors concluded that the initiative successfully established proof of concept for maple syrup urine disease and propionic acidemia screening of a high-risk population. Screening of newborns for maple syrup urine disease in the United Kingdom is a relatively recent practice. It was instituted following a 12-month pilot study at six centers in England, which found 12 confirmed cases of four rare conditions including maple syrup urine disease in just under 440,000 births, using blood samples taken from the heel prick blood test given to all newborns at 5 to 8 days of age (Hawkes, 2014). A systematic review and meta-analysis sought to estimate the birth prevalence in England for a variety of inherited metabolic disorders including maple syrup urine disease, homocystinuria (pyridoxine unresponsive), glutaric aciduria type I, isovaleric acidemia, and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency including trifunctional protein deficiency (Moorthie, 2014). Prevalence was based on targeted screening with tandem mass spectrometry introduced in 2009 to implement newborn bloodspot screening for medium-chain acyl-coa dehydrogenase deficiency. A study of maple syrup urine disease in Spain assessed the clinical features and neurological outcome of 14 patients diagnosed either by screening or by clinical symptoms (Couce, 2015). Eight patients were detected by screening, with average age at detection 4.6 days. The mean plasma concentration of leucine at diagnosis was 1,807 μm; the average number of days with leucine >1,000 μm was 0.7 (0 4), and the mean number of total hospitalizations was 1.6 (0 5). Mean follow-up time of 70 months found all remained asymptomatic, but two patients had attention-deficit/hyperactivity disorder. Six patients with late diagnosis presented with acute encephalopathy during the first month of life, mean leucine levels of 2,355 μm, mean number of days with leucine >1,000 μm of 6.6 (1 13), and mean number of total hospitalizations of 5.3 (4 7). Of this cohort, two patients had a psychomotor development index in the lower limit (80 and 83). For all patients, a good genotype-phenotype correlation was found and four novel mutations were identified: p.a311h, p.t84s, p.t397l, and p.l398p. A case report (Miryounesi, 2015) analyzed the nucleic acid sequences of BCKDHA and BCKDHB genes in an infant who suffered from maple syrup urine disease and found a new missense mutation in exon 5 of BCKDHB gene (c.508c>t). The heterozygosity of the parents for the nucleotide change was confirmed by direct sequence analysis of the corresponding segment. A retrospective study of Brazilian patients (n=83) with maple syrup urine disease diagnosed between 1992 and 2011 (Herber, 2015) found diagnosis occurred relatively late: Median age at onset of symptoms was 10 days (IQR 5-30), whereas median age at diagnosis was 60 days (IQR , p=0.001). Only three (3.6 percent) of the patients were diagnosed before the onset of clinical manifestations. A comparison between patients with (n=12) and without (n=71) an early diagnosis shows that early diagnosis is associated with the presence of positive family history and decreased prevalence of clinical manifestations at the time of diagnosis, but not with a better outcome. Overall, 98.8 percent of patients exhibited some psychomotor or neurodevelopmental delay. The authors attributed the neurological 5

6 involvement and comparatively poor outcomes to a paucity of specific public policies for diagnosis and treatment of maple syrup urine disease. Maple syrup urine disease newborn screening has proven efficacy in developing countries. A screening program in the Philippines identified 24 patients with maple syrup urine disease over its initial two-year period of study (De Castro-Hamoy, 2017). Out of the 24 individuals diagnosed, 16 are still alive, several with neurologic and non-neurologic complications observed during follow-up. The obstacles encountered in this study were late diagnosis, lack of access to metabolic specialists and medical supplies, nosocomial septicemia, and protein deficiency. The authors concluded that newborn screening improves outcomes in patients with maple syrup urine disease, but the success of the program in preventing disability is dependent on improvements in other aspects of third-world health care. Summary of clinical evidence: Citation ACOG (2017) Carrier screening for genetic conditions Wilson (2016) Joint opinion for reproductive genetic carrier screening Hawkes (2014) Newborn babies will be tested for four more disorders, committee decides De Castro-Hamoy (2017) Content, Methods, Recommendations ACOG offers direction in its Committee Opinion concerning carrier screening for genetic conditions, including uncommon conditions, in the Ashkenazi Jewish population. Among the disease entities identified by ACOG that should be considered in this cohort for individual testing is maple syrup urine disease. An SOGC-CCMG joint committee recommends that Ashkenazi Jewish carrier screening be offered when a positive family pedigree is elicited for one of the conditions known to be present at an increased frequency in this population (associated carrier frequencies are listed): Bloom syndrome 1/104; Fanconi anemia group C 1/89; Niemann-Pick type A 1/90; mucolipidosis type IV 1/ ; Gaucher disease 1/18; glycogen storage disease type 1a 1/64; familial hyperinsulinism 1/68; maple syrup urine disease 1/97; dihydrolipoamide hydrogenase deficiency 1/107; CF 1/28; Usher syndrome 1/120; nemaline myopathy 1/168; Joubert syndrome 1/92; and Walker-Warburg syndrome 1/150. Screening of newborns for maple syrup urine disease in the United Kingdom is a relatively recent practice. It was instituted following a 12-month pilot study at six centers in England, which found 12 confirmed cases of four rare conditions including maple syrup urine disease in just under 440,000 births, using blood samples taken from the heel prick blood test given to all newborns at 5 to 8 days of age. Challenges in the management of patients with maple syrup urine disease diagnosed by Maple syrup urine disease newborn screening has proven efficacy in developing countries. A screening program in the Philippines identified 24 patients with maple syrup urine disease over its initial two-year period of study. 6

7 Citation newborn screening in a developing country Kuhl (2017) Development of carrier testing for common inborn errors of metabolism in the Wisconsin Plain population Couce (2015) Evolution of maple syrup urine disease in patients diagnosed by newborn screening versus late diagnosis Miryounesi (2015) Content, Methods, Recommendations Out of the 24 individuals diagnosed, 16 are still alive, several with neurologic and nonneurologic complications observed during follow-up. The obstacles encountered in this study were late diagnosis, lack of access to metabolic specialists and medical supplies, nosocomial septicemia, and protein deficiency. The authors concluded that newborn screening improves outcomes in patients with maple syrup urine disease, but the success of the program in preventing disability is dependent on improvements in other aspects of third-world health care. A community project through the University of Wisconsin Biochemical Genetics Clinic and the Wisconsin Newborn Screening Program successfully provided testing of a highrisk population (n=80) for maple syrup urine disease and propionic acidemia to identify members of the population at risk for having children with these conditions. The intervention conducted targeted variant analysis of the common pathogenic variants in this population using blood spot testing kits offered to health care providers. Diagnosis was confirmed for three adults with propionic acidemia and one couple was identified as being at risk for having a child with propionic acidemia. Genetic counseling was provided to those identified and follow-up diagnostic testing was completed for the at-risk couple's children; none were found to be affected. Though no cases of maple syrup urine disease were found, the authors concluded that the initiative successfully establishes proof of concept for maple syrup urine disease and propionic acidemia screening of a high-risk population. A study of maple syrup urine disease in Spain assessed the clinical features and neurological outcome of 14 patients diagnosed either by screening or by clinical symptoms. Eight patients were detected by screening, with average age at detection 4.6 days. The mean plasma concentration of leucine at diagnosis was 1,807 μm, the average number of days with leucine >1,000 μm was 0.7 (0 4), and the mean number of total hospitalizations was 1.6 (0 5). Mean follow-up time of 70 months found all remained asymptomatic, but two patients have attention-deficit/hyperactivity disorder. Six patients with late diagnosis presented with acute encephalopathy during the first month of life, mean leucine levels of 2,355 μm, mean number of days with leucine >1,000 μm of 6.6 (1 13), and mean number of total hospitalizations of 5.3 (4 7). Of this cohort, two patients have a psychomotor development index in the lower limit (80 and 83). For all patients, a good genotype-phenotype correlation was found and four novel mutations were identified: p.a311h, p.t84s, p.t397l, and p.l398p. A new missense mutation in the BCKDHB gene causes the classic form of maple syrup urine disease A case report analyzed the nucleic acid sequences of BCKDHA and BCKDHB genes in an infant who suffered from maple syrup urine disease and found a new missense mutation in exon 5 of BCKDHB gene (c.508c>t). The heterozygosity of the parents for the nucleotide change was confirmed by direct 7

8 Citation Herber (2015) Maple syrup urine disease in Brazil: a panorama of the last two decades Moorthie (2014) Content, Methods, Recommendations sequence analysis of the corresponding segment. A retrospective study of Brazilian patients (n=83) with maple syrup urine disease diagnosed between 1992 and 2011 found diagnosis occurred relatively late: Median age at onset of symptoms was 10 days (IQR 5 30), whereas median age at diagnosis was 60 days (IQR , p=0.001). Only three (3.6%) of the patients were diagnosed before the onset of clinical manifestations. A comparison between patients with (n=12) and without (n=71) an early diagnosis shows that early diagnosis is associated with the presence of positive family history and decreased prevalence of clinical manifestations at the time of diagnosis, but not with a better outcome. Overall, 98.8% of patients exhibited some psychomotor or neurodevelopmental delay. The authors attributed the neurological involvement and comparatively poor outcomes to a paucity of specific public policies for diagnosis and treatment of maple syrup urine disease. Systematic review and meta-analysis to estimate the birth prevalence of five inherited metabolic diseases A systematic review and meta-analysis sought to estimate the birth prevalence in England for a variety of inherited metabolic disorders including maple syrup urine disease, homocystinuria (pyridoxine unresponsive), glutaric aciduria type I, isovaleric acidemia, and long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency including trifunctional protein deficiency. Prevalence was based on targeted screening with tandem mass spectrometry introduced in 2009 to implement newborn bloodspot screening for medium-chain acyl- CoA dehydrogenase deficiency. References Professional society guidelines/other: American College of Obstetricians and Gynecologists Committee Opinion (March 2017). Carrier screening for genetic conditions. ACOG website: Opinions/Committee-on-Genetics/co691.pdf?dmc=1&ts= T Accessed February 9, Save Babies Through Screening Foundation: Find out your state s screening. Website: Accessed March 27, Wilson RD, De Bie I, Armour CM, et al. Society of Obstetricians and Gynaecologists of Canada and Canadian College of Medical Geneticists. Joint Opinion for Reproductive Genetic Carrier Screening: An Update for All Canadian Providers of Maternity and Reproductive Healthcare in the Era of Direct-to- Consumer Testing. J Obstet Gynaecol Can Aug;38(8): e3. doi: /j.jogc

9 PubMed PMID: Peer-reviewed references: Adam MP, Ardinger HH, Pagon RA, et al., editors. Gene Reviews [internet]. Maple Syrup Urine Disease. Seattle (WA): University of Washington, Seattle; Couce ML, Ramos F, Bueno MA, et al. Evolution of maple syrup urine disease in patients diagnosed by newborn screening versus late diagnosis. Eur J Paediatr Neurol Nov;19(6): doi: /j.ejpn Epub 2015 Jul 20. PubMed PMID: De Castro-Hamoy LG, Chiong MA, Estrada SC, Cordero CP. Challenges in the management of patients with maple syrup urine disease diagnosed by newborn screening in a developing country. J Community Genet Jan;8(1):9-15. doi: /s Epub 2016 Oct 6. PubMed PMID: ; PubMed Central PMCID: PMC Hawkes N. Newborn babies will be tested for four more disorders, committee decides. BMJ May 12;348:g3267. doi: /bmj.g3267. PubMed PMID: Herber S, Schwartz IV, Nalin T, et al. Maple syrup urine disease in Brazil: a panorama of the last two decades. J Pediatr (Rio J) May-Jun;91(3): doi: /j.jped Epub 2014 Dec 12. PubMed PMID: Kuhl A, van Calcar S, Baker M, Seroogy CM, Rice G, Schwoerer J. Development of carrier testing for common inborn errors of metabolism in the Wisconsin Plain population. Genet Med Mar;19(3): doi: /gim Epub 2016 Aug 11. PubMed PMID: Miryounesi M, Ghafouri-Fard S, Goodarzi H, Fardaei M. A new missense mutation in the BCKDHB gene causes the classic form of maple syrup urine disease (MSUD). J Pediatr Endocrinol Metab May;28(5-6): doi: /jpem PubMed PMID: Moorthie S, Cameron L, Sagoo GS, Bonham JR, Burton H. Systematic review and meta-analysis to estimate the birth prevalence of five inherited metabolic diseases. J Inherit Metab Dis Nov;37(6): doi: /s Epub 2014 Jul 15. Review. PubMed PMID: Strauss KA, Puffenberger EG, Morton DH. One community's effort to control genetic disease. Am J Public Health. 2012;102(7): doi: /AJPH Epub 2012 May 17. PubMed PMID: ; PubMed Central PMCID: PMC

10 Su L, Lu Z, Li F, Shao Y, Sheng H, Cai Y, Liu L. Two homozygous mutations in the exon 5 of BCKDHB gene that may cause the classic form of maple syrup urine disease. Metab Brain Dis Jun;32(3): doi: /s Epub 2017 Feb 15. PubMed PMID: CMS National Coverage Determinations (NCDs): No NCDs identified as of the writing of this policy. Local Coverage Determinations (LCDs): No LCDs identified as of the writing of this policy. Commonly submitted codes Below are the most commonly submitted codes for the service(s)/item(s) subject to this policy. This is not an exhaustive list of codes. Providers are expected to consult the appropriate coding manuals and bill accordingly. CPT Code Description Comments Gene Analysis: Tier 1 Procedures Molecular Pathology Tier 2 Procedures ICD-10 Code Description Comments E71-E71.2 Disorders of branched-chain amino-acid metabolism and fatty-acid metabolism Z13.-Z13.79 Encounter for screening for other diseases and disorders HCPCS Level II Code N/A Description No applicable codes Comments 10