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180 Form

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180

Indications

(1) Meets any ONE 1 of the 3 diagnostic criteria for aromatic L-amino acid decarboxylase deficiency: i. Biallelic pathogenic/likely pathogenic variants in dopa decarboxylase (DDC) gene OR ii. One pathogenic/likely pathogenic variant plus a variant of uncertain significance AND aromatic L-amino acid decarboxylase enzyme activity in plasma < 5% OR cerebrospinal fluid or plasma neurotransmitter profile consistent with aromatic L-amino acid decarboxylase deficiency (see Policy Guidelines) OR iii. Two variants of uncertain significance AND aromatic L-amino acid decarboxylase enzyme activity in plasma < 5% OR cerebrospinal fluid or plasma neurotransmitter profile consistent with aromatic L-amino acid decarboxylase deficiency (see Policy Guidelines) AND 2. Has persistent neurological symptoms (e.g., autonomic dysfunction, hypotonia, dystonia and other movement disorders, etc.) AND 3. Has anti-AAV2 antibody titer <1:1,200 AND 4. Achieved skull maturity assessed by neuroimaging to allow placement of the stereotactic head frame for surgery AND 5. Does not have any contraindications that would preclude the surgical intraputaminal administration AND 6. Medication is being administered at United States Food and Drug Administration approved dosing by a healthcare professional of the appropriate specialty (e.g. neurosurgeon) (see Policy Guidelines) AND 7. Medication is planned to be administered in a medical center which specializes in stereotactic neurosurgery. Kebilidi (eladocagene exuparvovec) is considered INVESTIGATIONAL when the above criteria are not met. Kebilidi (eladocagene exuparvovec-tneq) is considered INVESTIGATIONAL for all other indications. Repeat treatment with Kebilidi (eladocagene exuparvovec-tneq) is considered INVESTIGATIONAL. Prior Authorization Information Inpatient • For services described in this policy, precertification/preauthorization IS REQUIRED for all products if the procedure is performed inpatient. Outpatient • For services described in this policy, see below for products where prior authorization might be required if the procedure is performed outpatient. Outpatient Commercial Managed Care (HMO and POS) Prior authorization is required. Commercial PPO and Indemnity Prior authorization is required. Medicare HMO BlueSM Prior authorization is required. Medicare PPO BlueSM Prior authorization is required. Requesting Prior Authorization Using Authorization Manager Providers will need to use Authorization Manager to submit initial authorization requests for services. Authorization Manager, available 24/7, is the quickest way to review authorization requirements, request authorizations, submit clinical documentation, check existing case status, and view/print the decision letter. For commercial members, the requests must meet medical policy guidelines. To ensure the service request is processed accurately and quickly: • Enter the facility’s NPI or provider ID for where services are being performed. • Enter the appropriate surgeon’s NPI or provider ID as the servicing provider, not the billing group. Authorization Manager Resources • Refer to our Authorization Manager page for tips, guides, and video demonstrations. Complete Prior Authorization Request Form for Kebilidi (180) using Authorization Manager. For out of network providers: Requests should still be faxed to 888-973-0726. Policy Guidelines Recommended Dose Per the FDA label, the recommended dose is 1.8×1011 vector genomes delivered as four 0.08 mL (0.45×1011 vg) infusions (two sites per putamen-anterior and posterior) at a rate of 0.003 mL/minute (0.18 mL/hour) for a total of 27 minutes per site, administered in a single stereotactic surgery using a cannula that is FDA-authorized for intraparenchymal infusion. Dosing Limits 1 injection per lifetime Supportive laboratory findings on neurometabolites panel Cerebrospinal fluid neurotransmitter profile typically demonstrates: • Low levels of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4- hydroxyphenylglycol (MHPG); • Normal concentrations of pterins (neopterin and biopterin); • High concentrations of levodopa, 3-O-methyldopa (3-methoxytyrosine; 3-OMD), and 5- hydroxytryptophan (5-HT). Plasma neurotransmitter (untargeted metabolomics) profile typically demonstrates: • High level of 3-OMD; • Low levels of 5-HIAA, vanillylmandelate (VMA), HVA, and dopamine-3-O-sulfate (D3OS); • Low to normal level of 3-methoxytyramine sulfate (3-MTS). Increased urinary concentration of vanillactic acid (VLA) Description Kebilidi (eladocagene exuparvovec) was evaluated in pivotal trial, NCT04903288. Aromatic L-amino Acid Decarboxylase Deficiency Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disorder caused by pathogenic variants in the DDC gene, which encodes the AADC enzyme).1, This enzyme is essential for synthesizing key neurotransmitters dopamine and serotonin by converting their precursors, L-DOPA and 5-hydroxytryptophan, respectively. AADC is expressed in both central and peripheral tissues. Loss or reduction of AADC activity leads to impaired production of dopamine, serotonin, norepinephrine, and epinephrine, resulting in accumulation of precursors and reduced levels of neurotransmitter metabolites.2, Clinical symptoms typically emerge in infancy and vary widely.3,2, This variability in clinical presentation is related to deficiencies in dopamine, epinephrine, norepinephrine, and serotonin. Generally, decreased dopamine levels are responsible for movement-related symptoms such as hypotonia, dystonia, delayed motor development, and oculogyric crisis. Epinephrine and norepinephrine deficiencies affect autonomic functions such as ptosis, hypoglycemia, or hypotension. Serotonin deficiency can affect cognitive function, voluntary movement, and emotional state. AADC deficiency is broadly categorized into mild, moderate, and severe phenotypes. • The severe phenotype is characterized by profound motor impairment, including the absence of head control and failure to achieve motor milestones. Affected individuals often experience severe hypotonia, feeding difficulties, oculogyric crises (prolonged dystonic eye and facial movements), and autonomic dysfunction. These patients are fully dependent on caregivers and may face early mortality due to complications from hypotonia and autonomic instability. • The moderate phenotype includes patients who attain some motor milestones, such as head control, sitting, or standing, but are unable to walk independently. Symptoms are less severe than in the severe form but still significantly impact daily function. • The mild phenotype involves less pronounced motor impairment, with individuals often achieving independent ambulation. These patients may live into adulthood and primarily exhibit autonomic symptoms, sleep disturbances, and behavioral issues, with minimal or no motor dysfunction Approximately 80% of patients exhibit a severe phenotype3, and require lifelong care. Disease symptoms do not spontaneously improve, and death often occurs in the first decade of life. The disease significantly impacts the quality of life of patients and their caregivers. Epidemiology Prevalence of AADC deficiency globally and within the United States is unknown, with fewer than 400 confirmed cases reported worldwide to date.4, Wassenberg et al (2017) has identified 117 case reports in the literature, and estimated prevalence is roughly 1-2 in 1,000,000 newborns per the National Organization for Rare Disorders.2, The condition appears to be more common in certain Asian populations, particularly in Taiwan, China, and Japan, likely due to a founder mutation.5,1, Diagnosis AADC deficiency is frequently underdiagnosed or misdiagnosed due to its rarity and overlapping symptoms with more common neurological disorders such as cerebral palsy or epilepsy.6,7, Although clinical signs typically emerge within the first few months of life, diagnosis is often delayed until childhood or even adulthood. Data from international patient registries show that while the average age of symptom onset is around 2.5 to 2.7 months, the average age at diagnosis can range from 9 months to over 3 years, with some cases diagnosed as late as the third decade of life.8,2, This delay can lead to inappropriate management, missed opportunities for early intervention, and worsening of disease-related complications. Timely and accurate diagnosis is essential to initiate appropriate therapies, support developmental outcomes, and reduce the burden on patients and caregivers.9,3, Core diagnostic tests for AADC deficiency include single gene or genetic panel testing, CSF neurotransmitter metabolites panel, and a plasma AADC enzyme assay.2, To confirm a diagnosis of AADC deficiency, at least 2 of the 3 core diagnostic tests should be positive. See Table 1. Table 1. Diagnostic Tests to Confirm AADC deficiency1,2, Test Description CSF neurotransmitter metabolites panel • Decreased 5-HIAA, HVA, and MHPG, plus • Increased 3-OMD, L-dopa, and 5-HTP, plus • Normal pterins Single gene or genetic panel testing Pathogenic variants in the DDC gene Plasma enzyme assay Low levels of AADC enzyme activity in plasma 3-OMD: 3-O-methyldopa; 5-HIAA: 5-hydroxyindoleacetic acid; 5-HTP: 5-hydroxytryptophan; AADC: aromatic L-amino acid decarboxylase; CSF: cerebrospinal fluid; DDC: dopa decarboxylase; HVA: homovanillic acid; L-dopa: levodopa; MHPG: 3-methoxy-4 hydroxyphenylglycol. 3-OMD: 3-O-methyldopa; 5-HIAA: 5-hydroxyindoleacetic acid; 5-HTP: 5-hydroxytryptophan; AADC: aromatic L-amino acid decarboxylase; CSF: cerebrospinal fluid; DDC: dopa decarboxylase; HVA: homovanillic acid; L-dopa: levodopa; MHPG: 3-methoxy-4 hydroxyphenylglycol. AADC deficiency is currently not on the Recommended Uniform Screening Panel (RUSP) list of health conditions that experts recommend newborn screening in the US. There is growing interest and research around the potential for newborn screening for AADC deficiency. A specific test that measures 3-O- methyldopa in dried blood spots has been evaluated in a clinical trial trial in Taiwan as a candidate screening test.10, Treatment Until recently, there were no FDA-approved therapies for AADC deficiency. Current approach has relied on off-label use of oral medications such as dopamine agonists, monoamine oxidase inhibitors, and pyridoxine (vitamin B6). These treatments have shown limited and variable effectiveness.11,. Patients with the severe phenotype typically show no improvement in motor function. In contrast, individuals with mild or moderate phenotypes may experience notable gains in motor milestones such as improved head control, sitting, standing, or walking following dopamine agonist therapy. Additional benefits may include reductions in hypotonia, oculogyric crises, and autonomic symptoms7,.However, due to the rarity of the disease and the limited number of published case reports, the response rate and long-term effectiveness of these therapies remain poorly characterized. Current management strategies may also be limited by undesirable side effects, which may lead to discontinuation of therapy. Consequently, there remains a significant unmet medical need for an FDA-approved therapy that can address the underlying cause of AADC deficiency across all phenotypes. Appendix Information Pertaining to All Blue Cross Blue Shield Medical Policies Click on any of the following terms to access the relevant information: Medical Policy Terms of Use Managed Care Guidelines Indemnity/PPO Guidelines Clinical Exception Process Medical Technology Assessment Guidelines Criteria Documentation Provider must submit supporting documentation (e.g., chart notes, lab results or other clinical information) to show that the member has met all approval criteria. Individual Consideration (for Atypical Patients) Our medical policies are written for most people with a given condition. Each policy is based on peer reviewed clinical evidence. We also take into consideration the needs of atypical patient populations and diagnoses. If the coverage criteria outlined is unlikely to be clinically effective for the prescribed purpose, the health care provider may request an exception to cover the requested medication based on an individual’s unique clinical circumstances. This is also referred to as “individual consideration” or an “exception request.” Some reasons why you may need us to make an exception include: therapeutic contraindications; history of adverse effects; expected to be ineffective or likely to cause harm (physical, mental, or adverse reaction). To facilitate a thorough and prompt review of an exception request, we encourage the provider to include additional supporting clinical documentation with their request. This may include: • Clinical notes or supporting clinical statements; • The name and strength of formulary alternatives tried and failed (if alternatives were tried) and specifics regarding the treatment failure, if applicable; • Clinical literature from reputable peer reviewed journals; • References from nationally recognized and approved drug compendia such as American Hospital Formulary Service® Drug Information (AHFS-DI), Lexi-Drug, Clinical Pharmacology, Micromedex or Drugdex®; and • References from consensus documents and/or nationally sanctioned guidelines Providers may call, fax or mail relevant clinical information, including clinical references for individual patient consideration, to: Blue Cross Blue Shield of Massachusetts Pharmacy Operations Department 25 Technology Place Hingham, MA 02043 Phone: 1-800-366-7778 Fax: 1-800-583-6289 CPT Codes / HCPCs Codes / ICD Codes Inclusion or exclusion of a code does not constitute or imply member coverage or provider reimbursement. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage as it applies to an individual member. Providers should report all services using the most up-to-date industry-standard procedure, revenue, and diagnosis codes, including modifiers where applicable. The following codes are included below for informational purposes only; this is not an all-inclusive list. The above medical necessity criteria MUST be met for the following codes to be covered for Commercial Members: Managed Care (HMO and POS), PPO, Indemnity, Medicare HMO Blue and Medicare PPO Blue: HCPCS Codes HCPCS codes: Code Description C9399 Unclassified drugs or biologicals J3490 Unclassified drugs J3590 Unclassified biologics The following ICD Diagnosis Codes are considered medically necessary when submitted with the HCPCS codes above if medical necessity criteria are met: ICD-10 Diagnosis Codes ICD-10-CM Diagnosis codes: Code Description E70.81 Aromatic L-amino acid decarboxylase deficiency Policy History Date Action 10/15/2025 Creation of new policy. References 1. Himmelreich N, Montioli R, Bertoldi M, et al. Aromatic amino acid decarboxylase deficiency: Molecular and metabolic basis and therapeutic outlook. Mol Genet Metab. May 2019; 127(1): 12-22. PMID 30952622 2. Wassenberg T, Molero-Luis M, Jeltsch K, et al. Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency. Orphanet J Rare Dis. Jan 18 2017; 12(1): 12. PMID 28100251 3. Rizzi S, Spagnoli C, Frattini D, et al. Clinical Features in Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency: A Systematic Review. Behav Neurol. 2022; 2022: 2210555. PMID 36268467 4. Himmelreich N, Bertoldi M, Alfadhel M, et al. Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes. Mol Genet Metab. Jul 2023; 139(3): 107624. PMID 37348148 5. Blau N, Pearson TS, Kurian MA, Elsea SH. Aromatic L-Amino Acid Decarboxylase Deficiency. 2023 Oct 12 [updated 2025 Jan 23]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 19932025. PMID: 37824694. 6. Pearson TS, Gupta N, San Sebastian W, et al. Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons. Nat Commun. Jul 12 2021; 12(1): 4251. PMID 34253733 7. Wen Y, Wang J, Zhang Q, et al. The genetic and clinical characteristics of aromatic L-amino acid decarboxylase deficiency in mainland China. J Hum Genet. Sep 2020; 65(9): 759-769. PMID 32409695 8. Opladen T, Cortès-Saladelafont E, Mastrangelo M, et al. The International Working Group on Neurotransmitter related Disorders (iNTD): A worldwide research project focused on primary and secondary neurotransmitter disorders. Mol Genet Metab Rep. Dec 2016; 9: 61-66. PMID 27830117 9. Abukhaled M, Alrakaf L, Aldhalaan H, et al. Case report: Aromatic L-amino acid decarboxylase deficiency in three patient cases from the Kingdom of Saudi Arabia. Front Pediatr. 2022; 10: 1016239. PMID 36727005 10. Newborn Screening for Aromatic L-amino Acid Decarboxylase Deficiency (NCT02399761). Available at https://clinicaltrials.gov/search?term=NCT02399761. Accessed July 31, 2027.? 
(2) Roubertie A, Opladen T, Brennenstuhl H, et al. Gene therapy for aromatic L-amino acid decarboxylase deficiency: Requirements for safe application and knowledge-generating follow-up. J Inherit Metab Dis. May 2024; 47(3): 463-475. PMID 37402126 12. Food and Drug Administration: Statistical Review for Eladocagene Exuparvovec (Approval History, Letters, Reviews, and Related Documents - Kebilidi). Available at https://www.fda.gov/vaccines- blood-biologics/kebilidi. Accessed on July 29, 2025. 13. Food and Drug Administration: Summary Basis for Regulatory Action for Eladocagene Exuparvovec. Available at https://www.fda.gov/media/184353/download?attachment. Accessed on July 29, 2025.? 

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Medical Policy Gene Therapies for Aromatic L-amino Acid Decarboxylase Deficiency

Table of Contents: Policy Commercial Authorization Information Policy Guidelines Description Appendix
Coding Information Policy History References

Policy Number: 180

Related Policies • Prior Authorization Request Form for Gene Therapies for Aromatic L-amino Acid Decarboxylase Deficiency #209

Policy: Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity
Medicare HMO BlueSM and Medicare PPO BlueSM Members

Kebilidi (eladocagene exuparvovec-tneq)

Kebilidi may be may be considered MEDICALLY NECESSARY for the treatment of aromatic L amino acid decarboxylase (AADC) deficiency when ALL of the following criteria are met:

  1. Meets any ONE 1 of the 3 diagnostic criteria for aromatic L-amino acid decarboxylase deficiency: i. Biallelic pathogenic/likely pathogenic variants in dopa decarboxylase (DDC) gene OR ii. One pathogenic/likely pathogenic variant plus a variant of uncertain significance AND aromatic L-amino acid decarboxylase enzyme activity in plasma < 5% OR cerebrospinal fluid or plasma neurotransmitter profile consistent with aromatic L-amino acid decarboxylase deficiency (see Policy Guidelines) OR iii. Two variants of uncertain significance AND aromatic L-amino acid decarboxylase enzyme activity in plasma < 5% OR cerebrospinal fluid or plasma neurotransmitter profile consistent with aromatic L-amino acid decarboxylase deficiency (see Policy Guidelines) AND
  2. Has persistent neurological symptoms (e.g., autonomic dysfunction, hypotonia, dystonia and other movement disorders, etc.) AND
  3. Has anti-AAV2 antibody titer <1:1,200 AND
  1. Achieved skull maturity assessed by neuroimaging to allow placement of the stereotactic head frame for surgery AND
  2. Does not have any contraindications that would preclude the surgical intraputaminal administration AND
  3. Medication is being administered at United States Food and Drug Administration approved dosing by a healthcare professional of the appropriate specialty (e.g. neurosurgeon) (see Policy Guidelines) AND

  4. Medication is planned to be administered in a medical center which specializes in stereotactic neurosurgery. Kebilidi (eladocagene exuparvovec) is considered INVESTIGATIONAL when the above criteria are not met. Kebilidi (eladocagene exuparvovec-tneq) is considered INVESTIGATIONAL for all other indications. Repeat treatment with Kebilidi (eladocagene exuparvovec-tneq) is considered INVESTIGATIONAL.

    Prior Authorization Information Inpatient • For services described in this policy, precertification/preauthorization IS REQUIRED for all products if the procedure is performed inpatient.
    Outpatient • For services described in this policy, see below for products where prior authorization might be required if the procedure is performed outpatient.
    Outpatient Commercial Managed Care (HMO and POS) Prior authorization is required. Commercial PPO and Indemnity Prior authorization is required. Medicare HMO BlueSM Prior authorization is required. Medicare PPO BlueSM Prior authorization is required.

    Requesting Prior Authorization Using Authorization Manager Providers will need to use Authorization Manager to submit initial authorization requests for services. Authorization Manager, available 24/7, is the quickest way to review authorization requirements, request authorizations, submit clinical documentation, check existing case status, and view/print the decision letter. For commercial members, the requests must meet medical policy guidelines.

    To ensure the service request is processed accurately and quickly: • Enter the facility’s NPI or provider ID for where services are being performed. • Enter the appropriate surgeon’s NPI or provider ID as the servicing provider, not the billing group.

    Authorization Manager Resources • Refer to our Authorization Manager page for tips, guides, and video demonstrations.

    Complete Prior Authorization Request Form for Kebilidi (180) using Authorization Manager. For out of network providers: Requests should still be faxed to 888-973-0726.

Policy Guidelines Recommended Dose Per the FDA label, the recommended dose is 1.8×1011 vector genomes delivered as four 0.08 mL (0.45×1011 vg) infusions (two sites per putamen-anterior and posterior) at a rate of 0.003 mL/minute (0.18 mL/hour) for a total of 27 minutes per site, administered in a single stereotactic surgery using a cannula that is FDA-authorized for intraparenchymal infusion.

Dosing Limits 1 injection per lifetime

Supportive laboratory findings on neurometabolites panel

Cerebrospinal fluid neurotransmitter profile typically demonstrates: • Low levels of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4- hydroxyphenylglycol (MHPG); • Normal concentrations of pterins (neopterin and biopterin); • High concentrations of levodopa, 3-O-methyldopa (3-methoxytyrosine; 3-OMD), and 5- hydroxytryptophan (5-HT).

Plasma neurotransmitter (untargeted metabolomics) profile typically demonstrates: • High level of 3-OMD; • Low levels of 5-HIAA, vanillylmandelate (VMA), HVA, and dopamine-3-O-sulfate (D3OS); • Low to normal level of 3-methoxytyramine sulfate (3-MTS).

Increased urinary concentration of vanillactic acid (VLA)

Description

Kebilidi (eladocagene exuparvovec) was evaluated in pivotal trial, NCT04903288.

Aromatic L-amino Acid Decarboxylase Deficiency Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disorder caused by pathogenic variants in the DDC gene, which encodes the AADC enzyme).1, This enzyme is essential for synthesizing key neurotransmitters dopamine and serotonin by converting their precursors, L-DOPA and 5-hydroxytryptophan, respectively. AADC is expressed in both central and peripheral tissues. Loss or reduction of AADC activity leads to impaired production of dopamine, serotonin, norepinephrine, and epinephrine, resulting in accumulation of precursors and reduced levels of neurotransmitter metabolites.2, Clinical symptoms typically emerge in infancy and vary widely.3,2, This variability in clinical presentation is related to deficiencies in dopamine, epinephrine, norepinephrine, and serotonin. Generally, decreased dopamine levels are responsible for movement-related symptoms such as hypotonia, dystonia, delayed motor development, and oculogyric crisis. Epinephrine and norepinephrine deficiencies affect autonomic functions such as ptosis, hypoglycemia, or hypotension. Serotonin deficiency can affect cognitive function, voluntary movement, and emotional state. AADC deficiency is broadly categorized into mild, moderate, and severe phenotypes. • The severe phenotype is characterized by profound motor impairment, including the absence of head control and failure to achieve motor milestones. Affected individuals often experience severe hypotonia, feeding difficulties, oculogyric crises (prolonged dystonic eye and facial movements), and autonomic dysfunction. These patients are fully dependent on caregivers and may face early mortality due to complications from hypotonia and autonomic instability.

• The moderate phenotype includes patients who attain some motor milestones, such as head control, sitting, or standing, but are unable to walk independently. Symptoms are less severe than in the severe form but still significantly impact daily function. • The mild phenotype involves less pronounced motor impairment, with individuals often achieving independent ambulation. These patients may live into adulthood and primarily exhibit autonomic symptoms, sleep disturbances, and behavioral issues, with minimal or no motor dysfunction Approximately 80% of patients exhibit a severe phenotype3, and require lifelong care. Disease symptoms do not spontaneously improve, and death often occurs in the first decade of life. The disease significantly impacts the quality of life of patients and their caregivers.

Epidemiology Prevalence of AADC deficiency globally and within the United States is unknown, with fewer than 400 confirmed cases reported worldwide to date.4, Wassenberg et al (2017) has identified 117 case reports in the literature, and estimated prevalence is roughly 1-2 in 1,000,000 newborns per the National Organization for Rare Disorders.2, The condition appears to be more common in certain Asian populations, particularly in Taiwan, China, and Japan, likely due to a founder mutation.5,1,

Diagnosis AADC deficiency is frequently underdiagnosed or misdiagnosed due to its rarity and overlapping symptoms with more common neurological disorders such as cerebral palsy or epilepsy.6,7, Although clinical signs typically emerge within the first few months of life, diagnosis is often delayed until childhood or even adulthood. Data from international patient registries show that while the average age of symptom onset is around 2.5 to 2.7 months, the average age at diagnosis can range from 9 months to over 3 years, with some cases diagnosed as late as the third decade of life.8,2, This delay can lead to inappropriate management, missed opportunities for early intervention, and worsening of disease-related complications. Timely and accurate diagnosis is essential to initiate appropriate therapies, support developmental outcomes, and reduce the burden on patients and caregivers.9,3, Core diagnostic tests for AADC deficiency include single gene or genetic panel testing, CSF neurotransmitter metabolites panel, and a plasma AADC enzyme assay.2, To confirm a diagnosis of AADC deficiency, at least 2 of the 3 core diagnostic tests should be positive. See Table 1.

Table 1. Diagnostic Tests to Confirm AADC deficiency1,2, Test Description CSF neurotransmitter metabolites panel • Decreased 5-HIAA, HVA, and MHPG, plus • Increased 3-OMD, L-dopa, and 5-HTP, plus • Normal pterins Single gene or genetic panel testing Pathogenic variants in the DDC gene Plasma enzyme assay Low levels of AADC enzyme activity in plasma 3-OMD: 3-O-methyldopa; 5-HIAA: 5-hydroxyindoleacetic acid; 5-HTP: 5-hydroxytryptophan; AADC: aromatic L-amino acid decarboxylase; CSF: cerebrospinal fluid; DDC: dopa decarboxylase; HVA: homovanillic acid; L-dopa: levodopa; MHPG: 3-methoxy-4 hydroxyphenylglycol.

3-OMD: 3-O-methyldopa; 5-HIAA: 5-hydroxyindoleacetic acid; 5-HTP: 5-hydroxytryptophan; AADC: aromatic L-amino acid decarboxylase; CSF: cerebrospinal fluid; DDC: dopa decarboxylase; HVA: homovanillic acid; L-dopa: levodopa; MHPG: 3-methoxy-4 hydroxyphenylglycol. AADC deficiency is currently not on the Recommended Uniform Screening Panel (RUSP) list of health conditions that experts recommend newborn screening in the US. There is growing interest and research around the potential for newborn screening for AADC deficiency. A specific test that measures 3-O-

methyldopa in dried blood spots has been evaluated in a clinical trial trial in Taiwan as a candidate screening test.10,

Treatment Until recently, there were no FDA-approved therapies for AADC deficiency. Current approach has relied on off-label use of oral medications such as dopamine agonists, monoamine oxidase inhibitors, and pyridoxine (vitamin B6). These treatments have shown limited and variable effectiveness.11,. Patients with the severe phenotype typically show no improvement in motor function. In contrast, individuals with mild or moderate phenotypes may experience notable gains in motor milestones such as improved head control, sitting, standing, or walking following dopamine agonist therapy. Additional benefits may include reductions in hypotonia, oculogyric crises, and autonomic symptoms7,.However, due to the rarity of the disease and the limited number of published case reports, the response rate and long-term effectiveness of these therapies remain poorly characterized. Current management strategies may also be limited by undesirable side effects, which may lead to discontinuation of therapy. Consequently, there remains a significant unmet medical need for an FDA-approved therapy that can address the underlying cause of AADC deficiency across all phenotypes.

Appendix Information Pertaining to All Blue Cross Blue Shield Medical Policies Click on any of the following terms to access the relevant information: Medical Policy Terms of Use Managed Care Guidelines Indemnity/PPO Guidelines Clinical Exception Process Medical Technology Assessment Guidelines Criteria Documentation Provider must submit supporting documentation (e.g., chart notes, lab results or other clinical information) to show that the member has met all approval criteria. Individual Consideration (for Atypical Patients) Our medical policies are written for most people with a given condition. Each policy is based on peer reviewed clinical evidence. We also take into consideration the needs of atypical patient populations and diagnoses.
If the coverage criteria outlined is unlikely to be clinically effective for the prescribed purpose, the health care provider may request an exception to cover the requested medication based on an individual’s unique clinical circumstances. This is also referred to as “individual consideration” or an “exception request.”
Some reasons why you may need us to make an exception include: therapeutic contraindications; history of adverse effects; expected to be ineffective or likely to cause harm (physical, mental, or adverse reaction).
To facilitate a thorough and prompt review of an exception request, we encourage the provider to include additional supporting clinical documentation with their request. This may include: • Clinical notes or supporting clinical statements; • The name and strength of formulary alternatives tried and failed (if alternatives were tried) and specifics regarding the treatment failure, if applicable; • Clinical literature from reputable peer reviewed journals; • References from nationally recognized and approved drug compendia such as American Hospital Formulary Service® Drug Information (AHFS-DI), Lexi-Drug, Clinical Pharmacology, Micromedex or Drugdex®; and • References from consensus documents and/or nationally sanctioned guidelines

Providers may call, fax or mail relevant clinical information, including clinical references for individual patient consideration, to:

Blue Cross Blue Shield of Massachusetts Pharmacy Operations Department 25 Technology Place Hingham, MA 02043 Phone: 1-800-366-7778 Fax: 1-800-583-6289

CPT Codes / HCPCs Codes / ICD Codes Inclusion or exclusion of a code does not constitute or imply member coverage or provider reimbursement. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage as it applies to an individual member.

Providers should report all services using the most up-to-date industry-standard procedure, revenue, and diagnosis codes, including modifiers where applicable.

The following codes are included below for informational purposes only; this is not an all-inclusive list.

The above medical necessity criteria MUST be met for the following codes to be covered for Commercial Members: Managed Care (HMO and POS), PPO, Indemnity, Medicare HMO Blue and Medicare PPO Blue: HCPCS Codes HCPCS codes: Code Description C9399 Unclassified drugs or biologicals J3490 Unclassified drugs J3590 Unclassified biologics The following ICD Diagnosis Codes are considered medically necessary when submitted with the HCPCS codes above if medical necessity criteria are met:
ICD-10 Diagnosis Codes ICD-10-CM Diagnosis codes: Code Description E70.81 Aromatic L-amino acid decarboxylase deficiency

Policy History Date Action 10/15/2025 Creation of new policy.

References

  1. Himmelreich N, Montioli R, Bertoldi M, et al. Aromatic amino acid decarboxylase deficiency: Molecular and metabolic basis and therapeutic outlook. Mol Genet Metab. May 2019; 127(1): 12-22. PMID 30952622
  2. Wassenberg T, Molero-Luis M, Jeltsch K, et al. Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency. Orphanet J Rare Dis. Jan 18 2017; 12(1):
  3. PMID 28100251
  1. Rizzi S, Spagnoli C, Frattini D, et al. Clinical Features in Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency: A Systematic Review. Behav Neurol. 2022; 2022: 2210555. PMID 36268467
  2. Himmelreich N, Bertoldi M, Alfadhel M, et al. Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes. Mol Genet Metab. Jul 2023; 139(3): 107624. PMID 37348148
  3. Blau N, Pearson TS, Kurian MA, Elsea SH. Aromatic L-Amino Acid Decarboxylase Deficiency. 2023 Oct 12 [updated 2025 Jan 23]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle;
  4. PMID: 37824694.
  5. Pearson TS, Gupta N, San Sebastian W, et al. Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons. Nat Commun. Jul 12 2021; 12(1): 4251. PMID 34253733
  6. Wen Y, Wang J, Zhang Q, et al. The genetic and clinical characteristics of aromatic L-amino acid decarboxylase deficiency in mainland China. J Hum Genet. Sep 2020; 65(9): 759-769. PMID 32409695
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  10. Newborn Screening for Aromatic L-amino Acid Decarboxylase Deficiency (NCT02399761). Available at https://clinicaltrials.gov/search?term=NCT02399761. Accessed July 31, 2027.
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  12. Food and Drug Administration: Statistical Review for Eladocagene Exuparvovec (Approval History, Letters, Reviews, and Related Documents - Kebilidi). Available at https://www.fda.gov/vaccines- blood-biologics/kebilidi. Accessed on July 29, 2025.
  13. Food and Drug Administration: Summary Basis for Regulatory Action for Eladocagene Exuparvovec. Available at https://www.fda.gov/media/184353/download?attachment. Accessed on July 29, 2025.
  14. Chien YH, Lee NC, Tseng SH, et al. Efficacy and safety of AAV2 gene therapy in children with aromatic L-amino acid decarboxylase deficiency: an open-label, phase 1/2 trial. Lancet Child Adolesc Health. Dec 2017; 1(4): 265-273. PMID 30169182
  15. Tai CH, Lee NC, Chien YH, et al. Long-term efficacy and safety of eladocagene exuparvovec in patients with AADC deficiency. Mol Ther. Feb 02 2022; 30(2): 509-518. PMID 34763085
  16. Prescribing label for KEBILIDI (eladocagene exuparvovec-tneq) suspension for intraputaminal infusion. Available at https://www.kebilidi.com/prescribing-information.pdf. Accessed on July 29,
  18. National Institute for Health and Care Excellence: Eladocagene exuparvovec for treating aromatic L- amino acid decarboxylase deficiency (Highly specialized technologies guidance). Published: 19 April
  19. Available at www.nice.org.uk/guidance/hst26. Accessed on July 29, 2025.
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