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Forging a Path to Diagnosis of AADC Deficiency
Raising Clinical Awareness Moderator Panelist Keith Hyland, PhD Executive Vice President Director Neurochemistry Diagnostic Unit Medical Neurogenetics Laboratories Atlanta, Georgia Irina Anselm, MD Assistant Professor of Neurology Harvard Medical School Child Neurologist Boston Children's Hospital Boston, Massachusetts AADC = aromatic L-amino acid decarboxylase
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Aromatic L-Amino Acid Decarboxylase
Aromatic L-amino acid decarboxylase (AADC) AADC deficiency is an autosomal recessive disorder of neurotransmitter synthesis[a] Ultra rare disease that affects brain metabolism[b] First reported in 1992 ~117 patients diagnosed worldwide[c] Prevalence (predicted birthrates)[d]: 1 in 90,000 in United States 1 in 118,000 in Europe 1 in 182,000 in Japan Brun L, Ngu LH, Keng WT, et al. Clinical and biochemical features of aromatic L-amino acid decarboxylase deficiency. Neurology. 2010;75:64-71. Hyland K, Surtees RA, Rodeck C, et al. Aromatic L-amino acid decarboxylase deficiency: clinical features, diagnosis, and treatment of a new inborn error of neurotransmitter amine synthesis. Neurology. 1992;42: 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. 2017;12:12. a. Brun L, et al. Neurology. 2010;75:64-71; b. Hyland K, et al. Neurology. 1992;42: ; c. Wassenberg T, et al. Orphanet J Rare Dis. 2017;12:12; d. Pre-published data courtesy of Keith Hyland, PhD.
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What Is AADC? AADC is a protein that functions as an enzyme
Required for synthesis of several neurotransmitters AADC aids in the production of: Dopamine Serotonin Norepinephrine Epinephrine Melatonin Effect of AADC Deficiency in Neurotransmitter Synthesis Tyrosine hydroxylase L-Dopa Tryptophan 5-HTP Dopamine Serotonin AADC Norepinephrine Epinephrine Melatonin Shih DF, Hsiao CD, Min MY, et al. Aromatic L-Amino Acid Decarboxylase (AADC) Is Crucial for Brain Development and Motor Functions. PLoS One. 2013;8:e71741. Pappan KL, Kennedy AD, Magoulas PL, et al. Clinical Metabolomics to Segregate Aromatic Amino Acid Decarboxylase Deficiency From Drug-Induced Metabolite Elevations. Pediatr Neurol. 2017;75:66-72. Shih DF, et al. PLoS One. 2013;8:e71741; Pappan KL, et al. Pediatr Neurol. 2017;75:66-72.
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Enzyme Structure L-Dopa AADC © Medscape, LLC S250F F309L A91V A275T G102S G123R S147R AADC deficiency in humans occurs as a result of genetic changes These changes alter the structure of the enzyme Can no longer function in the production of neurotransmitters Over 80 pathogenic variants identified Chang YT, Sharma R, Marsh JL, et al. Levodopa-responsive aromatic L-amino acid decarboxylase deficiency. Ann Neurol. 2004;55: Chang YT, et al. Ann Neurol. 2004;55:
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Role of Neurotransmitters
Exocytosis Tyrosine Dopamine L-DOPA Synaptic cleft AADC Postsynaptic neuron Presynaptic terminal Postsynaptic receptor and ionic channel Vesicle containing neurotransmitter Transporter Tyrosine hydroxylase Monoamine oxidase (MAO) COMT MAO COMT © Medscape, LLC Vesicular Transporter Liver Rilstone JJ, Alkhater RA, Minassian BA. Brain dopamine-serotonin vesicular transport disease and its treatment. N Engl J Med. 2013;368: Rilstone JJ, et al. N Engl J Med. 2013;368:
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Developmental Delay Symptom onset occurs during first months of life
Not diagnosed until much later in life Key symptom is developmental delay Do not reach any motor milestones Motor delay Speech delay Cognitive delay Later, some milestones may be reached Majority will remain very delayed for the rest of their lives Dopamine and serotonin are necessary for normal nervous system function Wassenberg T, et al. Orphanet J Rare Dis. 2017;12:12 Genetics Home Reference (GHR) Website. Aromatic l-amino acid decarboxylase deficiency. May Available at: Accessed January 9, 2019. Hwu WL, et al. [Published online August 31, 2017]. J Inherit Metab Dis Rep. doi: /8904_2017_54. Wassenberg T, et al. Orphanet J Rare Dis. 2017;12:12; GHR Website. AADC Deficiency 2008.
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Signs in AADC Deficiency
Axial hypotonia Truncal Limb hypertonia Dystonia Hypokinesia Bradykinesia Tremor Athetosis Myoclonic jerks Blepharospasm Oculogyric crises Clue to diagnosis Can persist for several hours and recur every 2 to 5 days Feeding/swallowing problems Wassenberg T, et al. Orphanet J Rare Dis. 2017 Genetics Home Reference (GHR) Website. Aromatic l-amino acid decarboxylase deficiency. May Available at: Accessed January 9, 2019. Hwu WL, Muramatsu S, Tseng SH, et al. Gene therapy for aromatic L-amino acid decarboxylase deficiency. Sci Transl Med. 2012;4:134ra61. Wassenberg T, et al. Orphanet J Rare Dis GHR Website. AADC Deficiency 2008. Hwu WL, et al. Sci Transl Med. 2012;4:134ra61.
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Patient Video 1 Age: 22 years
Diagnosed with AADC deficiency at 5 months by CSF analysis. Symptoms: Developed symptoms immediately after birth Tremor in arm and legs Rigidity Oculogyric crisis Other conditions: Gastrointestinal dysmotility Restrictive lung disease caused by severe scoliosis She developed symptoms immediately after birth (hypothermia, hypotonia, problems with breastfeeding). She developed oculogyric crises at several months, as well as dystonia and hypokinesia. She had normal brain MRI and non-specific EEG. Diagnosed with AADC deficiency at 5 months by CSF analysis. Over the years she continued to have oculogyric crises, severe movement disorder and multiple medical problems, including gastro intestinal dysmotility. She required tracheostonmy (seen on the video) secondary to restrictive lung disease caused by severe scoliosis. Video courtesy of Irina Anselm, MD.
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Lee HF, et al. Eur J Paediatr Neurol. 2009;13:135-140
Oculogyric Crisis Rare movement disorder characterized by paroxysmal, conjugate, tonic, usually upwards, deviation of the eyes May last for minutes, but frequently last for hours These spasms may mimic other conditions: Brain stem encephalitis Seizures Drug induced Lee HF, et al. Eur J Paediatr Neurol. 2009;13: Normal EEG and/or failure to respond to antiepileptic medications are important clues to distinguish oculogyric crises from seizures EEG = electroencephalography Slow EJ, Lang AE. Oculogyric crises: A review of phenomenology, etiology, pathogenesis, and treatment. Mov Disord. 2017;32: Lee HF, Tsai CR, Chi CS, et al. Aromatic l-amino acid decarboxylase deficiency in Taiwan. Eur J Paediatr Neurol. 2009;13: Slow EJ, et al. Mov Disord. 2017;32: ; Lee HF, et al. Eur J Paediatr Neurol. 2009;13:
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Monoamine Metabolic Pathways
Melatonin AADC Epinephrine Allen GF, Land JM, Heales SJ. A new perspective on the treatment of aromatic L-amino acid decarboxylase deficiency. Mol Genet Metab. 2009;97:6-14. AADC Allen GF, et al. Mol Genet Metab. 2009;97:6-14. Hare EE, et al. BMC Evolutionary Biology. 2004;4:1-20.
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Symptoms in AADC Deficiency
Autonomic dysfunction/instability Ptosis Excessive sweating Nasal congestion Arterial hypotension Temperature instability Mood instability Irritability Sleep disturbance Insomnia and/or hypersomnia Changes in melatonin levels Wassenberg T, et al. Orphanet J Rare Dis Wassenberg T, et al. Orphanet J Rare Dis. 2017;12:12.
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Recognition and Diagnosis
Most patients develop symptoms very early Mean age of diagnosis 3.5 years Some diagnosed later than that Some are not diagnosed at all Uncertainty about child's condition can be very distressing Wassenberg T, et al. Orphanet J Rare Dis Wassenberg T, et al. Orphanet J Rare Dis. 2017;12:12.
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Delay in Diagnosis Lack of awareness of AADC deficiency
Initial suspected diagnoses Epilepsy Cerebral palsy Hyperekplexia Congenital myasthenia Mitochondrial disorder Swoboda KJ, Saul JP, McKenna CE, et al. Aromatic L-amino acid decarboxylase deficiency: overview of clinical features and outcomes. Ann Neurol. 2003;54 Suppl 6:S49-55. Swoboda KJ, et al. Ann Neurol. 2003;54(Suppl 6):S49-S55.
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Diagnostic Testing Useful diagnostic tests
Lumbar puncture Analysis of metabolites of neurotransmitters in CSF Special arrangements to send to lab Genetic testing with next-generation sequencing Whole exome sequencing Measurement of AADC enzyme activity in plasma Diagnostic test not useful for diagnosis Catecholamine metabolites in urine MRI EEG CSF = cerebrospinal fluid MRI = magnetic resonance imaging Wassenberg T, et al. Orphanet J Rare Dis Wassenberg T, et al. Orphanet J Rare Dis. 2017;12:12.
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Blood Diagnostic Test AADC
In the absence of AADC, the substrate L- dopa accumulates and gets converted to 3-O- methyldopa (3-OMD) 3-OMD then accumulates to high levels in blood and acts as a biomarker for diagnosing AADC deficiency Tyrosine hydroxylase L-Dopa Tryptophan 5-HTP Dopamine Serotonin AADC Norepinephrine Epinephrine Melatonin 3-OMD 3-OMD = 3-O-methyldopa Wassenberg T, et al. Orphanet J Rare Dis Wassenberg T, et al. Orphanet J Rare Dis. 2017;12:12.
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Blood Diagnostic Test (cont)
Test uses mass spectrometry Allows for mass screening in target populations Incorporation of this simple blood test into newborn screening programs will improve diagnostic delay Figure courtesy of Dr Keith Hyland.
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Treatment Options First line treatment:
Dopamine agonists Pramipexole Ropinerol Rotigotine MAO inhibitors Tranylcypromine Selegiline Phenelzine Pyridoxine (vitamin B6) Additional symptomatic medications: Anticholinergic Benzodiazepines Sleep aids Current medications cannot improve the developmental trajectory of these children with AADC deficiency MAO = monoamine oxidase Wassenberg Brun L, et al. Neurology. 2010;75:64-71 Wassenberg T, et al. Orphanet J Rare Dis. 2017;12:12; Brun L, et al. Neurology. 2010;75:64-71.
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Gene Therapy for AADC Deficiency
Mutation of the dopa decarboxylase (DDC) gene causes AADC deficiency Gene therapy Directly injects the normal non-mutated DDC gene, that codes for AADC, into specific regions of the brain Restores AADC function and dopamine expression in the putamen Improves motor function and development L-Dopa Dopamine AADC Dopamine Synthesis Putamen © Medscape, LLC DDC = dopa carboxylase Chien Y, Lee N, Tseng S, et al. Gene Therapy with AGIL‐AADC in Children with AADC Deficiency Leads to De Novo Dopamine Production and Sustained Improvement in Motor Milestones Over 5 Years. Child Neurology Society 47th Annual Meeting; October 15-18, 2018; Chicago, IL. Presentation PL1-1. Chien Y, et al. CNS Presentation PL1-1.
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Gene Therapy Clinical Trial Study Design
Eighteen patients with severe AADC deficiency 10 girls, 8 boys Ages ranged from 21 months to 8.5 years at the time of administration None had reached any milestones, including head control, at the time of enrollment All received AGIL-AADC: Vector genomes were administered as bilateral intraputaminal stereotactic infusions during a single operative session Chien Y, Lee N, Tseng S, et al. Gene Therapy with AGIL‐AADC in Children with AADC Deficiency Leads to De Novo Dopamine Production and Sustained Improvement in Motor Milestones Over 5 Years. Child Neurology Society 47th Annual Meeting; October 15-18, 2018; Chicago, IL. Presentation PL1-1. Chien Y, et al. CNS Presentation PL1-1.
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Gene Therapy Clinical Trial Results
At interim analysis, all patients are 2 years post-gene therapy 7 are 5 years post–gene therapy One patient died at 11 months post–gene therapy Death was unrelated to AGIL-AADC administration Two years after AGIL-AADC administration: 8/18 (44%) patients gained full head control (P <.0001) 6/18 (33%) could sit unassisted (P <.0001) 3/18 (17%) could stand with support (P =.0050) Chien Y, Lee N, Tseng S, et al. Gene Therapy with AGIL‐AADC in Children with AADC Deficiency Leads to De Novo Dopamine Production and Sustained Improvement in Motor Milestones Over 5 Years. Child Neurology Society 47th Annual Meeting; October 15-18, 2018; Chicago, IL. Presentation PL1-1. Chien Y, et al. CNS Presentation PL1-1.
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Gene Therapy Clinical Trial Results (cont)
Beyond 2 years, half of all patients have achieved a milestone 7/18 (39%) sit unassisted 5/18 (28%) stand with support Of these 5 patients: 2 gained locomotor activity with a wheeled walker 1 is learning to walk without assistance Overall safety data is good Chien Y, Lee N, Tseng S, et al. Gene Therapy with AGIL‐AADC in Children with AADC Deficiency Leads to De Novo Dopamine Production and Sustained Improvement in Motor Milestones Over 5 Years. Child Neurology Society 47th Annual Meeting; October 15-18, 2018; Chicago, IL. Presentation PL1-1. Chien Y, et al. CNS Presentation PL1-1.
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Patient Video 2 AADC-Deficient Patient Baseline Age: 2 years 5 months
Severe motor delay and hypertonia 2 Years Post-Gene Therapy Able to crawl, stand and make few steps with support AAV2 gene therapy in children with aromatic L-amino acid decarboxylase deficiency: Part 1 Reprinted from Publication title, Efficacy and Reprinted from The Lancet Child & Adolescent Healthsafety of AAV2 gene therapy in children with aromatic L-amino acid decarboxylase deficiency: an open-label, phase 1/2 trial, with permission from Elsevier.
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Conclusions Gene therapy will transform the outcome of AADC-deficient children and their families There is a need for improved education of healthcare providers to allow better recognition of this disorder Better recognition will lead to earlier diagnosis, treatment and improved outcomes. Gene therapy will also move AADC deficiency into the "treatable" disorder category In the near future, testing for this disorder may be incorporated into newborn screening programs throughout the world Allowing for diagnosis and commencement of treatment soon after birth
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