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Last updated: 11/14/2024
Years published: 2020, 2024
NORD gratefully acknowledges Prof. Dr. Nenad Blau, Division of Metabolism, University Childrenโs Hospital Zurich, and Etienne Leveille, MD, Yale School of Medicine, for assistance in the preparation of this report.
Summary
Aromatic l-amino acid decarboxylase (AADC) deficiency is a very rare genetic disorder. Affected individuals can appear normal at birth, but most will develop symptoms during the first months of life. Symptoms can include abnormal eye movements, movement disorders (especially dystonia) and autonomic dysfunction (excessive sweating, temperature instability, drooping eyelids [ptosis}, nasal congestion and a low level of glucose in the blood [hypoglycemic episodes]). Sleep disturbances are common and may include difficulty sleeping, difficulty staying awake or both. Mood disturbances such as irritability and anxiety are also frequently observed. Brain MRI results are typically normal or may show non-specific abnormalities. Seizures are rare. People with AADC deficiency have a decreased activity of aromatic l-amino acid decarboxylase, an enzyme involved in the building (synthesis) of neurotransmitters (dopamine and serotonin), which are responsible for the communication between neurons in the nervous system.
Medication is available to manage the symptoms, but response to treatment greatly varies among affected individuals, and an optimal treatment regimen can be difficult to achieve. The gene therapy eladocagene exuparvovec (Upstaza) has been approved in the European Union and United Kingdom for individuals aged 18 months and older diagnosed with AADC deficiency, confirmed clinically, molecularly and genetically, who have severe disease. This treatment is not currently approved by the FDA for use in the United States.
The symptoms of AADC deficiency can begin shortly after birth or when the child is a few months old. There is a wide range of possible symptoms, and the severity of the disease varies among affected individuals. The two most common symptoms are low muscle tone (hypotonia) in the trunk and oculogyric crises. These crises are characterized by abnormal rotation of the eyeballs and gaze deviation, uncontrolled movements of the head and neck, muscle spasms, agitation and irritability. They can last several hours and tend to recur every 2 to 5 days. Other movement disorders can be present such as decreased movements (hypokinesia), increased muscle tone (hypertonia) in the limbs, sustained muscle contraction and abnormal postures (dystonia), involuntary writhing movements (athetosis), involuntary and irregular movements of the hands and feet (chorea) and tremors.
Another prominent feature of AADC deficiency is dysfunction of the autonomic nervous system. This part of the nervous system is not under voluntarily control and is involved in self-regulation of the body. Dysfunction of the autonomic nervous system can lead to symptoms such as excessive sweating and salivation (hypersalivation), droopy eyelids (ptosis), nasal congestion, temperature instability, low blood pressure (hypotension) and low blood sugar (hypoglycemia). Less common symptoms include seizures, behavioral problems such as irritability and excessive crying, decreased or increased sleep (insomnia and hypersomnia, respectively) and decreased or increased reflexes (hyporeflexia and hyperreflexia, respectively).
Another relatively common non-neurologic feature is gastrointestinal problems such as diarrhea, constipation and reflux. Because of the disease itself and because of the numerous possible symptoms, children with AADC deficiency have developmental delay and are not able to reach normal milestones such as walking and talking, have feeding difficulties and decreased growth (failure to thrive) and are prone to many medical complications. Patients might also have difficulty adapting to those complications as their autonomic nervous system is dysfunctional and can react inappropriately to stressors such as surgery or infections. Many affected children unfortunately do not live through childhood, but some with milder disease do reach adulthood. Importantly, the condition of people living with the disease can deteriorate because of complications, but the symptoms do not tend to worsen with time. Some patients eventually develop cerebral palsy.
AADC deficiency can be caused by more than 580 changes (variants) in a gene called DDC (which stands for DOPA decarboxylase, another name for AADC). A disease-causing DDC gene variant leads to production of a dysfunctional AADC enzyme that cannot accomplish its normal functions. Enzymes are a type of protein widely present in the body and their role is to facilitate and accelerate (catalyze) chemical reactions that must take place for the body to function correctly. AADC catalyzes chemical reactions responsible for the formation (synthesis) of molecules called neurotransmitters that are essential for proper communication between neurons of the nervous system. The neurotransmitters affected by AADC deficiency are epinephrine and norepinephrine (products of dopamine and involved in the control of the sympathetic nervous system, the โfight or flightโ branch of the autonomic nervous system), dopamine (involved in motor control, reward and motivation) and serotonin (involved in sleep, memory, appetite and mood). Serotonin is also required for the synthesis of melatonin, which is primarily involved in the regulation of the sleep-wake cycle. The deficiency of those neurotransmitters is responsible for the health problems related to AADC deficiency.
AADC deficiency is an autosomal recessive genetic disorder. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
AADC deficiency is an extremely rare disorder; fewer than 350 patients have been reported in the medical literature. Half of these patients are Asian individuals, and a fifth are people with Taiwanese ancestry. Males and females seem to be equally affected. AADC deficiency is probably underdiagnosed. The estimated prevalence in the U.S. based on cerebrospinal fluid (CSF) analysis and genetic testing is roughly 1-2:1,000,000 live newborns.
AADC deficiency is a very rare and complex disease with features that overlap with many other disorders (see above). A complete clinical evaluation and a high index of suspicion are required to make the diagnosis. The evaluation of a child with neurodevelopmental delay starts with a perinatal and developmental history and a complete physical examination. Although many tests, such as a complete blood count, measurement of electrolyte levels and magnetic resonance imaging of the brain are usually performed in the diagnostic workup of a child presenting with neurodevelopmental delay, the laboratory diagnosis of AADC deficiency is centered about four specific tests:
1) A lumbar puncture, which is a procedure where a needle is placed in the spinal column of the patient to collect cerebrospinal fluid (CSF). The CSF is then analyzed to identify abnormal levels of certain substances (metabolites) involved in the molecular pathways of neurotransmitter synthesis. The synthesis of neurotransmitters involves a cascade of numerous chemical reactions. In patients with AADC deficiency, the cascade stops where AADC is usually required to catalyze the chemical reactions. As a result, in cases of enzyme deficiency, the metabolites โbeforeโ AADC in the chemical reaction cascade will be increased, and those โafterโ will be decreased.
2) Measurement of a specific metabolite 3-O-methyl-dopa (3OMD) in plasma or dried blood spots, which is increased in patients with the disease
3) Measurement of activity level of the AADC enzyme in the blood (serum), which will be reduced in patients with the disease
4) Genetic testing that can identify disease-causing (pathogenic) variants in the DDC gene
Treatment & Management
Numerous medications can help manage the symptoms. The optimal medication regimen greatly varies among affected individuals. There is limited scientific evidence for the efficacy of most treatment options due to the rarity of the disease. Each patient needs to have a personalized approach and should be followed by a pediatric neurologist and potentially many other physicians to assist in trials of medications to determine the best combination for the patient. Some of the most used treatments include medications to increase the concentration of dopamine in the nervous system (dopamine agonists) or to decrease its degradation (monoamine oxidase B [MAO-B] inhibitors). Vitamin B6 (pyridoxine) or its active form, pyridoxal phosphate (PLP) are often tried, as PLP normally assists AADC in its role as a cofactor and might therefore increase the residual activity of the enzyme. Other medications might be considered depending on the patient. For example, melatonin can be tried for sleep disturbances, and benzodiazepines (a class of medication that acts as central nervous system depressants) or anticholinergics (which counteract activity of acetylcholine, a neurotransmitter) might help patients with oculogyric crises and other motor symptoms.
The optimal management of a patient with AADC deficiency is a multidisciplinary approach to address the specific needs of the affected individual. Members of the team commonly include physiotherapists, speech therapists, dieticians, psychologists, social workers and physiatrists (physicians specialized in rehabilitation).
The gene therapy eladocagene exuparvovec (Upstaza) is approved in the European Union and United Kingdom for the treatment of individuals aged 18 months and older with a clinical, molecular and genetically confirmed diagnosis of AADC deficiency with a severe phenotype (i.e., individuals who cannot sit, stand or walk). Upstaza is given by infusion into the brain.
In 2024, the gene therapy eladocagene exuparvovec-tneq (Kebilidi) was approved by the U.S. Food and Drug Administration (FDA) to treat adult and pediatric patients with AADC deficiency. Kebilidi is given by infusion into the brain.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials are also posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
For more information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Reischl-Hajiabadi AT, Okun JG, Kohlmรผller D, et al. Newborn screening for aromatic l-amino acid decarboxylase deficiency โ Strategies, results, and implication for prevalence calculations. Mol Genet Metab. 2024;141(3):108148. doi:10.1016/j.ymgme.2024.108148
Himmelreich N, Bertoldi M, Alfadhel M, et al. Corrigendum to: 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. 2023;139(4):107647. doi:10.1016/j.ymgme.2023.107647
Tai CH, Lee NC, Chien YH, et al. Long-term efficacy and safety of eladocagene exuparvovec in patients with AADC deficiency. Mol Ther. 2022;30(2):509-518. doi:10.1016/j.ymthe.2021.11.005
Hwu WL, Chien YH, Lee NC, Li MH. Natural history of aromatic L-amino acid decarboxylase deficiency in Taiwan. JIMD Rep. 2018;40:1-6. doi:10.1007/8904_2017_54
Himmelreich N, Montioli R, Bertoldi M, et al. Aromatic amino acid decarboxylase deficiency: Molecular and metabolic basis and therapeutic outlook. Mol Genet Metab. 2019;127:12-22.
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.
Ng J, Papandreou A, Heales SJ, Kurian MA. Monoamine neurotransmitter disordersโclinical advances and future perspectives. Nat Rev Neurol. 2015;11(10):567-84.
Hwu WL, Muramatsu S, Tseng SH, et al. Gene therapy for aromatic L-amino acid decarboxylase deficiency. Sci Transl Med. 2012;4:134ra61.
Brun L, Ngu LH, Keng WT, et al. Clinical and biochemical features of aromatic L-amino acid decarboxylase deficiency. Neurology 2010;75:64-71.
Lee W-T. Disorders of monoamine metabolism: inherited disorders frequently
misdiagnosed as epilepsy. Epilepsy & Seizure 2010;3(1):147-53.
Anselm IA, Darras BT. Catecholamine toxicity in aromatic L-amino acid decarboxylase deficiency. Pediatr Neurol. 2006;35:142-4.
Pons R, Ford B, Chiriboga CA, et al. Aromatic L-amino acid decarboxylase deficiency: clinical features, treatment, and prognosis. Neurology 2004;62:1058-65.
Swoboda KJ, Saul JP, McKenna CE, Speller NB, Hyland K. Aromatic L-amino acid decarboxylase deficiency: overview of clinical features and outcomes. Ann Neurol. 2003;54 Suppl 6:S49-55.
Hyland K, Surtees RA, Rodeck C, Clayton PT. Aromatic L-amino acid decarboxylase deficiency: clinical features, diagnosis, and treatment of a new inborn error of neurotransmitter amine synthesis. Neurology 1992;42:1980-8.
INTERNET
Blau N, Pearson TS, Kurian MA, et al. Aromatic L-Amino Acid Decarboxylase Deficiency. 2023 Oct 12. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviewsยฎ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK595821/ Accessed July 24, 2024.
Aromatic L-Amino Acid Decarboxylase Deficiency. Genetic and Rare Diseases Information Center. Last updated: Jul 2017.
https://rarediseases.info.nih.gov/diseases/770/aromatic-l-amino-acid-decarboxylase-deficiency Accessed July 24, 2024.
Aromatic L-Amino Acid Decarboxylase Deficiency, Online Mendelian Inheritance in Man (OMIM). Last updated: 12/04/2023. https://www.omim.org/entry/608643
Accessed July 24, 2024.
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The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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