#ShareForRare: AADC deficiency
What’s AADC deficiency?
The Orphan Drug Act, the iconic law designed to accelerate the development of therapies for rare disorders, defined in 1983 that a condition should be classified as a rare disease if it affects less than 200,000 patients in the United States (approximately 620 patients per million of population). Recently, the interest in these “orphan” diseases has grown, mainly due to the increasing availability of technologies for their diagnosis and treatments. On top of that, a new subcategory of disorders has recently been introduced: the ultra-rare diseases, with less than 20 patients per million of population.
This would be the classification of aromatic L-amino acid decarboxylase (AADC) deficiency, an extremely uncommon disorder that has been reported in less than 200 cases in the literature worldwide. This monogenic autosomal recessive disorder is caused by the absence of a functional allele of the DDC gene, resulting in complex neurodevelopmental anomalies, caused by the deficiency of catecholamines and serotonin.
The exact global incidence of AADC deficiency is unknown, given the fact that the disease is not currently included in any newborn screening programs. However, it is known that AADC deficiency is more prevalent in certain Asian populations, especially among Taiwanese and Japanese patients, probably due to a founder effect in the region. Still, it is estimated that more than 90% of the cases are undiagnosed.
Molecular aspects of AADC deficiency
DDC, the gene encoding the AADC enzyme, is located on chromosome 7, and consists of 15 exons that contain the sequence for the 480-aminoacid protein. This enzyme catalyzes the synthesis of dopamine and serotonin from their respective precursors, L-DOPA and 5-HTP, so it is crucial for the production of these two vital neurotransmitters– as well as the dopamine-derived neurotransmitters norepinephrine and epinephrine.
Neurotransmitters are natural chemicals that nerve cells use to communicate with each other and with the rest of the body. The proper production and functioning of these neurotransmitters are crucial for coordinating a wide range of bodily processes.
As of April 2023, there are approximately 61 mutations in the DDC gene that have been associated with AADC deficiency. According to Franklin, 23 of these variants have a loss of function (LOF) effect, while 34 of them were missense amino acid changes or inframe indels, and only 4 were located in a non-coding region. Interestingly, there are no benign null variants reported in this gene, resulting in sufficient evidence for the Franklin algorithm to predict a high sensitivity to LOF variants.
Defects in the DDC gene lead to insufficient levels of AADC enzyme and/or a dysfunctional form of the enzyme, ultimately leading to abnormally low production of neurotransmitters in the patient’s brain. The impaired synthesis of dopamine, noradrenaline, adrenaline, and serotonin leads to a complex syndrome of motor, behavioral, and autonomic symptoms.
Clinical features and diagnosis of AADC deficiency
This neurodevelopmental disorder typically presents in early infancy, with most of the symptoms being noticed from about 10 weeks old and before the first year of life. Some of the most common phenotypic aspects associated with AADC are:
- Oculogyric crisis, present in nearly all AADC deficiency patients
- Other body movement disorders such as dystonia or hypokinesia
- Abnormal muscle tone, such as hypotonia
- Developmental delay in milestones such as head control, crawling, speech and other areas
- Autonomic dysfunction, leading to hypersalivation, ptosis of the eyelids, and low blood pressure
- Gastrointestinal problems
- Mental health and mood disorders
- Sleep disturbances
A complete list of associated phenotypes can be found here. While most patients present severe symptomatology with early onset of many of these manifestations, a few patients with a milder disease course are known.
Being an extremely rare disease, and because its symptoms are similar to those of other disorders, AADC deficiency is sometimes mistaken for cerebral palsy, epilepsy, and even autism. Once there is a clinical suspicion of this disorder, it is recommended that a diagnosis of AADC deficiency should be made based on positive findings in 2 of the 3 core diagnostic tests:
- Analysis of neurotransmitter metabolites in cerebrospinal fluid (CSF) from a lumbar puncture
- Measurement of plasma AADC enzyme activity
- Molecular testing of the DDC gene
Treatments and clinical trials
There have been exciting recent developments regarding the treatment of this disease.
Up until recently, there was no available cure for AADC deficiency. The typical treatment consisted of mitigating symptoms with more general treatments, such as occupational or physical therapies that can help improve the child’s quality of life. The treating pediatrician may also refer the patient to a pediatric neurologist, a movement disorder specialist, a clinical geneticist, or another specialist who can provide relevant and helpful insights into the treatment.
However, in 2022 an investigational gene therapy utilizing viral vectors to introduce normal DDC genes into the body advanced into the clinic. The orphan drug, called eladocagene exuparvovec, is a one-time treatment that restores the production of neurotransmitters. After promising Phase I/II results were published in 2021, the gene therapy received a positive opinion from the European Medicines Agency (EMA) in May, and was approved in the UK for the treatment of children over 2 years old later in November.
As of March 2023, the novel therapy has marketing authorization in all 27 European Union member states, as well as Great Britain, Northern Ireland, Iceland, Norway, and Liechtenstein. While it is still waiting for final approval from FDA to become an approved treatment for AADC deficiency in the US, a larger trial focused on the efficacy of the treatment is now actively recruiting patients in this country.
Resources
There are interesting resources for families and caregivers, such as the NIH’s Genetic and Rare Disease (GARD) Information Center and MedlinePlus. More relevant information can be found at About AADC, the website provided by PTC Therapeutics Ltd, the company behind the development of the gene therapy eladocagene exuparvovec, for the benefit of AADC deficiency patients and their caregivers.
For doctors and other healthcare professionals, the website AADC Insights and the NIH’s Genetic Testing Registry offer information to help with diagnosis and testing. It is also recommendable to stay up-to-date with the latest clinical trial information, which can be found on ClinicalTrials.gov.
Regarding advocacy, the NORD (National Organization for Rare Disorders) offers programs of education, advocacy, research, and patient services for many rare diseases, and has resources for patients, caregivers, clinicians, and researchers.
Organized and funded by PTC Therapeutics GT | Date of preparation: April 2023
MED-ALL-AADC-2300003
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In line with Franklin’s commitment to advancing the field of rare disease diagnosis and treatment, this initiative aims to raise awareness of uncommon disorders in the Franklin Community and encourage collaboration among community members.
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Sources:
- Franklin by Genoox: https://franklin.genoox.com/
- OMIM: https://www.omim.org/
- ClinicalTrials.gov: https://clinicaltrials.gov/
- Medline Plus: https://medlineplus.gov/
- Orphanet: https://orpha.net/
- UniProt
- FDA website
References:
- Brun L, et al. Clinical and biochemical features of aromatic L-amino acid decarboxylase deficiency. Neurology. 2010 Jul 6;75(1):64–71.
- Wassenberg T, et al. Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency. Orphanet J. Rare Dis. 2017;12:12.
- Hwu WL, et al. Natural History of Aromatic L-Amino Acid Decarboxylase Deficiency in Taiwan. JIMD Rep. 2018;40:1–6.
- Himmelreich N, et al. Aromatic amino acid decarboxylase deficiency: Molecular and metabolic basis and therapeutic outlook. Mol Genet Metab. 2019 May;127(1):12–22.
- Bräutigam C, et al. (2000), The influence of L-dopa on methylation capacity in aromatic L-amino acid decarboxylase deficiency: Biochemical findings in two patients. J Inherit Metab Dis, 23: 321–324.
- Sardella M, et al. Pharmacovigilance of medicines for rare and ultrarare diseases. Ther Adv Drug Saf. 2018 Aug 14;9(11):631–638.
- Harari S. Why we should care about ultra-rare disease. Eur Respir Rev. 2016 Jun;25(140):101–3.
