Clinical characteristics.

Individuals with aromatic L-amino acid decarboxylase (AADC) deficiency typically have complex symptoms, including motor, behavioral, cognitive, and autonomic findings. Symptom onset is in early infancy, typically within the first six months of life. The most common initial symptoms are often nonspecific, and include feeding difficulties, hypotonia, and developmental delay. More specific symptoms include oculogyric crises (which occur in the vast majority of affected individuals, typically starting in infancy), movement disorders (especially dystonia), and autonomic dysfunction (excessive sweating, temperature instability, ptosis, nasal congestion, hypoglycemic episodes). Sleep disturbance is present in a majority of affected individuals and can include insomnia, hypersomnia, or both. Mood disturbance, including irritability and anxiety, are also common. Brain MRI is typically either normal or may demonstrate nonspecific abnormalities, such as mild diffuse cerebral atrophy or delayed myelination. Seizures are an uncommon finding, occurring in fewer than 5% of affected individuals.

Diagnosis/testing.

The diagnosis of AADC deficiency is established in a proband who has the following core diagnostic testing results: biallelic pathogenic variants in DDC identified by molecular genetic testing OR cerebrospinal fluid (CSF) or plasma neurotransmitter profile consistent with AADC deficiency AND significantly reduced AADC enzyme activity in plasma.

Management.

Targeted therapies: Treatments can include the use of dopamine agonists (pramipexole, ropinirole, rotigotine patch, or bromocriptine), MAO inhibitors (selegiline or tranylcypromine), vitamin B₆ (pyridoxine, pyridoxal phosphate), folinic acid, and (in rare cases) levodopa in a preparation without carbidopa. Putaminal delivery of eladocagene exuparvovec (Upstaza^®) was 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); this treatment is not currently FDA approved for use in the United States.

Supportive care: Feeding therapy with consideration of gastrostomy tube placement or jejunal feeding; anticholinergic drugs and/or sleep induction for movement disorders / oculogyric crisis; xylometazoline or oxymetazoline nasal drops for autonomic dysfunction; melatonin or clonidine for sleep disturbance; and standard therapies for epilepsy, developmental delay / intellectual disability, musculoskeletal issues, bowel dysfunction (constipation, diarrhea, or gastroesophageal reflux disease), strabismus, visual impairment, obstructive sleep apnea, hypoglycemia, and hearing loss.

Surveillance: At each visit: measurement of growth parameters; evaluation of nutritional status and safety of oral intake; monitor frequency and severity of oculogyric crises and movement disorders; assess for new manifestations, such as seizures, changes in tone, and movement disorders; monitor developmental progress and educational needs; monitor for behavioral issues and symptoms of anxiety, ADHD, ASD, aggression, & self-injury; clinical assessment for kyphoscoliosis and hip dislocation; monitor for constipation, diarrhea, gastroesophageal reflux, and abdominal discomfort or pain; and monitor for evidence of aspiration, respiratory insufficiency, sleep disturbance, and frequency of respiratory infections. Annually: obtain hip and spinal radiographs (until skeletal maturity); consider cardiology evaluation; consider continuous glucose monitoring, especially in younger affected individuals. Per treating clinicians: ophthalmology evaluation; monitor for cardiac function and rhythm defects; monitor for symptoms of obstructive sleep apnea and nasal congestion. In those on levodopa treatment: monitor CSF neurotransmitters, including 5-methyltetrahydrofolate levels, as clinically indicated to assess for secondary folate deficiency, particularly if neurologic symptoms worsen. In those on bromocriptine therapy: echocardiogram and EKG every 6-12 months to monitor for vavlulopathy caused by valve fibrosis (the risk is lower than with other ergot-derived dopamine agonists such as pergolide, but not absent).

Agents/circumstances to avoid: Ergot-derived dopamine agonists with strong serotonergic (5-HT2B) agonist action (pergolide and cabergoline) due to risk of cardiac valvulopathy and other fibrotic complications; levodopa in most affected individuals who do not have ligand binding site pathogenic variants; dopamine receptor antagonists (e.g., metoclopramide, antipsychotic medications), which may worsen primary disease symptoms.

Evaluation of relatives at risk: Testing of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment of AADC deficiency. Molecular genetic testing is recommended if the pathogenic variants in the family are known; measurement of CSF neurotransmitters (to evaluate for the characteristic profile) and plasma AADC enzyme activity is recommended if the pathogenic variants in the family are not known.

Pregnancy management: Successful pregnancy has been documented in an affected woman with a mild phenotype who took low-dose pramipexole and selegiline during pregnancy.

Genetic counseling.

AADC deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a DDC pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic. If both DDC pathogenic variants have been identified in an affected family member, molecular genetic carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.

Suggestive Findings

AADC deficiency should be considered in individuals with the following clinical and supportive laboratory findings and family history.

Clinical findings

• Infantile hypotonia
• Ptosis
• Oculogyric crises (an involuntary and prolonged upward deviation of the eyes, often precipitated by such factors as fatigue, diurnal variation, intercurrent illness, or metabolic stress)
• Dystonia and other hyperkinetic movement disorders
• Hypokinesia and other features of parkinsonism
• Excessive sweating
• Stridor and nasal congestion
• Sleep disorder (hypersomnolence or insomnia)
• Autonomic dysfunction
• Developmental delay / intellectual disability, most often in the severe to profound range

Supportive laboratory findings

• Cerebrospinal fluid (CSF) 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)
• Low whole-blood serotonin concentration
• Increased serum prolactin concentration, which is nonspecific

Note: Because elevations of these metabolites individually are not entirely specific to AADC deficiency, more specific testing is required to establish or rule out the diagnosis of AADC deficiency (see Establishing the Diagnosis).

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of AADC deficiency is established in a proband who has the following core diagnostic testing results (see Figure 1):

Figure 1.

Diagnostic flowchart to establish a diagnosis of AADC deficiency

• Biallelic pathogenic (or likely pathogenic) variants in DDC identified by molecular genetic testing (see Table 1)

OR

• CSF or plasma neurotransmitter profile consistent with AADC deficiency (see above) AND
• Significantly reduced activity of the enzyme AADC in plasma

Because of its relatively high sensitivity, DDC molecular genetic testing demonstrating biallelic pathogenic or likely pathogenic variants can obviate the need for enzymatic testing or even neurotransmitter profiling; therefore, DDC molecular genetic testing is increasingly the first-line diagnostic test for AADC deficiency.

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic DDC variants of uncertain significance (or of one known DDC pathogenic variant and one DDC variant of uncertain significance) does not establish or rule out the diagnosis (see Figure 1). (3) If genetic testing reveals a variant of unknown clinical significance (or biallelic variants of unknown clinical significance), a CSF neurotransmitter profile consistent with AADC deficiency can support the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of AADC deficiency has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

The aromatic L-amino acid decarboxylase (AADC) enzyme catalyzes the last step in the biosynthesis of the monoamine neurotransmitters dopamine and serotonin. Dopamine itself is a precursor for the synthesis of epinephrine and norepinephrine. Therefore, the clinical features of AADC deficiency are caused by a severe combined deficiency of dopamine, serotonin, epinephrine, and norepinephrine.

Individuals with AADC deficiency typically have complex symptoms, including motor, behavioral, cognitive, and autonomic findings. Symptom onset is in early infancy, typically within the first six months of life [Wassenberg et al 2017, Pearson et al 2020, Rizzi et al 2022]. The most common initial symptoms are often nonspecific, and include feeding difficulties, hypotonia, and developmental delay. The key to clinical diagnosis lies in the subsequent recognition of a constellation of symptoms that suggest a monoamine neurotransmitter disorder: oculogyric crises (which occur in the vast majority of affected individuals, typically starting in infancy), movement disorders (especially dystonia), and autonomic dysfunction (excessive sweating, temperature instability, ptosis, nasal congestion, hypoglycemic episodes) [Wassenberg et al 2017, Pearson et al 2020, Rizzi et al 2022]. To date, about 350 individuals have been reported with AADC deficiency [Himmelreich et al 2022, Himmelreich et al 2023]. The following description of the phenotypic features associated with this condition is based on these reports.

Developmental delay (DD) and intellectual disability (ID). Delay in acquisition of motor milestones during infancy (e.g., head control, independent sitting) is a common early symptom. Motor and speech delay ranges from mild to severe. Affected individuals with severe disease (approximately 80% of reported affected individuals) typically have very limited development of motor skills; those with milder disease (approximately 5%-10% of reported affected individuals) may walk independently, typically by age eight years, in those who achieve ambulation. The degree of intellectual disability also tends to correlate with the severity of motor disability and the number and severity of other symptoms.

Neurologic features. AADC deficiency is a developmental rather than a neurodegenerative disorder, but neurologic symptoms commonly evolve over time. For example, oculogyric crises tend to peak in severity during infancy and early childhood and become less frequent during late adolescence, even in those with severe disease.

• Hypotonia is the most common initial symptom and is often noticed in early infancy. Low tone is prominent in the neck and trunk muscles; tone in the limbs may fluctuate from low to high due to the variable presence of dystonia (see below).
• Oculogyric crises are episodes characterized by intermittent or sustained eye deviation, usually upward or to the side, which may be accompanied by involuntary movements of the face, trunk, and/or limbs. Mild episodes may last for several minutes and involve the eyes only. Severe episodes last for many hours, and symptoms may include whole-body dystonic posturing, difficulty breathing, and sweating. Oculogyric crises occur in more than 90% of people with AADC deficiency and typically begin within the first six months of life. Episodes may initially be mistaken for seizures. Clinical features that distinguish an oculogyric crisis from a seizure are the long duration (an oculogyric crisis can last for many hours) and intact alertness (during an oculogyric crisis, a person remains awake and alert).
• Movement disorders
  • Hypokinesia is common. The combination of hypotonia, hypokinesia, and ptosis (see below) in infancy may be mistaken for a neuromuscular condition. Differentiating features of AADC deficiency on neurologic examination are the presence of normal or brisk deep tendon reflexes and recognition of dystonia in the limbs, if present.
  • Dystonia (involuntary movements or postures) is the most common hyperkinetic movement disorder experienced by affected individuals. Dystonia typically fluctuates with activity and state, worsening in the context of action, stress, discomfort, and fatigue. Older children may experience a pattern of diurnal variation, with worsening at the end of the day and improvement following sleep.
  • Other hyperkinetic movement disorders including chorea, athetosis, myoclonus, and tremor may occur, usually intermittently.
• Dysautonomia. Autonomic dysfunction may manifest with a variety of symptoms:
  • Excessive sweating
  • Temperature instability
  • Ptosis, miosis
  • Cardiovascular abnormalities, including hypotension, bradycardia, and other heart rhythm disturbances
  • Upper airway obstruction (see below)
  • Hypoglycemic episodes (see below)
  • Gastrointestinal symptoms (see below)
• Epilepsy. Seizures are uncommon (<5% of reported individuals) [Rizzi et al 2022]. Oculogyric crises can be mistaken for seizures (see above).

Behavioral problems. Mood symptoms, including irritability and anxiety, occur in 50%-60% of affected individuals [Pearson et al 2020]. Behavioral features consistent with autism spectrum disorder have been reported in some individuals.

Neuroimaging. Brain MRI is typically either normal or may demonstrate nonspecific abnormalities, such as mild diffuse cerebral atrophy or delayed myelination [Wassenberg et al 2017].

Growth. Many affected individuals experience growth impairment, including short stature and poor weight gain.

Other associated features

• Respiratory abnormalities
  • Upper airway obstruction. Nasal congestion and stridor are common (due to a combination of airway hypotonia and catecholamine deficiency). This symptom is most pronounced in infants and young children, who can have audible breathing.
  • Acute worsening of upper airway obstruction may occur during an oculogyric crisis, leading to a need for airway support in some affected individuals.
• Sleep disorder. Hypersomnia is common in infancy. Children and adolescents may experience a range of sleep difficulties, including problems with sleep induction and insomnia with frequent nocturnal waking. Sleep apnea is also reported, which can result in premature mortality [Wassenberg et al 2017]. Sleep difficulties may be treated with melatonin (to aid induction) and clonidine (see Management).
• Gastrointestinal problems may include gastrointestinal dysmotility leading to gastroesophageal reflux disease, feeding intolerance, vomiting, diarrhea, and/or constipation. More severely affected individuals may have issues with aspiration, which can lead to aspiration pneumonia. Many affected individuals benefit from placement of a gastrostomy tube (see Management).
• Endocrinologic. Episodic hypoglycemia occurs in about one third of affected individuals and presents with typical symptoms such as lethargy, unresponsiveness, pallor, and sweating. Common triggers are concurrent illness, stress, and prolonged fasting.
• Other ophthalmologic involvement. Many individuals with AADC deficiency have bilateral ptosis as an autonomic manifestation of catecholamine deficiency. Ptosis may be present in infancy and can persist into adulthood. In some it may fluctuate (e.g., it may be worse in the context of fatigue, illness, or metabolic stress). However, most affected individuals do not required treatment for ptosis. Some affected individuals experience strabismus, for which ophthalmology evaluation and consideration of treatment is recommended (see Management).

Prognosis. There is an increased risk of early death due to medical complications such as pneumonia and aspiration. Sudden unexplained death may occur at any age, presumed to be due to an acute cardiorespiratory event. Current survival data is derived from retrospective cohorts. Hwu et al [2012] described 20 living affected individuals and ten deceased affected individuals who died between the ages of one and seven years, all of whom had a severe phenotype, suggesting about a one third childhood mortality risk in a population from Taiwan. However, the risk of death also depends upon choices about supportive medical interventions, such as tracheostomy/gastrostomy tube placement. Survival into the third decade of life has been reported in several individuals with mild-to-moderate phenotypes, and at least one affected individual was known to be living at age 36.8 years [Pearson et al 2020]. Successful pregnancy has been documented in a female age 26 years with a mild phenotype [Mastrangelo et al 2018] (see Pregnancy Management).

Genotype-Phenotype Correlations

No genotype-phenotype correlations for DDC have been identified. However, one individual has been reported with a c.304G>A (p.Gly102Ser) pathogenic variant who was responsive to levodopa therapy (see Targeted Therapies) [Chang et al 2004]. This specific pathogenic variant is located very close to the levodopa substrate binding pocket between Ile101 and Phe103. It is possible that other pathogenic variants in and around the levodopa substrate binding pocket may affect access to the active site and may confer levodopa responsiveness, but this has not yet been proven.

Nomenclature

AADC deficiency has also been referred to as dopa decarboxylase deficiency.

Prevalence

The worldwide incidence of AADC deficiency is not known. The condition is thought to be more prevalent in certain populations that originate from Asia, particularly Taiwan, Japan, and China, due to a founder pathogenic variant (c.714+4A>T) [Lee et al 2009, Hwu et al 2018, Dai et al 2020, Wen et al 2020, Himmelreich et al 2022]. A recent gnomAD-based study estimated worldwide incidence of AADC deficiency to be about 1:1,300,000 [Park et al 2023].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with AADC deficiency, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

There is no cure for AADC deficiency; however, gene therapy trials are currently under way (see Therapies Under Investigation).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.

Agents/Circumstances to Avoid

Avoid the following:

• Ergot-derived dopamine agonists with strong serotonergic (5-HT2B) agonist action (pergolide and cabergoline) due to risk of cardiac valvulopathy caused by valve fibrosis [Antonini & Poewe 2007, Wassenberg et al 2017]
• Levodopa in most affected individuals who do not have ligand binding site pathogenic variants
• Dopamine receptor antagonists (e.g., metoclopramide, antipsychotic medications), which may worsen primary disease symptoms

Evaluation of Relatives at Risk

Testing of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment of AADC deficiency. For at-risk sibs when prenatal testing was not performed:

• Molecular genetic testing is recommended, if the pathogenic variants in the family are known; and/or
• Measure CSF neurotransmitters (to evaluate for the characteristic profile) and plasma AADC enzyme activity.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Successful pregnancy has been documented in a 26-year-old female with a mild phenotype [Mastrangelo et al 2018]. This individual was being treated with escitalopram, pyridoxine, pramipexole (0.78 mg/day), and selegiline (up to 7.5 mg/day) around the time of conception. Both escitalopram and pyridoxine were discontinued and the doses of pramipexole and selegiline were decreased to 0.26 mg/day and 5 mg/day, respectively, without worsening of her neurologic symptoms. While this pregnant woman did develop preeclampsia at 31 weeks' gestation, she ultimately was able to deliver a small birth weight (small for gestational age) male infant at 38 weeks' gestation (term) who experienced transient hypoglycemia and tachypnea in the first few days of life. The infant was noted to be healthy with typical growth in the following months of life; long-term outcome information for the infant was not reported. The authors concluded that low dosages of pramipexole and selegiline during pregnancy could have good efficacy for the affected pregnant woman and may have a good safety profile [Mastrangelo et al 2018].

In general, selegiline use during pregnancy is often avoided due to concerns about potential vasoconstrictive effects. One infant in a set of twins exposed to this medication and to levodopa/carbidopa and entacapone for the treatment of Parkinson disease during pregnancy was found to have a ventricular septal defect [Seier & Hiller 2017].

In general, pramipexole is not anticipated to increase the rate of malformations in exposed human pregnancies, and there have been limited reports of normal birth outcomes in exposed infants [Seier & Hiller 2017].

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Gene therapy using one-time targeted delivery of a gene vector (AAV2-AADC) directly to the brain has been developed. Two different brain target sites have been studied for AADC deficiency: the putamen and the midbrain [Hwu et al 2012, Chien et al 2017, Pearson et al 2021, Tai et al 2022]. Studies are ongoing to determine the optimal target site and dose.

• Eladocagene exuparvovec (Upstaza^®). In 2022, putamenal delivery of eladocagene exuparvovec (Upstaza^®) was approved in the European Union and United Kingdom for the treatment of patients age 18 months and older with a clinical, molecular, and genetically confirmed diagnosis of AADC deficiency with a severe phenotype (i.e., patients who cannot sit, stand, or walk). Approval of the treatment followed reported improvements in symptoms and motor function in 26 affected individuals (ages 1.7-8.5 years) who were enrolled in three consecutive clinical trials (compassionate use, Phase I/II, Phase IIb) [Tai et al 2022]. Oculogyric crises were reported to decrease in severity after gene therapy, and three of the 24 individuals who had long-term follow up (2-10 years) gained the ability to walk independently.
• Midbrain gene delivery is being studied in an ongoing Phase I/II trial (NCT02852213). In an initial study of seven affected individuals (ages 4-9 years) with severe motor impairment, midbrain gene delivery resulted in complete resolution of oculogyric crises in 6/7 individuals, attainment of independent sitting within 12 months in 4/7, walking with two-hand support by 18 months in 2/7, and improved mood and sleep [Pearson et al 2021].

Both the putamenal and midbrain delivery approaches to gene therapy lead to detectable increases in the concentration of the dopamine metabolite homovanillic acid in cerebrospinal fluid. Greater increases are observed following midbrain gene delivery, which directly targets dopaminergic neurons. Neither approach addresses the serotonin deficiency that is also part of AADC deficiency.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Aromatic L-amino acid decarboxylase (AADC) deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for a DDC pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a DDC pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for a DDC pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Affected sibs tend to have similar clinical disease severity, although some variability has been observed (e.g., mild and moderate phenotypes described in the same family) [Pearson et al 2020]. Differences in response and tolerance to medications may influence the clinical course.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with AADC deficiency are obligate heterozygotes (carriers) for a pathogenic variant in DDC.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a DDC pathogenic variant.

Carrier Detection

Molecular genetic carrier testing for at-risk relatives requires prior identification of the DDC pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of individuals known to be carriers of AADC deficiency, particularly if both partners are of the same ancestral background. A pathogenic founder variant has been observed in individuals of Asian (particularly Chinese, Taiwanese, or Japanese) ancestry (see Table 9).

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. If both DDC pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Biochemical genetic testing. Prenatal enzyme testing of amniocytes, amniotic fluid, or chorionic villi has not been reported to date.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

DDC encodes aromatic L-amino acid decarboxylase (AADC), a homodimeric pyridoxal 5-prime phosphate (PLP)-dependent enzyme that catalyzes the decarboxylation of L-3,4-dihydroxyphenylalanine (DOPA) to dopamine, L-5-hydroxytryptophan to serotonin, and L-tryptophan to tryptamine [Bertoldi 2014]. This is the final step in the biosynthesis of the monoamine neurotransmitters serotonin and dopamine; dopamine is the precursor for norepinephrine and epinephrine. Most of the clinical manifestations of AADC deficiency can be explained by the deficiency of these four neurotransmitters. Dopamine deficiency affects cognitive function, emotion, and voluntary movement. Reduced expression of norepinephrine and epinephrine can impact attention, mood, sleep patterns, cognition, and stress hormone levels. Lastly, disturbance of serotonin can affect memory, learning, mood, sleep patterns, cardiovascular function, body temperature, and endocrine function [Brun et al 2010].

Mechanism of disease causation. Loss of function

Biochemical genetic testing. Dopamine-containing medications may falsely elevate the levels of 3-O-methyldopa (3-OMD), creating a false positive result. These same medications also may enhance in vitro enzyme activity, masking true enzyme deficiency.

Author Notes

Nenad Blau, PhD, and Sarah Elsea, PhD, FACMG, are chairs and Toni Pearson, MD, MBBS, is a member of the ClinGen Dopa Decarboxylase (Aromatic L-Amino Acid Decarboxylase) Variant Curation Expert Panel (VCEP), a panel of clinical, academic, and industry experts in the fields of genetics, pediatric neurology, functional genetics, and biochemistry assembled in pursuit of providing high-quality and systematic curation of DDC variants. With research progressing and gene therapy emerging, determining the pathogenicity of variants is critical to ongoing efforts toward diagnosis and patient care. Curation efforts will synergize with ongoing functional studies, analyses of function and genotype-phenotype correlations, and efforts to identify effective precision medications.

Sarah H Elsea is a clinical biochemical geneticist, Professor of Molecular & Human Genetics at Baylor College of Medicine, and Director of Clinical Genomics in the BCM-Human Genome Sequencing Center. Web page: www.bcm.edu/people-search/sarah-elsea-21035

Acknowledgments

This work was supported in part by Nenad Blau IEMbase Endowment Fund of the MCF, Marin County, CA, USA.

Sarah Elsea acknowledges research support for AADC deficiency research from PTC Therapeutics, support for metabolomics, genomics, and newborn screening research and development in neurotransmitter deficiencies from Speragen, Inc., and the SSADH Association.

Revision History

• 12 October 2023 (ma) Review posted live
• 9 January 2023 (nb) Original submission

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