Overview of the disease
A rare neurometabolic disorder with autosomal recessive inheritance.
The main manifestations are hypotonia, dyskinesia, developmental delay, ptosis, and excessive sweating.
Caused by a mutation in the dopa decarboxylase (DDC) gene on chromosome 7p12.2-p12.1.
Medication is the mainstay of treatment, with optional adjunctive therapeutic measures available
Definition
Aromatic L-amino acid decarboxylase deficiency (AADCD) is a rare autosomal recessive inherited neurometabolic disorder [1].
Aromatic L-amino acid decarboxylase (AADC) is also known as dopa decarboxylase (DDC), and mutations in its associated gene can lead to the development of the disease.
Aromatic L-amino acid decarboxylase deficiency is an early-onset disease that can develop as early as the neonatal period [2], and if diagnosed in time and treated with the appropriate medication, the symptoms can be controlled and the quality of survival of the child can be improved.
Morbidity
Aromatic L-amino acid decarboxylase deficiency was first reported in 1990 [3].
Currently, patients are mainly concentrated in Asia, especially in China and Japan [4-5]. The incidence of aromatic L-amino acid decarboxylase deficiency in Taiwan, China is 1:32,000 [6].
The vast majority of patients with aromatic L-amino acid decarboxylase deficiency present with signs and symptoms within the first 6 months of life. Males outnumber females by a ratio of approximately 4:3 [4].
Etiology
Pathogenesis
Aromatic L-amino acid decarboxylase deficiency is caused by mutations in the DDC gene localized on chromosome 7p12.2-p12.1.
Mutations are mostly missense or nonsense mutations, i.e., abnormalities in protein structure and function due to changes in the genetic material followed by changes in the corresponding amino acids within the protein (missense mutations) or premature termination of peptide chain synthesis (nonsense mutations) [7].
High risk factors
Aromatic L-amino acid decarboxylase deficiency is an autosomal recessive disorder with an elevated risk in those with a family history of the disease.
Pathogenesis
Aromatic L-amino acid decarboxylase plays an important role in the synthesis of serotonin and monoamine neurotransmitters such as dopamine, epinephrine, norepinephrine and other catecholamines.
Decreased activity of aromatic L-amino acid decarboxylase in children with aromatic L-amino acid decarboxylase deficiency can lead to decreased production of monoamine neurotransmitters, while substances that synthesize monoamine neurotransmitters (5-hydroxytryptophan, levodopa) are not consumed in a timely manner and deposition occurs [2].
These changes lead to a disturbance in the metabolism associated with these neurotransmitters, which in turn manifests itself in the corresponding symptoms of aromatic L-amino acid decarboxylase deficiency.
Symptoms
Main Symptoms
Hypotonia
Myotonia is the tension of a muscle in its resting relaxed state and the resistance it encounters during passive movement, and is the contractile response of skeletal muscle when pulled by an external force.
In hypotonia, when the child’s limbs are pulled to passive movement in a resting state, the resistance is felt to decrease or disappear; the limbs are in a state where the joints are over-extended and easily dislocated.
Dyskinesia
Eye movement crisis
This is characterized by involuntary eye movements, mostly frequent (episodic) upward movements of both eyes, lasting from a few seconds to several hours, which may be accompanied by spasms of the neck, perioral muscles, and tongue muscles.
It is present in the majority of patients of all ages, and is most severe in the early years of life, when about 97% of children between the ages of 2 and 12 years have the symptoms.
Dystonia
This is characterized by repetitive, sustained involuntary movements of part of the body and abnormal postures.
Dyskinesia
Weakness in motor skills compared to normal individuals of the same age.
Developmental delay
This is characterized by delayed motor, cognitive and language development, i.e., the level of motor, cognitive and language functioning is weaker than that of a normal person of the same age.
Autonomic symptoms
Manifested as ptosis, excessive sweating, nasal congestion, etc. [8].
Other symptoms
Some children may have seizures [1], behavioral abnormalities such as irritability, excessive crying, and restlessness [9], as well as sleep disorders such as insomnia, drowsiness, and severe sleep apnea.
In addition, gastrointestinal symptoms such as diarrhea, constipation, and difficulty in eating may occur.
Complications
Bradycardia
Children with aromatic L-amino acid decarboxylase deficiency may develop bradycardia, which may be asymptomatic or present with transient dizziness, black haze, palpitations, weakness, or syncope.
Cardiac arrest
The sudden termination of the heartbeat, which can be life-threatening.
Consultation
Department
Obstetrics
If a prenatal screening test reveals that the fetus may have the disease, it is recommended that you seek medical attention.
Neonatology
If a newborn baby has hypotonia, dyskinesia, autonomic symptoms, etc., it is recommended to consult a doctor promptly.
Pediatrics
If a child has hypotonia, dyskinesia, developmental delay, autonomic symptoms, etc., it is recommended to consult a doctor promptly.
Preparation for medical treatment
Consultation: Registration, Preparation of documents, Frequently Asked Questions
Tips for seeking medical treatment
If abnormalities are detected during prenatal checkups, it is important to pay attention to them and bring the results with you to the doctor. It is also advisable to find out if there are any similar patients in the family for the doctor’s reference before seeking medical treatment.
Aromatic L-amino acid decarboxylase deficiency can develop as early as during the neonatal period. Therefore, guardians should pay attention to the condition of the child after birth, and if abnormalities are detected, they should record the time of onset and duration of the abnormalities, and consult a doctor promptly.
Checklist for medical preparation
Symptom list
Particular attention should be paid to the time of onset of symptoms, special manifestations, etc.
What are the abnormalities in the child? Have you noticed any involuntary eye movements, abnormal body movements, drooping upper eyelids, excessive sweating, etc.?
What was the earliest abnormality noticed?
How long do the symptoms usually last? Under what circumstances do most of them appear?
Are there any differences in the child’s physical development, cognition, speech, etc. compared to his/her peers?
Medical History Checklist
Has anyone in the family had a similar condition?
Was there any abnormality found in the mother’s labor and delivery during pregnancy?
Checklist
Test results from the last six months, which can be brought to the doctor’s office
Laboratory tests: genetic tests, measurement of enzyme activity and hormone levels.
Imaging tests: ultrasonography, magnetic resonance imaging (MRI)
Others: electrocardiogram (ECG), electroencephalogram (EEG)
Diagnosis
Diagnosis is based on
Medical history
The child may have a family history of aromatic L-amino acid decarboxylase deficiency.
Clinical manifestations
Symptoms
Children may present with hypotonia, dyskinesia, dyspraxia, dysgraphia, autonomic symptoms, and in some cases seizures, irritability, and diarrhea.
Physical signs
Examination of the child’s muscle tone may reveal hypotonia.
Laboratory tests
Genetic examination
Genetic testing for pure or compound heterozygous mutations in the DDC gene is the “gold standard” for diagnosing aromatic L-amino acid decarboxylase deficiency.
Measurement of enzyme activity and hormone levels
Samples of cerebrospinal fluid and blood are taken and the levels of relevant enzymes and hormones are measured to assist in the diagnosis.
For example, cerebrospinal fluid levels of 5-HIAA, homovanillic acid, and phenylethanol are decreased, and levels of 3-methyldopa, levodopa, and 5-hydroxytryptophan are increased, which are of diagnostic value.
AADC activity measurement in plasma reveals a decrease in the level of AADC enzyme activity has diagnostic value.
Imaging examination
Echocardiography
Echocardiography can help with screening to understand the structure and function of the heart.
MRI
If the child has neurodevelopmental delay, cranial MRI may be performed to understand the brain.
Other
Electrocardiogram (ECG)
Electrocardiogram can screen for arrhythmias such as bradycardia and understand any cardiac complications.
Electroencephalogram (EEG)
Electroencephalogram can be used to find out about epilepsy in the child.
Diagnostic Criteria
A definitive diagnosis of aromatic L-amino acid decarboxylase deficiency can be made by meeting 2 of the following 3 criteria [10].
Decreased cerebrospinal fluid levels of 5-hydroxyindoleacetic acid and homovanillic acid, increased levels of 3-methoxy-4-hydroxyphenylethylene glycol, 3-methyldopa, levodopa, and 5-hydroxytryptophan, and normal cerebrospinal fluid natriuresis.
Complex heterozygous or pure pathogenic DDC gene variants.
Decreased plasma AADC enzyme activity.
Differential Diagnosis
Aromatic L-amino acid decarboxylase deficiency requires differential diagnosis from other causes of hypotonia, such as hypotonia due to cerebral palsy and Prader-Willi syndrome.
The diagnosis is confirmed by the detection of mutations in the DDC gene, mainly through genetic testing.
Treatment
Aim of treatment: to improve the quality of life of the children.
Treatment principle: drug treatment is gradual, the dose is low and then slow, and the drug is stopped or gradually discontinued [10].
Medication
维生素B6类药物
Primarily pyridoxine, but also pyridoxal 5-phosphate can be used.
Pyridoxine can cause occasional adverse effects such as nausea and vomiting, and prolonged high dose use may lead to severe sensorimotor polyneuropathy [10].
Dopamine agonists
These include drugs such as dobasic hydrazide, ropinirole, rotigotine, and bromocriptine.
Dobas hydrazide can be taken with food and has adverse effects such as dyskinesia.
Ropinirole is contraindicated in individuals with severe renal dysfunction, but may increase the risk of dyskinesia.
There is a lack of data on rotigotine for use in children under 12 years of age and under 15 kg, and adverse reactions include skin reactions and dyskinesia.
Bromocriptine is generally not used as a drug of choice and carries a risk of concomitant cardiac damage [10].
Monoamine oxidase inhibitors
Mainly selegiline (propargylamine), avoid nighttime administration in those with insomnia [10].
Antiphencyclidine
Mainly non-selective monoamine oxidase A and B inhibitors.
Avoid nighttime administration in those with insomnia [10].
Targeted therapeutic agents
Upstaza has been approved by the European Commission for the treatment of aromatic L-amino acid decarboxylase deficiency.
The drug consists of a modified virus containing a functional version of the normal DDC gene, and when injected into the brain, the virus is expected to carry the normal gene into nerve cells, enabling them to produce the missing enzyme, thus improving the associated symptoms.
This drug is not currently approved for marketing in China.
Other symptomatic drugs
Anticholinergic drugs such as phenazopyridine are available for dystonia; adverse effects include sedation at high doses.
Nasal congestion can be treated with hydroxymetazoline nasal drops, and if a monoamine enzyme inhibitor is used concomitantly, try to include a non-treatment interval to preserve the medication interval and prevent hypertensive crises.
Sleep disorders can be treated with melatonin and colistin.
Irritability can also be treated with colistin [10].
Adjunctive therapy
There are no studies on adjuvant therapy for aromatic L-amino acid decarboxylase deficiency, but physical therapy, speech therapy, occupational therapy, and psychotherapy are important for promoting development and preventing complications in children with dystonia, dyskinesia, and developmental disorders [2].
Prognosis
Cure
Aromatic L-amino acid decarboxylase deficiency can develop in the neonatal period and the maximum age of diagnosis is 43 years [11].
Treatment with medication can improve dystonia and dyskinesia and enhance the quality of survival.
Prognostic factors
Early detection, early diagnosis and immediate intervention therapy might help to improve the prognosis [5].
Critically ill patients have a significant risk of death in childhood [12].
Hazards
Aromatic L-amino acid decarboxylase deficiency can lead to hypotonia, dyskinesia, and developmental disorders, which can severely affect the growth, development, learning, and life of affected children.
As a result of hypotonia, children may develop severe motor injuries that further affect normal activities.
Children with reduced mobility require repeated hospitalization and are at risk of fatal infections [2].
Aromatic L-amino acid decarboxylase deficiency is a genetic disorder with an elevated risk of development in those with a family history.
Aromatic L-amino acid decarboxylase deficiency has a long course and requires long-term family support and care, and children may develop negative emotions such as self-blame and low self-esteem during their growth.
Daily
Daily management
Dietary management
Breastfeeding is recommended for children under 6 months of age, while children over 6 months of age should be fed with complementary foods in a timely and reasonable manner according to their nutritional needs.
For children who have difficulty in eating, small amount of multiple feedings can be considered to ensure their nutritional supply. Some patients need to have gastric tube or gastrostomy to improve feeding.
Exercise management
The child has low muscle tone, so care should be taken when picking up the child to avoid injury.
According to the muscle strength of the child, choose the appropriate form of exercise and strengthen the protection, if necessary, under the guidance of professionals (e.g., rehabilitation trainer, etc.) to carry out activities.
Psychological support
Guardians should help the child to build up an optimistic mindset when growing up. If the child is found to have negative emotions such as self-doubt or low self-esteem, he/she should be counseled in time.
Prevention
Genetic counseling is recommended before childbearing for those with a family history of aromatic L-amino acid decarboxylase deficiency.
Prenatal screening during pregnancy also helps in prenatal diagnosis.