Aromatic L-amino acid decarboxylase deficiency

Neurogenetic Disorders

Updated 08.03.2023
Released 11.28.1994
Expires For CME 08.03.2026

Aromatic L-amino acid decarboxylase deficiency

Authors: Thomas Opladen MD, Georg F Hoffmann MD

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Editor: Barry Wolf MD PhD

Aromatic L-amino acid decarboxylase deficiency

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Introduction

Overview

Aromatic L-amino acid decarboxylase deficiency was identified as an autosomal recessively inherited disorder of biogenic amine metabolism resulting in combined generalized deficiency of serotonin and all catecholamines. The main clinical features typically present in infancy developmental delay, hypokinesia, truncal muscular hypotonia, often combined with limb rigidity, a progressive extrapyramidal movement disorder, especially parkinsonism-dystonia and chorea, oculogyric crises, as well as autonomic symptoms, sleeping difficulties, and irritability. Initial suspicion of the diagnosis can be made by newborn screening. Today, confirmation of diagnosis is primarily by molecular genetic analysis of the affected DDC gene.

Because the products of the defective enzyme, serotonin and dopamine, cannot pass through the blood-brain barrier, aromatic L-amino acid decarboxylase deficiency is one of the most difficult neurotransmitter disorders to treat. Consensus-based treatment guidelines are available. Adeno-associated virus vector–mediated gene delivery of the dopa decarboxylase (DCC) gene bilaterally into the putamen or to the substantia nigra plus the ventral tegmental area demonstrated safety and efficacy in clinical studies. Putamen-based gene therapy was approved by the EMA in Europe in July 2022. It is hoped that the outlook of this often-devastating disorder will be improved with early detection by newborn screening followed by optimized therapy (ie, gene therapy).

The International Working Group on Neurotransmitter related Disorders has been instrumental in these positive developments with the first international, longitudinal (patient registry) and (evidence-based guidelines for diagnosis and treatment).

A nonprofit international support group, the AADC Research Trust Children’s Charity, has also been instrumental in helping to provide information and linking families and professionals involved in diagnosis, care, and research.

Key points

	• Aromatic L-amino acid decarboxylase deficiency presents with severe autonomic developmental and neurologic dysfunction. It should be considered in infants and children with features suggestive of dystonic or athetoid cerebral palsy, hypotonia, developmental delay, oculogyric crises, and autonomic symptoms of unknown etiology.
	• Aromatic L-amino acid decarboxylase deficiency is inherited in an autosomal recessive manner, and some genotype-phenotype correlations have been described.
	• Aromatic L-amino acid decarboxylase deficiency leads to severe deficiency of serotonin as well as all catecholamines.
	• Diagnosis is based on molecular genetic analysis of the affected DDC gene, either as part of a broad genetic workup or specifically after finding a suggestive pattern of neurotransmitters in CSF.
	• Gene therapy approaches to the putamen or substantia nigra are showing promising results.

Historical note and terminology

For many years, disorders leading to severe deficiencies of biogenic amines (serotonin, dopamine, epinephrine, and norepinephrine) in infants and children were exclusively associated with biochemical defects of tetrahydrobiopterin metabolism (38). Tetrahydrobiopterin is the cofactor for tyrosine hydroxylase and tryptophan hydroxylase, the rate-limiting enzymes required for dopamine and serotonin biosynthesis. Fortunately, children with these disorders are often detected early because tetrahydrobiopterin is also the cofactor for phenylalanine hydroxylase, which causes hyperphenylalaninemia and is detected in newborn screening programs. The next step in the biosynthesis is decarboxylation by aromatic L-amino acid decarboxylase encoded by the DDC gene. Autosomal recessively inherited mutations in the DDC gene impair the synthesis of both serotonin and the catecholamines. Over 80 different pathogenic mutations have been published: http://www.biopku.org.

In 1988, monozygotic twins presented at the Hospital for Sick Children, Great Ormond Street, London, with the neurologic symptoms of biogenic amine deficiency, reminiscent of defects of tetrahydrobiopterin metabolism. Central and peripheral neurotransmitter deficiency was confirmed, but the children were not hyperphenylalaninemic, nor did they have any abnormality of tetrahydrobiopterin metabolism.

The step after tyrosine hydroxylase and tryptophan hydroxylase in the biosynthetic pathway for dopamine and serotonin is common to both pathways and involves the vitamin B₆ (pyridoxal 5’-phosphate) dependent decarboxylation of levodopa and 5-hydroxytryptophan to form dopamine and serotonin, respectively. These reactions are catalyzed by a single enzyme, aromatic L-amino acid decarboxylase (29). This enzyme is often named according to the substrate being metabolized (ie, levodopa decarboxylase or 5-hydroxytryptophan decarboxylase).

Confirmation of the diagnosis in the twins described was made by measuring levodopa and 5-hydroxytryptophan decarboxylase activity in liver biopsy (21; 22).

Since the initial description of aromatic L-amino acid decarboxylase deficiency, about 350 cases have been identified, with 143 DDC variants and 151 genotypes (19). They are listed in the Pediatric Neurotransmitter Disorders database.

Clinical manifestations

Presentation and course

Age of onset. There are no specific maternal health problems or specific perinatal difficulties that have been documented during pregnancies with a child with aromatic L-amino acid decarboxylase deficiency. In aromatic L-amino acid decarboxylase deficiency, a high frequency of small-for-gestational age babies was noted (25). The mean age of onset of signs and symptoms was within the first year of life (2.7 months); however, neonatal onset can also exhibit lethargy, hypotonia, metabolic acidosis, apnea, and hypoglycemia (01).

The original description of the twins (21) encompasses most of the clinical features of this disease, with signs being virtually identical in many other reported cases (30; 43; 31; 18). For detailed description, see the clinical vignette section.

Based on clinical presentations, cases were broadly classified as mild (mild delay in developmental milestones, ambulatory without assistance, mild intellectual disability), severe (no or very limited developmental milestones, fully dependent), and moderate (in between). It should be noted that this classification is far too nonspecific and a multifactorial assessment of clinical, biochemical, genetic as well as other factors is needed for a detailed severity classification.

Key symptoms of aromatic L-amino acid decarboxylase deficiency include muscular hypotonia, movement disorders, developmental delay, oculogyric crises, and autonomic symptoms.

Summaries of the clinical features have been published (10; 48; 40; 25). Patients typically show muscular hypotonia, poor sucking, feeding difficulties, and a tendency to hypoglycemia from birth. In the first few months of life, symptoms of dystonia or intermittent limb spasticity, axial and truncal hypotonia, extreme irritability, oculogyric crises, and psychomotor retardation develop. Head control and development of further motor milestones is poor in infancy. Progressive neurologic dysfunction, especially extrapyramidal movement disorders comprising parkinsonism-dystonia, occurs in early childhood. Dystonia may be accompanied by athetosis or chorea. Eye fixation is poor. Voluntary movements are difficult. Physical examination may reveal brisk knee reflexes and extensor plantar responses. Speech is dysarthric or absent. Associated features are sleep disturbances, labile temperature regulation, autonomic dysfunction, nasal congestion, irritability, and cognitive impairment.

Along with ptosis, miosis, and paroxysmal sweating, other autonomic symptoms in aromatic L-amino acid decarboxylase deficiency include chronic nasal congestion, temperature instability, hypotension, hypersalivation, and especially complex feeding difficulties related to disturbed intestinal motility, reflux, diarrhea, and constipation. One patient was not diagnosed until 15 years of age, with chronic diarrhea being his most prominent symptom resulting in dehydration and malnutrition (27). Patients may have difficulty swallowing or eating. This can be so severe that gastrostomy is necessary. Gastroesophageal reflux disease can require fundoplication. Providing enough energy and fluid is often problematic, and patients are at risk of becoming cachectic (43). Two patients also suffered from inflammatory bowel disease.

Periodic sleep disturbances and episodes of excessive crying can be very troublesome and cause severe problems for families and caregivers. Endocrine abnormalities, including (tendency to) hypoglycemia, elevated prolactin levels, and growth (hormone) deficiency, have also been reported (43). Reduced catecholamine production puts patients at risk for apnea or sudden cardiac arrest, especially when exposed to stressful situations including hospitalization for diagnostic procedures or surgeries (05).

About a third of patients have single seizures with corresponding EEG abnormalities, but rarely develop severe epilepsy (43; 23; 31). Before the definitive diagnosis is established, oculogyric crises are often mistaken as seizures and many antiepileptic therapies are initiated, all with little effect on these dopamine-deficiency phenomena. When seizures occur, they are grand mal or complex focal types. An ictal electroencephalographic study in an 11-year-old male demonstrated the presence of epileptic spasms and generalized tonic seizures together with involuntary nonepileptic movements. Epileptic attacks were controlled with antiepileptic drugs. This study demonstrates that differentiation between epileptic and nonepileptic episodes in aromatic L-amino acid decarboxylase deficiency is vital.

Within the clinical spectrum, milder forms of the disease have been described. Those with the milder form predominantly exhibit autonomic symptoms (diarrhea, episodic hypoglycemia, nasal congestion), even without an evident movement disorder (06; 40). Psychomotor retardation was noted in a girl at 9 months of age. Hypotonia, short periods of hypertonicity, and oculogyric crises were also present. By 2 years of age, the child could sit without support and could communicate nonverbally. Muscle tone still varied between hypo- and hypertonicity. Excessive sweating was noted, and oculogyric crises persisted (02). Two Chinese siblings were found to have aromatic L-amino acid decarboxylase deficiency at 10 and 12 years of age. At the time of diagnosis, both had excessive fatigability, hypersomnolence and dystonia. Early symptoms were mild in comparison to those observed in most other individuals with aromatic L-amino acid decarboxylase deficiency. First presentation was between 3 and 6 months with truncal hypotonia, bilateral ptosis, and mild developmental delay. Both siblings had appropriate speech development; one was able to walk independently and the other with assistance. Both functioned better in the morning. Treatment with selegiline, vitamin B6, and bromocriptine led to marked improvement in muscle strength and dystonic symptoms and to the ability to walk independently in the sibling who previously required assistance (45). Three patients (2 siblings and a cousin) have been diagnosed with syndromic intellectual disability. They showed craniofacial dysmorphisms, chronic diarrhea with or without recurrent hypoglycemia, gastroesophageal reflux, and progressive kyphoscoliosis, but were lacking specific clinical features, including oculogyric crises or severe hypotonia. Only as adults were they diagnosed with aromatic L-amino acid decarboxylase deficiency by whole exome sequencing (17). Two sisters were also diagnosed in adulthood with a stable to improving symptomatology, which was thought to be congenital myasthenia (28). A case has been described in which there was striking autistic behavior in an untreated boy by 4 years of age (11). It is expected that with the spread of newborn screening for the disorder, more patients with mild phenotype will be identified.

Psychiatric disorders in carriers. In several case series there was a high incidence of psychiatric disorders in first- and second-degree relatives (43; 31). These psychiatric disorders were depression, psychosis, suicide, or suicide attempts. The extreme stress related to the very demanding care for patients must, however, be considered.

Prognosis and complications

Until now, the overall prognosis is guarded. About half the patients stabilize with a combined therapy of pyridoxine, dopamine agonists, and monoamine oxidase inhibitors acquiring different degrees of motor and psychosocial skills. The others do not show any sustained improvements (31; 10; 48; 40). About 20% clearly improve to the point that they successfully manage regular schooling as long as some help is provided for the remaining motor handicap. Despite all therapeutic interventions, the disease course is often severe and can be fatal at a young age or any time.

Gene therapy has had a clear impact on prognosis and is being developed as a novel causal and disease-changing approach for the treatment of aromatic L-amino acid decarboxylase deficiency (20; 16; 24; 46; 41). The viral vector-mediated gene transfer of the human DDC gene into the putamen or substantia nigra, as well as into the ventral tegmental area, permits learning of motor (and in some cases cognitive) milestones for the first time in patents with a severe phenotype (41; 44).

Clinical vignette

Male identical twins of normal birth weight were born following a normal pregnancy and delivery. No neonatal problems were reported. Generalized hypotonia was present at 2 months, together with developmental delay and paroxysmal movements consisting of a cry followed by extension of arms and legs, eyes rolling up, and cyanosis. Anticonvulsant therapy was ineffective. Social smiling developed at 3 months and babbling speech at 9 months.

At 9 months, the twins were within the normal range for weight (10th percentile), length (10th percentile), and head circumference (50th percentile). Thereafter, linear growth, growth in head circumference, and weight gain had virtually ceased until 1 year of age. Clinical signs included irritability, incessant crying, poor head control, and skin pallor. Despite normal muscle bulk, they were floppy with central and peripheral hypotonia; there was paucity of spontaneous movements and flattening of the occiput. There was fine chorea of the distal limbs when the twins were awake. Direct tendon reflexes were brisk, and superficial reflexes were present. Both twins produced excessive sweat, had normal tear production, and had unstable temperature in the absence of any obvious infection. There was miosis, ptosis, and a reverse Argyll Robertson pupil. Extraocular movements and the ocular fundi were normal. ECG showed normal beat-to-beat variation. Postural drop in blood pressure was not present at 9 months but was noted at 1 year. Motor and sensory peripheral nerve conduction velocities were normal; EMG showed no spontaneous activity; and recruited potentials were normal. CT and MRI of their brains demonstrated cerebral atrophy.

Two distinct paroxysmal movements occasionally occurred. The first commenced with a cry, followed by extension of the legs and ankles, extension of the arms with internal rotation at the shoulder, flexion and ulnar deviation at the wrists, finger extension, and abdominal rigidity. The second also began with a cry but was followed by deviation of the eyes either up or down for up to 30 seconds. The limb and eye movements could occur simultaneously. The eye movements were conjugate when upward but convergent when downward. Doll's head maneuvers did not affect the eye position. EEG showed normal awake and asleep activities, and the awake pattern was not affected during the paroxysmal movements. The abnormal eye movements disappeared on treatment with bromocriptine (a dopamine D2 receptor agonist) and were considered extrapyramidal in nature.

After 1 year of treatment with pyridoxine (100 mg twice daily), tranylcypromine (4 mg twice daily), and bromocriptine (2.5 mg twice daily) in combination, weights and lengths were at the 10th percentile, and head circumferences were at the 50th percentile. The twins crawled at 4 years of age and walked at 5 years. They were saying only a few words but were adept at nonverbal communication and had good comprehension. At 8 years of age, fine hand coordination allowed the tying of shoes, writing, and feeding with utensils. Language comprehension was good, but speech was limited to about 10 words, and academic function was 3 years behind grade level. There was absence of bowel and bladder control. A striking diurnal fluctuation in motor function and tone was apparent with the twins becoming floppy, weak, parkinsonian, dystonic, and ataxic and with development of ptosis of the eyelids and postural instability during the progression of the day. A short nap was sufficient to restore motor function to near that seen in the morning. There were no signs of major autonomic failure. Head circumference was at the 50th percentile. Over the following 25 years the clinical picture did not change significantly.

Another instructive case of aromatic L-amino acid decarboxylase deficiency was well documented, undiagnosed, and untreated until 5 years of age. From birth, there were muscle hypotonia, poor sucking, and feeding difficulties. At 4 months of age, paroxysmal episodes of inconsolable crying developed together with rolling of the eyes, temperature instability, and extension of the extremities. At 10 months of age, global developmental delay and profound muscle hypotonia were present. Brain MRI was normal, and head circumference was at the 25th percentile. At 5 years of age, brain MRI was again found to be normal, and head circumference remained at the 25th percentile. Episodes of eye-rolling continued, and there were persistent and profound axial hypotonia and increased muscle tone of the extremities, with brisk deep tendon reflexes and extensor plantar responses. Spontaneous movements were choreoathetoid in nature. This male child was socially interactive and appeared to understand verbal commands but was unable to vocalize. He was noted to sweat excessively (30). At baseline, patients are predominantly hypotonic-hypokinetic, but with stress (eg, febrile illness), dystonic or dyskinetic crises may occur, and rhabdomyolysis has been reported (33).

Biological basis

Etiology and pathogenesis

Aromatic L-amino acid decarboxylase deficiency is an autosomal recessive disorder caused by variants in the DDC gene. The human DDC gene is encoded by a single-gene copy that is over 85 kb in length. It is located on chromosome 7p12.1-p12.3 and contains 15 exons (03). The enzyme requires pyridoxal phosphate as a cofactor and is a homodimer composed of identical subunits with a molecular mass of 53.9 kDa. Differential splicing leads to two forms of aromatic L-amino acid decarboxylase mRNA that code for a single amino acid sequence. These mRNAs differ in their 5’ untranslated regions and are encoded by two distinct exons, exon N1 being designated the neuronal type and exon L1 the nonneuronal type. The two forms of mRNA are produced by alternative use of these two first exons. Alternative splicing also exists in the coding region of the human aromatic L-amino acid decarboxylase mRNA. Differential splicing in this area leads to the formation of a short-version transcript that lacks exon 3 and appears not to have any enzyme activity (12). Genomic sequencing of the DDC gene has revealed more than 143 different variants, which are collected in the Pediatric Neurotransmitter Disorders database (19). Detailed studies of the structural and functional consequences of different mutations delineate varying consequences that lead to specific enzymatic phenotypes (35; 18). It is hoped that these studies will help to guide therapeutic decisions including the prevention of individually inappropriate therapy.

About half of the patients diagnosed to date are of Southeast Asian descent, especially from China, Taiwan, and Japan. They carry a common mutation, IVS6+4A>T (26). The variant is a splicing site alteration that results in the insertion of 37 nucleotides into the DDC mRNA, leading to a very severe phenotype.

In one family, three patients had an L-DOPA-responsive movement disorder. Sequencing revealed a homozygous G-to-A substitution converting glycine to serine at position 102 (G102S) in exon 3. Kinetic studies and analysis of the enzyme structure revealed that the mutation increased the apparent K_m for L-DOPA, altering the protein configuration near the substrate-binding site (13). Optimal clinical response was achieved after additional treatment with pyridoxal phosphate. The pyridoxal phosphate forms a Schiff base, rearranges the substrate pouch, and may act as a chaperone (35).

Decreased activity of aromatic L-amino acid decarboxylase leads to reduced synthesis of catecholamines and serotonin and an accumulation of 3-O-methyldopa, 5-hydroxytryptophan, and levodopa in CSF, plasma, and urine. The methylation of levodopa to form 3-O-methyldopa reduces the levels of S-adenosylmethionine within the central nervous system and sometimes the level of 5-methyltetrahydrofolate (18).

The clinical symptoms are attributed to severe deficiency of biogenic amine neurotransmitters. Dopamine deficiency results in progressive extrapyramidal movement disorders, especially hypokinesia, parkinsonism-dystonia, and chorea. Dopamine not only plays a central role in the control of movement, but also is important for cognition and emotion/affect, and neuroendocrine, pituitary gland hormones (prolactin and growth hormone) (18; 40). Under physiological circumstances, dopamine concentrations are also high in the kidney, where it is involved in control of sodium and water transport. In the gastrointestinal tract, dopamine controls motility. Reduction or inappropriately low response of norepinephrine and epinephrine can lead to hypoglycemia, ptosis, and autonomic disturbances with loss of regulation of body temperature, vascular tone and blood flow, decreased blood pressure, and inappropriate stress response. It also affects attention, mood, sleep, and cognition. Deficiency of serotonin does not appear to lead to the severe neurologic symptoms, but affects appetite, sleep, memory, learning, mood, modulation of pain mechanisms, as well as cardiovascular and endocrine functions. This description outlines the pathophysiology of the complex, severe, and difficult to treat consequences of aromatic L-amino acid decarboxylase deficiency (18).

Epidemiology

The exact prevalence of aromatic L-amino acid decarboxylase deficiency and the number of patients are not known. About 350 cases of aromatic L-amino acid decarboxylase deficiency have been identified since the initial description of the index family in different ethnicities. A larger cohort of patients has been described from Taiwan where newborn screening has now been started as a pilot project by measuring 3-O-methyldopa in dried blood spots of newborns (26; 15). Four newborns with elevated 3-O-methyldopa were identified out of 130,000 newborns and were confirmed as having aromatic L-amino acid decarboxylase deficiency, giving an estimated incidence of aromatic L-amino acid decarboxylase deficiency in Taiwan of 1 in 32,000 (95% confidence interval: 1 in 12,443 to 1 in 82,279). A comparable newborn screening pilot project in Germany identified one aromatic L-amino acid decarboxylase–deficient patient in 585,735 children screened.

Whitehead and colleagues used whole-genome sequencing and whole-exome sequencing data to probe genomic DNA sequence databases for the frequency of pathogenic DDC variant alleles in the United States, European Union, and Japan (49). Variants already described in patients with aromatic L-amino acid decarboxylase deficiency and known to be pathogenic as well as variants predicted to be pathogenic based on the impact of missense mutations and splice site variants were found. Based on analysis of approximately 200,000 individual genomes, 33 previously known and 183 predicted pathogenic variants were identified. The predicted birth rates of newborns with aromatic L-amino acid decarboxylase deficiency are 1 in 90,000 in the United States, 1 in 118,000 in the European Union, and 1 in 182,000 in Japan, respectively. These birth rates translate into a current estimate of about 1800 living patients with aromatic L-amino acid decarboxylase deficiency in the United States (estimated n = 840), European Union (estimated n = 853), and Japan (estimated n = 125).

This estimate differs from the above-mentioned incidences found in national newborn screening pilot studies. Further studies are needed to confirm the incidences in different populations. However, aromatic L-amino acid decarboxylase deficiency is a rare to ultrarare disorder, and a relatively large number of individuals worldwide may go undiagnosed.

Differential diagnosis

Confusing conditions

Aromatic L-amino acid decarboxylase deficiency can mimic neuromuscular disorders. Descriptions of individuals with aromatic L-amino acid decarboxylase deficiency initially designated as having cerebral palsy occur in the literature; therefore, aromatic L-amino acid decarboxylase deficiency should be considered in infants and children with features suggestive of neuromuscular disorders, dystonic or athetoid cerebral palsy, hypotonia, developmental delay, and autonomic symptoms of unknown etiology (43; 48; 18; 40).

All inborn errors of dopamine metabolism, including L-amino acid decarboxylase deficiency, have many similar clinical characteristics. However, the diseases are easily separated by biochemical indices. Tetrahydrobiopterin deficiency, DNAJ12 deficiency, and aromatic L-amino acid decarboxylase deficiency ultimately lead to deficiencies of catecholamines and serotonin, resulting in lower concentrations of homovanillic acid and 5-hydroxyindoleacetic acid in CSF. In contrast to primary enzyme defects in monoamine biosynthesis, tetrahydrobiopterin deficiencies or DNAJ12 deficiency result in accumulation of plasma phenylalanine and lead to phenylketonuria (38; 04).

Elevation of phenylalanine is not seen in aromatic L-amino acid decarboxylase deficiency, and tetrahydrobiopterin and neopterin in CSF are normal (22; 31; 48; 18). In tyrosine hydroxylase deficiency, phenylalanine, serotonin, and tetrahydrobiopterin metabolism are not affected, but an isolated deficiency of homovanillic acid in CSF does occur. The opposite, extremely elevated dopamine metabolites in cerebrospinal fluid are the hallmark of the dopamine transporter deficiency syndrome, whereas neurotransmitter determinations are usually unremarkable in the vesicular monoamine transporter 2 deficiency (37; 36). The accumulation of 3-O-methyldopa, 5-hydroxytryptophan, and levodopa in peripheral and central fluids in aromatic L-amino acid decarboxylase deficiency is not seen in any of the defects that affect tetrahydrobiopterin metabolism or in tyrosine hydroxylase deficiency. Similarly, elevations of these metabolites are not seen in conditions in which there might be nonspecific destruction of serotonergic or catecholaminergic neuronal pathways; such conditions would also lead to reduced levels of homovanillic acid and 5-hydroxyindoleacetic acid in CSF.

Associated or underlying disorders

Several reports of aromatic L-amino acid decarboxylase deficiency arising secondarily to pyridoxal 5’-phoshate deficiency have been described (34). These patients presented in infancy with a severe seizure disorder. Cerebrospinal fluid neurotransmitter metabolite profiles suggested aromatic L-amino acid decarboxylase deficiency, but primary deficiency of this enzyme was excluded by molecular analysis and by a finding of normal enzyme activity in plasma. In 2005, this disorder was shown to be caused by mutations in the PNPO gene encoding pridox(am)ine 5’-phosphate oxidase (34).

Diagnostic workup

	• Genetic analysis of the DDC gene should be performed to diagnose aromatic L-amino acid decarboxylase deficiency.
	• Metabolic key findings include the following:
		-- Increased concentrations of 3-O-methyldopa in dried blood spots in newborn screening or during diagnostic work-up
		-- Markedly reduced concentrations of homovanillic acid and 5-hydroxyindoleacetic acid in CSF, together with elevated concentrations of 3-O-methyldopa, L-dopa, and 5-hydroxytryptophan
		-- Decreased levodopa decarboxylase activity in plasma
		-- Low whole blood serotonin concentrations and elevated urinary vanillactic acid and vanillactic acid/vanillylmandelic acid ratios

The presence of generalized hypotonia associated with oculogyric crises, ptosis, temperature instability, and sweating after about 2 months of age should suggest the possibility of aromatic L-amino acid decarboxylase deficiency.

The aromatic L-amino acid decarboxylase consensus guidelines originally suggested three core diagnostic keys for identifying aromatic L-amino acid decarboxylase deficiency: (I) low CSF concentrations of 5-hydroxyindoleacetic acid, homovanillic acid; increased CSF concentrations of 3-ortho-methyldopa, L-dopa, and 5-hydroxytryptophan; and normal CSF pterins; (II) compound heterozygous or homozygous pathogenic variants in the DDC gene; and (III) decreased aromatic L-amino acid decarboxylase enzyme activity in plasma (48). To confirm the diagnosis, at least two out of three core diagnostic tests should be positive.

With the better availability of genetic diagnostic tools, molecular genetic analysis of the DDC gene is currently the first-line diagnostic step. Biochemical confirmation after positive molecular genetic findings has become less important. Molecular genetic analysis is especially important for the clarification of variants of unknown significance. Today, 143 different variants of the DDC gene are known (19).

Detection of elevated concentrations of 3-O-methyldopa in dried blood spots may be the first indication of a diagnosis of aromatic L-amino acid decarboxylase deficiency and is, therefore, a diagnostic biomarker that appears suitable for newborn screening programs (09). 3-O-methyldopa remains elevated in patients with aromatic L-amino acid decarboxylase deficiency and has been shown to be a reliable marker until about 18 years of age (09).

One additional peripheral marker is the variable elevation of urinary vanillactic acid. The ratio of vanillactic acid/vanillylmandelic acid in urine is a reliable diagnostic marker (08). Peripheral deficiency of the biogenic amines can be confirmed by measurement of catecholamines in plasma and of serotonin in whole blood. Measurement of the urinary concentrations of the neurotransmitters themselves may lead to (paradoxical) normal findings while whole blood serotonin is low.

Measurement of neurotransmitter metabolites homovanillic acid and 5-hydroxyindoleacetic acid in CSF is required to document a central deficiency of dopamine and serotonin. The concentrations of homovanillic acid and 5-hydroxyindoleacetic acid are markedly reduced in CSF. Unfortunately, neurotransmitter metabolites are still rarely investigated in children with suspected (neuro-) metabolic disease. A CSF pattern of reduced concentrations of homovanillic acid and 5-hydroxyindoleacetic acid, together with elevated concentrations of 3-O-methyldopa, is highly suggestive of the condition, but a similar profile has been seen in patients with a defect in the synthesis of pyridoxal 5'-phosphate (34).

Final confirmation of the diagnosis can be made by measurement of levodopa decarboxylase activity in plasma or DDC gene analysis (48; 19). In all patients in whom activity of the aromatic L-amino acid decarboxylase enzyme in plasma has been measured, the activities were very low or undetectable (43; 10; 40). The activity of levodopa decarboxylase in the plasma of parents has varied between 16% and 58% of that found in controls. Levodopa decarboxylase measurement in plasma can also differentiate between a primary aromatic L-amino acid decarboxylase deficiency and a secondary deficiency due to altered pyridoxal 5'-phosphate metabolism. In the latter, levodopa decarboxylase activity is either normal or elevated (34).

If a DDC variant is detected, this provides an ideal method for prenatal diagnosis and heterozygote detection (48; 18; 40).

Management

	• Dopamine agonists should be tried in the treatment of aromatic L-amino acid decarboxylase deficiency. Non-ergot-derived dopamine agonists (pramipexole, ropinirole, rotigotine) are preferred.
	• Patients with aromatic L-amino acid decarboxylase deficiency should receive a trial of MAO inhibitors. Doses at breakfast and lunch are preferred because nighttime doses might cause insomnia.
	• Vitamin B6 is also considered a first-line treatment, but dose limits should be respected because of possible side effects.
	• The AAV2-based gene therapy directed towards the primary underlying cause of the disease will change the outcome of this disorder.

Treatment should be commenced as soon as possible following diagnosis. The therapeutic management is very challenging, and the response to treatment for most patients cannot be predicted. All medication has to be prescribed “off-label” and without established pediatric dosage regimens (48; 37). A detailed guideline for all aspects of treatment of aromatic L-amino acid decarboxylase deficiency has been published and should be consulted (48). Treatment is aimed at correcting the disturbed serotonergic and dopaminergic function. One cornerstone of treatment is the use of dopamine agonists (eg, pramipexole, bromocriptine, and ropinirole) or nonselective MAO inhibitors (eg, tranylcypromine, selegiline, and phenelzine).

Optimum treatment has resulted from bromocriptine (0.5 mg/kg, start 0.1 to 0.2 mg/kg) or pramipexole (5 µg/kg/day to start, up to 35 µg/kg/d of base) followed by a monoamine oxidase inhibitor, such as selegiline (0.2 mg/kg/d, range 0.03 to 1.5 mg/kg/d) or tranylcypromine (0.4 to 0.8 mg/kg/d) (48; 37). Anticholinergic treatment (trihexiphenidyl) can be added for the control of dystonia. The younger the patient the greater the tolerance of anticholinergic treatments. In pediatric patients we, therefore, often exceed the dosages recommended for adults if they are well tolerated. However, the process of dose titration has to be very slow and tapering should be performed with caution. Essentially, the occurrence of side effects is what defines the dosage, which is then chosen at just below the threshold for producing side effects. Amantadine with 4 mg/kg/d helps prevent drug-induced dyskinesias.

Aromatic L-amino acid decarboxylase requires pyridoxal 5’-phosphate as a cofactor, and pyridoxal 5’-phosphate deficiency decreases aromatic L-amino acid decarboxylase activity (34). Pyridoxine (up to 200 mg daily) is considered a first-line treatment from a biochemical standpoint; however, no clinical effect has been observed in most patients (30; 43; 48; 40). Dose limits should be respected because of possible side effects. Molecular modeling suggests an increase in the expression of the enzyme by pyridoxine plus L-dopa for several variants, including the frequently occurring S250F variant (35). A trial of B6 and L-dopa monotherapy and not the usual combination of L-dopa with a decarboxylase inhibitor, such as carbidopa, may be considered for patients with aromatic L-amino acid decarboxylase deficiency. The response should be monitored clinically, but also by CSF analysis of neurotransmitters.

Response to treatment is variable and often poor (31; 10; 48; 40). Most cases have had residual low enzymatic activities in plasma and presumably some activity in the brain as low concentrations of homovanillic acid and 5-hydroxyindoleacetic acid were present in CSF. In three patients, administration of a nonspecific monoamine oxidase inhibitor (tranylcypromine, 4 mg twice daily) raised plasma norepinephrine and whole blood serotonin concentrations; reduced sweating; and improved spontaneous movement, muscle tone, and color (43). In another case, it had no obvious effect (43).

Further treatment options

Sustained oculogyric crisis, or even status dystonicus, is potentially life threatening, with hyperthermia and rhabdomyolysis as major complications (48; 33). Benzodiazepines are helpful with a continuous midazolam perfusion. The current medication should be optimized if dosages are changed. Tone reduction, sedation, and pain killers are necessary. In some cases, intubation and inhalative anesthesia is sometimes the only way to maintain body temperature and minimize rhabdomyolysis. Physical cooling, avoidance of constipation with discomfort, physiotherapy for mobilization of pulmonary secretions, regular checks for urinary tract infections (discomfort), etc., are important. It is essential to maintain hydration and provide extremely high caloric intake because dystonic muscles have excessive energy consumption. For example, 130 kcal/kg/day in a school-age child may be necessary to reverse the catabolic state.

Mutation analysis is recommended in aromatic L-amino acid decarboxylase deficiency to confirm the diagnosis. A glycine to serine conversion at amino acid 102 in exon 3 has been shown to affect the binding of the levodopa substrate to the enzyme. Three siblings carrying homozygous mutations at this site were shown to be responsive to levodopa and pyridoxine (13; 35).

It is also necessary to examine folate metabolism in aromatic L-amino acid decarboxylase deficiency because there is a report of the secondary changes in plasma homocysteine and low concentrations of CSF 5-methyltetrahydrofolate in children with this condition (07). Folinic acid supplementation in doses of 10 to 20 mg/day may be necessary if elevated plasma homocysteine is found or if central concentrations of 5-methyltetrahydrofolate are low.

Nasal congestion is a frequent problem for patients probably because of their deficit in catecholamines. Topical application of oxymetazoline or xylometazoline is necessary in most cases. Application should be accompanied by local care (eg, with dexpanthenol containing ointments). The package insert and major textbooks warn of use of the combination of MAO inhibitors and topical alpha-adrenoreceptor agonists nose drops because severe hypertensive crises may occur. In aromatic L-amino acid decarboxylase deficient patients, however, catecholamines are reduced and in practice, we are not aware of such complications using this combination in most of our patients (48; 37). Sleep disturbances are a major issue in aromatic L-amino acid decarboxylase deficiency; a trial of melatonin (5 to 8 mg) can be helpful.

In addition to pharmacotherapy, physiotherapy is important to prevent the development of progressive contractions. Gastrostomy is often necessary. Many patients suffer from constipation and some from diarrhea. Gastroesophageal reflux can occur requiring fundoplication.

AAV2-based gene therapy

Gene therapy is the first therapy for aromatic L-amino acid decarboxylase deficiency directed towards the primary underlying cause of the disease. Infusion of a recombinant adeno-associated virus type 2 vector containing the human aromatic L-amino acid decarboxylase gene into both putamina or substantia nigra plus the ventral tegmental area by stereotactic surgery has demonstrated safety and efficacy (20; 41).

For the putaminal approach safety and efficacy was demonstrated in a total of 26 patients enrolled in three consecutive trials. Patients showed rapid improvements in motor function within 12 months after initiating gene therapy. Therapeutic effects were sustained during follow-up for over 5 years. An increase in dopamine production was demonstrated by positron emission tomography and neurotransmitter analysis. Improvement in motor function could be associated with improvement in white matter microstructural integrity following gene therapy (46). Patient symptoms (mood, sweating, temperature, and oculogyric crises), patient growth, and patient caretaker quality of life improved. Importantly, younger age at treatment was associated with greater improvement (44). Apart from mild to moderate dyskinesia that resolved in a few months, there were no treatment-associated side effects.

In addition, the MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons was safe and well-tolerated. All seven children, aged 4 to 9 years, showed increased dopamine metabolism in the CSF together with enhanced FDOPA uptake within the midbrain and the striatum. The treatment led to clinical improvements in symptoms and motor function. Twelve months after surgery, the majority of subjects gained normal head control and the ability to sit independently for the first time. At 18 months, two subjects could walk with two-hand support. In addition, oculogyric crises resolved completely in all but one subject three months after surgery (41).

In July 2022, the EMA declared the marketing authorization of eladocagene exuparvovec for intraputaminal administration. This was followed by the British Medicines and Healthcare products Regulatory Agency (MHRA) in February 2023. Approval was granted for treating aromatic L-amino acid decarboxylase deficiency in individuals 18 months of age and older with a clinical, molecular, and genetically confirmed diagnosis of aromatic L-amino acid decarboxylase deficiency with a severe phenotype. Treatment requires prehospital, inpatient, and posthospital care by a multidisciplinary team in a specialized and qualified therapy center. A structured follow-up plan and systematic documentation of outcomes in a suitable, industry-independent registry study are required (42)

Outcomes

Overall, response to treatment is variable, but outcome appears to be slightly better in males than in females and after early treatment initiation (31; 10; 18). Monitoring of therapy with respect to the complex movement disorder, as well as weight gain, swallowing problems, communication issues, arising orthopedic complications, etc., requires repeated careful clinical evaluation by a (pediatric) neurologist, ideally including video documentation (48). Despite all therapeutic interventions, the disease course was often severe and sometimes fatal at a young age. Early detection by newborn screening (16; 08) and gene therapy directed towards the primary underlying cause of the disease will likely change the outlook of this disorder (46; 41).

Special considerations

In patients with aromatic L-amino acid decarboxylase deficiency the synthesis of epinephrine and norepinephrine is also compromised, which likely requires admission to the ICU. Hypoglycemia is often reported and careful monitoring of glucose concentrations in conditions leading to increased glucose demand or fasting is indispensable. There appears to be a dangerous impairment of sympathotonic stress reaction, which can result in sudden apneas, arterial hypotension, or dysrhythmias such as atrial fibrillation (43; 05; 47). Patients should, therefore, receive an emergency card including a summary about the disorder, possible complications, and drugs to avoid (48).

Pregnancy

A successful pregnancy was reported in a 26-year-old woman with aromatic L-amino acid decarboxylase defect who was treated with low doses of pramipexole (0.26 mg/day) and selegiline (5 mg/day) (32).

Anesthesia

Patients with aromatic L-amino acid decarboxylase deficiency must be carefully monitored during intercurrent illnesses, especially during severe illnesses, surgeries, ICU admissions, or anesthesia. Stressful situations, including hospital admission for diagnostic procedures and stimuli, eg, venous puncture, can lead to severe bradycardia, hypoglycemia, or cardiopulmonary arrest (43). Opioids can result in severe bradycardia and hypotension. On the other hand, patients were reported to react very sensitively to dopamine with an unusually marked increase of blood pressure and heart rhythm (47). Apparently, there is a deficiency of catecholamines in the periphery combined with upregulated receptors and consequently increased sensitivity to pharmacotherapy with catecholamines, which must be administered carefully with possibly lower dosages than usually.

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Thomas Opladen MD

Dr. Opladen of University Children’s Hospital in Heidelberg, Germany received travel support from PTC Therapeutics as a speaker.
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Georg F Hoffmann MD

Dr. Hoffmann of the University Center for Child and Adolescent Medicine in Heidelberg has no relevant financial relationships to disclose.
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Editor

Barry Wolf MD PhD

Dr. Wolf of Lurie Children's Hospital of Chicago has no relevant financial relationships to disclose.
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Former Authors

Keith Hyland PhD

Patient Profile

Age range of presentation: 0 to 23 months
Sex preponderance: male=female
Heredity: heredity may be a factor

heredity typical

autosomal recessive
Population groups selectively affected: More common in East Asians
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Other disturbances of aromatic amino-acid metabolism: 270.2
ICD-10: Aromatic L-amino acid decarboxylase deficiency: E70.81
OMIM: Aromatic L-amino acid decarboxylase deficiency: #608643

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Aromatic L-amino acid decarboxylase deficiency

Differential Diagnosis

neuromuscular disorders
dystonic or athetoid cerebral palsy of unknown etiology
tetrahydrobiopterin deficiency
tyrosine hydroxylase deficiency
pyridox(am)ine 5'-phosphate oxidase deficiency

Aromatic L-amino acid decarboxylase deficiency

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

Further treatment options

AAV2-based gene therapy

Outcomes

Special considerations

Pregnancy

Anesthesia

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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