Alternative titles; symbolsAADC DEFICIENCYDOPA DECARBOXYLASE DEFICIENCYDDC DEFICIENCY▼ DescriptionAromatic L-amino acid decarboxylase deficiency (AADCD) is an au...
Alternative titles; symbols
Aromatic L-amino acid decarboxylase deficiency (AADCD) is an autosomal recessive inborn error in neurotransmitter metabolism that leads to combined serotonin and catecholamine deficiency (Abeling et al., 2000). The disorder is clinically characterized by vegetative symptoms, oculogyric crises, dystonia, and severe neurologic dysfunction, usually beginning in infancy or childhood (summary by Brun et al., 2010).
▼ Clinical Features
Hyland and Clayton (1990) and Hyland et al. (1992) reported male monozygotic twins born to first-cousin parents who presented at the age of 2 months with severe hypotonia and paroxysmal movements consisting of crying followed by extension of the arms and legs, oculogyric crises, and cyanosis. They also showed occasional choreoathetoid movements of the extremities. Later, defects in temperature regulation and postural hypotension were observed. Laboratory analyses showed a greatly decreased concentration of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the CSF, as well as decreased whole blood serotonin and plasma catecholamines. There was a significant elevation in the urinary excretion of L-DOPA, 5-hydroxytryptophan (5HTP), and 3-methoxytyrosine, all of which precede the AADC step in the biochemical pathway. The findings demonstrated that serotonin and dopamine synthesis were affected in both the central and peripheral nervous systems, consistent with a deficiency of AADC. AADC enzyme activity was severely reduced in plasma and in liver tissue (1% of control). Treatment with a monoamine oxidase inhibitor, a dopamine agonist, and pyridoxine resulted in a striking improvement in tone and movement. The parents were asymptomatic, but had biochemical profiles consistent with their being heterozygous for AADC deficiency.
Maller et al. (1997) reported an Iranian patient born of consanguineous parents who presented in infancy with hypotonia, paroxysmal episodes of inconsolable crying with eyes 'rolling backwards,' extension of extremities, and temperature instability. At age 5 years, he had severe developmental delay, profound hypotonia, and increased muscle tone in the extremities with brisk tendon reflexes and extensor plantar responses. Spontaneous movements were choreoathetoid, and he had increased sweating. CSF, blood, and urine analyses, as well as low AADC enzyme activity, were consistent with AADC deficiency. Korenke et al. (1997) reported a German patient with AADC born of unrelated parents. The clinical phenotype and laboratory findings were similar to previously reported cases. Korenke et al. (1997) and Maller et al. (1997) noted the clinical similarities between AADC deficiency and dihydropteridine reductase deficiency (261630).
Abeling et al. (1998) reported a Dutch girl with AADC deficiency who had a milder clinical phenotype, although she still exhibited psychomotor retardation and the characteristic hypertonic episodes with oculogyric crises. CSF showed decreased 5-HIAA and HVA, and urine showed decreased 5-HIAA, vanillylmandelic acid (VMA), and norepinephrine, elevated L-DOPA, but also elevated dopamine and HVA, which should have been decreased on the basis of the enzyme defect. Plasma AADC activity was undetectable. Abeling et al. (1998) suggested that the AADC deficiency was confined to the cerebral compartment. In examining several AADC patients, including the patient reported by Abeling et al. (1998), Abeling et al. (2000) found that all patients had hyperdopaminuria, which was increased after L-DOPA administration. HVA was also increased. The authors noted that dopamine is produced in the kidney by a renal form of AADC which is present in the proximal renal tubules and involved in the renal handling of sodium. In AADC-deficient patients, these renal cells receive increased amounts of the accumulated substrate L-DOPA, which is rapidly converted to dopamine and HVA.
Swoboda et al. (2003) reviewed the clinical phenotype of 11 patients with AADC deficiency, including 4 previously reported patients. Neonatal symptoms included poor feeding, lethargy, ptosis, hypothermia, and hypotension. All patients demonstrated intermittent eye movement abnormalities, truncal hypotonia, limb hypertonia, and impaired voluntary movements. The majority also showed emotional lability and irritability. Other features included myoclonus, dystonia, paroxysmal sweating, and gastrointestinal problems, such as reflux disease, constipation, and diarrhea. Functional clinical outcomes were poor.
Brun et al. (2010) reviewed the clinical courses of 78 patients with AADC deficiency, including 32 patients who were reported for the first time. Most (96%) had symptoms evidence in infancy or childhood, including hypotonia (95%), oculogyric crises (86%), and developmental retardation (63%). The disorder became apparent during adolescence or adulthood in 6 patients. Other more variable features included autonomic symptoms, such as excessive sweating or temperature instability, feeding or speech difficulty, and movement disorders, including hypokinesia, dystonia, athetosis, and chorea. Many had insomnia and irritability, and 49 had motor or mental retardation. Laboratory data consistently showed low CSF levels of homovanillic acid, 5-hydroxyindoleacidic acid, and 3-methoxy-4-hydroxyphenolglycole, with increased 3-O-methyl-L-DOPA, L-DOPA, and 5-hydroxytryptophan. Urinary vanillactic acid was found in a few cases. Plasma AADC activity, when measured, was low or absent. About 24% of patients had an abnormal brain MRI, with cerebral atrophy, degenerative changes of the white matter, thinning of the corpus callosum, or a leukodystrophy-like pattern.
Montioli et al. (2019) reported a 5-year-old boy with a history of fluctuating eyelid ptosis since birth, early-onset hypotonia, fatigue, fluctuation of alertness, mild psychomotor delay, and language impairment. At 2 years of age, he developed oculogyric crises and dystonic upper limb movements. CSF analysis showed low homovanillic acid and 5-hydroxyindoleacetic acid and elevated 3-O-methyldopa and 5-HTP. Ptosis and oculogyric crises improved with levodopa/carbidopa, and fatigue and fluctuation of neurologic symptoms improved with transdermal rotigotine. At age 5 years, he had ptosis, episodic oculogyric crises without other movement abnormalities, mild global development delay, severe expressive language impairment, and behavioral abnormalities.
▼ Biochemical Features
Verbeek et al. (2007) described assays for plasma AADC enzyme activity using both of its substrates, 5-hydroxytryptophan (5-HTP) and 3,4-dihydroxyphenylalanine (L-DOPA). They found that AADC enzyme activity in control plasma on average is a factor 8 to 12 higher with L-DOPA as substrate than with 5-HTP. Both substrates of AADC compete for the same active site of the enzyme resulting in equally decreased residual enzyme activities in AADC-deficient patients. In AADC-deficient patients, the enzyme activities towards both substrates are equally decreased, as are the CSF concentrations of HVA, 5-HIAA, and MHPG, whereas heterozygotes have intermediate AADC activity levels. These enzymes and assays can be performed on blood.
In a clinical and molecular review of AADC deficiency, Himmelreich et al. (2019) stated that a diagnosis of AADC deficiency should be made based on positive findings in 2 of 3 diagnostic modalities: plasma AADC enzyme activity, molecular testing of the DDC gene, and/or CSF neurotransmitter metabolites. Himmelreich et al. (2019) noted that, if possible, all 3 tests should be performed, but that initiation of therapy should not be delayed if plasma and CSF studies are positive and molecular testing is pending.
Brennenstuhl et al. (2020) established a gas chromatography-mass spectrometry method to perform semiquantitative measurements of vanillactic acid (VLA) and vanillylmandelic acid (VMA) in urine, and tested the applicability of these measurements in the diagnosis of AADC deficiency. Testing in urine samples from 10,095 controls and 14 patients with AADC deficiency showed that VLA concentration correlated negatively with age, whereas VMA was stable with age. The mean VLA/VMA ratio was 0.07 (range, 0.0-23.24) in controls and 23.16 (range, 0.97-74.1) in patients. The VLA/VMA ratio was found to be age-dependent, and Brennenstuhl et al. (2020) proposed age-related normal cut-off values in 3 age groups: a cut-off value of 8 for individuals between 0-1 years of age, a cut-off value of 6 for individuals between 1-10 years of age, and a cut-off value of 0.8 for individuals over 10 years of age. With these age-related normal values, the VLA/VMA ratio was highly sensitive for the diagnosis of AADC deficiency. Individually, VMA and VLA urinary concentrations were not sufficient to identify individuals with AADC deficiency. Brennenstuhl et al. (2020) concluded that the VLA/VMA ratio was a reliable parameter for the diagnosis of AADC deficiency.
Burlina et al. (2021) developed a method for newborn screening for AADC deficiency by measurement of 3-O-methyldopa (3-OMD) in dried blood spots (DBS) using flow-injection analysis tandem mass-spectrometry with 13C-labeled tyrosine as an internal standard. The authors stated that because 13C-labeled tyrosine is already used as a standard reagent in newborn screening assays, this represents a simplification of prior proposed methodologies that use a deuterated 3-OMD as an internal standard. For those DBS measurements that fell above the established cutoff on this first-tier 3-OMD measurement, a second-tier test was used to measure 3-OMD by LC-MS/MS. The assay was shown to have a low coefficient of variation (less than 15%) and was validated in dried blood spots from 1,000 healthy newborns, 100 healthy control subjects, 81 patients receiving L-DOPA therapy, and a 25-year-old patient with AADC deficiency. Once validated, this assay was incorporated into an expanded newborn screening program in northeastern regions of Italy. No affected newborns were detected among 21,867 samples in the screening program; however, 1 infant had a false-positive result attributed to maternal L-DOPA therapy.
▼ Clinical Management
Pons et al. (2004) noted that clinical management of AADC deficiency usually involves vitamin B6, dopamine agonists, and MAO inhibitors to potentiate monoaminergic transmission. In assessing treatment response among a group of AADC patients, the authors detected 2 main groups: one with 5 males who responded to treatment and made developmental progress, and a second of 5 females and 1 male who responded poorly to treatment and often developed drug-induced dyskinesias. The findings suggested a sex difference in the monoaminergic system, with females being more dependent on the dopamine system.
Therapy is aimed at correcting the neurotransmitter abnormalities, especially those of serotonin and the catecholamines. Some may respond to L-DOPA. Brun et al. (2010) reported 15 patients with a relatively mild form of the disorder who improved on a combined therapy with pyridoxine (B6)/pyridoxal phosphate, dopamine agonists, and monoamine oxidase B inhibitors. However, the authors remarked that drug treatment options are limited, in many cases not beneficial, and prognosis is uncertain.
Hwu et al. (2012) performed AAV vector-mediated gene transfer of the human AADC gene (AAV2-hAADC) bilaterally into the putamen of 4 patients from Taiwan aged 4 to 6 years with AADC deficiency. All of the patients were bedridden, without head control and unable to talk. All of the patients showed improvements in motor performance. One patient was able to stand 16 months after gene transfer, and the other 3 patients achieved supported sitting 6 to 15 months after gene transfer. In all patients choreic dyskinesia occurred approximately 1 month after gene transfer; as dyskinesia resolved, motor development started. After 6 months, positron emission tomography (PET) in 3 patients revealed increased uptake of fluorodopa, a tracer for AADC, by the putamen. CSF analysis showed increased dopamine and serotonin levels after gene transfer. Hwu et al. (2012) concluded that gene therapy targeting primary AADC deficiency is well tolerated and leads to improved motor function.
To establish the efficacy and safety of intraputaminal injection of AAV2-hAADC in patients with AADC deficiency, Chien et al. (2017) performed an open-label phase 1/2 trial of 10 patients (median age at surgery 2.71 years). Chien et al. (2017) assessed patients at baseline and at 3, 6, 9, and 12 months after gene therapy, and every 6 months thereafter for 1 further year. All patients tolerated the surgeries and vector injections. Primary efficacy outcomes were an increase in the Peabody Developmental Motor Scales (PDMS-2) score of greater than 10 points and an increase in homovanillic acid (HVA) or 5-hydroxyindoleacetic acid (5-HIAA) concentrations in the cerebrospinal fluid 12 months after gene therapy. All patients met the primary efficacy endpoints: 12 months after gene therapy, PDMS-2 scores were increased by a median of 62 points, and HVA concentrations by a median of 25 nmol/L; however, there was no significant change in 5-HIAA concentrations. In total, 101 adverse events were reported, with the most common being pyrexia (16%) and orofacial dyskinesia (10%). Twelve serious adverse events occurred in 6 patients, including 1 death (treatment-unrelated encephalitis due to influenza B infection), 1 life-threatening pyrexia, and 10 events that led to hospital admission. Transient post-gene therapy dyskinesia occurred in all patients but was resolved with risperidone. Of 31 treatment-related adverse events, only one (patient 1) was severe in intensity, and none led to hospital admission or death.
Kojima et al. (2019) conducted an open-label phase 1/2 study of older patients, including adolescents, with different degrees of severity. Six patients were enrolled: 4 males (ages 4, 10, 15, and 19 years) and 1 female (age 12 years) with a severe phenotype who were not capable of voluntary movement or speech, and 1 female (age 5 years) with a moderate phenotype who could walk with support. The patients were genetically diverse. At up to 2 years after gene therapy, the motor function was remarkably improved in all patients. Three patients with the severe phenotype were able to stand with support, and one patient could walk with a walker. The patient with the moderate phenotype could run and ride a bicycle, and also showed improvement in her mental function, being able to converse fluently and perform simple arithmetic. Dystonia disappeared and oculogyric crisis was markedly decreased in all patients. The patients exhibited transient choreic dyskinesia for several months, but no adverse events caused by vector were observed. PET showed increased uptake of fluoro-L-m-tyrosine (FMT) in the bilateral putamen.
▼ Molecular Genetics
In 6 patients with AADC deficiency, Chang et al. (1998) identified 6 point mutations in the AADC gene (107930.0001-107930.0006). Four patients were homozygous, and 2 were compound heterozygous.
In monozygotic twin boys of Arab descent with AADC deficiency, who were first reported by Hyland et al. (1992), Pons et al. (2004) identified homozygosity for a mutation in the AADC gene (107930.0002).
Among 49 patients with genetically confirmed AADC deficiency, Brun et al. (2010) reported 24 different mutations in the AADC gene, including 8 novel mutations. A splice site mutation (IVS6+4A-T; 107930.0007) was by far the most common mutation with an allele frequency of 45%. All patients with the IVS6+4A-T mutation were of Chinese or Taiwanese origin or lived in Taiwan. Other common mutations included S250F (107930.0002), with an allele frequency of 10%, and G102S (107930.0001), with an allele frequency of 8%.
In a 5-year-old boy with AADC deficiency, Montioli et al. (2019) identified compound heterozygous mutations in the AADC gene (A91V, 107930.0005 and C410G, 107930.0008). Montioli et al. (2019) expressed A91V and C410G AADC homodimers in E. coli, and found that both showed decreased PLP binding affinity. In addition, an A91V/C410G heterodimer constructed via a dual-vector prokaryotic expression strategy showed decreased catalytic activity compared to the catalytic activity of either individual mutant homodimer, indicating a potential negative complementation effect.
Himmelreich et al. (2019) reviewed the 79 disease-causing mutations reported in the DDC locus-specific database (Pediatric Neurotransmitter Diseases database, PNDdb), which included 58 missense, 9 splice site, 6 frameshift, 1 in-frame, 3 complex, and 2 nonsense mutations. Fourteen mutations were predicted to affect the catalytic loop of the DDC protein, 4 were predicted to impair PLP binding, and 2 synonymous mutations were predicted to lead to abnormal splicing.