Views & Reviews CME
Aromatic L-amino acid decarboxylase deficiency Clinical features, treatment, and prognosis
R. Pons, MD; B. Ford, MD; C.A. Chiriboga, MD; P.T. Clayton, MD; V. Hinton, PhD; K. Hyland, PhD; R. Sharma, PhD; and D.C. De Vivo, MD
Abstract—Background: Deficiency of aromatic L-amino acid decarboxylase (AADC) is associated with severe developmental delay, oculogyric crises (OGC), and autonomic dysfunction. Treatment with dopamine agonists and MAO inhibitors is beneficial, yet long-term prognosis is unclear. Objective: To delineate the clinical and molecular spectrum of AADC deficiency, its management, and long-term follow-up. Results: The authors present six patients with AADC deficiency and review seven cases from the literature. All patients showed reduced catecholamine metabolites and elevation of 3-Omethyldopa in CSF. Residual plasma AADC activity ranged from undetectable to 8% of normal. Mutational spectrum was heterogeneous. All patients presented with hypotonia, hypokinesia, OGC, and signs of autonomic dysfunction since early life. Diurnal fluctuation or improvement of symptoms after sleep were noted in half of the patients. Treatment response was variable. Two groups of patients were detected: Group I (five males) responded to treatment and made developmental progress. Group II (one male, five females) responded poorly to treatment, and often developed drug-induced dyskinesias. Conclusions: The molecular and clinical spectrum of AADC deficiency is heterogeneous. Two groups, one with predominant male sex and favorable response to treatment, and the other with predominant female sex and poor response to treatment, can be discerned. NEUROLOGY 2004;62:1058 –1065
Disorders of monoamine neurotransmitter metabolism have been increasingly recognized. Monoamines, also called biogenic amines, include serotonin and the two catecholamines dopamine and norepinephrine. These compounds have numerous roles including modulation of psychomotor function; hormone secretion; cardiovascular, respiratory, and gastrointestinal control; sleep mechanisms; body temperature; and pain.1 The starting substrate for the formation of catecholamines is tyrosine and for serotonin is tryptophan. Specific tetrahydrobiopterin-dependent amino acid hydroxylases convert tyrosine to levodopa and tryptophan to 5-hydroxytryptophan (5-HTP). Levodopa and 5-HTP then undergo decarboxylation through the action of the pyridoxine-dependent aromatic L-amino acid decarboxylase (AADC), which leads to the formation of dopamine and serotonin. Within noradrenergic neurons dopamine is converted to norepinephrine using dopamine -hydroxylase
and within the pineal gland, serotonin is methylated to melatonin (figure). Monoamine catabolism involves the action of monoamine oxidase (MAO) and catechol-O-methyltransferase, with the formation of homovanillic acid (HVA) from dopamine and 5-hydroxyindolacetic acid (5-HIAA) from serotonin (see the figure). The levels of these metabolites in CSF reflect the turnover of monoamines within the brain.1 Several enzyme defects leading to individual or combined deficiencies of monoamine neurotransmitters have been described.1 In 1992, Hyland et al. described the first patients with AADC deficiency.2 These twin boys presented with motor, extrapyramidal, and autonomic symptoms. CSF monoamine metabolites pointed to a deficiency in the synthesis of catecholamines and serotonin, and enzyme assay in plasma confirmed the AADC deficiency.2 Since that first description, seven more patients have been described in detail3-7 and five more as short communi-
From the Departments of Neurology and Pediatrics (Drs. Pons, Ford, Chiriboga, Hinton, and De Vivo), College of Physicians and Surgeons of Columbia University, New York, NY; Biochemistry Endocrinology and Metabolism Unit (Dr. Clayton), Institute of Child Health at Great Ormond Street Hospital, University College London, UK; Institute of Metabolic Disease (Drs. Hyland and Sharma), Baylor University Medical Center, Dallas, TX; and Universitat Autonoma de Barcelona (Dr. Pons), Spain. Received June 17, 2003. Accepted in final form November 24, 2003. Address correspondence and reprint requests to Dr. Darryl C. De Vivo, Neurological Institute, 710 West 168th Street, New York, NY 10032; e-mail:
[email protected] 1058
Copyright © 2004 by AAN Enterprises, Inc.
Figure. Central synthesis and catabolism of the catecholamines and serotonin. GTP ⫽ guanosine triphosphate; GTPCH ⫽ GTP cyclohydrolase; NH2TP ⫽ dihydroneopterin triphosphate; PTPS ⫽ 6-pyruvoyltetrahydropterin synthase; 6PTP ⫽ 6-pyruvoyltetrahydropterin; SR ⫽ sepiapterin reductase; BH4 ⫽ tetrahydrobiopterin; DHPR ⫽ dihydropteridine reductase; qBH2 ⫽ quinonoid dihydrobiopterin; Tyr ⫽ tyrosine; Trp ⫽ tryptophan; 5-HTP ⫽ 5-hydroxytryptophan; TH ⫽ tyrosine hydroxylase; TPH ⫽ tryptophan hydroxylase; COMT ⫽ catechol-O-methyltransferase; DH ⫽ dopamine -hydroxylase; AADC ⫽ aromatic L-amino acid decarboxylase; 3OMD ⫽ 3-O-methyldopa; 5HIAA ⫽ 5-hydroxyindoleacetic acid; MAO ⫽ monoamine oxidase; HVA ⫽ homovanillic acid; MHPG ⫽ 3-methoxy-4-hydroxyphenylglycol; SNA ⫽ serotonin n-acetyltransferase; HIOMT ⫽ hydroxyindole-O-methyltransferase. The large black arrows show an increase or decrease in the cerebrospinal marker metabolites for AADC deficiency.
cations or in abstract form.8-10 Patients are treated with dopamine agonists, MAO inhibitors, and pyridoxine (vitamin B6). Although the clinical features and management of these patients has been delineated, it is becoming apparent that the clinical phenotype and response to treatment are variable and their long-term follow-up and functional outcome is unknown.5-7 Since 1996, we have followed six patients with AADC deficiency, including the two patients who were described in the original report.2 In this report, based on the retrospective analysis of our patients and the review of the literature, we expand the clinical and molecular spectrum, response to treatment, and course of AADC-deficient patients. Materials and methods. From 1996 to 2003 we studied six patients with AADC deficiency. The case histories of four of these patients are briefly illustrated below. Analysis of CSF biogenic amines, plasma AADC activity, and AADC gene sequencing was done in all patients. The main goal of treatment was to improve the patients’ clinical status with minimal adverse effects. The treatment strategies used in our patients included the following: 1) cofactor administration with vitamin B6 in all patients; 2) potentiation of catecholamine and serotonin transmission with nonselective MAO inhibitors (tranylcypromine and phenelzine) in all patients; 3) potentiation of dopaminergic transmission with dopamine agonist (bromocriptine and pergolide) in all patients; 4) melatonin in Patients 1 and 3; 5) anticholinergics in Patients 2, 5, and
6; and 6) intranasal sympathomimetics in Patient 1. Potentiation of serotonin transmission with serotonin reuptake inhibitors and treatment with the substrate precursor levodopa or 5-HTP were not administered in any of our patients. Assessment of the response to treatment was based on the parents’ report, neurologic assessment in all patients, and neuropsychological evaluation in Patients 1, 5, and 6. Biochemical analysis. Aromatic amino acids and metabolites in CSF and AADC activity in plasma were analyzed as previously described by Hyland et al.2 Molecular analysis. Direct sequencing of the AADC genomic DNA was performed as previously described.7 Literature review. Cases of AADC deficiency published in the literature from 1992 to 2003 were reviewed3-10 and only those with confirmed AADC deficiency and sufficient clinical data were included in the present study.3-7 The following parameters were considered: age at onset, sex, perinatal history, family history, clinical findings, biochemical and other laboratory findings, treatment strategies, and treatment response. Case histories. Patient 1. This 4.5-year-old English boy was born full term. He showed poor suck and irritability during his first days of life. At age 2 months he developed episodes of tonic upward eye deviation of several minutes to 1 hour duration that resolved with sleeping. He showed minimal spontaneous movements and his development was poor. He was irritable and easily distressed. At age 2 years, he experienced daily episodes of brief flexor spasms. He had nasal congestion and sweated profusely. He had recurrent respiratory illnesses and reactive airway disease. He had chronic constipation alternating with diarrhea. He suffered several episodes of dehydration with hypoglycemia during intercurrent illnesses. At age 3 years, he could sit with assistance and commando crawl. He could finger feed and pass the pages of a book. He was more active after awakening. He awoke frequently at night. He was alert, interactive, and had a labile mood. He had axial hypotonia and his appendicular tone was decreased when relaxed and increased when distressed. He had resting and action dystonia of the left arm. Tendon reflexes were brisk and plantar responses were equivocal. At age 3.5 years he was diagnosed with AADC deficiency. He was started on vitamin B6 (100 mg twice daily). He appeared calmer and more active and receptive to surroundings. Melatonin (3 mg at bedtime) was started with a favorable response in his sleep pattern. Soon afterwards he was started on tranylcypromine (6 mg three times a day), with improvement in head and trunk control and in hand coordination. He developed a tendency to aggressiveness and mood swings. The oculogyric crises (OGC) decreased in frequency, although they continued when tired, mainly in the afternoon. Pergolide was added (162 mcg three times a day). At age 4.5 years he was walking with assistance. He was dysarthric and could say single words. He was hypotonic with slow movements and dystonic limb posturing. Neuropsychological evaluation demonstrated variability across cognitive skills. He had limited expressive language but his single word comprehension and vocabulary were appropriate for his age. His comprehension of multi-word statements was impaired, and he was unable to follow two-step verbal commands. On a measure of visuo-motor integration, his performance was in the borderline range. Patient 2. Patient 2 is an 8-year-old Chinese girl. At age 2 months she developed episodes of opisthotonic posturing, extension of extremities, and upward eye deviation. Since early life she slept most of the day. She had nasal congestion, fed poorly, and cried weakly. She sweated profusely. She suffered recurrent episodes of aspiration pneumonia and had reactive airway disease. She had gastroesophageal reflux and diarrhea. Her developmental progress was minimal. At age 6 years her growth parameters were below the third percentile. She had a flat occiput, low arched palate, micrognathia, and small feet and hands. She was alert and fixed and followed. She had poor interaction and no verbal output. She was hypomimic and profoundly hypotonic. She showed no spontaneous movement of her limbs except for random flickering of fingers, hands, and toes. Tendon reflexes were present and plantar responses were equivocal. She was diagnosed with AADC deficiency. She was started on vitamin B6 (50 mg three times a day) with no major changes. Soon afterwards pergolide (2.5 mg three times a day) was added. Her alertness, social interaction, and limb tone April (1 of 2) 2004
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Table 1 Summary of clinical data from current series Characteristics
Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
Patient 6
Sex
Male
Female
Female
Female
Male
Male
Ancestry
English
Chinese
Indian
Spanish, Italian, Russian, Polish
Arabic
Arabic
Consanguinity
⫺
⫺
⫹
⫺
⫹
⫹
Onset of neurologic 2 symptoms, mo
2
2
4
2
2
Age at diagnosis
31⁄2 y
6y
9 mo
9 mo
9 mo
9 mo
Treatment*
Vitamin B6, MAO inhibitor, DA agonist, melatonin, intranasal sympathomimetic
Vitamin B6, Vitamin B6, Vitamin B6, MAO MAO MAO inhibitor, DA inhibitor, DA inhibitor, DA agonist agonist† agonist
Vitamin B6, MAO inhibitor, DA agonist†
Vitamin B6, MAO inhibitor, DA agonist†
Time of follow-up, y
1
2
1
1
6
6
Response
Favorable
Poor
Poor
Poor
Favorable
Favorable
* Patients 2, 3, 5, and 6 had been treated with antiepileptics prior to the diagnosis of aromatic L-amino acid decarboxylase when their oculogyric crises were interpreted as seizures. † Patient failed trial of trihexyphenidyl. DA ⫽ dopamine. improved slightly. She began to develop guttural sounds and to flex and extend her legs voluntarily. Her OGC decreased in intensity and duration. Her sleep during daytime decreased. Diaphoresis did not improve. After her initial improvement on the dopamine agonist, there were no major changes and the MAO inhibitor phenelzine was added (7.5 mg three times a day). She developed facial dyskinesias and jaw, axial, and limb dystonia and phenelzine was gradually discontinued. Her dyskinesias improved, but did not disappear. Her pergolide dose was reduced with no major changes in her dyskinesias or her neurologic status. A trial of trihexyphenidyl did not offer any benefit. At age 8 years she is receiving pergolide and vitamin B6. She interacts by smiling, laughing, and visually following. She has no head control and does not roll over or use her hands. She flexes and extends her arms and legs and has distal chorea involving fingers, toes, and face. Patient 4. This 2.5-year-old girl of Spanish and Italian origin on the mother’s side and Russian and Polish origin on the father’s side had a transient episode of hypothermia on her second day of life. At age 4 months she developed daily episodes of eye deviation with arm abduction and flexion lasting several minutes. She had minimal developmental progress. She suffered excessive diaphoresis. She was diagnosed with AADC deficiency at 9 months of age and was started on bromocriptine (1.25 mg/day). She developed some spontaneous movement of her lower extremities and the episodes of eye deviation decreased in frequency. She was alert and interactive. She fixed and followed. She was diffusely hypotonic and had minimal spontaneous movement. Periodically she startled and this was followed by dystonic posturing of her arms. She had repeated upward eye deviation of a few seconds duration. Tendon reflexes were normal and plantar responses were flexor. Vitamin B6 was added. Attempts to increase bromocriptine failed due to restlessness, irritability, dyskinesias, and vomiting. She had insomnia and developed light hypersensitivity. At 15 months of age tranylcypromine was added. Currently she is on bromocriptine (1.25 mg in the morning) and tranylcypromine (2.5 mg twice daily). She remains hypotonic and has a fluctuating limb tone. She does not have head control and cannot roll over. She is very shy and cries easily. Patient 5. This patient and his monozygotic twin brothers were the first described patients with AADC deficiency.2 They were diagnosed at 9 months of age and were started on vitamin B6 (200 mg/day) and bromocriptine (2.5 mg twice daily). Later tranylcypromine (4 mg twice daily) was added. They crawled at 4 years and walked independently at 5 years, at which point they 1060
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began to vocalize single words. Their clinical course and developmental progress were similar, so in this report we will only present one of them. At 6 years, Patient 5 developed diurnal deterioration of neurologic function, with inability to walk and talk and with multiple brief OGC in the afternoon. These symptoms resolved with sleep. At age 8 years he was hypotonic and had dysarthria, distal chorea, and occasional startle myoclonus. Rapid alternating movements were slow and clumsy. Gait was broad based with dystonic posturing of one arm and leg. Postural reflexes were abnormal. Examination in the afternoon showed dysphoria, hypomimia, ptosis, hypophonia, drooling, stooped posture, bradykinesia, and worse hypotonia and postural instability. These symptoms did not improve by increasing the dose of bromocriptine. Pergolide (1.5 mg/ day divided twice a day) was then started and the episodes of deterioration in the afternoon occurred less frequently and were less severe. He developed mild dyskinesias that improved with reduction of the dose (1.25 mg/day). Later, attempts to increase the dose of pergolide caused adverse effects including insomnia, aggression, inattentiveness, and oppositional behavior. A trial of trihexyphenidyl caused aggressive behavior. At 11 years of age neuropsychological testing showed a performance in the mild-to-moderate mental retardation range across measures with little variability between brothers. He had a verbal performance of 4 years 5 months and a nonverbal performance of less than 5 years old level. His visual motor abilities were at the 6 year 4 month, and fine motor abilities at the 4 year old level. At 13 years he is dysarthric and speaks in single words. Tone is normal. There is no resting or action tremor. He shows evidence of multifocal myoclonic jerks, decrement on rapid alternating movements, and mild twisting posture of one arm when walking. His postural reflexes are normal. Further clinical data of the remaining patients are depicted in tables 1 and 2.
Results. Biochemical studies. The results of the CSF analysis are depicted in table 3. All patients showed reduced neurotransmitter metabolites (5-HIAA and HVA) and marked elevation of 3-O-methyldopa. Tetrahydrobiopterin and neopterin were normal in all patients (data not shown). AADC plasma activity in all patients is depicted in table 3. We did not find any correlation between the severity
Table 2 AADC deficiency: Main clinical findings
Findings
Reviewed cases (references 3–7)*
Current series (Patients 1 to 6)
Neonatal period
Total percentage 54
Feeding difficulties
4, 6a, 6b
1
Autonomic dysfunction
6a, 6b
3, 4
Hypotonia
4, 7b
Motor symptoms
100
Axial hypotonia
3, 4, 5, 6a, 6b, 7a, 7b
1, 2, 3, 4, 5, 6
Limb hypertonia
3, 4, 6a, 6b
Fluctuating limb tone
5, 7a
1, 2, 4
Hypokinesia
3, 4, 5, 6a, 6b, 7a, 7b
1, 2, 3, 4, 5, 6
Minimal acquisitions
3, 4, 6a, 6b, 7a, 7b
2, 3, 4, 5, 6
Axial control
5
1
Development at diagnosis
Oculogyric crises
100
Prolonged†
3, 4, 5, 6a, 6b, 7a
2, 3, 4, 5, 6
Brief
7b
4, 5, 6
Normal
3, 4, 7b
1, 5, 6
Nonspecific changes
6a, 6b, 7a
2, 3
Limb dystonia
6a
1, 5, 6
Stimulus-provoked dystonia
7a
4
Cervicofacial dystonia
6b
Myoclonus/prominent startle
6a, 6b, 7a
EEG
Other movement disorders
69
Distal chorea
4, 5, 6 2, 5, 6
Choreoathetosis
4
Athetosis
6a
Parkinsonism
5, 6
Flexor spasms
6b
Tremor
6b, 7a
1
Drug-induced dyskinesias Chorea Dystonia Diurnal variation/improvement of neurologic symptoms after sleep
46 6b
2, 4, 5, 6
6a, 6b
2
3, 6a, 7a
1, 4, 5, 6
Autonomic dysfunction
54
92
Diaphoresis
3, 4, 5, 6a, 6b, 7a
1, 2, 4, 5, 6
Temperature instability
3, 4, 7a
2, 3, 4, 5, 6
Nasal congestion
6a, 6b
1, 2, 3, 4
Ptosis/pupillary changes
6a, 6b, 7a
3, 5, 6
Hypotension/bradyarrhythmia
6a
3
RAD/GI dysmotility
1, 2
Dysphoria
4, 6a, 6b, 7a
1, 3, 4, 5, 6
69
Sleep disturbance
4, 7a
1, 2, 3, 4, 5, 6
62
* References 6 and 7 report two patients. The first and second patients of each report are presented in this table as a and b following the reference number. † Associated with motor symptoms. AADC ⫽ aromatic L-amino acid decarboxylase; RAD ⫽ reactive airway disease; GI ⫽ gastrointestinal. April (1 of 2) 2004
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Table 3 Biochemical findings CSF metabolite concentrations, nmol/L* Patient 1
Plasma AADC, pmol/min/mL
5-HIAA
HVA
3-O-methyldopa
52 (74–345)
22 (233–928)
589 (⬍150)
⬍1
495 (⬍100)
⬍1
2
14 (66–338)
⬍5 (218–852)
3
⬍5 (129–520)
21 (294–1115)
1493 (⬍300)
4
⬍5 (129–520)
19 (294–1115)
2458 (⬍300)
5
10 (129–520)
60 (294–1115)
1650 (⬍300)
6
21 (129–520)
60 (294–1115)
1585 (⬍300)
Pediatric controls, n ⫽ 7
1.2 ⬍1 5.32 4.22 36–129
* Values in parentheses are appropriate age-related reference ranges. AADC ⫽ aromatic L-amino acid decarboxylase.
of the clinical phenotype and the residual enzyme activity or the abnormalities in CSF metabolites. Molecular studies. Patient 1 was heterozygous for a missense mutation in exon 11 (Leu408Isoleu) and a nonsense mutation in exon 2 causing a premature stop codon. He was also heterozygous for a polymorphism in intron 11 (A4961G). Patient 2 was homozygous for the same polymorphism in intron 11 (A4961G). No mutations could be detected despite thorough sequence analysis of the AADC coding region, the exon/intron boundaries, and flanking untranslated regions. It is possible that this patient carries a mutation in a yet unknown regulatory region. Patient 3 was homozygous for a missense mutation in exon 2 (Pro47His). Patient 4 was heterozygous for a missense mutation in exon 11 (Arg347Glu) and a single base deletion in exon 2 (delC209 –211). In addition she showed two polymorphisms: a heterozygous 4 base deletion (GAGA) in the noncoding region of exon 1 and homozygous A4961G polymorphism in intron 11. Patients 5 and 6 were homozygous for a missense mutation in exon 7 (Ser250Phe). Work is in progress to assess the pathogenicity of these mutations. A summary of the mutations found is depicted in table 4.
Table 4 AADC gene mutations Patient 1
2
Mutation
Predicted amino acid change
A1: C1305A
Leu408Isoleu
A2: C102T
Premature stop codon
A1: NF A2: NF
3
4
5
6
A1: C175A
Pro47His
A2: C175A
Pro47His
A1: G1124A
Arg347Glu
A2: 209–211 ⌬ (C)
Frame shift
A1: C832T
Ser250Phe
A2: C832T
Ser250Phe
A1: C832T
Ser250Phe
A2: C832T
Ser250Phe
AADC ⫽ aromatic L-amino acid decarboxylase. A1 ⫽ allele 1; A2 ⫽ allele 2; NF ⫽ not found. 1062
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Literature review. Clinical data from the literature are summarized in table 2. All patients showed reduced levels of HVA and 5-HIAA and increased levels of 3-Omethyldopa in CSF and deficient AADC activity in plasma (data not shown).
Discussion. Diagnosis. All the patients from our series and the literature showed the same pattern of CSF metabolites that pointed to a deficiency in the synthesis of monoamine neurotransmitters3-7 (see table 3). The reduced levels of HVA and 5-HIAA indicate decreased synthesis of catecholamines and of serotonin. Increased levels of 3-O-methyldopa in all patients are the result of methylation of the accumulated precursor levodopa. AADC deficiency was confirmed in all patients in plasma, with residual activities ranging from undetectable to approximately 8% of normal values3-7 (see table 3). Screening of the AADC gene led to the identification of six mutations, five of which are novel, thus confirming that the mutational spectrum is highly heterogeneous7,11,12 (see table 4). Clinical presentation. Approximately half of the patients were symptomatic during the neonatal period. Feeding difficulties, autonomic dysfunction, and hypotonia were the most common findings (see table 2). Motor symptoms were noted within the first months of life in all patients with axial hypotonia, decreased spontaneous movements, and failure to make motor acquisitions (see tables 1 and 2). Limb hypertonia was noted in four patients and fluctuating tone in five patients (see table 2). Motor acquisitions were minimal in nine patients, while in two patients axial control had developed by age 2 to 3 years (see table 2). All patients developed paroxysmal events within the first months of life. These events were OGC, a form of paroxysmal dystonia. Patients had eye deviation upward, convergent, or to the side. The majority had associated motor changes such as opisthotonic posturing and tonic or dystonic posturing of the limbs (see table 2). During the events patients appeared conscious. The majority looked up-
set, very distressed, or cried inconsolably. OGC ranged from a few seconds to hours and from several times a day to several times a week. Prior to the diagnosis of AADC deficiency, OGC were often thought to be seizures. EEG was normal in five patients and nonspecific in four others (see table 2). OGC are a feature of acquired or congenital states of dopamine deficiency and the pathophysiology is not fully understood. Neurotransmitter imbalance with deficient dopaminergic and increased cholinergic transmission is a postulated mechanism.13 Other movement disorders were noted in 69% of the patients. Variable types of dystonia followed by startle myoclonus were the most frequent movements noted (see table 2). In our experience distal chorea was seen in half of the patients, although this was not noted in the cases reported in the literature (see table 2). In one of the previous reports, a brief mention was made of drug-induced dyskinesias provoked by treatment with a dopamine agonist and a serotonin reuptake inhibitor.6 We found such dyskinesias to be especially common in our patients, occurring in four out of six (see table 2). Dopamine agonists induced chorea in three patients and a MAO inhibitor induced dystonia in another (see table 2). Levodopa-induced dyskinesias are commonly seen in Parkinson disease and are attributed to hypersensitivity of dopamine receptors, abnormalities in non-dopamine transmitter systems, and alterations in the firing patterns that signal between the basal ganglia and the cortex.14 The occurrence of drug-induced dyskinesias in AADC deficient patients suggests similar pathophysiologic mechanisms. Aggravation of neurologic symptoms late in the day or improvement by sleep was noted in half of the patients (see table 2). These phenomena are known features of dopamine deficiency states,15 and are thought to be secondary to circadian fluctuations in the regulation of monoamine metabolism in central serotoninergic and dopaminergic neurons.15,16 Features of autonomic dysfunction were noted in most patients, most frequently excessive diaphoresis, temperature instability, nasal congestion, ptosis, and miosis (see table 2). These symptoms likely represent imbalance of the autonomic nervous system due to catecholaminergic deficiency. Temperature instability is thought to be secondary to serotonergic and noradrenergic deficiency, given their role in thermoregulation.17 Dysphoric mood was often noted (see table 2). It is thought that serotonin deficiency has a role in these symptoms, because it is implicated in anxiety disorders and pain mediation.18 Sleep disturbances were seen in all the patients of our series, and were reported in two patients in the literature (see table 2). Serotonin lowers arousal and facilitates sleep16 and is the precursor for the synthesis of melatonin. Thus, serotonin deficiency probably plays an important role in the sleep disturbances of these patients. Cognitive functions were highly variable across patients, ranging from “low average” to “severely im-
paired.” The majority of patients were described as able to interact with the environment3-7 (Patients 2 through 4). However, their cognition was difficult to assess due to severe motor impairment. The three more functional patients from our series (Patients 1, 5, and 6) made significant cognitive acquisitions. One patient achieved normal vocabulary comprehension for his age, even though his expressive language was limited (Patient 1). Most skills for the three evaluated patients were in the mild-to-moderate retardation range. Further, all three were cognizant of their surroundings, were able to make their needs known, and were responsive to educational interventions. Based on their neuropsychological assessment and their gradual developmental acquisitions, each seemed likely to continue to develop cognitive skills over time. The early effects of monoamine deficiency in the developing brain may account for the cognitive deficits of these patients. This is supported by animal models of prenatal manipulation of the monoaminergic system, which have shown structural abnormalities in brain development, particularly in the growth and laminar organization of the cerebral cortex.19 Other features noted in AADC deficiency include recurrent episodes of hypoglycemia, noted in two patients3 (Patient 1), that are thought to reflect the relative lack of catecholamines as anti-insulinergic hormones.3 Hypersensitivity to light stimulation was noted in two patients6 (Patient 4) and may reflect dopamine receptor hypersensitivity in the retina in patients treated with dopamine agonists (Patient 4). Treatment. The main goal of management is to potentiate monoaminergic transmission. Almost all patients were treated with vitamin B6, which is the cofactor of AADC. One patient with a mutation in the pyridoxal phosphate binding site in the AADC gene showed a beneficial but transient response to high-dose vitamin B6.7 None of the other patients showed any significant clinical improvement3,4,6 (see table 1). The main types of drugs used are dopamine agonists and MAO inhibitors. The majority of patients were started on one type of drug and then a second type was added3,4,6 (see table 1). A D2 receptor dopamine agonist (bromocriptine, pergolide) and a nonselective MAO inhibitor (tranylcypromine, phenelzine) was the most common combination therapy used3,4,6 (see table 1). Assessment of the response to treatment in these patients is difficult, because there is variability in the clinical status and age at the onset of treatment, in the period of follow-up, and in the doses and combination of drugs used. Despite these difficulties, by reviewing the literature and with our own experience we detected two groups of patients based on their response to treatment. One group (Group 1) comprised of five males4,6 (Patients 1, 5, and 6) responded to a dopamine agonist or a nonselective MAO inhibitor. These patients showed improvement of tone and hypokinesia, decrease in frequency or duration of OGC, and improvement of April (1 of 2) 2004
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autonomic dysfunction. Although variable, four patients had documented evidence of developmental progress4 (Patients 1, 5, and 6). It is unclear whether starting with an MAO inhibitor or with a dopamine agonist influences the clinical response. The second group of patients (Group 2), comprised of five females and one male3,6,7 (Patients 2 through 4), showed a transient response or poor response to one drug and no further improvement when a second drug was added. This group of patients tended to have adverse effects from the medications, such as vomiting, dysphoria, insomnia, and drug-induced dyskinesias (see table 2). It is unclear whether these patients would have shown a favorable response if they had been able to tolerate higher doses of medication, or whether they represent a subtype of AADC deficiency with a worse clinical phenotype. The favorable outcome of Patients 5 and 6 who were started on treatment at 9 months of age, the developmental acceleration of Patient 1 after treatment, and the poor response of Patient 2 who initiated therapy at 6 years suggest that early treatment improves prognosis. Although this point is not firmly established, it appears prudent to initiate therapy as soon as the diagnosis is made. It is interesting to note that the AADC deficient patients with poor response to drugs (Group 2) were females, while the majority of patients with a positive response (Group 1) were males. Several studies have shown sex differences in morphology and function of monoaminergic systems in rats.20 Clinical data suggest that sex differences in the monoaminergic system are also present in humans.20 Dopamine responsive dystonia shows a marked sex-related penetrance of the GTP cyclohydrolase gene mutations with predominance of symptomatic females. Higher dependency on the dopamine system in females might contribute to clinical differences in deficiencies of monoamine synthesis and this could explain the worse phenotype and poorer response to treatment of the female patients with AADC deficiency. Patients are generally not treated with dopamine or serotonin precursors, because deficient AADC activity would preclude monoamine production and would promote further accumulation of precursor metabolites. 5-HT produced lethargy and worsening hypotonia in one patient6 and severe abdominal pain in another.7 Trials of levodopa therapy in two reported patients showed no response.3,6 Three siblings with AADC deficiency showed favorable response to levodopa.8 Molecular studies demonstrated a mutation in the AADC gene that caused changes in the Km of the enzyme suggesting that the mutation affected the enzyme-binding site for levodopa.12 Recently, another patient treated with levodopa showed evidence of gradual improvement in his function that plateaued after 24 months of therapy.7 These findings indicate that a trial of levodopa therapy could be attempted in these patients, although caution is recommended since levodopa administration may lead to decrease in methylation capacity.8 1064
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A number of other therapeutic strategies have been used in AADC deficient patients. Anticholinergic therapy (trihexyphenidyl) produced a modest response in three patients6,7 but caused aggressive behavior in two others (Patients 5 and 6). Melatonin helped to better control sleep disturbance in two patients (Patients 1 and 3). Buspirone, an anxiolytic with serotonergic and D2 agonist activity, improved rigidity and irritability but produced dyskinesias in two patients.6 Serotonin reuptake inhibitors caused rigidity and drug induced dystonia in one patient.6 Indirect catecholaminomimetics (dexamphetamine) and amine reuptake inhibitors (imipramine) were not beneficial in two patients.2 Ergotamine produced lethargy and worsened hypotonia in one patient.6 Local application of a sympathomimetic (oxymetazoline hydrochloride) was useful for nasal congestion in two patients6 (Patient 1). AADC deficiency presents early in life with hypotonia, hypokinesia, OGC, autonomic dysfunction, dysphoric mood, and sleep disturbance. Patients may show a number of movement disorders, most frequently dystonia. Diurnal fluctuation and improvement of symptoms after sleep is characteristic. The severity of the clinical phenotype is variable, but the majority of patients show minimal motor development in the absence of treatment. CSF analysis shows reduced levels of monoamine metabolites and increased 3-O-methyldopa. Deficient AADC activity in plasma confirms the diagnosis. Mutational spectrum is heterogenous. Potentiation of monoaminergic activity with dopamine agonist or nonselective MAO inhibitors is the mainstay of treatment. Response to treatment is variable. Two groups of patients have been detected: Group 1, with male predominance, favorable response to treatment, and evidence of developmental progress; and Group 2, with female predominance, poor or transient response to treatment, frequent adverse effects, and drug-induced dyskinesias. Cognition in the highest functioning patients is impaired but responsive to therapeutic intervention. Acknowledgment The authors thank Leonidas Stefanis, Paul Green, and members of the Pediatric Neurotransmitter Disease Association and The Colleen Giblin Foundation for Pediatric Neurology Research for critical comments during the preparation of the manuscript.
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