Journal of Inherited Metabolic Disease

, Volume 32, Issue 3, pp 371–380

Aromatic l-amino acid decarboxylase deficiency: clinical features, drug therapy and follow-up

Authors

  • C. Manegold
    • Division of Inherited Metabolic DiseasesUniversity Children’s Hospital
  • G. F. Hoffmann
    • Division of Inherited Metabolic DiseasesUniversity Children’s Hospital
  • I. Degen
    • Department of PediatricsMarienhaus Klinikum
  • H. Ikonomidou
    • Department of Pediatric NeurologyUniversity of Technology Dresden
  • A. Knust
    • Department of NeuropediatricsDRK-Children’s Hospital Siegen
  • M. W. Laaß
    • Department of PediatricsUniversity of Technology Dresden
  • M. Pritsch
    • Department of NeuropediatricsDRK-Children’s Hospital Siegen
  • E. Wilichowski
    • Department of NeuropediatricsUniversity of Göttingen
    • Division of Inherited Metabolic DiseasesUniversity Children’s Hospital
Symposium on Neurotransmitter Disorders

DOI: 10.1007/s10545-009-1076-1

Cite this article as:
Manegold, C., Hoffmann, G.F., Degen, I. et al. J Inherit Metab Dis (2009) 32: 371. doi:10.1007/s10545-009-1076-1

Summary

Background

Aromatic l-amino acid decarboxylase (AADC) deficiency is a disorder of biogenic amine metabolism resulting in generalized combined deficiency of serotonin, dopamine and catecholamines. Main clinical features are developmental delay, muscular hypotonia, dystonia, oculogyric crises and additional extraneurological symptoms. Response to therapy has been variable and unsatisfactory; the overall prognosis is guarded.

Methods

To gain more insight into this rare disorder we collected clinical and laboratory data of nine German patients. All patients were clinically examined by one investigator, and their responses to different drug regimes were evaluated by the patients’ charts.

Results

Symptoms were obvious from early infancy. Later, main neurological features were truncal muscular hypotonia, hypokinesia, oculogyric crises and rigor. Three patients had single seizures. All patients presented distinct extraneurological symptoms, such as hypersalivation, hyperhidrosis, nasal congestion, sleep disturbances and hypoglycaemia. In CSF all patients revealed the pattern typical of AADC with decreased concentrations of homovanillic and 5-hydroxyindoleacetic acid and elevated concentration of 3-ortho-methyldopa. Diagnosis was confirmed by measurement of AADC activity in plasma in all patients. Drug regimes consisted of vitamin B6, dopamine agonists, MAO inhibitors and anticholinergics in different combinations. No patient achieved a complete recovery from neurological symptoms, but partial improvement of mobility and mood could be achieved in some.

Conclusion

AADC deficiency is a severe neurometabolic disorder, characterized by muscular hypotonia, dystonia, oculogyric crises and additional extraneurological symptoms. Medical treatment is challenging, but a systematic trial of the different drugs is worthwhile.

Abbreviations

3-OMD

3-ortho-methyldopa

5-HIAA

5-hydroxyindoleacetic acid

5-MTHF

5-methyltetrahydrofolate

AADC

aromatic l-amino acid decarboxylase

CSF

cerebrospinal fluid

HVA

homovanillic acid

MAO

monoamine oxidase

Introduction

Aromatic l-amino acid decarboxylase (AADC, EC 4.1.1.28) is central in the synthesis of biogenic monoamine neurotransmitters. These include serotonin as well as the catecholamines dopamine and norepinephrine (noradrenaline). AADC follows the initial and rate-limiting step of synthesis, which is the formation of levodopa and 5-hydroxytryptophan from tyrosine and tryptophan by specific tetrahydrobiopterin-dependent hydroxylases. Levodopa and 5-hydroxytryptophan are then decarboxylated by AADC to dopamine and serotonin. This reaction requires pyridoxal-5′-phosphate as a cofactor. Within noradrenergic neurons dopamine is converted to norepinephrine by dopamine β-hydroxylase and within the pineal gland serotonin is converted to melatonin (Fig. 1).
https://static-content.springer.com/image/art%3A10.1007%2Fs10545-009-1076-1/MediaObjects/10545_2009_1076_Fig1_HTML.gif
Fig. 1

Metabolism of dopamine and serotonin. Abbreviations: 3-OMD = 3-ortho-methyldopa; VLA = vanillactic acid; HVA = homovanillic acid; 5-HIAA = 5-hydroxyindoleacetic acid; MHPG = 3-methoxy-4-hydroxyphenylglycol; COMT = catechol-O-methyltransferase; MAO = monoamine oxidase; DbH = dopamine β-hydroxylase; SNA = serotonin N-acetyltransferase; HIOMT = hydroxyindole-O-methyltransferase

Recessively inherited deficiency of AADC (OMIM #608643) results in a severe neurometabolic disorder with developmental delay, abnormal movements, oculogyric crises and vegetative symptoms.

In 1990 Hyland and Clayton reported the first patients with AADC deficiency. They presented monozygotic twins with severe muscular hypotonia and oculogyric crises (Hyland and Clayton 1990; Hyland etal 1992). To date, more than 20 patients have been reported (Abeling etal 1998; Chang etal 2004; Fiumara etal 2002; Korenke etal 1997; Lee etal 2008; Maller etal 1997; Pons etal 2004; Swoboda etal 1999, 2003; Tay etal 2007).

Onset of symptoms is typically in the first months of life. However, neonatal manifestations have been described (Abdenur etal 2006; Maller etal 1997; Pons etal 2004; Swoboda etal 2003). Neonatal symptoms could be muscular hypotonia, sucking difficulties, irritability, ptosis, hypotension and/or hypoglycaemia, i.e. a problematic postnatal adaptation. The most prominent clinical feature of AADC deficiency is a severe movement disorder. Patients suffer from truncal hypotonia, limb hypertonia, dystonia, athetosis and hypokinesia. All patients described so far presented oculogyric crises and severe irritability. Beside the neurological symptoms, patients may have vegetative symptoms such as hypersalivation, nasal congestion, excessive sweating and gastro-oesophageal reflux disease. In addition, they can develop endocrinological symptoms, e.g. elevated prolactin, hypoglycaemia and growth hormone deficiency (Swoboda etal 1999, 2003). Only a few more mildly affected patients have been described (Burlina etal 2001; Tay etal 2007).

The first step in reaching the diagnosis is the investigation of neurotransmitters in CSF. Patients display a typical pattern with a distinct reduction of the stable degradation products of dopamine and serotonin pathways, homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), as well as an elevation of the precursors of dopamine and serotonin, levodopa and 5-hydroxytryptophan. Additionally 3-ortho-methyldopa (3-OMD) resulting from methylation of accumulating levodopa is clearly elevated (Hyland etal 1992). It was thought that this pattern was unique but a similar pattern was recently described in patients with mutations in the PNPO gene (Mills etal 2005). These patients have a secondary AADC deficiency due to a defect in synthesis of pyridoxal phosphate. The clinical picture is a severe epileptic encephalopathy (Brautigam etal 2002; Mills etal 2005).

Another laboratory finding pointing to AADC deficiency is an elevated concentration of vanillactic acid in urine (Hyland etal 1992). Vanillactic acid accumulates following transamination of 3-OMD.

The diagnosis is confirmed by measuring the enzyme activity of AADC in plasma or cells (Hyland and Clayton 1992). Mutation analysis of the AADC gene can be performed and several mutations have already been described (Chang etal 1998, 2004; Lee etal 2008).

The therapeutic management is challenging. No systematic studies on drug therapy are available, and there are no guidelines or therapeutic recommendations. Patients have been treated with the cofactor of AADC (vitamin B6), monoamine oxidase inhibitors, dopamine agonists, anticholinergics, melatonin and others.

Response to treatment has been variable, but overall outcome remains poor. However, Pons and colleagues postulated that there may be two groups of patients: one predominantly male with a favourable response and a second predominantly female with poor response to drug treatment (Pons etal 2004).

The aim of this study was to summarize a detailed clinical description of nine German AADC patients, five of them previously unreported, and to collect data about medical treatment and the individual responses to different drugs.

Patients and methods

We investigated eight German patients diagnosed with AADC deficiency. Additionally, we evaluated the data of one deceased sibling. The study was approved by the Institutional Review Board (S-035/2007) and informed parental consent was obtained before including patients in the study.

Data concerning clinical symptoms, disease course, family history, and laboratory investigations (especially neurotransmitters in CSF), drug treatment and neuroimaging were collected from patients’ charts and personal information of treating physicians using a standardized evaluation protocol. In addition, a detailed clinical and neurological examination was performed by one investigator and recorded with a video camera.

Details on the study population are summarized in Table 1. Nine patients were included (6 male, 3 female). Three patients (patients nos. 7, 8 and 9) were siblings; one of them died at the age of 23 years. Age at study was 2–35 years (median 8 years). Four patients have been published before, but in less detail (Brautigam etal 2000; Chang etal 2004; Korenke etal 1997).
Table 1

Study population and clinical presentation

 

Patient number

1

2

3

4

5

6

7

8

9a

Σ

Sex sibling

Male

Female

Male

Male

Male

Female

Female ×

Male ×

Male ×

 

Age at diagnosis (years)

4/12

6 9/12

5 10/12

3 5/12

6/12

5

24

23

13

 

Age at investigation (years)

2 4/12

9

7 3/12

6 10/12

3 5/12

17

35

34

  

Mental retardation

×

×

×

×

×

×

×

×

×

9

Truncal muscular hypotonia

×

×

×

×

×

×

×

×

×

9

Limb hypotonia

×

     

×

 

×

3

Limb hypertonia

 

×

 

×

×

×

 

×

×

6

Hypokinesia/hypomimia

×

×

×

×

×

×

×

×

×

9

Dystonia of limbs

×

×

 

×

×

×

×

×

×

8

Truncal dystonia

 

×

   

×

×

×

×

5

Cervicofacial dystonia

×

×

   

×

×

×

×

6

Rigor

 

×

×

 

×

×

×

×

×

7

Chorea

 

×

 

×

     

2

Tremor

     

×

 

×

 

2

Oculogyric crises

×

×

 

×

×

×

×

×

×

8

Epileptic seizures

   

×

  

×

 

×

3

Deterioration during the day

×

×

×

 

×

×

×

×

×

7

Ptosis

×

×

×

×

×

    

5

Hyperhidrosis

×

×

 

×

×

 

×

 

×

6

Hypersalivation

 

×

×

×

×

×

×

×

×

8

Hypotension

         

Temperature instability

     

×

×

×

×

4

Hypoglycemia

×

    

×

   

2

Sleep disturbance

×

×

 

×

×

    

4

Dysphoria/ Excessive crying

×

×

  

×

    

3

Gatroesophageal reflux

       

×

 

1

Constipation

×

×

  

×

×

   

4

Diarrhea

   

×

×

    

2

Feeding problems/Swallowing difficulties

×

×

 

×

×

×

×

×

×

8

Gastrostomy

×

×

   

×

   

3

aDeceased at the age of 23 years.

Initial symptoms were obvious in all patients in the first 6 months of life (median 2 months, range: neonatal period to 6 months). These initial symptoms were muscular hypotonia in 8 patients, oculogyric crisis in 3 and dystonia in 2 patients. Two patients already presented with neonatal symptoms. They suffered from sucking difficulties, hypoglycaemia and muscular hypotonia. The age at diagnosis varied from 4 months to 23 years (median 6 years).

Clinical symptoms and disease course

All patients were mentally retarded; milestones of motor development were delayed or never reached.

Neurological symptoms became evident in all patients during the first 6 months of life. Neurological symptoms included mental retardation, truncal hypotonia, hypokinesia and hypomimia in all patients, and dystonic movements and typical oculogyric crises in 8 of 9 patients. One more mildly affected patient (patient 6) never suffered from oculogyric crises or other paroxysmal movements. Diurnal variation with deterioration of symptoms during the day was present in 7 patients.

Three patients showed single epileptic seizures with corresponding EEG abnormalities, but none developed severe epilepsy. Seizure types were grand mal and complex focal seizures. One patient suffered only one single seizure; the other two required antiepileptic therapy. It was difficult to discriminate seizures from oculogyric crises and paroxysmal dystonia. All patients were socially interactive, but their cognition was difficult to assess owing to the severe motor impairment.

All patients presented additional autonomic symptoms due to catecholamine deficiency. Ptosis occurred in 5 patients, hyperhidrosis in 6, hypersalivation in 8 and nasal congestion in 5 patients. Four patients suffered from temperature instability in the first year of life and two from hypoglycaemia.

In 4 patients sleeping disturbances and in 3 patients episodes of excessive crying occurred, which caused severe problems for families and caregivers.

Gastrointestinal symptoms were also prominent. Swallowing difficulties were reported in 8 patients; gastrostomy was necessary in 3 patients. Four patients suffered from constipation and 2 from diarrhoea. One patient had gastro-oesophageal reflux disease requiring fundoplication.

Brain imaging

Brain imaging was performed in all 9 patients: in 2 patients only a CT scan was available, the other patients received MRI imaging. In most cases only a single study was available. Only 2 patients had repeated MRI scans. In 4 patients results of brain imaging were normal. One patient showed delayed myelination at the age of 6 months and leukodystrophic changes at the age of 2 years. Other MRI findings were atrophy and reduced myelination at the age of 7 months, and possible white-matter changes in one CT scan. MR spectroscopy in 2 patients gave normal results.

Psychiatric disorders in carriers

Family history was obtained by interview of the parents. In 6 of the 7 investigated families there was a high incidence of psychiatric disorders in relatives of first or second degree. In three families the parents were affected. Psychiatric disorders were depression, psychosis, suicide or suicide attempts.

Biochemical findings

All patients showed the typical AADC pattern in CSF (Table 2). Concentrations of the degradation products HVA representing the dopaminergic pathway and of 5HIAA representing the serotoninergic pathway were clearly reduced. Precursors were elevated. All patients showed a marked elevation of 3-OMD and a moderate elevation of 5-hydroxytryptophan. An elevation of l-dopa was seen only in 2 of 7 patients; the concentrations were normal in the other 5 patients. Additional laboratory investigations were performed: the investigation of serotonin in whole blood, prolactin in plasma and vanillactic acid in urine. As expected, all patients had a clearly reduced concentration of serotonin in blood. Prolactin in serum was elevated only in 2 of 6 patients investigated. Vanillactic acid in urine was elevated in all 6 investigated patients; however, all patients underwent prior routine investigation of organic acids that revealed normal results.
Table 2

Laboratory findings in CSF and enzyme activity

Laboratory values in CSF (nmol/L)

Patient number (age at investigation [years])

1 (4/12)

2 (1 10/12)

3 (6)

4 (3 6/12)

5 (6/12)

6 (4 9/12)

7 (23)

8 (22)

9 (12)

HVA

15

22

80

21

81

22

<2

12

17

(reference range)

(484–1446)

(211–871)

(313–824)

(313–824)

(427–989)

(211–871)

(58–190)

(58–190)

(58–190)

5-HIAA

4

2

11

53

31

2

<2

<2

2

(reference range)

(302–1952)

(105–299)

(130–362)

(130–362)

(159–989)

(105–299)

(87–372)

(87–372)

(87–372)

3-OMD

1920

575

655

775

>2300

575

402

54

907

(reference range)

(<310)

(14–35)

(<50)

(<50)

(<128)

(14–35)

(<50)

(<50)

(<50)

l-Dopa

<2

 

<2

<2

<2

 

45

408

<5

(reference range)

(<15)

 

<15

<15

(<15)

 

(<25)

(<25)

(<25)

5-Hydroxytryptophan

177

 

115

74

180

 

51

 

65

(reference range)

(<20)

 

(<17)

(<17)

(<17)

 

(<10)

 

(<10)

5-Methyltetrahydrofolate

78

 

69

45

145

118

15

71

107

(reference range)

(41–276)

 

(32–148)

(32–148)

(41–276)

(40–170)

(28–118)

(28–118)

(28–118)

Enzyme activity in plasma (pmol/ml per min)

0.2

<1 U/L

0.6

0

4

1.6

0

0.6

0

(reference range)

(47–119)

(18–34)

(33–79)

(33–79)

(47–119)

(36–129)

(23–34)

(23–34)

(23–34)

Enzyme acitivity as % of lower reference range

0.4

<6

2

0

9

4

0

3

0

5-Methyltetrahydrofolate (5-MTHF) was measured in 8 patients before treatment (Table 2). Follow-up investigations were available only in 4 patients (patients 4, 7, 8 and 9, values not listed). Before treatment most patients showed normal concentrations of 5-MTHF. In patients 7 and 8 (two of three siblings) concentration of 5-MTHF declined during l-dopa treatment. In the third sibling (patient 9) 5-MTHF declined during l-dopa treatment but remained within the normal range.

All patients had a distinctly reduced activity of AADC in plasma. Enzyme activity was between 0 and 9% of the lower normal range (median 2%) (Table 2).

Mutation analysis was performed in 8 patients, revealing point mutations in the AADC gene in all (Table 3).
Table 3

Mutation spectrum of AADC-deficient patients

Patient

Mutation

 

1

Not performed

 

2

Homozygous

c.214C>T (p.H72Y) in exon 3

3

Homozygous

c.206C>T (p.T69M) in exon 3

4

Homozygous

G to A (p.A447H) in exon 14

5

Homozygous

CAC to TAC (p.H70T) in exon 3

6

Compound heterozygous

c.206C>T (p.T69M) in exon 3

c.439A>C (p.S147R) in exon 5

7, 8 and 9

Homozygous

c.387G>A (p.G102S) in exon 3

Drug therapy

We evaluated the clinical response on treatment with vitamin B6, dopamine agonists, monoamine oxidase inhibitors, anticholinergics, levodopa and serotonin reuptake inhibitors, which were almost always given in combination. The effects of other drugs, e.g. antiepileptics, melatonin, benzodiazepines, botulinum toxin, were not evaluated.

Vitamin B6

All patients received a therapeutic trial with vitamin B6, the essential cofactor of AADC. Individual dosage varied between 150 and 4800 mg/day (20–160 mg/kg per day) divided into 2 or 3 doses. Three patients received vitamin B6 monotherapy for some time. One of them (patient 8) showed a slight improvement of tremor and dystonia on vitamin B6; the other two patients showed no improvement of movement disorder; one of them seemed to have a better vigilance. The other 6 patients received vitamin B6 only in combination with other drugs (bromocriptine, selegiline, levodopa).

In summary, 4 patients improved slightly on vitamin B6 (three of them were siblings with a special l-dopa-responsive mutation (Chang etal 2004)). There was no change in CSF neurotransmitter findings in all investigated patients. Side effects were predominantly gastrointestinal, such as nausea, vomiting and abdominal pain.

Dopamine agonists

All patients received a trial with the dopamine agonist bromocriptine. Dosage was between 2.5 and 10 mg/day (0.14–0.53 mg/kg per day). In one patient with a milder clinical course (patient 3) monotherapy with bromocriptine resulted in a dramatic improvement of the clinical picture. Hypokinesia and muscular hypotonia improved, ptosis and hypersalivation disappeared. One other patient (patient 5) improved slightly on the combination of bromocriptine, trihexyphenidyl (anticholinergic) and tranylcypromine (MAO inhibitor). One other patient (patient 6) improved on bromocriptine at the beginning, but this effect weakened in the following weeks. However, discontinuation of therapy resulted in further deterioration of symptoms. The other patients showed no clinical improvement.

One patient (patient 6) received a therapy with another dopamine agonist, pergolide (in combination with vitamin B6 and selegiline) in a dosage of 0.8 mg divided into three doses (0.06 mg/kg per day). On this treatment he improved slightly, with less muscular hypotonia.

Other drugs

Patients were additionally treated with the monoamine oxidase (MAO) inhibitors selegiline and tranylcypromine. Selegiline was administered in 3 patients (2, 4, and 6). It was always given in combination with other drugs; individual dosage was between 9 and 12.5 mg/day divided into 2 or 3 single doses (0.5–1.1 mg/kg per day). In one patient (patient 6) muscle tone, oculogyric crisis and constipation improved, but this was only a temporary effect, while in another patient oculogyric crises deteriorated on selegiline.

Tranylcypromine was administered in two patients (5 and 6); the dosage was 8–10 mg divided into two doses (0.7–0.8 mg/kg per day). One patient (patient 5) responded to a combination of bromocriptine and trihexyphenidyl; oculogyric crises improved and he showed a slight improvement of motor development. In the other patient, oculogyric crises deteriorated.

Only one patient was treated with the anticholinergic drug trihexyphenidyl, individual dosage was 11.5 mg/day divided into 3 doses (1.2 mg/kg per day). He improved on combination with bromocriptine, tranylcypromine and trihexyphenidyl and showed slight developmental progress.

A therapeutic trial with the serotonin reuptake inhibitor paroxetine was carried out in another patient (patient 6); individual dosage was 16 mg/day (1.19 mg/kg per day) divided into two doses. On this treatment, oculogyric crises deteriorated and the trial was paroxetine stopped after 4 months.

Levodopa

Six patients received a therapeutic trial with levodopa. Three siblings (patients 7, 8 and 9) responded dramatically on this treatment. After administration of levodopa, patient 8 was able to walk without assistance, the other two with assistance. Dystonia, truncal hypotonia and speech improved, oculogyric crisis diminished. These three patients have been reported before (Chang etal 2004). They have a specific mutation in the AADC gene decreasing the binding affinity of AADC for the substrate. None of the other patients showed any clinical response on levodopa.

Overall, systematic evaluation of the response to drug treatment was difficult. Table 4 presents the overall treatment responses. Four patients (3 male, 1 female) showed a good clinical response. All these 4 patients had a milder disease course than the others, and all of them had reached milestones of motor development before treatment. The other 5 patients initially presented with a more severe clinical picture with no developmental progress before initiation of treatment. Four of them (2 male, 2 female) showed no clinical response to any combination of therapy and no developmental progress. One male patient showed a mild clinical improvement on treatment. However, in no patient did symptoms resolve completely.
Table 4

Summary of drug therapy and individual responses to treatment

Patient

Sex

Start of treatment

Medication

Response to drug treatment

1

Male

4 mo

Bromocriptine

No response to drug treatment

Vitamin B6

No motor development

2

Female

6 y 9 mo

Vitamin B6

No response to drug treatment

Pergolide

No motor development

Selegiline

3

Male

5 y 10 mo

Bromocriptine

Clear motor and mental development

Vitamin B6

Improvement of hypotonia and vegetative symptoms

4

Male

3 y 5 mo

Vitamin B6

No response to drug treatment

Selegiline

No motor development

Bromocriptine

l-Dopa

5-Hydroxytryptophan

5

Male

6 mo

Bromocriptine

Slow motor development

Trihexyphenidyl

Tranylcypromin

Vitamin B6

Pergolide

6

Female

5 y

Vitamin B6

No response to drug treatment

Selegiline

No motor development

Pergolide

l-Dopa

Tranylcypromin

Bromocriptine

7

Female

24 y

Vitamin B6

Clear improvement of dystonia, oculogyric crises and autonomic symptoms

l-Dopa

Improvement of motor competence

5-Hydroxytryptophan

Bromocriptine

8

Male

23 y

Vitamin B6

Clear improvement of dystonia, oculogyric crises and autonomic symptoms

l-Dopa

Improvement of motor competence

5-Hydroxytryptophan

Bromocriptine

9

Male

13 y

Vitamin B6

Clear improvement of dystonia, oculogyric crises and autonomic symptoms

l-Dopa

Improvement of motor competence

5-Hydroxytryptophan

Bromocriptine

y, year(s); mo, month(s).

Discussion

We present 9 patients with AADC deficiency from Germany; 5 of them have not been published previously. Essentially, the presentation of these patients confirms the clinical picture described in literature. All patients developed symptoms in the first 6 months of life. Most frequent was a severe neurological presentation with marked mental retardation and a severe movement disorder with predominantly axial muscular hypotonia, hypokinesia, dystonia and rigor. All patients were described as socially interactive, but in most cases cognitive evaluation was not possible owing to the severe motor impairment.

Eight of 9 patients suffered from oculogyric crises. Only one more mildly affected patient never developed oculogyric crises or other paroxysmal movement disturbances. This is remarkable because all patients described so far presented with oculogyric crises, most of them during the first year of life. Tay and colleagues described two more mildly affected Chinese sisters with AADC deficiency (Tay etal 2007); the older one did not present the first oculogyric crises before the age of 12 years. Our patient was 7 years old at the time of investigation; it is possible that he would have developed this movement disorder in the future if he had remained untreated. Although oculogyric crises are typical symptoms of AADC deficiency, their absence does not exclude this disorder.

Remarkably, three patients presented clear epileptic seizures with typical EEG findings. There are only few reported AADC patient with epileptic seizures (Ito etal 2008; Swoboda etal 2003). More often the paroxysmal movement disorder in AADC deficiency is misinterpreted as epileptic seizures. One should therefore be aware that epileptic seizures can occur in AADC patients and sometimes have to be treated with antiepileptics.

Beside the neurological picture, all patients developed additional non-neurological symptoms, especially autonomic symptoms due to catecholamine deficiency. Typical were ptosis, hyperhidrosis, hypersalivation, hypoglycaemia and nasal congestion. Hypoglycaemia in AADC deficiency could be due to catecholamine deficiency. As hypoglycaemia is often reported in AADC deficiency, there should be careful monitoring of glucose levels in conditions leading to increased glucose demand or fasting. Lack of catecholamines may also render patients susceptible to sudden cardiac arrest, especially when they are exposed to stressful situations (Anselm and Darras 2006). Dysphoria and sleeping disturbances occurred in some patients; these symptoms were a severe problem for caregivers.

In 6 of the 7 investigated families there was an occurrence of psychiatric disorders in relatives of first or second degree. Swoboda and colleagues also described an increased occurrence of psychiatric disorders in families with AADC (Swoboda etal 2003). This has to be evaluated in detail in further studies.

Brain imaging revealed normal findings or nonspecific abnormalities that are not helpful in diagnosing AADC deficiency.

All patients presented with the typical pattern of neurotransmitters in CSF, specifically massively reduced concentrations of HVA and 5-HIAA reflecting deficiency of dopamine and serotonin together with a distinctly elevated concentration of 3-OMD, resulting from methylation of the accumulating precursor levodopa. Levodopa itself was elevated only in 2 of 7 patients investigated; otherwise its concentration was normal.

Even though measurement of biogenic amines in CSF remains the gold standard for diagnosis, additional laboratory investigations may be helpful: the investigation of serotonin in whole blood, prolactin in plasma and vanillactic acid in urine. Concentration of serotonin was clearly reduced in all patients; prolactin was elevated only in two. Vanillactic acid was elevated in the urine of all patients when specifically investigated; however, in routine investigations of organic acids the elevated vanillactic acid was never recognized.

In AADC deficiency, accumulating l-dopa is further methylated to 3-OMD. This process requires a lot of supplementary methyl groups, so cerebral folate depletion appears possible. l-Dopa therapy further increases the need for methyl groups and may aggravate folate depletion.

In our study only two siblings (patients 7 and 8) showed reduced concentrations of 5-MTHF in CSF, which had already been reported by Bräutigam and colleagues (Bräutigam etal 2000). These patients showed a particular response to l-dopa treatment owing to a specific mutation. The third sibling (patient 9) always had normal concentration of 5-MTHF, but 5-MTHF concentration declined while on l-dopa treatment. In all other patients investigated, the concentration of 5-MTHF was normal. As a consequence, monitoring of folate metabolism in AADC patients is recommended by measurement of 5-MTHF in CSF, especially if a patient is on l-dopa treatment. If folate depletion is suspected, substitution with folinic acid should be considered.

AADC deficiency was confirmed in all patients by demonstrating almost absent enzyme activity ranging from undetectable to 9% of normal values. In 8 patients (6 families) mutation analyses of the AADC gene was performed. In all of them, different point mutations were identified, five of which have not previously been reported in other AADC-deficient patients.

Drug therapy in patients with AADC deficiency aims at correcting the central and peripheral deficiency of serotonin and catecholamines. However, treatment is very challenging. There are no established treatment schemes or clear dosages for the individual drugs. No systematic studies on drug therapy are available. Overall outcome is disappointing. Pons and colleagues postulated that there would be two groups of patients: one predominantly male with favourable response and a second predominantly female with poor response to drug treatment (Pons etal 2004). We could not confirm this finding in our study population.

Our patients received vitamin B6, dopamine agonists, monoamine oxidase inhibitors, anticholinergics, levodopa and serotonin reuptake inhibitors. Interpretation of treatment response was difficult. There was a wide variation of symptoms and severity between the individual patients. Drugs were almost always given in combinations; response was therefore hard to attribute to a single drug. There were no clear end points or objective scales for treatment efficacy. Only subjective evaluation of parents and physicians was available and documentation of treatment efficacy was sometimes very sparse. This is an area for urgent future development.

All patients received a trial with the essential cofactor of AADC, vitamin B6, to possibly potentate residual enzyme activity. Only four patients improved slightly, three of them with a special homozygous mutation affecting the binding of the substrate levodopa (Chang etal 2004). Also, all patients were treated with dopamine agonists, either bromocriptine or pergolide. One of them responded dramatically to bromocriptine, the others showed only slight or no clinical improvement. Four patients received MAO inhibitors; one patient improved slightly on selegiline and another one slightly on tranylcypromine treatment.

Only one patient was treated with the anticholinergic drug trihexyphenidyl to restore the equilibrium between inhibitory dopaminergic and excitatory cholinergic neurons, which is disturbed due to dopamine deficiency. This approach, also used in treatment of Parkinson disease, resulted in slight clinical improvement.

A therapeutic trial with the serotonin reuptake inhibitor paroxetine was performed in another patient, resulting in deterioration of oculogyric crises.

Six patients received a therapeutic trial of levodopa. Three siblings responded dramatically to this treatment. They carry a homozygous mutation affecting the binding of the substrate levodopa to the enzyme as reported before (Chang etal 2004). No other patient improved on levodopa.

The overall evaluation response to drug treatment was difficult. It was good in four patients (three of them siblings), moderate in one and poor in four. There appeared to be no difference in severity and response to treatment between males and females, but the number of patients investigated is small. All four patients with good clinical outcome had presented with milder disease course compared to the others, all of them had reached milestones of motor development before treatment. Hence the treatment response may depend on clinical severity. However, even in patients with good treatment response, clinical symptoms never resolved completely.

Conclusion

AADC deficiency is a severe neurometabolic disorder that is characterized mainly by muscular hypotonia, dystonia, oculogyric crises, severe developmental delay and additional non-neurological symptoms. The clinical picture of AADC deficiency is heterogeneous, and more mildly affected patients exist.

Diagnostic work-up should start with the investigation of neurotransmitters in CSF. Investigation of serotonin in blood, prolactin in plasma and vanillactic acid in urine can also be helpful. Confirmation of the diagnosis should be performed by the measurement of AADC activity in plasma and mutation analysis of the AADC gene.

Drug treatment is difficult and requires both a systematic approach and patience from doctors and parents. A combination of vitamin B6, dopamine agonists and MAO inhibitors should be tested. Anticholinergics and levodopa could be introduced as a second line. If there is no response, it is worth trying different drugs of the same group because efficacy may vary even within one substance class.

Acknowledgement

The authors thank Professor Keith Hyland (Horizon Molecular Medicine, Atlanta, GA, USA) and Dr Rüdiger Kläs and Dr Friedrich W. Cremer (Zentrum für Humangenetik, Mannheim, Germany) for performing molecular genetic investigations of the AADC gene.

Copyright information

© Springer Science+Business Media B.V. 2009