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Aromatic l -amino acid decarboxylase deficiency: An extrapyramidal movement disorder with oculogyric crises
European Journal of Paediatric Neurology 1997; 2•3:67-71 ORIGINAL
ARTICLE
Aromatic L-amino acid decarboxylase deficiency: An extrapyramidal movement disorder with oculogyric crises G CHRISTOPH KORENKE, a HANS-JORGEN CHRISTEN, a KEITH H Y L A N D , b D O N A L D H H U N N E M A N , a FOLKER HANEFELD a
aDepartment of Paediatrics and Neuropaediatrics, University of Gf~'ttingen, Germany; blnstitute of Metabolic Disease, Baylor University Medical Center, Dallas, Texas, USA
Aromatic L-amino acid decarboxylase (AADC) deficiency results in an impaired synthesis of catecholamines and serotonin, and has been reported only in two middle eastern families. We report on a European family with an affected child. The child showed the characteristic clinical picture of an extrapyramidal movement disorder, oculogyric crises and vegetative symptoms seen in the three patients described previously. Treatment with a combination of the AADC cofactor pyridoxine, the monoamine oxidase B inhibitor selegiline and bromocriptine was started during the fifth year of life and showed only a moderate clinical improvement in contrast to patients who have been treated since the first year of life. L-Amino acid decarboxylasedeficiency. Pyridoxine, selegiline and bromocriptine treatment. Extrapyramidalmovement disorder. Oculogyric crises.
Introduction Defective synthesis of biogenic amines in the central nervous system (CNS) was first described in patients with hyperphenylalaninaemia due to defects in the synthesis of tetrahydrobiopterin (BH4), the cofactor for phenyalanine hydroxylase, tyrosine hydroxylase and tryptophan hydroxylase. 1 These patients show progressive neurological deterioration, truncal hypotonia, rigor, oculogyric spasms and hyperthermia manifesting during the first months of life. Similar symptoms were observed by Hyland et al. 2 in monozygotic twins, the first-reported patients with a deficiency of L-aromatic amino acid decarboxylase (AADC). This enzyme catalyses the decarboxylation of L-dopa to dopamine and 5hydroxytryptophan to serotonin (5HT) and hence deficiency of AADC leads to a severe deficiency of these two neurotransmitters in cerebrospinal fluid
(CSF). At the age of 2 months, these patients showed an extrapyramidal movement disorder with generalized hypotonia, oculogyric crises and developmental delay. Liver and plasma AADC activities were very low and CSF levels of biogenic amine metabolites homovanillic acid (HVA) and 5hydroxyindoleacetic acid (HIAA) were decreased. Recently, a second family with AADC deficiency has been reported; the affected child had very similar clinical symptoms.3 We report the clinical features, laboratory investigations and experience of 1 year of therapy in a child of a third family with AADC deficiency.
Case report The female patient was the second child of nonconsanguineous parents. The dizygotic twin brother was healthy and there was no family
Received 30.12.96. Revised9.5.97. Accepted 16.5.97.
Correspondence: Prof Dr F Hanefeld, Department of Paediatricsand Neuropaediatrics, University of G~ttingen, Robert-Koch-Strasse40, D-37075 G6ttingen,
Germany
1090-3798197102130067+5 $I 8.00
© 1997 European Paediatric Neurology Society
Original article: G C Korenke et al.
68 history of neurological disorders. Pregnancy was uncomplicated, birth was at the 36th week of gestation (Apgar scores 7-8-9, body weight 1990 g, length 48cm and head circumference 33.5cm). During the first weeks of life the patient was normal and seemed to be more active than her brother. During the third month of life, feeding difficulties developed. From the fourth month, repeated periods with tremulous rotating of the arms and simultaneous upwards movements of the eyes were observed several times during the day. Even during these periods, electroencephalogram (EEG) was normal and anticonvulsive treatment with phenobarbital and clonazepam was not effective. The tremor disappeared within 6 months and a persistent status of hypokinesia and hypotonia developed. A diurnal variation of hypokinesia with only some movements early in the morning was noticed during the second year of life. Turning over or antigravital movements were not possible. There were additional disturbances of temperature regulation with hypothermia (down to 35°C) and hyperthermia (up to 40°C), exaggerated sweating and constipation requiring constant use of laxatives. The oculogyric crises continued with a tonic conjugated upward deviation of the eyes mostly to the right side, once to several times each day, lasting between a few minutes and several hours. They could be stopped only by rectal application of diazepam. During these crises the patient was awake and capable of reactive smiling. All examinations including cerebral and spinal magnetic resonance imaging (MRI), EEG, evoked potentials, nerve conduction velocity, CSF routine Table
examination, screening for amino and organic acidurias, muscle, nerve and skin biopsy were normal. No indications for mitochondrial, peroxisomal or lyosomal disorders were found. After MRI examination the patient did not wake up adequately due to hypoglycaemia (<0.1 m g / d l by glucose stick examination). A fasting test showed no hypoglycaemia and normal ketone body production and urine organic acids. The patient was first seen in our department at the age of 2 years 6 months. Body weight (9.5 kg) was below the 3rd percentile, head circumference at the 3rd percentile (46 cm) and body length at the 25th percentile (88cm). The girl was alert and socially interactive without active speech. Her cognitive development was at the stage of a 9- to 12-month-old child. She showed hypersalivation, hypokinesia with very little spontaneous or reactive movement and a severe truncial hypotonia with increased limb tone and rigor. The deep tendon reflexes were exaggerated without pyramidal signs. Blood pressure and pupillary reaction were normal. Under the clinical suspicion of an extrapyramidal movement disorder we started a therapeutical trial with L-dopa (up to 15 mg per kg body weight) during 1 year without a clear clinical benefit. Low values of CSF HVA and HIAA found with a gas chromatography-mass spectroscopy (GC-MS) screening method 4 could be confirmed with high performance liquid chromatography (HPLC) s with additionally elevated levels of 3-O-methyldopa (3O-MD) and reduced AADC activity in plasma (Table 1).
1 Biochemical data from the patient (CSF, plasma and urine)
CSF Patient age Therapy
4 years 9 months --
4 years 11 months Vitamin B6
5 years 2 months Vitamin B6
Normal range
Phe
1200
--
Tyr HVA HIAA 3-O-MD
1100 35 0 736
-40 0 510
--19 0 308
<2000 <2500 71-565 58-220 <100
535 3790 2.6
---
----
<20 <100 36-129
20
--
--
<1
Plasma
L-Dopa 3-O-MD AADC"
1.6
Urine VLAb
Data are given in nM, except: apmol/min/ml, b#g/mg creatinine, --: not performed; HVA: homovanillic acid; 3-O-MD: 3-0methyldopa;AADC:L-aromaticamino acid decarboxylase;VLA:vaniUyllactate.
Original article: Aromatic amino acid decarboxylase deficiency At the age of 4 years and 9 months we started treatment with pyridoxine, the cofactor of AADC, in mega doses up to 3 x 400 mg daily (110 m g / k g daily). There was an initial clinical improvement with decreasing frequency of oculogyric crises and slight improvement of muscle tone. After a period of 4 weeks this amelioration disappeared in spite of a further increase of pyridoxine (145 m g / k g daily). Because of gastrointestinal side-effects the dosage was reduced and has been kept at 110 m g / k g daily, Examination of CSF under pyridoxine treatment showed no increase of HVA and HIAA concentrations (Table 1). After 8 weeks, additional treatment, with the monoamine oxidase (MAO) B inhibitor selegiline (Anteparkin©) was started. A dosage of 6rag daily resulted in a temporary complete disappearance of oculogyric crises, an improvement of muscle tone and bowel function. However, again all these positive phenomena weakened within 6 weeks. Additional treatment with the dopaminergic bromocriptine was initiated in a dosage of up to 6 mg daily. The combined medication led to sustained neurological improvement of hypokinesia and hypotonia; however turning over was still not possible. She showed a change in behaviour, was more socially interactive with more vocalization and had a better participation in the family's social life. No further maturation of cognitive findings was observed. Her appetite improved which was reflected by a slight increase of weight and body length. A marked retardation of bone maturation was demonstrated showing a bone age of 2 years at the age of 5 years. Basal hGH, IGF-1 and IGFBF-3 were normal. A trial of changing selegiline by trancylpromine (up to 10 mg daily) resulted in no further improvement and has been revised after 2 months.
Methods Lumbar CSF was collected from the first drop into four separate tubes and frozen in liquid nitrogen at the bedside. The first 0.5 ml was used for analysis of amino acids, the second and third 0.5 ml were examined for biogenic amine metabolites. The fourth 0.5ml was kept for long-term storage. Samples were stored at -80°C until analysed. Blood was collected into heparin tubes and plasma was separated and stored at -80°C within 15 min. As described previously HVA, HIAA and 3-O-MD in CSF and AADC plasma activity were determined. 2 Biopterins in CSF were measured by Dr Blau also as described previously. 6
69
Organic acids were extracted from acidified urine with ethylacetate. Derivatization to the trimethylsilyl esters was with 50% N-methyl-N(trimethylsilyl)-trifluoroacetamide in chloroform. The trimethylsilyl derivative of vanillyllactate (VLA) has significant mass spectral peaks at m / e 209, 338, 413 and 428 (m +) and on DB-1 or DB-5 elutes after hippuric and citric acids
Results Repeated CSF examination in our patient revealed diminished HVA and HIAA concentrations and elevated levels of 3-O-MD with normal concentrations of aromatic amino acids without any evidence of a defect of biopterin metabolism (Table 1). Urinary excretion of VLA was elevated. These symptoms and the biochemical findings were very suggestive for AADC deficiency, which was confirmed by enzyme plasma analysis (Table 1). Elevated levels of L-dopa and 3-O-MD were also demonstrated in plasma. Examination of the parents revealed a reduced plasma AADC activity in the patient's mother (12.3 p m o l / m i n / m l , control range 24--43) whilst the father showed normal plasma AADC activity (34.2 and 36 p m o l / m i n / m l ) , but he had clearly elevated plasma L-dopa levels (202 nM, control range <20). The AADC activity of the monozygotic twin brother was in the heterozygous range (22.5pmol/min/ml, control range 36-129).
Discussion After the first description of Hyland et al. z a n d t h e second report of Mailer et al., 3 we now report a third family with AADC deficiency. There is strong clinical similarity in the four patients known to date. All patients developed non-specific neurological symptoms during the first 2 months of life and showed within 4 months a characteristic extrapyramidal movement disorder with oculogyric crises. The pathogenesis of the oculogyric crises is still unknown, but there is evidence that they might be caused by an imbalance between reduced dopaminergic and increased cholinergic and GABA (y-aminobutyric acid)-ergic activity. 7,s Additional autonomic symtoms such as sweating and temperature dysregulation have also been observed in all patients. In concordance with this clinical similarity there is a biochemical similarity with respect to plasma AADC activity and CSF
Original article: G C Korenke et al.
70
catecholamine and serotonin metabolites. The twins reported by Hyland et al. 2 were treated early and clearly showed a better clinical course than the two patients reported by Mailer et al. 3 a n d here. These late-treated patients have a predominantly extrapyramidal movement disorder, are socially interactive but are not able to speak. Both have normal head growth, a normal MRI scan of the brain at the age of 5 years and no seizures. These findings are in contrast to patients with defects in BH4 metabolism who also have low HVA and HIAA but may develop cerebral convulsions and MRI findings typical of white matter disease. 9 There are some clinical findings in our patient which have not been reported before but may be related to AADC deficiency. A tendency to hypoglycaemia was observed several times in different hospitals and may be due to the relative lack of catecholamines as anti-insulinergic hormones. Furthermore the reduced bone maturation of our patient with growth retardation may be associated with the lack of catecholamines which increase the effect of growth hormone. TM The monozygotic twins described 2 were treated with a combination of pyridoxine, bromocriptine and the global MAO inhibitor trancylpromine since the first year of life; they showed a striking neurological improvement, whereas an older brother had died of a very similar disease at 9 months of age without therapy. The twins are now about 7 years old, are walking well but show a mild mental retardation with a more strongly retarded speech development (unpublished observations). In our patient, treatment with nearly the same therapy resulted in only a slight clinical amelioration. The modifications of the therapy in our patient in comparison with the treated twins had no clear advantage. We gave pyridoxine in higher dosage (3 x 400 mg daily instead of 100 mg daily) and saw a temporary clinical improvement without clear biochemical effects. A selective MAO B inhibitor instead of a generalized MAO inhibitor was chosen to minimize gastrointestinal and systemic side-effects. The clinical improvement after bromocriptine administration could be related to activation of both dopamine and serotonin functions, since this drug shows comparable affinity for dopamine D2 and serotonin 5-HT-2 receptors, n Extrapyramidal symptoms due to dopaminergic dysfunction in adults can be modulated by serotoninergic drugs. 12-14 In our patient the combined treatment of pyridoxine (3 x 400 mg daily), selegilin (6rag daily) and bromocriptine (6 mg daily) resulted in the optimal effect. However after 1 year of therapy the girl (aged 6 years) is still not able to roll over or sit freely. Her clinical
course is similar to the patient reported by Maller et al., 3 who was treated with the same substances and showed only a moderate clinical improvement. The role of serotonin in the brain is not completely understood, however involvement of serotonin in modulating both brain development is and extrapyramidal function 16 has been suggested. In neonatal rats, disruption of the developing dopaminergic pathways induces striatal sprouting of serotoninergic fibres which partially compensates for the dopaminergic deficit. 1~ The combination of oculogyric crises, extrapyramidal movement disorder and vegetative symptoms beginning during the first months of life is highly suggestive for AADC deficiency. Because of the striking clinical improvement in the patients treated within the first year of life, early diagnosis and treatment seem to be essential for patients with AADC deficiency. In comparison with the patients reported previously, 2,3 who were products of consanguineous parents of Arabian (Hyland, personal communication) and Iranian origin, our patient is a child of a non-consanguineous German marriage, indicating that this enzyme deficiency may be more widespread than expected up to now. Patients with AADC deficiency may be detected by an elevated concentration of VLA in urine or lowered concentration of HVA and HIAA in CSF followed by determination of enzyme activity in plasma. In the usual methods for the determination of organic acids VLA may be easily missed since even when increased it remains a small peak and elutes in a region which is often ignored. Mass fragmentography at characteristic ions, however, can easily detect the levels found in AADC deficiency. There are now several metabolic diseases which affect biogenic amine metabolite concentration in CSF and hence we emphasize the importance of measuring biogenic amines metabolites in CSF in all patients with the suspection of a neurometabolic disorder.
Acknowledgements We thank Dr N Blau, Department of Paediatrics, University of Basel, Switzerland, for determination of biopterins in CSF.
References Kaufrnann S, Holtzman N, Milstien S et al. Phenylketonuria due to a deficiency of dihydropteridine reductase. New Engl J Med 1975; 293: 785-789.
Original article: Aromatic amino acid decarboxylase deficiency 2 Hyland K, Surtees RAH, Rodeck C, Clayton PT. Aromatic amino acid decarboxylase deficiency: Clinical features, diagnosis, and treatment of a new inborn error of neurotransmitter amine synthesis. Neurology 1992; 42: 2980-1988. 3 Mailer A, Hyland K, Milstien S e t al. Aromatic Lamino acid decarboxylase deficiency: Clinical features, diagnosis, and treatment of a second family. J Child Neurol (in press). 4 Hunneman DH. Mass fragmento-graphic determination of homovanillic and 4-hydroxy-3-methoxymandelic acids in 50/~1 plasma. Clin Chim Acta 1983; 135: 24052410. 5 Hyland K, Clapton PT. Aromatic L-amino acid decarboxylase deficiency: Diagnostic methodology. Clin Chem 1992; 38: 2405--2410. 6 Blau N, Heizmann CW, Sperl Wet al. Atypical (mild) forms of dihydropteridine reductase deficiency: neurochemical evaluation and mutation detection. Pediatr Res 1992; 32: 726-730. 7 Leigh RJ, Foley JM, Remler BF, Civil RH. Oculogyric crisis: a syndrome of thought disorder and ocular deviation. Ann Neurol 1987; 22: 13-17. 8 Aramideh M, Bour LJ, Koelman JH et al. Abnormal eye movements in blepharospasm and involuntary levator palpebrae inhibition. Clinical and pathophysiological considerations. Brain 1994; 117: 1457-1474. 9 Brismar J, Aqeel A, Gascon G, Ozand P. Malignant hyperphenylalaninemia: CT and MRI of the brain. Am J Neuroradiol 1990; 11: 135-138.
71
10 Muller EE, Rolla M, Ghigo E et al. Involvement of brain catecholamines and acetylcholine in growth hormone hypersecretory states. Pathophysiological, diagnostic and therapeutic implications. Drugs 1995; 50: 805-837. 11 Suchy I, Schneide HH, Riederer P, Horowski R. Considerations of the clinical relevance of differences in receptor of various dopaminergic ergot alkaloids. Psychopharmacol Bull 1983; 19: 743-746. 12 Meltzer HY, Young M, Metz Jet al. Extrapyramidal side effects and increased serum prolactin following fluoxetine, a new antidepressant. J Neural Transm 1979; 45: 165-175. 13 Adityanjee, Lindenmeyer JP. Precipitation of dystonia by m-CPP in a schizophrenic patient treated with haloperidol. Am J Psychiat 1993; 150: 837-838. 14 Zuddas A, Cianchetti C. Efficacy of risperidone in idiopathic segmental dystonia. Lancet 1996; 347: 127128. 15 Gromova HA, Chubakov AR, Chumasov EI, Konovalor HV. Serotonin as a stimulator of hippocampal cell differentiation in tissue culture. Int J Dev Neurosci 1983; 1: 339-349. 16 Ferre S, Cortes R, Artigas F. Dopaminergic regulation of the serotonergic raphe-striatal pathway: microdialysis studies in freely moving rats. J Neurosci 1994; 14: 4839--4846. 17 Stachowiack MK, Bruno JP, Snyder AM et al. Apparent sprouting of striatal serotonergic terminals after dopamine-depleting brain lesions in neonatal rats. Brain Res 1984; 291: 164-167.
ARTICLE
Aromatic L-amino acid decarboxylase deficiency: An extrapyramidal movement disorder with oculogyric crises G CHRISTOPH KORENKE, a HANS-JORGEN CHRISTEN, a KEITH H Y L A N D , b D O N A L D H H U N N E M A N , a FOLKER HANEFELD a
aDepartment of Paediatrics and Neuropaediatrics, University of Gf~'ttingen, Germany; blnstitute of Metabolic Disease, Baylor University Medical Center, Dallas, Texas, USA
Aromatic L-amino acid decarboxylase (AADC) deficiency results in an impaired synthesis of catecholamines and serotonin, and has been reported only in two middle eastern families. We report on a European family with an affected child. The child showed the characteristic clinical picture of an extrapyramidal movement disorder, oculogyric crises and vegetative symptoms seen in the three patients described previously. Treatment with a combination of the AADC cofactor pyridoxine, the monoamine oxidase B inhibitor selegiline and bromocriptine was started during the fifth year of life and showed only a moderate clinical improvement in contrast to patients who have been treated since the first year of life. L-Amino acid decarboxylasedeficiency. Pyridoxine, selegiline and bromocriptine treatment. Extrapyramidalmovement disorder. Oculogyric crises.
Introduction Defective synthesis of biogenic amines in the central nervous system (CNS) was first described in patients with hyperphenylalaninaemia due to defects in the synthesis of tetrahydrobiopterin (BH4), the cofactor for phenyalanine hydroxylase, tyrosine hydroxylase and tryptophan hydroxylase. 1 These patients show progressive neurological deterioration, truncal hypotonia, rigor, oculogyric spasms and hyperthermia manifesting during the first months of life. Similar symptoms were observed by Hyland et al. 2 in monozygotic twins, the first-reported patients with a deficiency of L-aromatic amino acid decarboxylase (AADC). This enzyme catalyses the decarboxylation of L-dopa to dopamine and 5hydroxytryptophan to serotonin (5HT) and hence deficiency of AADC leads to a severe deficiency of these two neurotransmitters in cerebrospinal fluid
(CSF). At the age of 2 months, these patients showed an extrapyramidal movement disorder with generalized hypotonia, oculogyric crises and developmental delay. Liver and plasma AADC activities were very low and CSF levels of biogenic amine metabolites homovanillic acid (HVA) and 5hydroxyindoleacetic acid (HIAA) were decreased. Recently, a second family with AADC deficiency has been reported; the affected child had very similar clinical symptoms.3 We report the clinical features, laboratory investigations and experience of 1 year of therapy in a child of a third family with AADC deficiency.
Case report The female patient was the second child of nonconsanguineous parents. The dizygotic twin brother was healthy and there was no family
Received 30.12.96. Revised9.5.97. Accepted 16.5.97.
Correspondence: Prof Dr F Hanefeld, Department of Paediatricsand Neuropaediatrics, University of G~ttingen, Robert-Koch-Strasse40, D-37075 G6ttingen,
Germany
1090-3798197102130067+5 $I 8.00
© 1997 European Paediatric Neurology Society
Original article: G C Korenke et al.
68 history of neurological disorders. Pregnancy was uncomplicated, birth was at the 36th week of gestation (Apgar scores 7-8-9, body weight 1990 g, length 48cm and head circumference 33.5cm). During the first weeks of life the patient was normal and seemed to be more active than her brother. During the third month of life, feeding difficulties developed. From the fourth month, repeated periods with tremulous rotating of the arms and simultaneous upwards movements of the eyes were observed several times during the day. Even during these periods, electroencephalogram (EEG) was normal and anticonvulsive treatment with phenobarbital and clonazepam was not effective. The tremor disappeared within 6 months and a persistent status of hypokinesia and hypotonia developed. A diurnal variation of hypokinesia with only some movements early in the morning was noticed during the second year of life. Turning over or antigravital movements were not possible. There were additional disturbances of temperature regulation with hypothermia (down to 35°C) and hyperthermia (up to 40°C), exaggerated sweating and constipation requiring constant use of laxatives. The oculogyric crises continued with a tonic conjugated upward deviation of the eyes mostly to the right side, once to several times each day, lasting between a few minutes and several hours. They could be stopped only by rectal application of diazepam. During these crises the patient was awake and capable of reactive smiling. All examinations including cerebral and spinal magnetic resonance imaging (MRI), EEG, evoked potentials, nerve conduction velocity, CSF routine Table
examination, screening for amino and organic acidurias, muscle, nerve and skin biopsy were normal. No indications for mitochondrial, peroxisomal or lyosomal disorders were found. After MRI examination the patient did not wake up adequately due to hypoglycaemia (<0.1 m g / d l by glucose stick examination). A fasting test showed no hypoglycaemia and normal ketone body production and urine organic acids. The patient was first seen in our department at the age of 2 years 6 months. Body weight (9.5 kg) was below the 3rd percentile, head circumference at the 3rd percentile (46 cm) and body length at the 25th percentile (88cm). The girl was alert and socially interactive without active speech. Her cognitive development was at the stage of a 9- to 12-month-old child. She showed hypersalivation, hypokinesia with very little spontaneous or reactive movement and a severe truncial hypotonia with increased limb tone and rigor. The deep tendon reflexes were exaggerated without pyramidal signs. Blood pressure and pupillary reaction were normal. Under the clinical suspicion of an extrapyramidal movement disorder we started a therapeutical trial with L-dopa (up to 15 mg per kg body weight) during 1 year without a clear clinical benefit. Low values of CSF HVA and HIAA found with a gas chromatography-mass spectroscopy (GC-MS) screening method 4 could be confirmed with high performance liquid chromatography (HPLC) s with additionally elevated levels of 3-O-methyldopa (3O-MD) and reduced AADC activity in plasma (Table 1).
1 Biochemical data from the patient (CSF, plasma and urine)
CSF Patient age Therapy
4 years 9 months --
4 years 11 months Vitamin B6
5 years 2 months Vitamin B6
Normal range
Phe
1200
--
Tyr HVA HIAA 3-O-MD
1100 35 0 736
-40 0 510
--19 0 308
<2000 <2500 71-565 58-220 <100
535 3790 2.6
---
----
<20 <100 36-129
20
--
--
<1
Plasma
L-Dopa 3-O-MD AADC"
1.6
Urine VLAb
Data are given in nM, except: apmol/min/ml, b#g/mg creatinine, --: not performed; HVA: homovanillic acid; 3-O-MD: 3-0methyldopa;AADC:L-aromaticamino acid decarboxylase;VLA:vaniUyllactate.
Original article: Aromatic amino acid decarboxylase deficiency At the age of 4 years and 9 months we started treatment with pyridoxine, the cofactor of AADC, in mega doses up to 3 x 400 mg daily (110 m g / k g daily). There was an initial clinical improvement with decreasing frequency of oculogyric crises and slight improvement of muscle tone. After a period of 4 weeks this amelioration disappeared in spite of a further increase of pyridoxine (145 m g / k g daily). Because of gastrointestinal side-effects the dosage was reduced and has been kept at 110 m g / k g daily, Examination of CSF under pyridoxine treatment showed no increase of HVA and HIAA concentrations (Table 1). After 8 weeks, additional treatment, with the monoamine oxidase (MAO) B inhibitor selegiline (Anteparkin©) was started. A dosage of 6rag daily resulted in a temporary complete disappearance of oculogyric crises, an improvement of muscle tone and bowel function. However, again all these positive phenomena weakened within 6 weeks. Additional treatment with the dopaminergic bromocriptine was initiated in a dosage of up to 6 mg daily. The combined medication led to sustained neurological improvement of hypokinesia and hypotonia; however turning over was still not possible. She showed a change in behaviour, was more socially interactive with more vocalization and had a better participation in the family's social life. No further maturation of cognitive findings was observed. Her appetite improved which was reflected by a slight increase of weight and body length. A marked retardation of bone maturation was demonstrated showing a bone age of 2 years at the age of 5 years. Basal hGH, IGF-1 and IGFBF-3 were normal. A trial of changing selegiline by trancylpromine (up to 10 mg daily) resulted in no further improvement and has been revised after 2 months.
Methods Lumbar CSF was collected from the first drop into four separate tubes and frozen in liquid nitrogen at the bedside. The first 0.5 ml was used for analysis of amino acids, the second and third 0.5 ml were examined for biogenic amine metabolites. The fourth 0.5ml was kept for long-term storage. Samples were stored at -80°C until analysed. Blood was collected into heparin tubes and plasma was separated and stored at -80°C within 15 min. As described previously HVA, HIAA and 3-O-MD in CSF and AADC plasma activity were determined. 2 Biopterins in CSF were measured by Dr Blau also as described previously. 6
69
Organic acids were extracted from acidified urine with ethylacetate. Derivatization to the trimethylsilyl esters was with 50% N-methyl-N(trimethylsilyl)-trifluoroacetamide in chloroform. The trimethylsilyl derivative of vanillyllactate (VLA) has significant mass spectral peaks at m / e 209, 338, 413 and 428 (m +) and on DB-1 or DB-5 elutes after hippuric and citric acids
Results Repeated CSF examination in our patient revealed diminished HVA and HIAA concentrations and elevated levels of 3-O-MD with normal concentrations of aromatic amino acids without any evidence of a defect of biopterin metabolism (Table 1). Urinary excretion of VLA was elevated. These symptoms and the biochemical findings were very suggestive for AADC deficiency, which was confirmed by enzyme plasma analysis (Table 1). Elevated levels of L-dopa and 3-O-MD were also demonstrated in plasma. Examination of the parents revealed a reduced plasma AADC activity in the patient's mother (12.3 p m o l / m i n / m l , control range 24--43) whilst the father showed normal plasma AADC activity (34.2 and 36 p m o l / m i n / m l ) , but he had clearly elevated plasma L-dopa levels (202 nM, control range <20). The AADC activity of the monozygotic twin brother was in the heterozygous range (22.5pmol/min/ml, control range 36-129).
Discussion After the first description of Hyland et al. z a n d t h e second report of Mailer et al., 3 we now report a third family with AADC deficiency. There is strong clinical similarity in the four patients known to date. All patients developed non-specific neurological symptoms during the first 2 months of life and showed within 4 months a characteristic extrapyramidal movement disorder with oculogyric crises. The pathogenesis of the oculogyric crises is still unknown, but there is evidence that they might be caused by an imbalance between reduced dopaminergic and increased cholinergic and GABA (y-aminobutyric acid)-ergic activity. 7,s Additional autonomic symtoms such as sweating and temperature dysregulation have also been observed in all patients. In concordance with this clinical similarity there is a biochemical similarity with respect to plasma AADC activity and CSF
Original article: G C Korenke et al.
70
catecholamine and serotonin metabolites. The twins reported by Hyland et al. 2 were treated early and clearly showed a better clinical course than the two patients reported by Mailer et al. 3 a n d here. These late-treated patients have a predominantly extrapyramidal movement disorder, are socially interactive but are not able to speak. Both have normal head growth, a normal MRI scan of the brain at the age of 5 years and no seizures. These findings are in contrast to patients with defects in BH4 metabolism who also have low HVA and HIAA but may develop cerebral convulsions and MRI findings typical of white matter disease. 9 There are some clinical findings in our patient which have not been reported before but may be related to AADC deficiency. A tendency to hypoglycaemia was observed several times in different hospitals and may be due to the relative lack of catecholamines as anti-insulinergic hormones. Furthermore the reduced bone maturation of our patient with growth retardation may be associated with the lack of catecholamines which increase the effect of growth hormone. TM The monozygotic twins described 2 were treated with a combination of pyridoxine, bromocriptine and the global MAO inhibitor trancylpromine since the first year of life; they showed a striking neurological improvement, whereas an older brother had died of a very similar disease at 9 months of age without therapy. The twins are now about 7 years old, are walking well but show a mild mental retardation with a more strongly retarded speech development (unpublished observations). In our patient, treatment with nearly the same therapy resulted in only a slight clinical amelioration. The modifications of the therapy in our patient in comparison with the treated twins had no clear advantage. We gave pyridoxine in higher dosage (3 x 400 mg daily instead of 100 mg daily) and saw a temporary clinical improvement without clear biochemical effects. A selective MAO B inhibitor instead of a generalized MAO inhibitor was chosen to minimize gastrointestinal and systemic side-effects. The clinical improvement after bromocriptine administration could be related to activation of both dopamine and serotonin functions, since this drug shows comparable affinity for dopamine D2 and serotonin 5-HT-2 receptors, n Extrapyramidal symptoms due to dopaminergic dysfunction in adults can be modulated by serotoninergic drugs. 12-14 In our patient the combined treatment of pyridoxine (3 x 400 mg daily), selegilin (6rag daily) and bromocriptine (6 mg daily) resulted in the optimal effect. However after 1 year of therapy the girl (aged 6 years) is still not able to roll over or sit freely. Her clinical
course is similar to the patient reported by Maller et al., 3 who was treated with the same substances and showed only a moderate clinical improvement. The role of serotonin in the brain is not completely understood, however involvement of serotonin in modulating both brain development is and extrapyramidal function 16 has been suggested. In neonatal rats, disruption of the developing dopaminergic pathways induces striatal sprouting of serotoninergic fibres which partially compensates for the dopaminergic deficit. 1~ The combination of oculogyric crises, extrapyramidal movement disorder and vegetative symptoms beginning during the first months of life is highly suggestive for AADC deficiency. Because of the striking clinical improvement in the patients treated within the first year of life, early diagnosis and treatment seem to be essential for patients with AADC deficiency. In comparison with the patients reported previously, 2,3 who were products of consanguineous parents of Arabian (Hyland, personal communication) and Iranian origin, our patient is a child of a non-consanguineous German marriage, indicating that this enzyme deficiency may be more widespread than expected up to now. Patients with AADC deficiency may be detected by an elevated concentration of VLA in urine or lowered concentration of HVA and HIAA in CSF followed by determination of enzyme activity in plasma. In the usual methods for the determination of organic acids VLA may be easily missed since even when increased it remains a small peak and elutes in a region which is often ignored. Mass fragmentography at characteristic ions, however, can easily detect the levels found in AADC deficiency. There are now several metabolic diseases which affect biogenic amine metabolite concentration in CSF and hence we emphasize the importance of measuring biogenic amines metabolites in CSF in all patients with the suspection of a neurometabolic disorder.
Acknowledgements We thank Dr N Blau, Department of Paediatrics, University of Basel, Switzerland, for determination of biopterins in CSF.
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