- Email: [email protected]
Aromatic Amino Acid Decarboxylase Deficiency
64
Aromatic Amino Acid Decarboxylase Deficiency
the possible neural mechanisms. Based on this information, we have proposed an anatomically distributed modular network that is responsible for mediating purposeful skilled movements. When a person determines that something needs to be altered, he/she must decide whether a tool is needed, and if so, what tool can best accomplish this goal. The person must also know what action that tool performs. When the correct tool is not available or a new tool is needed, the person also needs to know the mechanical advantage that tools afford and how this could be accomplished by alternatives. A loss of this knowledge is called conceptual apraxia. In right-handed people, this knowledge is stored in the left hemisphere, but the exact locations of these representations are unknown. After a person selects a tool, he/she has to have the knowledge of the posture needed to hold and use this tool as well as the egocentric movements that permit this tool to be properly moved through space and the allocentrically oriented movements that allows the tool to work on objects that require action. In this model, movement (temporo-spatial) representations are stored in the left parietal lobe, and degradation of these movement representations or damage to the premotor cortex that translates these spatial-temporal representations into motor programs induces IMA. These movement representations have to be activated by auditory (speech), visual, or kinesthetic systems input. If one of these input modalities cannot activate these movement representations, there is a modality-specific deficit in performing these learned skilled acts, and this disorder is called dissociation apraxia. The motor program formulated by the premotor cortex must be implemented by the motor cortex that activates the motor neurons in the spinal cord. Injury to the corticospinal system induces a loss of deftness, which is called limb-kinetic apraxia. Many goals require a series of independent acts that must be performed in a specific temporal sequence; an inability to correctly sequence a series of acts
to achieve a goal is called ideational apraxia, which might be a sign of frontal-executive dysfunction. See also: Corticobasal Degeneration; Dementia, Movement Disorders.
Further Reading DeRenzi E, Faglioni P, and Sorgato P (1982) Modality-specific and supramodal mechanisms of apraxia. Brain 105: 301–312. Geschwind N (1965) Disconnection syndromes in animals and man. Brain 88: 237–294, 585–644. Goodglass H and Kaplan E (1963) Disturbance of gesture and pantomime in aphasia. Brain 86: 703–720. Haaland KY, Harrington DL, and Knight RT (2000) Neural representations of skilled movement. Brain 123(Pt 11): 2306–2313. Hanna-Pladdy B, Heilman KM, and Foundas AL (2001) Cortical and subcortical contributions to ideomotor apraxia: Analysis of task demands and error types. Brain 124: 2513–2527. Hanna-Pladdy B, Mendoza JE, Apostolos GT, and Heilman KM (2002) Lateralised motor control: Hemispheric damage and the loss of deftness. Journal of Neurology, Neurosurgery, and Psychiatry 73: 574–577. Heilman KM (1973) Ideational apraxia – A re-definition. Brain 96: 861–864. Heilman KM, Maher LM, Greenwald ML, and Rothi LJR (1997) Conceptual apraxia from lateralized lesions. Neurology 49: 457–464. Heilman KM, Rothi LJG, and Valenstein E (1982) Two forms of ideomotor apraxia. Neurology 32: 415–426. Lawrence DG and Kuypers HG (1968) The functional organization of the motor system in the monkey. II. The effects of lesions of the descending brain-stem pathways. Brain 91(1): 15–36. Liepmann H (1920) Apraxia. Erbgn der ges Med 1: 516–543. Ochipa C, Rothi LJG, and Heilman KM (1992) Conceptual apraxia in Alzheimers disease. Brain 114: 2593–2603. Poizner H, Mack L, Verfaellie M, Rothi LJG, and Heilman KM (1990) Three dimensional computer graphic analysis of apraxia. Brain 113: 85–101. Rothi LJG, Heilman KM, and Watson RT (1985) Pantomime comprehension and ideomotor apraxia. Journal of Neurology, Neurosurgery and Psychiatry 48: 207–210. Watson RT, Fleet WS, Rothi LJG, and Heilman KM (1986) Apraxia and the supplementary motor area. Archives of Neurology 43: 787–792. Watson RT and Heilman KM (1983) Callosal apraxia. Brain 106: 391–403.
Aromatic Amino Acid Decarboxylase Deficiency R Pons, University of Athens, Athens, Greece ã 2010 Elsevier Ltd. All rights reserved.
Glossary Aromatic L-amino acid decarboxylase (AADC) – Enzyme that catalyzes the conversion of 5-hydroxy-tryptophan and levodopa into serotonin and dopamine, respectively. Biogenic amines – Naturally occurring monoamines that act primarily as
neurotransmitters. They include serotonin and catecholamines (dopamine, epinephrine, and norepinephrine). Oculogyric crisis – Paroxysmal dystonia characterized by eye deviation associated or not with axial and limb dystonia. It is characteristic, thought not exclusive, of inherited disorders leading to dopamine deficiency.
Aromatic Amino Acid Decarboxylase Deficiency
Pediatric neurotransmitter diseases – Group of genetic disorders involving the metabolism of neurotransmitters.
Definition and History Aromatic L-amino acid decarboxylase (AADC) deficiency is an autosomal recessive inborn error of metabolism that involves the biosynthesis of monoamine neurotransmitters. This disorder was first described in 1990 by Hyland et al. in two twin boys who presented early in life with motor, extrapyramidal, and autonomic symptoms; decreased monoamine metabolites in cerebrospinal fluid (CSF), and severely reduced AADC activity in plasma. Since then, 75 patients have been diagnosed. In 1998, the first mutations in the AADC gene were reported and it became evident that the spectrum of mutations is heterogeneous.
Pathophysiology Monoamine neurotransmitters include serotonin and the catecholamines dopamine, adrenaline, and noradrenaline. These compounds have multiple functions including
65
modulation of psychomotor function, cardiovascular, respiratory and gastrointestinal control, sleep mechanisms, hormone secretion, body temperature, and pain. AADC plays an important role in the synthesis of monoamines. It is a pyridoxal-phosphate-dependent enzyme that converts levodopa to dopamine and 5-hydroxytryptophan to serotonin. The catabolism of monoamines leads to the formation of 5-hydroxyindolacetic acid (5-HIAA) from serotonin, homovanillic acid (HVA) from dopamine, and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) from norepinephrine (Figure 1). Decreased activity of AADC leads to decreased production of the monoamine neurotransmitters and to the accumulation of their precursors 5-hydroxytryptophan and levodopa. It also leads to the accumulation of 3-O-methyldopa, which is the result of methylation of levodopa (Figure 1). The clinical manifestations in AADC deficiency derive from the deficiency of monoamine neurotransmitters in the developing brain and in the peripheral nervous system. Reduced levels of dopamine are thought to be the origin of the motor symptoms. Norepinephrine and epinephrine deficiency are responsible for the manifestations of autonomic sympathetic dysfunction, while serotonin deficiency is associated with sleep disturbances. Yet, some manifestations cannot be attributed to one specific neurotransmitter deficit, such as cognitive and behavioral
GTP GTPCH NH2TP PTPS 6PTP
3OMD
SR BH4 DHPR
TH
TPH L-dopa
qBH2 COMT/MAO HVA
Trp
Tyr
AADC
Dopamine DβH
MHPG
5-HTP
Norepinephrine
MAO Serotonin
5HIAA
SNA HIOMT Melatonin N-acetylserotonin
Figure 1 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-HTTP: 5-hydroxytryptophan; TH: tyrosine hydroxylase; TPH: tryptophan hydroxylase; COMT: catechol-O-methyltransferase; DbH: dopamine b-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 fluid marker metabolites for AADC deficiency.
66
Aromatic Amino Acid Decarboxylase Deficiency
disturbances. Given the role of monoamines in hormonal function, evidence of endocrine dysfunction is also characteristic. Other factors implicated in the pathophysiology of this disorder are neurotransmitter imbalance and changes in receptor sensitivity.
Epidemiology Currently, 75 patients have been diagnosed with AADC deficiency. Over half of the total patients are in Asia. The largest single population is in Taiwan, with 30 patients. A common splicing mutation has been identified in 81.3% of patients from Taiwan, and haplotype analyses have been consistent with a common ancestral origin. The calculated allele frequency for this mutation among the Taiwanese population is 1:508.
Clinical Features and Diagnostic Criteria Clinical onset occurs within the first months of life, with more than half of patients presenting some symptoms during the neonatal period, including feeding difficulties, hypotonia, autonomic dysfunction, and/or hypoglycemia. The majority of patients come to medical attention due to motor symptoms and paroxysmal events. The motor symptoms include axial hypotonia with fluctuating appendicular tone, decreased spontaneous movements with poor facial expression, and delayed motor development. The latter is so severe that patients fail to make any motor acquisition. Although tremor is not often seen in these infants, their striking hypokinesia and their fluctuating limb tone with rigidity, at times, are consistent with infantile parkinsonism. The majority of patients develop paroxysmal dystonic events within the first months of life. These events are oculogyric crises. They are characterized by eye deviation upward, convergent, or to the side, that may occur on and off from minutes-to-hours. They may be associated with prolonged dystonic posturing of the limbs and/or the trunk. During these events patients are conscious but distressed. Seldom, some patients with AADC deficiency suffer from generalized tonic–clonic seizures. Often, AADC-deficient patients show other types of movement disorders, especially dystonia, in particular limb, stimulus-induced and segmental cranial dystonia. They may also show prominent startle, myoclonus, and distal chorea. Less often patients develop choreoathetosis, nonepileptic flexor spasms or tremor. Aggravation of neurologic symptoms late in the day and/or improvement by sleep is noted in many patients. Additionally, the occurrence of oculogyric crises is mainly in the afternoon or in the evening.
The majority of patients show some feature of autonomic dysfunction including ptosis and miosis, excessive diaphoresis, nasal congestion, temperature instability, and gastrointestinal dysmotility. Recurrent episodes of cardiorespiratory arrest with painful stimuli, hypersensitivity to exogenous cathecolamines and cardiac arrhythmias may also occur. Sleep disturbances including increased sleeping time, frequent awakenings at night and insomnia are often noted. Also common are dysphoric mood with inconsolable cry, irritability, and moodiness. The majority of patients are nonverbal, though they are often able to interact with the environment. Cognitive testing in the more functional patients indicates mild-to-moderate mental retardation. Seldom, autistic syndrome and features of pervasive developmental disorders have been identified. Although endocrine dysfunction is not documented very often, AADC-deficient patients can show recurrent episodes of hypoglycemia early in life, probably due to the lack of catecholamines as anti-insulinergic hormones. Delayed bone maturation and short stature reported in some patients is considered to be due to the lack of induction of growth hormone by catecholamines. Hyperprolactinemia due to dopamine deficiency is also documented. Other features include failure to thrive, small hands and feet, hypersensitivity to light stimulation, tendency to breath-holding and apneic spells. There have been occasional reports of patients with variable milder phenotypes. A few patients showed development of axial control by 2–3 years; while one showed independent gait by at 2½ years of age with remarkable fatigability.
Differential Diagnosis The differential diagnosis of AADC deficiency includes neuromuscular disorders given their profound hypotonia and hypokinesia. The possibility of congenital myasthenia was raised in a mild case with ptosis, fatigability, and weakness of the cranial musculature. Prolonged oculogyric crises associated with limb and/ or axial dystonia may be misdiagnosed as seizures, while temperature instability during the neonatal period may be considered as an early sign of a serious infection. Hypoglycemia early in life may raise the diagnosis of an inborn error of intermediary metabolism, while prominent startle response may raise the diagnosis of hyperekplexia. The clinical manifestations of other pediatric neurotransmitter disorders may be very similar. The pattern in CSF of monoamine metabolites and pterins, together with enzymatic and molecular analysis, points to the precise diagnosis.
Aromatic Amino Acid Decarboxylase Deficiency
A CSF pattern suggesting AADC deficiency has been detected in some patients with a severe infantile epileptic encephalopathy due to pyridoxamine 50 -phosphate oxidase deficiency. This disorder leads to decreased production of the biologically active form of pyridoxine; consequently the pyridoxine-dependent enzyme AADC is secondarily affected.
Diagnostic Work Up The measurement of monoamine metabolites in peripheral fluids is generally uninformative, while their levels in CSF reflect the turnover of serotonin and catecholamine neurotransmitters within the brain. So, when there is clinical suspicion that a patient suffers from a pediatric neurotransmitter disease, a spinal tap is necessary. The diagnosis of AADC deficiency is based on the pattern of monoamine metabolites in CSF showing reduced levels of HVA, 5-HIAA, and MHPG; increased levels of the precursors levodopa and 5-hydroxytryptophan; and increased levels of 3-O-methyldopa (Figure 1). Urine organic analysis searching for elevation of vanillactic acid, the result of 3-O-methyldopa transamination, may be used to further support the diagnosis. Amino acid analysis in blood is usually noninformative in AADC deficiency. However, if differential diagnosis with disorders of tetrabiopterin metabolism is raised, measurement of phenylalanine levels and analysis of tyrosine and phenylalanine levels after a load of phenylalanine may be of help. Definite diagnosis with the analysis of AADC activity in plasma is done in a few laboratories, while molecular analysis of the AADC gene is more easily available in research and commercial laboratories. Analysis of AADC activity in plasma reveals residual activities ranging from undetectable to 8% of control values. When enzyme analysis is not available, diagnosis can be made with molecular analysis of the AADC gene. Screening of the gene has led to the identification of a number of mutations and the majority correspond to missense mutations. Patients are either homozygous for a given mutation or compound heterozygous. Recently, a common splice site mutation has been detected in a group of patients from Taiwan. Neuroimaging studies are often normal, though in some cases they may show brain atrophy. F-18 Dopa positron emission tomography scan has shown virtually absent uptake of tracer. EEG studies are either normal or they show nonspecific findings. Epileptiform discharges have been reported in patients with epilepsy.
Treatment The main goal in the management of AADC deficiency is to potentiate monoaminergic transmission. The main
67
drugs used are dopamine agonists and monoamine oxidase (MAO) inhibitors, often administered in combination. Early patients were treated with the dopamine agonists bromocriptine and pergolide. Given the potential adverse effects associated with these medications (severe fibrotic reaction), more recently ropirinole and pramipexole have been used instead. MAO inhibitors include the nonselective inhibitors tranylcypromine and phenelzine and the MAO B inhibitor selegiline. Treatment with levodopa is not given, since deficient AADC activity precludes monoamine production and administration of levodopa would promote further accumulation of the precursor. However, levodopa provided a favorable response in three siblings who had a mutation in the AADC gene that involved the enzyme-binding site for levodopa. Because pyridoxine is a cofactor of AADC, patients are generally supplemented with pyridoxine. However, no significant clinical response is usually noted. A number of other of therapeutic strategies have been used erratically in AADC-deficient patients, including anticholinergics, melatonin, buspirone, serotonin reuptake inhibitors, indirect cathecholaminomimetics, amine reuptake inhibitors, ergotamine and local sympathomimetics. Some patients show elevated plasma homocysteine and low CSF 5-methyltetrahydrofolate levels due to reduced methylation capacity, since S-adenosylmethionine is the methyl donor for the methylation of levodopa to 3-Omethyldopa. For this reason, folate supplementation is given in some patients. Finally, because of the risk of cardiac arrhythmia and abnormal responses to pressors in AADC-deficient patients, anesthesia procedures in these patients should be conducted with close cardiac and hemodynamic monitoring.
Prognosis Treatment with dopamine agonists and/or MAO inhibitors offers variable degrees of improvement in tone and hypokinesia, reduces the frequency and duration of oculogyric crises and improves autonomic dysfunction. In general, response to the other therapeutic strategies has not been encouraging, because of poor clinical response or poor tolerance. Many patients, despite the improvements noted above, are not able to make meaningful motor development; while a few are able to make significant developmental progress, become verbal, ambulant, and responsive to educational interventions. Earlier series of AADC-deficient patients suggested better response to treatment and prognosis in males than in females, but this has not been supported with the description of further cases. It appears that patients with
68
Asterixis
milder presentations show better response to treatment; thus neurological status at the time of diagnosis is an important prognostic factor. Early onset of treatment appears to be a favorable prognostic factor. However, numerous patients who started treatment early in life show poor motor progress. On the other hand, tolerance to treatment also has prognostic implications. Patients may show drug-induced dyskinesias such as chorea or dystonia; or they may develop prominent adverse effects. Generally these patients show a poorer clinical outcome and it is unclear whether they 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. Monoamine metabolite concentration in CSF and residual AADC activity in plasma do not appear to correlate with prognosis. It is unknown if there is any correlation between specific mutations and the severity of the clinical manifestations.
Acknowledgments The author would like to thank Lisa Flint for providing unpublished data on the frequency of AADC deficiency reported worldwide. See also: 6-OH Dopamine Rat Model; Movement Disorders: Overview.
Further Reading Blau N, Tho¨ny B, Cotton RGH, and Hyland K (2001) Disorders of tetrahydrobiopterin and related biogenic amines. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, and Vogelstein B (eds.) The Metabolic and Molecular Bases of Inherited Disease, 8th edn. vol 2., pp. 1725–1776. New York: McGraw-Hill. Hyland K (2008) Clinical utility of monoamine neurotransmitter metabolite analysis in cerebrospinal fluid. Clinical Chemistry 54: 633–641. Hyland K, Surtees RA, Rodeck C, and Clayton PT (1992) Aromatic L-amino acid decarboxylase deficiency: clinical features, diagnosis, and treatment of a new inborn error of neurotransmitter amine synthesis. Neurology 42: 1980–1988. Lee HF, Tsai CR, Chi CS, Chang TM, and Lee HJ (2009) Aromatic L-amino acid decarboxylase deficiency in Taiwan. European Journal of Paediatric Neurology 13: 135–140. Pearl PL, Taylor JL, Trzcinski S, and Sokohl A (2007) The pediatric neurotransmitter disorders. Journal of Child Neurology 22: 606–616. Pons R, Ford B, Chiriboga CA, et al. (2004) Aromatic L-amino acid decarboxylase deficiency: clinical features, treatment, and prognosis. Neurology 62: 1058–1065. Pons R, Ford B, Chiriboga CA, et al. (2005) Clinical, biochemical and molecular spectrum of aromatic L-amino acid decarboxylase deficiency. In: Fernanadez-Alvarez E, Arzimanoglou A, and Tolosa E (eds.) Paediatric Movement Disorder. Progress in Understanding, 1st edn., pp. 185–194. Montrouge, France: John Libbey Eurotext. Swoboda KJ, Hyland K, Goldstein DS, et al. (2003) Clinical and therapeutic observations in aromatic L-amino acid decarboxylase deficiency. Neurology 53: 1205–1211.
Relevant Websites http://www.aadcresearch.org – The AADC research trust. www.pndassoc.org – The Pediatric Neurotransmitter Disease association. http://www.orpha.net – Orphan net. http://www.bh4.org – Tetrabiopterin.
Asterixis L B Bahroo and E A Shamim, Georgetown University Hospital, Washington, DC, USA ã 2010 Elsevier Ltd. All rights reserved.
Glossary Asterixis – An involuntary jerking movement typically considered to be a form of subcortical negative myoclonus and characterized by variable rhythmic EMG-silent periods without any detectible standard electroencephalographic (EEG) correlate. Miniasterixis – A variant of asterixis with jerk rates of 6–12 Hz. Myoclonus – Shock-like movements that can be generated at the spinal cord, brainstem, or cortex from a variety of causes including toxic-metabolic, drug effects and neurodegenerative diseases.
Negative myoclonus – A form of myoclonus involving lightning-like jerks due to rapid loss of postures.
Clinical Syndrome Asterixis is derived from the Greek words ‘a’ meaning ‘not’ and ‘ste¯rixis’ meaning ‘fixed position,’ and was used to describe the rhythmic motor phenomenon reported by Adams and Foley in 1949 for a bilateral flapping tremor of
Aromatic Amino Acid Decarboxylase Deficiency
the possible neural mechanisms. Based on this information, we have proposed an anatomically distributed modular network that is responsible for mediating purposeful skilled movements. When a person determines that something needs to be altered, he/she must decide whether a tool is needed, and if so, what tool can best accomplish this goal. The person must also know what action that tool performs. When the correct tool is not available or a new tool is needed, the person also needs to know the mechanical advantage that tools afford and how this could be accomplished by alternatives. A loss of this knowledge is called conceptual apraxia. In right-handed people, this knowledge is stored in the left hemisphere, but the exact locations of these representations are unknown. After a person selects a tool, he/she has to have the knowledge of the posture needed to hold and use this tool as well as the egocentric movements that permit this tool to be properly moved through space and the allocentrically oriented movements that allows the tool to work on objects that require action. In this model, movement (temporo-spatial) representations are stored in the left parietal lobe, and degradation of these movement representations or damage to the premotor cortex that translates these spatial-temporal representations into motor programs induces IMA. These movement representations have to be activated by auditory (speech), visual, or kinesthetic systems input. If one of these input modalities cannot activate these movement representations, there is a modality-specific deficit in performing these learned skilled acts, and this disorder is called dissociation apraxia. The motor program formulated by the premotor cortex must be implemented by the motor cortex that activates the motor neurons in the spinal cord. Injury to the corticospinal system induces a loss of deftness, which is called limb-kinetic apraxia. Many goals require a series of independent acts that must be performed in a specific temporal sequence; an inability to correctly sequence a series of acts
to achieve a goal is called ideational apraxia, which might be a sign of frontal-executive dysfunction. See also: Corticobasal Degeneration; Dementia, Movement Disorders.
Further Reading DeRenzi E, Faglioni P, and Sorgato P (1982) Modality-specific and supramodal mechanisms of apraxia. Brain 105: 301–312. Geschwind N (1965) Disconnection syndromes in animals and man. Brain 88: 237–294, 585–644. Goodglass H and Kaplan E (1963) Disturbance of gesture and pantomime in aphasia. Brain 86: 703–720. Haaland KY, Harrington DL, and Knight RT (2000) Neural representations of skilled movement. Brain 123(Pt 11): 2306–2313. Hanna-Pladdy B, Heilman KM, and Foundas AL (2001) Cortical and subcortical contributions to ideomotor apraxia: Analysis of task demands and error types. Brain 124: 2513–2527. Hanna-Pladdy B, Mendoza JE, Apostolos GT, and Heilman KM (2002) Lateralised motor control: Hemispheric damage and the loss of deftness. Journal of Neurology, Neurosurgery, and Psychiatry 73: 574–577. Heilman KM (1973) Ideational apraxia – A re-definition. Brain 96: 861–864. Heilman KM, Maher LM, Greenwald ML, and Rothi LJR (1997) Conceptual apraxia from lateralized lesions. Neurology 49: 457–464. Heilman KM, Rothi LJG, and Valenstein E (1982) Two forms of ideomotor apraxia. Neurology 32: 415–426. Lawrence DG and Kuypers HG (1968) The functional organization of the motor system in the monkey. II. The effects of lesions of the descending brain-stem pathways. Brain 91(1): 15–36. Liepmann H (1920) Apraxia. Erbgn der ges Med 1: 516–543. Ochipa C, Rothi LJG, and Heilman KM (1992) Conceptual apraxia in Alzheimers disease. Brain 114: 2593–2603. Poizner H, Mack L, Verfaellie M, Rothi LJG, and Heilman KM (1990) Three dimensional computer graphic analysis of apraxia. Brain 113: 85–101. Rothi LJG, Heilman KM, and Watson RT (1985) Pantomime comprehension and ideomotor apraxia. Journal of Neurology, Neurosurgery and Psychiatry 48: 207–210. Watson RT, Fleet WS, Rothi LJG, and Heilman KM (1986) Apraxia and the supplementary motor area. Archives of Neurology 43: 787–792. Watson RT and Heilman KM (1983) Callosal apraxia. Brain 106: 391–403.
Aromatic Amino Acid Decarboxylase Deficiency R Pons, University of Athens, Athens, Greece ã 2010 Elsevier Ltd. All rights reserved.
Glossary Aromatic L-amino acid decarboxylase (AADC) – Enzyme that catalyzes the conversion of 5-hydroxy-tryptophan and levodopa into serotonin and dopamine, respectively. Biogenic amines – Naturally occurring monoamines that act primarily as
neurotransmitters. They include serotonin and catecholamines (dopamine, epinephrine, and norepinephrine). Oculogyric crisis – Paroxysmal dystonia characterized by eye deviation associated or not with axial and limb dystonia. It is characteristic, thought not exclusive, of inherited disorders leading to dopamine deficiency.
Aromatic Amino Acid Decarboxylase Deficiency
Pediatric neurotransmitter diseases – Group of genetic disorders involving the metabolism of neurotransmitters.
Definition and History Aromatic L-amino acid decarboxylase (AADC) deficiency is an autosomal recessive inborn error of metabolism that involves the biosynthesis of monoamine neurotransmitters. This disorder was first described in 1990 by Hyland et al. in two twin boys who presented early in life with motor, extrapyramidal, and autonomic symptoms; decreased monoamine metabolites in cerebrospinal fluid (CSF), and severely reduced AADC activity in plasma. Since then, 75 patients have been diagnosed. In 1998, the first mutations in the AADC gene were reported and it became evident that the spectrum of mutations is heterogeneous.
Pathophysiology Monoamine neurotransmitters include serotonin and the catecholamines dopamine, adrenaline, and noradrenaline. These compounds have multiple functions including
65
modulation of psychomotor function, cardiovascular, respiratory and gastrointestinal control, sleep mechanisms, hormone secretion, body temperature, and pain. AADC plays an important role in the synthesis of monoamines. It is a pyridoxal-phosphate-dependent enzyme that converts levodopa to dopamine and 5-hydroxytryptophan to serotonin. The catabolism of monoamines leads to the formation of 5-hydroxyindolacetic acid (5-HIAA) from serotonin, homovanillic acid (HVA) from dopamine, and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) from norepinephrine (Figure 1). Decreased activity of AADC leads to decreased production of the monoamine neurotransmitters and to the accumulation of their precursors 5-hydroxytryptophan and levodopa. It also leads to the accumulation of 3-O-methyldopa, which is the result of methylation of levodopa (Figure 1). The clinical manifestations in AADC deficiency derive from the deficiency of monoamine neurotransmitters in the developing brain and in the peripheral nervous system. Reduced levels of dopamine are thought to be the origin of the motor symptoms. Norepinephrine and epinephrine deficiency are responsible for the manifestations of autonomic sympathetic dysfunction, while serotonin deficiency is associated with sleep disturbances. Yet, some manifestations cannot be attributed to one specific neurotransmitter deficit, such as cognitive and behavioral
GTP GTPCH NH2TP PTPS 6PTP
3OMD
SR BH4 DHPR
TH
TPH L-dopa
qBH2 COMT/MAO HVA
Trp
Tyr
AADC
Dopamine DβH
MHPG
5-HTP
Norepinephrine
MAO Serotonin
5HIAA
SNA HIOMT Melatonin N-acetylserotonin
Figure 1 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-HTTP: 5-hydroxytryptophan; TH: tyrosine hydroxylase; TPH: tryptophan hydroxylase; COMT: catechol-O-methyltransferase; DbH: dopamine b-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 fluid marker metabolites for AADC deficiency.
66
Aromatic Amino Acid Decarboxylase Deficiency
disturbances. Given the role of monoamines in hormonal function, evidence of endocrine dysfunction is also characteristic. Other factors implicated in the pathophysiology of this disorder are neurotransmitter imbalance and changes in receptor sensitivity.
Epidemiology Currently, 75 patients have been diagnosed with AADC deficiency. Over half of the total patients are in Asia. The largest single population is in Taiwan, with 30 patients. A common splicing mutation has been identified in 81.3% of patients from Taiwan, and haplotype analyses have been consistent with a common ancestral origin. The calculated allele frequency for this mutation among the Taiwanese population is 1:508.
Clinical Features and Diagnostic Criteria Clinical onset occurs within the first months of life, with more than half of patients presenting some symptoms during the neonatal period, including feeding difficulties, hypotonia, autonomic dysfunction, and/or hypoglycemia. The majority of patients come to medical attention due to motor symptoms and paroxysmal events. The motor symptoms include axial hypotonia with fluctuating appendicular tone, decreased spontaneous movements with poor facial expression, and delayed motor development. The latter is so severe that patients fail to make any motor acquisition. Although tremor is not often seen in these infants, their striking hypokinesia and their fluctuating limb tone with rigidity, at times, are consistent with infantile parkinsonism. The majority of patients develop paroxysmal dystonic events within the first months of life. These events are oculogyric crises. They are characterized by eye deviation upward, convergent, or to the side, that may occur on and off from minutes-to-hours. They may be associated with prolonged dystonic posturing of the limbs and/or the trunk. During these events patients are conscious but distressed. Seldom, some patients with AADC deficiency suffer from generalized tonic–clonic seizures. Often, AADC-deficient patients show other types of movement disorders, especially dystonia, in particular limb, stimulus-induced and segmental cranial dystonia. They may also show prominent startle, myoclonus, and distal chorea. Less often patients develop choreoathetosis, nonepileptic flexor spasms or tremor. Aggravation of neurologic symptoms late in the day and/or improvement by sleep is noted in many patients. Additionally, the occurrence of oculogyric crises is mainly in the afternoon or in the evening.
The majority of patients show some feature of autonomic dysfunction including ptosis and miosis, excessive diaphoresis, nasal congestion, temperature instability, and gastrointestinal dysmotility. Recurrent episodes of cardiorespiratory arrest with painful stimuli, hypersensitivity to exogenous cathecolamines and cardiac arrhythmias may also occur. Sleep disturbances including increased sleeping time, frequent awakenings at night and insomnia are often noted. Also common are dysphoric mood with inconsolable cry, irritability, and moodiness. The majority of patients are nonverbal, though they are often able to interact with the environment. Cognitive testing in the more functional patients indicates mild-to-moderate mental retardation. Seldom, autistic syndrome and features of pervasive developmental disorders have been identified. Although endocrine dysfunction is not documented very often, AADC-deficient patients can show recurrent episodes of hypoglycemia early in life, probably due to the lack of catecholamines as anti-insulinergic hormones. Delayed bone maturation and short stature reported in some patients is considered to be due to the lack of induction of growth hormone by catecholamines. Hyperprolactinemia due to dopamine deficiency is also documented. Other features include failure to thrive, small hands and feet, hypersensitivity to light stimulation, tendency to breath-holding and apneic spells. There have been occasional reports of patients with variable milder phenotypes. A few patients showed development of axial control by 2–3 years; while one showed independent gait by at 2½ years of age with remarkable fatigability.
Differential Diagnosis The differential diagnosis of AADC deficiency includes neuromuscular disorders given their profound hypotonia and hypokinesia. The possibility of congenital myasthenia was raised in a mild case with ptosis, fatigability, and weakness of the cranial musculature. Prolonged oculogyric crises associated with limb and/ or axial dystonia may be misdiagnosed as seizures, while temperature instability during the neonatal period may be considered as an early sign of a serious infection. Hypoglycemia early in life may raise the diagnosis of an inborn error of intermediary metabolism, while prominent startle response may raise the diagnosis of hyperekplexia. The clinical manifestations of other pediatric neurotransmitter disorders may be very similar. The pattern in CSF of monoamine metabolites and pterins, together with enzymatic and molecular analysis, points to the precise diagnosis.
Aromatic Amino Acid Decarboxylase Deficiency
A CSF pattern suggesting AADC deficiency has been detected in some patients with a severe infantile epileptic encephalopathy due to pyridoxamine 50 -phosphate oxidase deficiency. This disorder leads to decreased production of the biologically active form of pyridoxine; consequently the pyridoxine-dependent enzyme AADC is secondarily affected.
Diagnostic Work Up The measurement of monoamine metabolites in peripheral fluids is generally uninformative, while their levels in CSF reflect the turnover of serotonin and catecholamine neurotransmitters within the brain. So, when there is clinical suspicion that a patient suffers from a pediatric neurotransmitter disease, a spinal tap is necessary. The diagnosis of AADC deficiency is based on the pattern of monoamine metabolites in CSF showing reduced levels of HVA, 5-HIAA, and MHPG; increased levels of the precursors levodopa and 5-hydroxytryptophan; and increased levels of 3-O-methyldopa (Figure 1). Urine organic analysis searching for elevation of vanillactic acid, the result of 3-O-methyldopa transamination, may be used to further support the diagnosis. Amino acid analysis in blood is usually noninformative in AADC deficiency. However, if differential diagnosis with disorders of tetrabiopterin metabolism is raised, measurement of phenylalanine levels and analysis of tyrosine and phenylalanine levels after a load of phenylalanine may be of help. Definite diagnosis with the analysis of AADC activity in plasma is done in a few laboratories, while molecular analysis of the AADC gene is more easily available in research and commercial laboratories. Analysis of AADC activity in plasma reveals residual activities ranging from undetectable to 8% of control values. When enzyme analysis is not available, diagnosis can be made with molecular analysis of the AADC gene. Screening of the gene has led to the identification of a number of mutations and the majority correspond to missense mutations. Patients are either homozygous for a given mutation or compound heterozygous. Recently, a common splice site mutation has been detected in a group of patients from Taiwan. Neuroimaging studies are often normal, though in some cases they may show brain atrophy. F-18 Dopa positron emission tomography scan has shown virtually absent uptake of tracer. EEG studies are either normal or they show nonspecific findings. Epileptiform discharges have been reported in patients with epilepsy.
Treatment The main goal in the management of AADC deficiency is to potentiate monoaminergic transmission. The main
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drugs used are dopamine agonists and monoamine oxidase (MAO) inhibitors, often administered in combination. Early patients were treated with the dopamine agonists bromocriptine and pergolide. Given the potential adverse effects associated with these medications (severe fibrotic reaction), more recently ropirinole and pramipexole have been used instead. MAO inhibitors include the nonselective inhibitors tranylcypromine and phenelzine and the MAO B inhibitor selegiline. Treatment with levodopa is not given, since deficient AADC activity precludes monoamine production and administration of levodopa would promote further accumulation of the precursor. However, levodopa provided a favorable response in three siblings who had a mutation in the AADC gene that involved the enzyme-binding site for levodopa. Because pyridoxine is a cofactor of AADC, patients are generally supplemented with pyridoxine. However, no significant clinical response is usually noted. A number of other of therapeutic strategies have been used erratically in AADC-deficient patients, including anticholinergics, melatonin, buspirone, serotonin reuptake inhibitors, indirect cathecholaminomimetics, amine reuptake inhibitors, ergotamine and local sympathomimetics. Some patients show elevated plasma homocysteine and low CSF 5-methyltetrahydrofolate levels due to reduced methylation capacity, since S-adenosylmethionine is the methyl donor for the methylation of levodopa to 3-Omethyldopa. For this reason, folate supplementation is given in some patients. Finally, because of the risk of cardiac arrhythmia and abnormal responses to pressors in AADC-deficient patients, anesthesia procedures in these patients should be conducted with close cardiac and hemodynamic monitoring.
Prognosis Treatment with dopamine agonists and/or MAO inhibitors offers variable degrees of improvement in tone and hypokinesia, reduces the frequency and duration of oculogyric crises and improves autonomic dysfunction. In general, response to the other therapeutic strategies has not been encouraging, because of poor clinical response or poor tolerance. Many patients, despite the improvements noted above, are not able to make meaningful motor development; while a few are able to make significant developmental progress, become verbal, ambulant, and responsive to educational interventions. Earlier series of AADC-deficient patients suggested better response to treatment and prognosis in males than in females, but this has not been supported with the description of further cases. It appears that patients with
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Asterixis
milder presentations show better response to treatment; thus neurological status at the time of diagnosis is an important prognostic factor. Early onset of treatment appears to be a favorable prognostic factor. However, numerous patients who started treatment early in life show poor motor progress. On the other hand, tolerance to treatment also has prognostic implications. Patients may show drug-induced dyskinesias such as chorea or dystonia; or they may develop prominent adverse effects. Generally these patients show a poorer clinical outcome and it is unclear whether they 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. Monoamine metabolite concentration in CSF and residual AADC activity in plasma do not appear to correlate with prognosis. It is unknown if there is any correlation between specific mutations and the severity of the clinical manifestations.
Acknowledgments The author would like to thank Lisa Flint for providing unpublished data on the frequency of AADC deficiency reported worldwide. See also: 6-OH Dopamine Rat Model; Movement Disorders: Overview.
Further Reading Blau N, Tho¨ny B, Cotton RGH, and Hyland K (2001) Disorders of tetrahydrobiopterin and related biogenic amines. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, and Vogelstein B (eds.) The Metabolic and Molecular Bases of Inherited Disease, 8th edn. vol 2., pp. 1725–1776. New York: McGraw-Hill. Hyland K (2008) Clinical utility of monoamine neurotransmitter metabolite analysis in cerebrospinal fluid. Clinical Chemistry 54: 633–641. Hyland K, Surtees RA, Rodeck C, and Clayton PT (1992) Aromatic L-amino acid decarboxylase deficiency: clinical features, diagnosis, and treatment of a new inborn error of neurotransmitter amine synthesis. Neurology 42: 1980–1988. Lee HF, Tsai CR, Chi CS, Chang TM, and Lee HJ (2009) Aromatic L-amino acid decarboxylase deficiency in Taiwan. European Journal of Paediatric Neurology 13: 135–140. Pearl PL, Taylor JL, Trzcinski S, and Sokohl A (2007) The pediatric neurotransmitter disorders. Journal of Child Neurology 22: 606–616. Pons R, Ford B, Chiriboga CA, et al. (2004) Aromatic L-amino acid decarboxylase deficiency: clinical features, treatment, and prognosis. Neurology 62: 1058–1065. Pons R, Ford B, Chiriboga CA, et al. (2005) Clinical, biochemical and molecular spectrum of aromatic L-amino acid decarboxylase deficiency. In: Fernanadez-Alvarez E, Arzimanoglou A, and Tolosa E (eds.) Paediatric Movement Disorder. Progress in Understanding, 1st edn., pp. 185–194. Montrouge, France: John Libbey Eurotext. Swoboda KJ, Hyland K, Goldstein DS, et al. (2003) Clinical and therapeutic observations in aromatic L-amino acid decarboxylase deficiency. Neurology 53: 1205–1211.
Relevant Websites http://www.aadcresearch.org – The AADC research trust. www.pndassoc.org – The Pediatric Neurotransmitter Disease association. http://www.orpha.net – Orphan net. http://www.bh4.org – Tetrabiopterin.
Asterixis L B Bahroo and E A Shamim, Georgetown University Hospital, Washington, DC, USA ã 2010 Elsevier Ltd. All rights reserved.
Glossary Asterixis – An involuntary jerking movement typically considered to be a form of subcortical negative myoclonus and characterized by variable rhythmic EMG-silent periods without any detectible standard electroencephalographic (EEG) correlate. Miniasterixis – A variant of asterixis with jerk rates of 6–12 Hz. Myoclonus – Shock-like movements that can be generated at the spinal cord, brainstem, or cortex from a variety of causes including toxic-metabolic, drug effects and neurodegenerative diseases.
Negative myoclonus – A form of myoclonus involving lightning-like jerks due to rapid loss of postures.
Clinical Syndrome Asterixis is derived from the Greek words ‘a’ meaning ‘not’ and ‘ste¯rixis’ meaning ‘fixed position,’ and was used to describe the rhythmic motor phenomenon reported by Adams and Foley in 1949 for a bilateral flapping tremor of