Aromatic L-amino Acid Decarboxylase Deficiency Research Articles

Biochemical and Computational Approaches to Improve the Clinical Treatment of Dopa Decarboxylase-Related Diseases: An Overview

Dopa decarboxylase (DDC) is a pyridoxal 5’-phosphate (PLP)-dependent enzyme that by catalyzing the decarboxylation of L-Dopa and L-5-hydroxytryptophan produces the neurotransmitters dopamine and serotonin. The functional properties of pig kidney and human DDC enzymes have been extensively characterized, and the crystal structure of the enzyme in the holo- and apo-forms has been elucidated. DDC is a clinically relevant enzyme since it is involved in Parkinson’s disease (PD) and in aromatic amino acid decarboxylase (AADC) deficiency. PD, a chronic progressive neurological disorder characterized by tremor, bradykinesia, rigidity and postural instability, results from the degeneration of dopamine-producing cells in the substantia nigra of the brain. On the other hand, AADC deficiency is a rare debilitating recessive genetic disorder due to mutations in AADC gene leading to the inability to synthesize dopamine and serotonin. Development delay, abnormal movements, oculogyric crises and vegetative symptoms characterize this severe neurometabolic disease. This article is an up to date review of the therapies currently used in the treatment of PD and AADC deficiency as well as of the recent findings that, on one hand provide precious guidelines for the drug development process necessary to PD therapy, and, on the other, suggest an aimed therapeutic approach based on the elucidation of the molecular defects of each variant associated with AADC deficiency.

Gene Therapy for Aromatic l -Amino Acid Decarboxylase Deficiency

Aromatic L-amino acid decarboxylase (AADC) is required for the synthesis of the neurotransmitters dopamine and serotonin. Children with defects in the AADC gene show compromised development, particularly in motor function. Drug therapy has only marginal effects on some of the symptoms and does not change early childhood mortality. Here, we performed adeno-associated viral vector-mediated gene transfer of the human AADC gene bilaterally into the putamen of four patients 4 to 6 years of age. All of the patients showed improvements in motor performance: One patient was able to stand 16 months after gene transfer, and the other three patients achieved supported sitting 6 to 15 months after gene transfer. Choreic dyskinesia was observed in all patients, but this resolved after several months. Positron emission tomography revealed increased uptake by the putamen of 6-[(18)F]fluorodopa, a tracer for AADC. Cerebrospinal fluid analysis showed increased dopamine and serotonin levels after gene transfer. Thus, gene therapy targeting primary AADC deficiency is well tolerated and leads to improved motor function.

Multiple Applications of L-DOPA Therapy in Children with Neurological Disorders - 25 Year Review (P04.178)

Objective: L -Dopa is well known for its use in childhood neurological disorders. formost is Dopa-responsive dystonia, Segawa9s Disease, and its variants. L-Dopa has increasingly been cited in many other childhood neurological diosrders in the literature. This review summarizes athe applications of L-Dopa in childhood based upon extensive computerized literature review expanding the clinical applications in and young adults. Background Previously isloated reports have cited the application of L Dopa in childhood movement disorders but no single review has comprehensively reviewed all the disorders in which L Dopa has been used. Design/Methods: Summarization of medical literature in the past 25 years searching the term L-Dopa in childhood, L -Dopa in Childhood movement disorders, L Dopa in children utilizing Pubmed database and a Cochrane Review was performed.Citations were grouped upon frequency of citation and applicability to clincial practice. Both well known applications and less commonly cited therapies were included. Results: Over 25 years at least 26 different disorders have been reported in childhood utilizing L-Dopa. Most frequent are the disorders related to Dopa responsive dystonia, (Segawa9s disease)and its variants. This includes disorders in dopamine synthesis including tyrosine hydroxylase deficiency and tetrahydrobiopterin pathway disorders. Significant citations also include: Juvenile Parkinson9s disease, Myoclonus- Dystonia, Familial paroxysmal Dystonia, PKAN, Lower Limb Dystonia, Chediak -Hegashi synsdrome, Dystonia-Parkinsonism, Benign Paroxysmal Tonic Upgaze of Childhood, Amblyopia, Aromatic l-aminoacid decarboxylase Deficiency, Restless Legs Syndrome and Attention Deficit Hyperactivity Syndrome, and potential application in Angelman Syndrome. Conclusions: In the past 25 years, over 26 childhood neurological disorders have been described that are responsive to L-Dopa therapy. While many are well known an expanded current application is summarized. This summary brings up to date the prevalent citations and provides a review of the many less commonly and less frequently recognized disorders in childhood for which L-Dopa therapy plays a major role. Disclosure: Dr. Lavenstein has nothing to disclose. Dr. Hecht has nothing to disclose.

Preimplantation and prenatal genetic diagnosis of aromatic L-amino acid decarboxylase deficiency with an amplification refractory mutation system-quantitative polymerase chain reaction

Objectives To develop a diagnostic platform for preimplantation genetic diagnosis (PGD) and prenatal genetic diagnosis (PND) to prevent births of aromatic L-amino acid decarboxylase deficiency (AADC) patients. Materials and Methods Five Taiwanese families carrying AADC were enrolled. A novel technique, amplification refractory mutation system-quantitative polymerase chain reaction (ARMS-qPCR), was developed for both of PGD and PND. For PGD, blastomere biopsies of day-3 cleavage-stage embryos were subjected to ARMS-qPCR. Villi, cultured amniocytes, or both were used to confirm the PGD result; this approach could also be used as the sole method for PND after in vivo conception). Results Unaffected live births were achieved in four of the five families, except one with ongoing PGD. The ARMS-qPCR correctly classified blastomeres (from day-3 cleavage-stage embryos) as affected (homozygous mutant), carrier (heterozygous for mutant and wild-type alleles), or normal (homozygous wild-type) within 1 working day. Conclusions To our knowledge, this is the first report of successful PGD of AADC. The molecular technique we devised (ARMS-qPCR) was applicable for PGD as well as PND of AADC. Furthermore, it has great potential for similar applications in other monogenic disorders.

Non-invasive urinary screening for aromatic l-amino acid decarboxylase deficiency in high-prevalence areas: A pilot study

BackgroundThe diagnosis of aromatic l-amino acid decarboxylase (AADC) deficiency, one of the pediatric neurotransmitter disorders, is classically made with plasma enzyme level or cerebrospinal fluid (CSF) neurotransmitter profile, while both are technically demanding and the latter requires the invasive lumbar puncture. So far less than 100 cases have been reported worldwide with 20% from Taiwan. It was postulated that the condition might have been under-diagnosed among Chinese populations and a non-invasive screening tool should be developed in areas with high prevalence. MethodsUrine metabolic profiles performed by gas chromatography–mass spectrometry (GC-MS) in a 31-month period were retrospectively reviewed: those with vanilmandelic acid concentration lower than one percentile plus the presence of 3-o-methyldopa were defined as positive and the patients were further evaluated. ResultsAmong 1046 metabolic profiles (from 845 patients) reviewed, 3 profiles from 2 patients were screened positive: both cases had compatible CSF neurotransmitter profiles and the diagnosis was further confirmed by genetic analysis of DDC gene. 13 negative urinary metabolic profiles from 7 patients who had CSF neurotransmitters analyzed were identified as controls: all 7 CSF neurotransmitter profiles were not compatible for AADC deficiency. ConclusionsThe GC-MS-based urine metabolic profiling was shown to be a satisfactory screening tool for AADC deficiency. Further confirmation can be performed by mutation analysis in the DDC gene, thus avoiding risks of lumbar puncture. We advocate all ethnic Chinese patients presenting with dystonia have their urine organic acids analyzed before proceeding to CSF neurotransmitters analysis.

Molecular insights into the pathogenicity of variants associated with the aromatic amino acid decarboxylase deficiency

Dopa decarboxylase (DDC or AADC) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the decarboxylation of L-aromatic amino acids into the corresponding aromatic amines. AADC deficiency is an inborn error of neurotransmitters biosynthesis with an autosomal recessive inheritance. About 30 pathogenic mutations have been identified, but the enzymatic phenotypes causing AADC deficiency are unknown, and the therapeutic management is challenging. Here, we report biochemical and bioinformatic analyses of the human wild-type DDC and the pathogenic variants G102S, F309L, S147R and A275T whose mutations concern amino acid residues at or near the active site. We found that the mutations cause, even if to different extents, a decreased PLP binding affinity (in the range 1.4-170-fold), an altered state of the bound coenzyme and of its microenvironment, and a reduced catalytic efficiency (in the range 17-930-fold). Moreover, as compared to wild-type, the external aldimines formed by the variants with L-aromatic amino acids exhibit different spectroscopic features, do not protect against limited proteolysis, and lead to the formation, in addition to aromatic amines, of cyclic-substrate adducts. This suggests that these external Schiff bases are not properly oriented and anchored, i.e., in a conformation not completely productive for decarboxylation. The external aldimines that the variants form with D-Dopa also appear not to be correctly located at their active site, as suggested by the rate constants of PLP-L-Dopa adduct production higher than that of the wild-type. The possible therapeutic implications of the data are discussed in the light of the molecular defects of the pathogenic variants.

An Unusual Case of Feeding Intolerance in a 7 Month Old Female

Purpose: Background: Aromatic L-amino acid decarboxylase deficiency (AADC) is an inborn error in neurotransmitter metabolism caused by mutations in the dopa decarboxylase (aromatic L-amino acid decarboxylase) gene, which leads to combined serotonin and catecholamine deficiency. Symptoms include severe developmental delay, hypotonia, muscle stiffness, athetosis, lethargy, feeding intolerance, sleep disturbances, oculogyric crises, extreme irritability, pain, muscle spasms, and uncontrolled movements. Patient: A 7 month old Caucasian female with a history of hypotonia and developmental motor delay presented with excessive irritability and feeding intolerance. Clinical Course: She was well until 3-4 months of age, when she became inconsolable, had non-bilious, non-bloody emesis, and irritability with feeds. Symptoms worsened over the last 3 months. She had decreased activity, poor eye tracking, and hypotonia. Initial workup showed normal gastric emptying scan, MBS revealing frank aspiration, and pH probe showed copious reflux, so a Nissen fundoplication with gastric feeding tube was placed. Lorazepam and phenobarbital did not have a perceived effect. Additional workup included an EEG, head CT scan, head MRI, karyotype, serum lactate level, serum ammonia level, and plasma amino acids which were all within normal limits except for a low cysteine level. Urine organic acids showed minimal dicarboxylic acids and acetylcarnitine profile showed a mildly elevated C4OH due to diet or a ketotic state. Magnetic resonance spectroscopy (MRS) was notable for nonspecific lactate spikes. Because of suspicion of a possible mitochondrial or neurotransmitter disorder, a lumbar puncture was performed. Neurotransmitter analysis and plasma enzymology confirmed the diagnosis of AADC. Pyridoxal-5-phosphate (coenzyme B6) and ropinirole (a dopamine agonist) were added, in addition to hyoscyamine, pantoprazole, and sucralfate. Two months after diagnosis, she has been tolerating feeds with less irritability. Conclusion: Children with feeding disorder, developmental delay and hypotonia should have a work-up for inborn errors of metabolism. Initial laboratory workup should include CBC, electrolytes, LFTs, urine organic acids, blood amino acids and acylcarnitine profile, total and free carnitine levels, as well as an MRI and MRS.

Evaluation of comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry for the diagnosis of inherited metabolic disorders using an automated data processing strategy

Organic acidurias are a large group of inherited metabolic disorders (IMDs), commonly diagnosed by GC–MS analysis of organic acids in urine after acidic extraction and trimethylsilylation. In this study, a GC × GC-ToF-MS method has been optimized for the analysis of pathological metabolites in urine. An automated data processing strategy based on the use of mass spectra and GC retention times for the target search and quantification of pathological metabolites has been developed. Using this procedure, each unknown sample is automatically examined for the presence of markers of several diseases at the same time. The method has been applied for the analysis of 6 challenging proficiency testing samples from patients with IMDs (thymidine phosphorylase deficiency, mevalonic aciduria, hawkinsinuria, aromatic l-amino acid decarboxylase deficiency, propionic acidemia and medium-chain acyl-CoA dehydrogenase deficiency). Using the GC × GC-ToF-MS method, we were able to determine complete sets of markers for all the IMDs. The quality of the mass spectral matches for the pathological markers was higher than 800 (out of 1000).

Urinary dopamine in aromatic L-amino acid decarboxylase deficiency: The unsolved paradox

Introduction In aromatic L-amino acid decarboxylase (AADC) deficiency, a neurotransmitter biosynthesis defect, paradoxical normal or increased levels of urinary dopamine have been reported. Genotype/phenotype correlations or alternative metabolic pathways may explain this remarkable finding, but were never studied systematically. Methods We studied the mutational spectrum and urinary dopamine levels in 20 patients with AADC-deficiency. Experimental procedures were designed to test for alternative metabolic pathways of dopamine production, which included alternative substrates (tyramine and 3-methoxytyrosine) and alternative enzymes (tyrosinase and CYP2D6). Results/discussion In 85% of the patients the finding of normal or increased urinary levels of dopamine was confirmed, but a relation with AADC genotype could not be identified. Renal microsomes containing CYP2D were able to convert tyramine into dopamine (3.0 nmol/min/g protein) but because of low plasma levels of tyramine this is an unlikely explanation for urinary dopamine excretion in AADC-deficiency. No evidence was found for the production of dopamine from 3-methoxytyrosine. Tyrosinase was not expressed in human kidney. Conclusion Normal or increased levels of urinary dopamine are found in the majority of AADC-deficient patients. This finding can neither be explained by genotype/phenotype correlations nor by alternative metabolic pathways, although small amounts of dopamine may be formed via tyramine hydroxylation by renal CYP2D6. CYP2D6-mediated conversion of tyramine into dopamine might be an interesting target for the development of new therapeutic strategies in AADC-deficiency.

Clinical and biochemical features of aromatic l-amino acid decarboxylase deficiency

In the article “Clinical and biochemical features of aromatic l-amino acid decarboxylase deficiency” by L. Brun et al. ( Neurology 2010;75:64–71), there was a dosage error in the article …

Clinical and biochemical features of aromatic L-amino acid decarboxylase deficiency

To describe the current treatment; clinical, biochemical, and molecular findings; and clinical follow-up of patients with aromatic l-amino acid decarboxylase (AADC) deficiency. Clinical and biochemical data of 78 patients with AADC deficiency were tabulated in a database of pediatric neurotransmitter disorders (JAKE). A total of 46 patients have been previously reported; 32 patients are described for the first time. In 96% of AADC-deficient patients, symptoms (hypotonia 95%, oculogyric crises 86%, and developmental retardation 63%) became clinically evident during infancy or childhood. Laboratory diagnosis is based on typical CSF markers (low homovanillic acid, 5-hydroxyindoleacidic acid, and 3-methoxy-4-hydroxyphenolglycole, and elevated 3-O-methyl-l-dopa, l-dopa, and 5-hydroxytryptophan), absent plasma AADC activity, or elevated urinary vanillactic acid. A total of 24 mutations in the DDC gene were detected in 49 patients (8 reported for the first time: p.L38P, p.Y79C, p.A110Q, p.G123R, p.I42fs, c.876G>A, p.R412W, p.I433fs) with IVS6+ 4A>T being the most common one (allele frequency 45%). Based on clinical symptoms, CSF neurotransmitters profile is highly indicative for the diagnosis of aromatic l-amino acid decarboxylase deficiency. Treatment options are limited, in many cases not beneficial, and prognosis is uncertain. Only 15 patients with a relatively mild form clearly improved on a combined therapy with pyridoxine (B6)/pyridoxal phosphate, dopamine agonists, and monoamine oxidase B inhibitors.

Movers and shakers

Lumbar puncture was introduced by Wynter1 as a therapy for increased intracranial pressure in tuberculous meningitis, and was popularized as a diagnostic technique by Quincke.2 The test remains indispensable for diagnosing CNS infection, inflammatory diseases, and raised intracranial pressure. The diagnostic potential of the CSF has continued to expand, as methods have become available for reliably measuring analytes that are present in very low concentrations. In this issue of Neurology ®, Brun and colleagues3 report on a cohort of patients with aromatic l-amino acid decarboxylase (AADC) deficiency, one of a family of disorders of biogenic amine synthesis that have been recognized since the classic description of dopa-responsive dystonia by Segawa et al.4 more than 3 decades ago. Because they most often declare themselves in childhood, these diseases have become known as pediatric neurotransmitter disorders (PNDs). Although each of these disorders has characteristic clinical features, there are common manifestations that should suggest the presence of a PND: fluctuating movement disorders, intermittent disruption of eye movements, and variable delays in development, with or without seizures and hypotonia. A grasp of the basic biochemistry is essential to …

Pyridoxal 5′‐phosphate deficiency causes a loss of aromatic l‐amino acid decarboxylase in patients and human neuroblastoma cells, implications for aromatic l‐amino acid decarboxylase and vitamin B6 deficiency states

Pyridoxal 5'-phosphate, the active form of vitamin B(6), is an essential cofactor for multiple enzymes, including aromatic l-amino acid decarboxylase that catalyses the final stage in the production of the neurotransmitters dopamine and serotonin. In two patients with inherited disorders of vitamin B(6) metabolism, we observed reductions in plasma aromatic l-amino acid decarboxylase activity. In one patient, this change was related to an increase in K(m) for pyridoxal 5'-phosphate. Furthermore, pyridoxal 5'-phosphate-deficient human SH-SY5Y neuroblastoma cells were found to exhibit reduced levels of aromatic l-amino acid decarboxylase activity and protein but with no alteration in expression. Further reductions in activity and protein were observed with the addition of the vitamin B(6) antagonist 4-deoxypyridoxine, which also reduced aromatic l-amino acid decarboxylase mRNA levels. Neither pyridoxal 5'-phosphate deficiency nor the addition of 4-deoxypyridoxine affected aromatic l-amino acid decarboxylase stability over 8 h with protein synthesis inhibited. Increasing extracellular availability of pyridoxal 5'-phosphate was not found to have any significant effect on intracellular pyridoxal 5'-phosphate concentrations or on aromatic l-amino acid decarboxylase. These findings suggest that maintaining adequate pyridoxal 5'-phosphate availability may be important for optimal treatment of aromatic l-amino acid decarboxylase deficiency and l-dopa-responsive conditions.

Modified clinical protocol for the investigations of dystonia: NON-INVASIVE Biochemical diagnosis of aromatic L-amino acid decarboxylase deficiency in Chinese

Modified clinical protocol for the investigations of dystonia: NON-INVASIVE Biochemical diagnosis of aromatic L-amino acid decarboxylase deficiency in Chinese

Disorders of monoamine metabolism: inherited disorders frequently misdiagnosed as epilepsy

Pediatric neurotransmitter diseases are new emerging neurological diseases in children. They include tyrosine hydroxylase (TH) deficiency, aromatic L-amino acid decarboxylase (AADC) deficiency, succinic semialdehyde dehydrogenase (SSADH) deficiency, gua-nosine triphosphate cyclohydrolase I deficiency, sepiapterin reductase (SR) deficiency and cerebral folate deficiency. Of these, monoamine biosynthesis and metabolism disorders are one group of inherited disorders usually requiring specific diagnostic procedures. Children with disorders of neurotransmitters often present with psychomotor retardation, hypotonia and microcephaly. Although seizures may be more common in patients with SR deficiency, patients with TH or AADC deficiency only occasionally have non-epileptic myoclonus. However, the episodic dystonia and oculogyric crisis manifested in these patients are frequently misdiagnosed as epilepsy, and multiple anti-epileptic drugs (AEDs) may be given. In the present short review, the pathogenesis and diagnosis of these neurotransmitter disorders are discussed, with the hope that correct diagnosis of pediatric neurotransmitter diseases can reduce the unnecessary AED treatment.

Abnormal glucose metabolism in aromatic l-amino acid decarboxylase deficiency

We report sibling cases of aromatic L-amino acid decarboxylase (AADC) deficiency, which is a very rare congenital metabolic disorder. These patients were born to healthy and non-consanguineous parents, and presented oculogyric crises, paroxysmal dystonic attacks, and severe psychomotor retardation since early infancy. In cerebrospinal fluid the levels of homovanilic acid and 5-hydroxyindoleacetic acid were very low and the level of L-dopa was very high. The diagnosis was confirmed by the lack of AADC activity in plasma, and a point mutation in the AADC gene. MRI revealed a slightly small volume of the prefrontal areas and normal myelination in both patients. Positron emission tomography using 2-deoxy-2[(18)F] fluoro-D-glucose was performed in one patient, which revealed hypometabolism in the prefrontal cortex and bilateral basal ganglia with a little laterality. These findings suggested that the severe dystonic features were caused by abnormal function of bilateral basal ganglia and severe psychomotor retardation could be due to abnormalities in prefrontal cortical activity.

International Symposium on Pediatric Neurotransmitter Diseases

The second International Symposium on Pediatric Neurotransmitter Diseases (PNDs), entitled BMedical Management of Pediatric Neurotransmitter Diseases: A Multidisciplinary Approach^, was convened on July 18–19, 2008, in Washington, DC, USA. The meeting was sponsored conjointly by the National Institute of Neurological Disease and Stroke (NINDS), the Office of Rare Diseases (ORD), the Johns Hopkins School of Medicine and the PND Association. This second symposium followed almost six years to the day from the first International Symposium (May 18–19, 2002), the proceedings of which were presented in a supplement to Annals of Neurology (Volume 54 Issue S6, pages S1–S109 (2003)). There are currently five rare, inherited disorders that affect central neurotransmission and are housed under the umbrella of the PND Association. These are: succinic semialdehyde dehydrogenase (SSADH) deficiency (or g-hydroxybutyric aciduria), tyrosine hydroxylase (TH) deficiency, aromatic L-amino acid decarboxylase (AADC) deficiency, guanosine triphosphate cyclohydrolase I deficiency (GTP cyclohydrolase, or GTPCH deficiency), and sepiapterin reductase (SR) deficiency. Generally speaking, early presentation with an array of movement dysfunction is the rule in these disorders, and this umbrella is likely to expand as more disorders are recognized, and more parents join the ranks of the PND Association. The conference brought together scientists and clinicians to discuss current and potential treatments for PNDs, and to develop practical guidelines for multidisciplinary treatment of these disorders. The conference was attended by more than sixty medical professionals representing six countries, ten medical professionals from the National Institutes of Health, and more than thirty families whose child (or children) are affected with one of the PNDs. As it was with the first Symposium, the opening talks presented an overview of the phenotypes and metabolic features of the PNDs. The future prospects for gene therapy in this group of disorders was also discussed. As always, the exceptionally insightful comments of Prof. Segawa, who in 1971 first described autosomal-dominant GTP cyclohydrolase deficiency, provided thoughtful discussion for all in attendance. A goal of the second Symposium was to present a Bmultifaceted^ approach to treatment. The corresponding sessions highlighted traditional physiatry, sensory integration intervention and the potential for deep brain stimulation for amelioration of symptoms. These approaches generated lively discussion, and it is probable that these approaches will be discussed in future Symposia. The second Symposium afforded the opportunity for research updates by investigators funded through the PND Association, as well as other investigators who had important new data to present. An impressive update on neuroimaging in AADC deficiency was developed into one of the written contributions to the Symposium proceedings. One of the more rewarding J Inherit Metab Dis (2009) 32:319–320 DOI 10.1007/s10545-009-9961-1

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

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. 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. 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. 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.

Aromatic l‐amino acid decarboxylase deficiency associated with epilepsy mimicking non‐epileptic involuntary movements

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare inborn error of neurotransmitter biosynthesis that leads to a combined deficiency of catecholamines and serotonin and is characterized by global developmental delay, involuntary movements, and autonomic dysfunction. We report the case of an 11-year-old male patient with AADC deficiency who also had epileptic spasms and generalized tonic seizures with asymmetrical features, in addition to frequent involuntary non-epileptic movements. The clinical manifestation of the epileptic attacks apparently resembled that of non-epileptic attacks. It was difficult to differentiate between both attacks without the help of an ictal electroencephalographic study. The epileptic attacks were finally controlled by appropriate antiepileptic drugs. Because an association with epileptic seizures is uncommon in AADC deficiency, some cases may have been regarded as involuntary non-epileptic movements. This indicates that the differentiation of epileptic attacks from non-epileptic ones is indispensable for the adequate treatment of patients with AADC deficiency.

Aromatic l-amino acid decarboxylase deficiency in Taiwan

Background Aromatic l-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive disorder of neurotransmitter synthesis. It has unique clinical presentations. Aims The purpose of this study is to delineate the clinical features and molecular spectrum of AADC deficiency in Taiwanese infants and children. Methods We report eight patients with characteristic clinical manifestations of AADC deficiency. Clinical presentations, treatment response, outcome and mutations of DOPA decarboxylase ( DDC) gene were analyzed. Results The clinical manifestations were similar to those previously reported, including symptoms onset before age 1 year with features of severe floppiness, oculogyric crises, athetoid movement, prominent startle response, tongue thrusting, ptosis, paroxysmal diaphoresis, nasal congestion, diarrhea, irritability and sleep disorders. In addition, we observed that all patients (100.0%) had small hands and feet. During the period of follow-up, all of them (100.0%) presented severe floppiness in spite of therapeutic trials with vitamin B6, dopamine agonist, MAO inhibitor and/or anticholinergics. Three different mutations were identified in the DDC gene, including two novel mutations 1303 C > T and 1367ins A and one IVS 6 + 4 A > T mutation. The IVS 6 + 4 A > T was a splicing mutation, which inserted an additional 37 nt of intron 6 into the DDC mRNA. Thirteen out of 16 alleles (81.3%) carried IVS 6 + 4 A > T mutation and the IVS 6 + 4 A > T alleles shared a conserved haplotype. Conclusions Patients with AADC deficiency in Taiwan have particular clinical manifestations of small hands and feet, which have rarely been mentioned in the literature. The prevalence of IVS 6 + 4 A > T splicing mutation is high in our study group and the IVS 6 + 4 A > T mutation might have a founder effect.