Pediatric Neurotransmitter Research Articles

Inherited Pediatric Neurotransmitter Disorders: Case Studies and Long-Term Outcomes

AbstractPrimary pediatric neurotransmitter disorders include genetic defects of neurotransmitter metabolism that may mimic common neurological conditions in children. Our objective was to evaluate the clinical experience and outcomes of affected patients. Five patients with primary neurotransmitter defects were identified in the neurometabolic database between 2004 and 2022. Two patients with 6-pyruvoyltetrahydropterin synthase deficiency and one with pyridoxine-dependent epilepsy (PDE) presented in the neonatal period. One patient with succinic semialdehyde dehydrogenase (SSADH) deficiency and one with aromatic l-amino acid decarboxylase (AADC) deficiency presented in later life. A diagnosis of cerebral palsy was revised following biochemical confirmation of SSADH deficiency. AADC deficiency was confirmed via exome sequencing and reduced activity on enzyme assay. Late diagnosis in the latter two cases was likely due to a low index of suspicion and lack of access to diagnostic tests in the country of origin. In two children with tetrahydrobiopterin deficiency, newborn screening results and atypical clinical features prompted investigations. An early diagnosis of PDE was established based on presenting features, a high index of suspicion, the presence of an identifiable biochemical marker and molecular genetic testing. Pediatric neurotransmitter disorders can be diagnosed based on a high clinical index of suspicion, availability of biochemical markers, and molecular genetic testing. These disorders, though rare, need to be included in the differential diagnosis of common neurological presentations in children as they may be potentially treatable. Outcomes and influencing factors in the present series are discussed in comparison to published data.

Using the EQ-5D to measure caregiver health-related quality of life in rare pediatric disease: a study in aromatic L-amino acid decarboxylase deficiency

Aims: To evaluate how well the EQ-5D-5L, a generic preference-based measure of health-related quality of life, captures caregiver burden in a rare pediatric neurotransmitter disease. Materials & methods: Caregivers (n = 14) of individuals with aromatic L-amino acid decarboxylase (AADC) deficiency completed qualitative interviews on their experience as a caregiver, the EQ-5D-5L and a background questionnaire. Qualitative and quantitative data were compared to determine whether there was concordance or discordance in the findings. Results: No caregivers reported problems with mobility and self-care in either the qualitative interviews or on the EQ-5D-5L, and there was general concordance for pain/discomfort and anxiety/depression. However, discordance was found for usual activities, with 79% reporting no problems with this dimension on the EQ-5D-5L, compared with 100% describing substantial limitations during the interviews. Conclusion: The EQ-5D-5L may not be appropriate to evaluate caregiver burden in AADC deficiency, where caregivers' perceptions of “usual activities” differ substantially from the general population.

DNAJC6 Mutations Disrupt Dopamine Homeostasis in Juvenile Parkinsonism-Dystonia.

BackgroundJuvenile forms of parkinsonism are rare conditions with onset of bradykinesia, tremor and rigidity before the age of 21 years. These atypical presentations commonly have a genetic aetiology, highlighting important insights into underlying pathophysiology. Genetic defects may affect key proteins of the endocytic pathway and clathrin‐mediated endocytosis (CME), as in DNAJC6‐related juvenile parkinsonism.ObjectiveTo report on a new patient cohort with juvenile‐onset DNAJC6 parkinsonism‐dystonia and determine the functional consequences on auxilin and dopamine homeostasis.MethodsTwenty‐five children with juvenile parkinsonism were identified from a research cohort of patients with undiagnosed pediatric movement disorders. Molecular genetic investigations included autozygosity mapping studies and whole‐exome sequencing. Patient fibroblasts and CSF were analyzed for auxilin, cyclin G–associated kinase and synaptic proteins.ResultsWe identified 6 patients harboring previously unreported, homozygous nonsense DNAJC6 mutations. All presented with neurodevelopmental delay in infancy, progressive parkinsonism, and neurological regression in childhood. 123I‐FP‐CIT SPECT (DaTScan) was performed in 3 patients and demonstrated reduced or absent tracer uptake in the basal ganglia. CSF neurotransmitter analysis revealed an isolated reduction of homovanillic acid. Auxilin levels were significantly reduced in both patient fibroblasts and CSF. Cyclin G–associated kinase levels in CSF were significantly increased, whereas a number of presynaptic dopaminergic proteins were reduced.ConclusionsDNAJC6 is an emerging cause of recessive juvenile parkinsonism‐dystonia. DNAJC6 encodes the cochaperone protein auxilin, involved in CME of synaptic vesicles. The observed dopamine dyshomeostasis in patients is likely to be multifactorial, secondary to auxilin deficiency and/or neurodegeneration. Increased patient CSF cyclin G–associated kinase, in tandem with reduced auxilin levels, suggests a possible compensatory role of cyclin G–associated kinase, as observed in the auxilin knockout mouse. DNAJC6 parkinsonism‐dystonia should be considered as a differential diagnosis for pediatric neurotransmitter disorders associated with low homovanillic acid levels. Future research in elucidating disease pathogenesis will aid the development of better treatments for this pharmacoresistant disorder. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

An Inhibited Dopamine Synthesizing Cell Model of AADC Deficiency

Introduction: Aromatic L-amino acid decarboxylase deficiency (AADC) is a rare autosomal recessive pediatric neurotransmitter disease. To date it remains poorly understood mainly due to an absence of a disease model. The dopaminergic neuroblastoma cell SH-SY5Y was chosen to develop our AADC deficiency model. These cells are not native dopamine synthesizers. Objective: To develop a dopamine-producing cellular model of AADC deficiency using SH-SY5Y neuroblastoma cells. Methods: Dopamine pathway proteins were identified with Western Blotting. Dopaminergic differentiation was attempted using all-trans retinoic acid (ATRA) with dopamine detection via HPLC-ECD post alumina extraction. Treatment with L-DOPA provided SH-SY5Y with excess precursor. RT-PCR was used to determine the expression of markers of mature neurons. Results: Western Blot screening identified AADC, dopamine β-hydroxylase and tyrosine hyrdoxylase proteins, indicative of a dopaminergic pathway. ATRA was unsuccessful in producing dopamine from the cells. L-DOPA treatment however, generated dopamine first visible as a HPLC-ECD peak 30 minutes post-incubation. Prior to this, SH-SY5Y dopamine synthesis from L-DOPA has never been documented. This de novo synthesis is then inhibited using benserazide to form our AADC deficiency cell model. RT-PCR showed that SH-SY5Y cells express markers of mature neurons in its ‘native’ state and is not affected by L-DOPA and benserazide treatment. This cell model will potentially benefit many areas of AADC deficiency research. Conclusion: SH-SY5Y cells produced HPLC-ECD measureable amounts of dopamine with the addition of L-DOPA. Our model of AADC deficiency is generated by quelling the dopamine production with Benserazide.

Biomarkers in a Taurine Trial for Succinic Semialdehyde Dehydrogenase Deficiency.

We tested the hypothesis that patients with succinic semialdehyde dehydrogenase (SSADH) deficiency on taurine would have decreased cortical excitability as measured by transcranial magnetic stimulation (TMS) and improved cognition, due to taurine's partial GABA(A and B) receptor agonist effects and rescue in the null mouse model from status epilepticus and premature lethality. Biomarkers including neuropsychological testing, TMS, and CSF metabolites were studied in a cohort of patients on and off three months' taurine treatment. Seven patients (5M/2F; age range 12-33 years) were enrolled in this open-label crossover study. Baseline average full-scale IQ (FSIQ) was 44.1 (range 34-55). Of six who returned at 6-month follow-up, five completed cognitive testing (3M/2F) on therapy; average FSIQ = 43.4 (range 33-51). CSF biomarkers (n = 4 subjects) revealed elevation in taurine levels but no change in free or total GABA. Baseline cortical excitability measured with TMS agreed with previous findings in this population, with a short cortical silent period and lack of long-interval intracortical inhibition. Patients on taurine showed a decrease in cortical silent period and short-interval intracortical inhibition compared to their off taurine study. TMS demonstrated decreased inhibition in patients on taurine, in contrast to the study hypothesis, but consistent with its failure to produce clinical or cognitive improvement. TMS may be a useful biomarker for therapy in pediatric neurotransmitter disorders.

LC-MS/MS Analysis of Cerebrospinal Fluid Metabolites in the Pterin Biosynthetic Pathway.

The analysis of (6R)-5,6,7,8-tetrahydrobiopterin (BH4) and neopterin in cerebrospinal fluid (CSF) is often used to identify defects in the pterin biosynthetic pathway affecting monoamine metabolism that can lead to pediatric neurotransmitter diseases. Low levels of BH4 and neopterin alone may not be sufficient to determine the defect, and further testing is often required. We have developed a sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) method for determination of BH4, 7,8-dihydrobiopterin (BH2), neopterin, and sepiapterin in CSF, which provides a more comprehensive evaluation of the pterin pathway. The method utilizes labeled stable isotopes as internal standards and allows for a fast 10-minute analysis by LC/MS/MS over a linear working range of 3 to 200nmol/L. Total analytical imprecision is less than 14.4% for all pterin metabolites. Accuracy for BH4 and neopterin was determined by comparing data obtained by an alternative method using HPLC with EC and fluorescence detection. Excellent correlation was demonstrated for BH4 (r = 0.9646, 1/slope = 0.9397; n = 28; concentration range 3 to 63nmol/L) and neopterin (r = 0.9919, 1/slope = 0.9539; n = 13; concentration range 5 to 240nmol/L). CSF specimens from patients diagnosed with inborn errors of sepiapterin reductase (SR), 6-pyruvoyl-tetrahydropterin synthase (PTPS), dihydropteridine reductase (DHPR), and guanosine triphosphate cyclohydrolase (GTPCH) have been analyzed, and distinct pterin metabolite patterns were consistent with the initial diagnosis. This method differentiates patients with DHPR and SR deficiency from other pterin defects (GTPCH and PTPS) and will be useful for the diagnosis of specific defects in the pterin biosynthetic pathway.

An international survey of patients with tetrahydrobiopterin deficiencies presenting with hyperphenylalaninaemia

The present study summarizes clinical and biochemical findings, current treatment strategies and follow-up in patients with tetrahydrobiopterin (BH(4)) deficiencies. We analyzed the clinical, biochemical and treatment data of 626 patients with BH(4) deficiencies [355 with 6-pyruvoyl-tetrahydropterin synthase (PTPS), 217 with dihydropteridine reductase (DHPR), 31 with autosomal recessive GTP cyclohydrolase I (GTPCH), and 23 with pterin-4a-carbinolamine dehydratase (PCD) deficiencies] from the BIODEF Database. Patients with autosomal dominant GTPCH and SR deficiencies will not be discussed in detail. Up to 57 % of neonates with BH(4) deficiencies are already clinically symptomatic. During infancy and childhood, the predominant symptoms are muscular hypotonia, mental retardation and age-dependent movement disorders, including dystonia. The laboratory diagnosis of BH(4) deficiency is based on a positive newborn screening (NBS) for phenylketonuria (PKU), characteristic profiles of urinary or dried blood spot pterins (biopterin, neopterin, and primapterin), and the measurement of DHPR activity in blood. Some patients with autosomal recessive GTPCH deficiency and all with sepiapterin reductase deficiency may be diagnosed late due to normal blood phenylalanine in NBS. L-dopa, 5-hydroxytryptophan, and BH(4) are supplemented in PTPS and GTPCH-deficient patients, whereas L-dopa, 5-hydroxytryptophan, folinic acid and diet are used in DHPR-deficient patients. Medication doses vary widely among patients, and our understanding of the effects of dopamine agonists and monoamine catabolism inhibitors are limited. BH(4) deficiencies are a group of treatable pediatric neurotransmitter disorders that are characterized by motor dysfunction, mental retardation, impaired muscle tone, movement disorders and epileptic seizures. Although the outcomes of BH(4) deficiencies are highly variable, early diagnosis and treatment result in improved outcomes.

Pediatric Neurotransmitter Disease in Japan

Pediatric Neurotransmitter Disease in Japan

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.

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 …

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.

Neuroimaging findings in children with paediatric neurotransmitter diseases

Paediatric neurotransmitter diseases consist of a group of inherited neurometabolic diseases in children, and include disorders related to gamma-amino butyric acid (GABA) metabolism, monoamine biosynthesis, etc. The diagnosis of paediatric neurotransmitter diseases remain a great challenge for paediatricians and child neurologists. In addition to clinical manifestations and CSF neurotransmitter measurement, neuroimaging findings can also be very informative for the diagnosis and evaluation of the patients. For patients with monoamine biosynthesis disorders, the functional evaluation of dopaminergic transmission also plays an important role. Understanding of the possible neuroimaging changes in paediatric neurotransmitter diseases is therefore of great value for the investigation of these patients.

Increasing physical function through physiatric intervention for children with paediatric neurotransmitter disorders

Most children with paediatric neurotransmitter diseases have global functional deficits secondary to central nervous system damage. Paediatric physiatrists, working in conjunction with a multi-disciplinary team, help to improve physical function by normalizing muscle tone and improving body position. Components of spasticity, rigidity, and dystonia may all need to be considered in a comprehensive treatment programme. Complications of disordered tone include skin breakdown, pain, sleep disturbance, and dysphagia. With an integrated approach to use of medications and equipment as well as implementation of therapy and therapeutic exercise, physiatrists can help maximize functional independence for children with this group of disorders. Pharmacological treatment includes GABA-agonists including baclofen and benzodiazepines, alpha-2 adrenergic agonists, L: -dopa and dopaminergic agents, and dantrolene. Intrathecal baclofen may be used in patients refractory to these medications. In addition, physicians may utilize botulinum toxin, phenol, or surgical interventions such as selective dorsal rhizotomy or tendon lengthening. Pharmacological treatment must be used in conjunction with appropriate adaptive equipment in order to maximize therapeutic benefit. Focus on function in an attempt to increase independence is targeted to improve the child's quality of life. We present a framework and rationale to the management of the functional consequences of the paediatric neurotransmitter diseases.

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

Sensory integration intervention: Historical concepts, treatment strategies and clinical experiences in three patients with succinic semialdehyde dehydrogenase (SSADH) deficiency

This paper is a review of clinical experiences providing developmental therapy services for three boys diagnosed with paediatric neurotransmitter disease. The clinical presentation of paediatric neurotransmitter diseases might parallel other diagnostic characteristics seen in a typical paediatric therapy clinic (i.e. hypotonia, motor and cognitive delays, coordination, expressive speech, and ocular motor difficulties.) From the clinical perspective of the author, sensory integrative function is but one aspect of a thorough evaluation and treatment plan for all patients. The manifestations of sensory integration dysfunction (SID), also known as sensory processing dysfunction (SPD), can occur alone or be concurrent with a variety of known medical, behavioural and neurological diagnoses. These manifestations of SPD can include, but are not limited to: hypotonia, hyperactivity, irritability, distractibility, attention difficulties, learning difficulties, clumsiness and incoordination, instability, poor motor skills, social-emotional difficulties, and behavioural problems. This paper summarizes the theory and practice applications of sensory integration. The author discusses clinical experiences providing occupational therapy services utilizing sensory integration methods and strategies with clients who were eventually diagnosed with SSADH deficiency.

Consideration of gene therapy for paediatric neurotransmitter diseases

The paediatric neurotransmitter diseases (PNDs) are a group of inborn errors of metabolism characterized by abnormalities of neurotransmitter synthesis or metabolism. Although some children may react favourably to neurotransmitter augmentation treatment, optimal response is not universal and other modes of treatment should be sought. The genes involved in many of the currently known monoamine PNDs have been utilized in pre-clinical and in phase I clinical trials in Parkinson disease (PD) and the basic principles could be applied to the therapy of PNDs with some modifications regarding the targeting and distribution of vectors. However, issues that go beyond neurotransmitter replacement are important considerations in PD and even more so in PNDs. Understanding the pathophysiology of PNDs including abnormal development resulting from the neurotransmitter deficiency will be critical for rational therapeutic approaches. Better animal models of PNDs are necessary to test gene therapy before clinical trials can be attempted.

The phenotypic spectrum of paediatric neurotransmitter diseases and infantile parkinsonism

Paediatric neurotransmitter diseases are a group of inherited disorders attributable to a disturbance of neurotransmitter metabolism. The monoamines, catecholamines and serotonin, also called biogenic amines, are neurotransmitters with multiple roles including psychomotor function, hormone secretion, cardiovascular, respiratory and gastrointestinal control, sleep mechanisms, body temperature and pain. Given the multiple functions of monoamines, disorders of their metabolism comprise a wide spectrum of manifestations, with motor dysfunction being the most prominent clinical feature. The severity of the clinical manifestations ranges from mild to severe. Patients with severe and intermediate phenotypes may present with infantile parkinsonism that differs in a number of aspects from the parkinsonism in nigrostriatal degeneration. Analysis of monoamine metabolites and pterins in spinal fluid assists in the diagnosis of these disorders. Treatment options include tetrahydrobiopterin supplementation, L: -dopa, 5-hydroxytryptophan, and medications that potentiate monoamine transmission. Response to treatment is variable.

Mutations in human monoamine-related neurotransmitter pathway genes

Biosynthesis and metabolism of serotonin and catecholamines involve at least eight individual enzymes that are mainly expressed in tissues derived from the neuroectoderm, e.g., the central nervous system (CNS), pineal gland, adrenal medulla, enterochromaffin tissue, sympathetic nerves, and ganglia. Some of the enzymes appear to have additional biological functions and are also expressed in the heart and various other internal organs. The biosynthetic enzymes are tyrosine hydroxylase (TH), tryptophan hydroxylases type 1 and 2 (TPH1, TPH2), aromatic amino acid decarboxylase (AADC), dopamine beta-hydroxylase (DbetaH), and phenylethanolamine N-methyltransferase (PNMT), and the specific catabolic enzymes are monoamine oxidase A (MAO-A) and catechol O-methyltransferase (COMT). For the TH, DDC, DBH, and MAOA genes, many single nucleotide polymorphisms (SNPs) with unknown function, and small but increasing numbers of cases with autosomal recessive mutations have been recognized. For the remaining genes (TPH1, TPH2, PNMT, and COMT) several different genetic markers have been suggested to be associated with regulation of mood, pain perception, and aggression, as well as psychiatric disturbances such as schizophrenia, depression, suicidality, and attention deficit/hyperactivity disorder. The genetic markers may either have a functional role of their own, or be closely linked to other unknown functional variants. In the future, molecular testing may become important for the diagnosis of such conditions. Here we present an overview on mutations and polymorphisms in the group of genes encoding monoamine neurotransmitter metabolizing enzymes. At the same time we propose a unified nomenclature for the nucleic acid aberrations in these genes. New variations or details on mutations will be updated in the Pediatric Neurotransmitter Disorder Data Base (PNDDB) database (www.bioPKU.org).

The Pediatric Neurotransmitter Disorders

The pediatric neurotransmitter disorders represent an enlarging group of neurological syndromes characterized by abnormalities of neurotransmitter synthesis and breakdown. The disorders of dopamine and serotonin synthesis are aromatic amino acid decarboxylase deficiency, tyrosine hydroxylase deficiency, and disorders of tetrahydrobiopterin synthesis. Amino acid decarboxylase, tyrosine hydroxylase, sepiapterin reductase, and guanosine triphosphate cyclohydrolase (Segawa disease) deficiencies do not feature elevated serum phenylalanine and require cerebrospinal fluid analysis for diagnosis. Segawa disease is characterized by dramatic and lifelong responsiveness to levodopa. Glycine encephalopathy is typically manifested by refractory neonatal seizures secondary to a defect of the glycine degradative pathway. gamma-amino butyric acid (GABA) metabolism is associated with several disorders, including glutamic acid decarboxylase deficiency with nonsyndromic cleft lip/ palate, GABA-transaminase deficiency, and succinic semialdehyde dehydrogenase deficiency. The latter is characterized by elevated gamma-hydroxybutyric acid and includes a wide range of neuropsychiatric symptoms as well as epilepsy. Pyridoxine-dependent seizures have now been associated with deficiency of alpha-aminoadipic semialdehyde dehydrogenase, as well as a new variant requiring therapy with pyridoxal-5-phosphate, the biologically active form of pyridoxine.