Pediatric Neurotransmitter Diseases Research Articles

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.

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.

Pediatric neurotransmitter diseases.

The pediatric neurotransmitter disorders represent a challenging group of rare neurometabolic disorders classified on the basis of alterations in neurotransmitter metabolic pathways. The disorders are currently classified into disturbances of monoamine and gamma-aminobutyric acid (GABA) metabolism, although disorders of other neurotransmitters, such as glutamate and melatonin, may well be recognized in future investigations. This review summarizes the clinical and laboratory features of selected pediatric neurotransmitter disorders that have been partially delineated. Of the monoamine group, these are Segawa disease or guanosine triphosphate-cyclohydrolase I deficiency, aromatic L-amino acid decarboxylase deficiency, and tyrosine hydroxylase deficiency. Of the GABA disorders, these are pyridoxine-dependent epilepsy, GABA transaminase deficiency, and succinic semialdehyde dehydrogenase deficiency. As proper collection, handling, and interpretation of cerebrospinal fluid is required for assessment of most of these disorders, we end by summarizing important considerations for obtaining cerebrospinal fluid samples.

Differential Diagnosis of Dystonia

An approach to the early diagnosis of pediatric neurotransmitter diseases (PNTD), and especially dystonia, is outlined in a report from the University Children’s Hospital, Dusseldorf, Germany; and Institute of Child Health, University College, London, UK.

Potential of gene therapy for pediatric neurotransmitter diseases: lessons from Parkinson's disease.

Gene therapy methods have continued to develop rapidly, and many initial limitations that hampered clinical application have been overcome. Thus serious consideration of clinical application of gene therapy is warranted for selected disorders in which the pathogenesis is well defined. Parkinson's disease has been the most extensively studied target of gene therapy for central nervous system disorders and shares many features with pediatric neurotransmitter diseases. Neurotransmitter replacement therapy using catecholamine-synthesizing genes and delivery of neurotrophic factors such as glial cell line-derived neurotrophic factors has been successful in animal models of Parkinson's disease. Application of gene therapy for pediatric neurotransmitter diseases will require delineating the optimal set of genes to correct the consequences of the deficiencies. The optimal anatomical targets and proper timing of the gene replacement must be understood. Safety of gene therapy vehicles and the ability to regulate gene expression will be essential for eventual clinical application.

Approach to the diagnosis of neurotransmitter diseases exemplified by the differential diagnosis of childhood-onset dystonia.

We present our approach to the diagnosis of pediatric neurotransmitter diseases exemplified by the differential diagnosis of children presenting with dystonia. This approach is based upon the primary aim of early diagnosis of treatable conditions and the need for a logical series of investigations. We have tried to be comprehensive with our coverage but are aware that "new" pediatric neurotransmitter diseases continue to be delineated and that, similarly, a proportion of children presenting with dystonia remain undiagnosed. If this is the case, all of the investigations suggested here may need to be performed regardless of age and presentation. However, of more value is a careful clinical reevaluation.

The lumbar puncture for diagnosis of pediatric neurotransmitter diseases.

The investigation of infants and children with suspected pediatric neurotransmitter diseases affecting serotonin and catecholamine metabolism is complicated because the measurement of metabolites in peripheral fluids is generally uninformative. Disorders that affect catecholamine (dopamine and norepinephrine) and serotonin neurotransmission, and that do not present with hyperphenylalaninemia, require that a lumbar puncture be performed and that specific metabolites be assessed in the collected cerebrospinal fluid. This review will discuss the disorders affecting catecholamine and serotonin biosynthesis, sample collection and handling, diagnostic methods and expected profiles, problems with diagnosis, and as yet to be described conditions that might be detected using current diagnostic methodologies.