Cyclohydrolase Deficiency Research Articles

Psychiatric Manifestations in Patients with Biopterin Defects.

Psychiatric manifestations in patients with tetrahydrobiopterin (BH4) defects are common, and may occur even with treatment of the underlying disorder. The neurobiological background of these conditions has been linked to abnormalities of neurotransmitters, such as dopamine, serotonin, norepinephrine, and gamma-aminobutyric acid. Here, we review the psychiatric profile of all patients with BH4 defects followed in the pediatric and adult metabolic clinics at our center. Three patients with autosomal recessive (AR) guanosine triphosphate cyclohydrolase (GTPCH) deficiency and three patients with 6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency were reviewed.All patients had behavioral disturbances and two had significant psychiatric comorbidities. These included attention deficit/hyperactivity disorder, anxiety, depression, aggression, or oppositional defiant disorder. One patient with PTPS deficiency had a severe psychiatric presentation, requiring inpatient admission and temporary placement into foster care for intensive behavioral therapy. Another with AR GTPCH deficiency was diagnosed with aggressive behavioral dysregulation requiring intensive psychiatric treatment. Management of the psychiatric manifestations of BH4 defects can be challenging, due to lack of information and studies of interactions between psychiatric medications on the deficient neurotransmitters and their receptors in these conditions. Further studies are needed to establish safety and efficacy of these treatments.

Anxiety and depression in tyrosine hydroxylase deficiency: a case report

Background: Tyrosine hydroxylase (TH) deficiency is a very rare genetic disorder of monoamine synthesis which – alongside Guanosine triphosphate (GTP) cyclohydrolase deficiency - is one of the metabolic dopa-responsive dystonias. These disorders classically present as a dystonia with onset in adolescence which is non-progressive and responds to standard dopaminergic treatment: however, little is known about the relationship between TH deficiency and psychiatric illness. Case Presentation: We describe a case of a young woman who, in the absence of any heralding psychiatric symptomatology of any nature, developed a severe and limiting panic disorder at around the time of onset of her movement disorder in the setting of TH deficiency, which impacts dopamine synthesis. Conclusion: Neurometabolic disorders that affect neurotransmitter function frequently present with psychiatric symptomatology and can provide models for understanding some frequently presenting psychiatric illnesses such as depression and anxiety. We discuss the interplay between the dopaminergic and serotonergic systems, and how an ostensibly dopaminergic disorder could produce what has long been understood to be a serotonergically-driven anxiety syndrome.

PRO10 Identifying Appropriate PROXY Diseases for Estimating LONG-TERM Survival and IMPACT on Health-Related Quality of Life of Patients with Aromatic L-Amino Acid Decarboxylase Deficiency (AADC-D)

We aimed to identify diseases similar in characteristics to AADC deficiency (AADC-d) that can provide proxy estimates for health-related quality of life (HRQoL) and long-term survival of AADC-d patients. These estimates will be used to support the economic model development for eladocagene exuparvovec. A literature search and clinician survey were conducted to identify proxy diseases for AADC-d. The literature was searched for observational studies, single arm clinical trials, randomized clinical trials, systematic reviews, case studies and case reports between January 2015 and January 2020 from clinicaltrials.gov and PubMed.gov. Studies among paediatric patients with motor associated neurological, genetic, or inherited conditions were included. Additionally, a survey was administered electronically to 25 clinicians globally to assess appropriateness of anoxic encephalopathy, paraplegia, tyrosine hydroxylase (TH) deficiency, guanosine triphosphate cyclohydrolase deficiency, sepiapterin reductase deficiency (SR), dopamine transporter deficiency syndrome as proxies. Appropriateness of disease proxy was determined based on similarity in disease characteristics, disease onset, natural history of disease progression, and data availability. Spinal muscular atrophy (SMA), Duchenne muscular dystrophy, metachromatic leukodystrophy, and cerebral palsy (CP) were identified in the literature search as suitable proxies. Survival and HRQoL data were available for SMA type I and CP since motor specific developmental milestones were measured as an endpoint in the related clinical trials. Survey results indicate TH deficiency and SR deficiency could be suitable proxies, but a lack of published data on survival and HRQoL limit their use for economic modeling in AADC-d. CP was preferred by clinicians as an appropriate proxy in AADC-d, in the absence of required data for other proxies. This study provides evidence to fill a gap in the literature for AADC-d patients’ outcomes. The available mortality and HRQoL data for the proxy diseases may be used to estimate the long-term outcomes for patients with AADC-d.

Lessons from 30 years of selective screening for tetrahydrobiopterin deficiency

In addition to being hyperphenylalaninemic, patients lacking tetrahydrobiopterin (BH4) are deficient in the neurotransmitters whose synthesis depends on the normal activity of tetrahydrobiopterin-dependent tyrosine and tryptophan hydroxylases. Consequently, these patients have to be rapidly recognized among hyperphenylalaninemic babies, since they need specific and early substitutive therapy. Since 1980, BH4 metabolism has been investigated in 2,186 hyperphenylalaninemic babies, using HPLC measurement of pteridines in urine to recognize tetrahydrobiopterin synthesis deficiency (GTP cyclohydrolase and PTPS deficiency) and direct DHPR assay in dried blood samples to recognize DHPR deficiency. A total of 73 tetrahydrobiopterin deficient patients have been detected. Considering the group of neonates born in France (1,342), out of the 32 BH4 deficient patients which have been detected, only 8 were from caucasian families. The lessons from that experience are: (1) tests on blood and urine collected on filter paper cards commend itself by their convenience and simplicity, and samples can be collected on the first visit of the screened infants to the out-patient clinic; and (2) the preconceaved idea that newborns with moderate elevation of blood phenylalanine are false positives of the screening or mild forms of hyperphenylalaninemia explains that a significant number of cases were investigated after 1month of age; however, in half of BH4-deficient babies, blood phenylalanine was below 10mg/dl (0.6mmol/l).

Uneventful Electroconvulsive Therapy in a Patient With Dopa-Responsive Dystonia (Segawa Syndrome)

The Segawa syndrome is an autosomal dominant form of guanosine triphosphate cyclohydrolase deficiency, resulting in decreased dopamine and serotonin levels, typically presenting as a dopa-responsive dystonia. Case presentation of a 56-year-old man with dopa-responsive dystonia, treated with electroconvulsive therapy for a psychotic depression. Scores on the Inventory of Depressive Symptomatology dropped from 35 before treatment to 3 after the eighth treatment session. Etomidate and succinylcholine were used as anesthetics. Apart from 2 sessions with postictal agitation, the course of electroconvulsive therapy was finished uneventfully. Electroconvulsive therapy and anesthesia had no untoward effects on motor function. Electroconvulsive therapy can be administered safely and effectively in a patient with dopa-responsive dystonia (Segawa syndrome).

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

Expanded motor and psychiatric phenotype in autosomal dominant Segawa syndrome due to GTP cyclohydrolase deficiency

Background: Segawa syndrome due to GTP cyclohydrolase deficiency is an autosomal dominant disorder with variable expression, that is clinically characterised by l-dopa responsive, diurnally fluctuating dystonia and parkinsonian symptoms. Objective:...

A new deletion in autosomal dominant guanosine triphosphate cyclohydrolase I deficiency gene – Segawa disease

Hereditary Progressive Dystonia with marked diurnal fluctuation (HPD) is an autosomally dominantly inherited dystonia which is characterized by marked diurnal fluctuation of symptoms and by marked and sustained response to levodopa associated with mutations in guanosine triphosphate cyclohydrolase (GCH-1) deficiency gene. We report an italian patient with a new 18 bp deletion at 267 in exon 1 in the GCH-1 gene. The peculiarity of our patient is the new mutations never reported and mnemonic disturbances that are also not reported in the classical HPD.A genotype-phenotype relationship may be suggested between different gene mutations and non classical clinical manifestations.

The hph-1 mouse: a model for dominantly inherited GTP-cyclohydrolase deficiency.

Dominantly inherited guanosine triphosphate (GTP)-cyclohydrolase deficiency, otherwise known as Segawa's disease or dopa-responsive dystonia, has a wide spectrum of phenotypic expression ranging from asymptomatic to very severe. Penetrance is more frequent in women as compared with men, and there is a variable occurrence of diurnal variation in symptom intensity. Biochemical characterization of the disease has demonstrated lower cerebrospinal fluid levels of tetrahydrobiopterin (BH4), neopterin, and homovanillic acid and low levels of tyrosine hydroxylase protein in the striatum. To investigate the pathophysiology, we have begun to characterize biogenic amine and BH4 metabolism in the GTP cyclohydrolase deficient hph-1 mouse. The data show low brain levels of BH4, catecholamines, serotonin, and their metabolites together with low levels of tyrosine hydroxylase protein within the striatum. The hph-1 mouse therefore provides a good model system in which to study the human disease.

Oral phenylalanine loading profiles in symptomatic and asymptomatic gene carriers with dopa-responsive dystonia due to dominantly inherited GTP cyclohydrolase deficiency.

Journal of Inherited Metabolic DiseaseVolume 22, Issue 3 p. 213-215 Article Oral phenylalanine loading profiles in symptomatic and asymptomatic gene carriers with dopa-responsive dystonia due to dominantly inherited GTP cyclohydrolase deficiency K. Hyland, Corresponding Author K. Hyland k.hyland@baylordallas.edu Institute of Metabolic Disease, Dallas, Texas, USA Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas, USAk.hyland@baylordallas.eduSearch for more papers by this authorT. G. Nygaard, T. G. Nygaard Department of Neurology, Columbia Presbyterian Medical Center, New York, USASearch for more papers by this authorJ. M. Trugman, J. M. Trugman Department of Neurology, University Virginia Health Sciences Center, Charlottesville, Virginia, USASearch for more papers by this authorK. J. Swoboda, K. J. Swoboda Division of Genetics, Children's Hospital and Harvard Medical School Boston, Massachusetts, USASearch for more papers by this authorL. A. Arnold, L. A. Arnold Institute of Metabolic Disease, Dallas, Texas, USASearch for more papers by this authorS. P. Sparagana, S. P. Sparagana Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas, USA Texas Scottish Rite Hospital for Children, Dallas, Texas, USASearch for more papers by this author K. Hyland, Corresponding Author K. Hyland k.hyland@baylordallas.edu Institute of Metabolic Disease, Dallas, Texas, USA Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas, USAk.hyland@baylordallas.eduSearch for more papers by this authorT. G. Nygaard, T. G. Nygaard Department of Neurology, Columbia Presbyterian Medical Center, New York, USASearch for more papers by this authorJ. M. Trugman, J. M. Trugman Department of Neurology, University Virginia Health Sciences Center, Charlottesville, Virginia, USASearch for more papers by this authorK. J. Swoboda, K. J. Swoboda Division of Genetics, Children's Hospital and Harvard Medical School Boston, Massachusetts, USASearch for more papers by this authorL. A. Arnold, L. A. Arnold Institute of Metabolic Disease, Dallas, Texas, USASearch for more papers by this authorS. P. Sparagana, S. P. Sparagana Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas, USA Texas Scottish Rite Hospital for Children, Dallas, Texas, USASearch for more papers by this author First published: 01 May 1999 https://doi.org/10.1023/A:1005532610051Citations: 17AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume22, Issue3May 1999Pages 213-215 RelatedInformation

Tetrahydrobiopterin deficiency and brain nitric oxide synthase in the hph1 mouse.

Tetrahydrobiopterin (BH4) is the cofactor for the aromatic amino acid monoxygenase group of enzymes and for all known isoforms of nitric oxide synthase (NOS). Inborn errors of BH4 metabolism lead to hyperphenylalaninaemia and impaired catecholamine and serotonin turnover. The effects of BH4 deficiency on brain nitric oxide (NO) metabolism are not known. In this study we have used the hph-1 mouse, which displays GTP cyclohydrolase deficiency, to study the effects of BH4 deficiency on brain NOS. In the presence of exogenous BH4, NOS specific activity was virtually identical in the control and hph-1 preparations. However, omission of BH4 from the reaction buffer led to a significant 20% loss of activity in the hph-1 preparations only. The Km for arginine was virtually identical for the control and hph-1 NOS when BH4 was present in the reaction buffer. In the absence of cofactor, the Km for arginine was 3-fold greater for control and 5-fold greater for hph-1 preparations. It is concluded that (a) BH4 does not regulate the intracellular concentration of brain NOS; (b) less binding of BH4 to NOS occurs in BH4 deficiency states; (c) BH4 has a potent effect on the affinity of NOS for arginine; and (d) the availability of arginine for NOS activity may become severely limiting in BH4 deficiency states. Since, in the presence of suboptimal concentrations of BH4 or arginine, NOS may additionally form oxygen free-radicals, it is postulated that in severe BH4 deficiency states NO formation is impaired and the central nervous system is subjected to increased oxidative stress.

Tetrahydrobiopterin biosynthesis defects examined in cytokine-stimulated fibroblasts.

Incubation of primary skin fibroblast cultures with the cytokines interferon-gamma and tumour necrosis factor-alpha stimulates the de novo pathway of tetrahydrobiopterin biosynthesis. Fibroblasts from patients with the two most common types of genetic defects of tetrahydrobiopterin metabolism that cause hyperphenylalaninaemia show characteristic pterin responses predicted by the nature of the defect. Cells from a child with 6-pyruvoyl-tetrahydropterin synthase deficiency produce higher than normal levels of neopterin and no biopterin. Fibroblasts from dihydropteridine reductase-deficient children produce normal levels of tetrahydrobiopterin, which gradually becomes partially oxidized, and higher than normal levels of neopterin. As a model for cells with the rarest form of tetrahydrobiopterin deficiency, lack of GTP cyclohydrolase activity, normal fibroblasts were treated with 2,4-diamino-6-hydroxypyrimidine to inhibit GTP cyclohydrolase activity by > 90%, the level expected in patients with a GTP cyclohydrolase deficiency. Neopterin and biopterin synthesis rates of < 10% of normal levels were readily detectable. Therefore, analysis of the patterns of the pterins synthesized by fibroblasts can aid in the diagnosis of the hyperphenylalaninaemias caused by disorders of tetrahydrobiopterin metabolism.

Pterins analysis in amniotic fluid for the prenatal diagnosis of GTP cyclohydrolase deficiency

Hyperphenylalaninaemia due to tetrahydrobiopterin deficiency is a group of rare and severe diseases. Prenatal diagnosis of dihydropteridine reductase and pyruvoyltetrahydropterin synthetase deficiencies can be achieved by enzyme assay in cultured fluid cells and/or fetal blood. In contrast, prenatal diagnosis of GTP cyclohydrolase deficiency can only rely on the measurement of pterin metabolites in the amniotic fluid. A pregnancy at risk for GTP cyclohydrolase deficiency was investigated. HPLC analysis of amniotic fluid pterins revealed neopterin and biopterin concentrations below the lowest limit of normal age-matched gestations. The mother refused abortion. The early follow-up of the child confirmed the diagnosis of GTP cyclohydrolase deficiency (hyperphenylalaninaemia, abnormal profile of urinary pterins and neurological deterioration).