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Neuropediatrics 2022; 53(03): 176-181
DOI: 10.1055/s-0042-1742323
Original Article

Psychiatric Manifestations in Patients with Biopterin Defects

Maksim Parfyonov 
1   Division of Pediatric Neurology, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
,
Robin Friedlander
2   Division of Child and Adolescent Psychiatry, Department of Psychiatry, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
,
Brian Banno
2   Division of Child and Adolescent Psychiatry, Department of Psychiatry, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
,
Dean Elbe
2   Division of Child and Adolescent Psychiatry, Department of Psychiatry, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
3   Child & Adolescent Mental Health, Healthy Minds Centre, BC Children's Hospital, Vancouver, British Columbia, Canada
4   Department of Pharmacy, Children's and Women's Health Centre of British Columbia, Vancouver, British Columbia, Canada
,
Gabriella Horvath 
5   Division of Biochemical Genetics, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
6   Adult Metabolic Diseases Clinic, Vancouver General Hospital, Vancouver, British Columbia, Canada
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Abstract

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.

Keywords

inherited neurotransmitter disorders - tetrahydrobiopterin - levodopa/carbidopa

Note

Previously presented at the Annual Symposium of the Society for the Study of Inborn Errors of Metabolism (SSIEM). Rotterdam, Netherlands. September 3-4, 2019.




Publication History

Received: 18 July 2021

Accepted: 11 December 2021

Article published online:
28 January 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Longo N. Disorders of biopterin metabolism. J Inherit Metab Dis 2009; 32 (03) 333-342
    CrossrefPubMedGoogle Scholar
  • 2 Kurian MA, Gissen P, Smith M, Heales Jr S, Clayton PT. The monoamine neurotransmitter disorders: an expanding range of neurological syndromes. Lancet Neurol 2011; 10 (08) 721-733
    CrossrefPubMedGoogle Scholar
  • 3 Ng J, Papandreou A, Heales SJ, Kurian MA. Monoamine neurotransmitter disorders–clinical advances and future perspectives. Nat Rev Neurol 2015; 11 (10) 567-584
    CrossrefPubMedGoogle Scholar
  • 4 Pan L, McKain BW, Madan-Khetarpal S. et al. GTP-cyclohydrolase deficiency responsive to sapropterin and 5-HTP supplementation: relief of treatment-refractory depression and suicidal behaviour. BMJ Case Rep 2011; 2011: bcr0320113927
    PubMedGoogle Scholar
  • 5 Van Hove JL, Steyaert J, Matthijs G. et al. Expanded motor and psychiatric phenotype in autosomal dominant Segawa syndrome due to GTP cyclohydrolase deficiency. J Neurol Neurosurg Psychiatry 2006; 77 (01) 18-23
    CrossrefPubMedGoogle Scholar
  • 6 Latorre A, Salgado P, Salari M, Jesuthasan A, Bhatia KP. Combined dystonia with self-mutilation in 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency: a case report. Mov Disord Clin Pract (Hoboken) 2018; 6 (01) 81-82
    CrossrefPubMedGoogle Scholar
  • 7 Roze E, Vidailhet M, Blau N. et al. Long-term follow-up and adult outcome of 6-pyruvoyl-tetrahydropterin synthase deficiency. Mov Disord 2006; 21 (02) 263-266
    CrossrefPubMedGoogle Scholar
  • 8 Wang L, Yu W-M, He C. et al. Long-term outcome and neuroradiological findings of 31 patients with 6-pyruvoyltetrahydropterin synthase deficiency. J Inherit Metab Dis 2006; 29 (01) 127-134
    CrossrefPubMedGoogle Scholar
  • 9 Leuzzi V, Carducci CA, Carducci CL. et al. Phenotypic variability, neurological outcome and genetics background of 6-pyruvoyl-tetrahydropterin synthase deficiency. Clin Genet 2010; 77 (03) 249-257
    CrossrefPubMedGoogle Scholar
  • 10 Derwińska K, Mierzewska H, Goszczańska A. et al. Clinical improvement of the aggressive neurobehavioral phenotype in a patient with a deletion of PITX3 and the absence of L-DOPA in the cerebrospinal fluid. Am J Med Genet B Neuropsychiatr Genet 2012; 159B (02) 236-242
    CrossrefPubMedGoogle Scholar
  • 11 Horvath GA, Tarailo-Graovac M, Bartel T. et al. Improvement of self-injury with dopamine and serotonin replacement therapy in a patient with a hemizygous PAK3 mutation: a new therapeutic strategy for neuropsychiatric features of an intellectual disability syndrome. J Child Neurol 2018; 33 (01) 106-113
    CrossrefPubMedGoogle Scholar
  • 12 Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry 1965; 122 (05) 509-522
    CrossrefPubMedGoogle Scholar
  • 13 Asberg M. Neurotransmitters and suicidal behavior. The evidence from cerebrospinal fluid studies. Ann N Y Acad Sci 1997; 836: 158-181
    CrossrefPubMedGoogle Scholar
  • 14 van Erp AMM, Miczek KA. Aggressive behavior, increased accumbal dopamine, and decreased cortical serotonin in rats. J Neurosci 2000; 20 (24) 9320-9325
    CrossrefPubMedGoogle Scholar
  • 15 Moore TM, Scarpa A, Raine A. A meta-analysis of serotonin metabolite 5-HIAA and antisocial behavior. Aggress Behav 2002; 28 (04) 299-316
    CrossrefPubMedGoogle Scholar
  • 16 Seo D, Patrick CJ, Kennealy PJ. Role of serotonin and dopamine system interactions in the neurobiology of impulsive aggression and its comorbidity with other clinical disorders. Aggress Violent Behav 2008; 13 (05) 383-395
    CrossrefPubMedGoogle Scholar
  • 17 Mauri MC, Paletta S, Maffini M. et al. Clinical pharmacology of atypical antipsychotics: an update. EXCLI J 2014; 13: 1163-1191
    PubMedGoogle Scholar
  • 18 Swann AC. Neuroreceptor mechanisms of aggression and its treatment. J Clin Psychiatry 2003; 64 (Suppl. 04) 26-35
    PubMedGoogle Scholar
  • 19 Comai S, Tau M, Pavlovic Z, Gobbi G. The psychopharmacology of aggressive behavior: a translational approach: part 2: clinical studies using atypical antipsychotics, anticonvulsants, and lithium. J Clin Psychopharmacol 2012; 32 (02) 237-260
    CrossrefPubMedGoogle Scholar
  • 20 Tripp G, Wickens JR. Neurobiology of ADHD. Neuropharmacology 2009; 57 (7-8): 579-589
    CrossrefPubMedGoogle Scholar
  • 21 Dela Peña I, Gevorkiana R, Shi W-X. Psychostimulants affect dopamine transmission through both dopamine transporter-dependent and independent mechanisms. Eur J Pharmacol 2015; 764: 562-570
    CrossrefPubMedGoogle Scholar
  • 22 Kvernmo T, Härtter S, Burger E. A review of the receptor-binding and pharmacokinetic properties of dopamine agonists. Clin Ther 2006; 28 (08) 1065-1078
    CrossrefPubMedGoogle Scholar
  • 23 Andersohn F, Garbe E. Cardiac and noncardiac fibrotic reactions caused by ergot-and nonergot-derived dopamine agonists. Mov Disord 2009; 24 (01) 129-133
    CrossrefPubMedGoogle Scholar
  • 24 Kurlan R, Crespi G, Coffey B, Mueller-Vahl K, Koval S, Wunderlich G. Pramipexole for TS Trial Investigators. A multicenter randomized placebo-controlled clinical trial of pramipexole for Tourette's syndrome. Mov Disord 2012; 27 (06) 775-778
    CrossrefPubMedGoogle Scholar
  • 25 Newcorn JH, Schulz K, Harrison M, DeBellis MD, Udarbe JK, Halperin JM. Alpha 2 adrenergic agonists. Neurochemistry, efficacy, and clinical guidelines for use in children. Pediatr Clin North Am 1998; 45 (05) 1099-22 , viii -viii
    PubMedGoogle Scholar
  • 26 Opladen T, López-Laso E, Cortès-Saladelafont E. et al; International Working Group on Neurotransmitter related Disorders (iNTD). Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies. Orphanet J Rare Dis 2020; 15 (01) 126
    CrossrefPubMedGoogle Scholar