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Approaches for diagnosis and treatment in neurotransmitter disorders of childhood

Abstract

Neurotransmitter disorders are a group of neurometabolic syndromes caused by disturbances of neurotransmitter metabolism. The primary aim of this retrospective study is to present patients with disturbances of monoamine neurotransmitter metabolism. Cerebrospinal fluid (CSF) neurotransmitter measurements and genetic analysis were performed on five patients. Five patients who had various movement disorders and motor and cognitive disabilities were included. Four patients were diagnosed with sepiapterin reductase (SR) deficiency, and one was diagnosed with aromatic L-amino acid decarboxylase (AADC) deficiency. Different treatment responses appeared in patients with SR and AADC deficiency. The responses to drug treatment ranged from good to weak in our patients. The diagnosis process is challenging in patients with SR and AADC deficiency, which present similar clinical features to other neurological and metabolic diseases. Investigations of neurotransmitters in CSF and analysis of related genes are essential to differentiate disturbances of monoamine neurotransmitter metabolism from other neurometabolic diseases. For patients with monoamine neurotransmitter disorders, drugs that target these disturbances should be combined as necessary to produce the appropriate response.

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All data generated or analysed during this study are included in this published article (and its supplementary information files).

References

  1. Assmann B, Surtees R, Hoffmann GF (2003) Approach to the diagnosis of neurotransmitter diseases exemplified by the differential diagnosis of childhood-onset dystonia. Ann Neurol 54(Suppl 6):S18–S24

    CAS  Article  Google Scholar 

  2. Brennenstuhl H, Jung-Klawitter S, Assmann B, Opladen T (2019) Inherited disorders of neurotransmitters: classification and practical approaches for diagnosis and treatment. Neuropediatrics 50(1):2–14

    CAS  Article  Google Scholar 

  3. Brennenstuhl H et al (2020) High throughput newborn screening for aromatic ʟ-amino-acid decarboxylase deficiency by analysis of concentrations of 3-O-methyldopa from dried blood spots. J Inherit Metab Dis 43(3):602–610

    CAS  Article  Google Scholar 

  4. Hyland K (2003) The lumbar puncture for diagnosis of pediatric neurotransmitter diseases. Ann Neurol 54(Suppl 6):S13–S17

    CAS  Article  Google Scholar 

  5. Friedman J et al (2012) Sepiapterin reductase deficiency: a treatable mimic of cerebral palsy. Ann Neurol 71(4):520–530

    CAS  Article  Google Scholar 

  6. Kurian MA, Gissen P, Smith M, Heales S Jr, Clayton PT (2011) The monoamine neurotransmitter disorders: an expanding range of neurological syndromes. Lancet Neurol 10(8):721–733

    CAS  Article  Google Scholar 

  7. Kuseyri Hübschmann O et al (2021) Brain MR patterns in inherited disorders of monoamine neurotransmitters: an analysis of 70 patients. J Inherit Metab Dis 44(4):1070–1082

    Article  Google Scholar 

  8. Manegold C, Hoffmann GF, Degen I, Ikonomidou H, Knust A, Laass MW, Pritsch M, Wilichowski E, Hörster F (2009) Aromatic L-amino acid decarboxylase deficiency: clinical features, drug therapy and follow-up. J Inherit Metab Dis 32:371–380

    CAS  Article  Google Scholar 

  9. Opladen T, Hoffmann GF, Blau N (2012) An international survey of patients with tetrahydrobiopterin deficiencies presenting with hyperphenylalaninaemia. J Inherit Metab Dis 35(6):963–973

    CAS  Article  Google Scholar 

  10. Opladen T, López-Laso E, Cortès-Saladelafont E et al (2020) Consensus guideline for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies. Orphanet J Rare Dis 15:126. https://doi.org/10.1186/s13023-020-01379-8

    Article  PubMed  PubMed Central  Google Scholar 

  11. Pearl PL, Taylor JL, Trzcinski S, Sokohl A (2007) The pediatric neurotransmitter disorders. J Child Neurol 22(5):606–616

    Article  Google Scholar 

  12. Pearson TS et al (2020) AADC deficiency from infancy to adulthood: symptoms and developmental outcome in an international cohort of 63 patients. J Inherit Metab Dis 43(5):1121–1130

    CAS  Article  Google Scholar 

  13. Pearson TS et al (2021) Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons. Nat Commun 12(1):4251

    CAS  Article  Google Scholar 

  14. Rodan LH et al (2015) Clinical use of CSF neurotransmitters. Pediatr Neurol 53(4):277–286

    Article  Google Scholar 

  15. Saini AG, Sharma S (2020) Movement disorders in inherited metabolic diseases in children. Ann Indian Acad Neurol 23(3):332–337

    PubMed  PubMed Central  Google Scholar 

  16. Swoboda KJ, Walker MA (2018) Neurotransmitter-related disorders. Swaiman's pediatric neurology. Swaiman K.F.: 886–896.

  17. Wassenberg T et al (2017) Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency. Orphanet J Rare Dis 12(1):12

    Article  Google Scholar 

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Acknowledgements

The author would like to thank all our patients and their parents for teaching us about the diseases. Also, we thank Dr. Özkurt for his help in the laboratory.

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CH and SD wrote the manuscript. All authors contributed to the diagnosis, treatment and follow-up of patients and read and approved the final manuscript.

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Correspondence to Cengiz Havalı.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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No potential conflict of interest, this research was no partially or fully sponsored by any financial assistance.

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Supplementary Information

Pretreatment and posttreatment video recording of patient 1 (MP4 3081 kb)

Pretreatment and posttreatment video recording of patient 1 (MP4 1069 kb)

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Havalı, C., Dorum, S., Ekici, A. et al. Approaches for diagnosis and treatment in neurotransmitter disorders of childhood. Metab Brain Dis (2021). https://doi.org/10.1007/s11011-021-00838-w

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Keywords

  • Inherited neurotransmitter disorders
  • Sepiapterin reductase
  • AADC deficiency movement disorders
  • Monoamine metabolism