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Journal of Pediatric Neurology
DOI: 10.1055/s-0043-1778116
Original Article

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

Shyann Hang
1   Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
,
Chitra Prasad
1   Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
2   Genetics Metabolics Program of Southwestern Ontario, Department of Pediatrics, London Health Sciences Centre, London, Ontario, Canada
,
C. Anthony Rupar
1   Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
2   Genetics Metabolics Program of Southwestern Ontario, Department of Pediatrics, London Health Sciences Centre, London, Ontario, Canada
3   Department of Pathology and Laboratory Medicine, London, Ontario, Canada
,
Richa Agnihotri
4   Department of Medicine, McMaster University, London, Ontario, Canada
,
Asuri N. Prasad 
1   Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
5   Division of Pediatric Neurosciences, Department of Pediatrics, London Health Sciences Centre, London, Ontario, Canada
› Author Affiliations Funding The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: this work was supported by the Schulich School of Medicine and Dentistry's Summer Research Opportunities Program, the award was granted to Shyann Hang.
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Abstract

Primary 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.

Keywords

neurotransmitter disorders - PTPS deficiency - PDE - SSADH deficiency - AADC deficiency - cerebral palsy

Electronic Databases Accessed

https://www.ncbi.nlm.nih.gov/books/NBK1116/


https://www.omim.org/


Authors' Contribution

S.H. collected the data, wrote, and provided revision to the manuscript. A.N.P. and C.P. prepared the concept of the manuscript. C.P., A.N.P., C.A.R., and R.A. provided key edits and additions to the results and discussion. All authors approved the final manuscript.




Publication History

Received: 04 July 2023

Accepted: 02 December 2023

Article published online:
16 January 2024

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  • References

  • 1 Brennenstuhl H, Jung-Klawitter S, Assmann B, Opladen T. Inherited disorders of neurotransmitters: classification and practical approaches for diagnosis and treatment. Neuropediatrics 2019; 50 (01) 2-14
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 Stockler S, Plecko B, Gospe Jr SM. et al. Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up. Mol Genet Metab 2011; 104 (1-2): 48-60
    CrossrefPubMedGoogle Scholar
  • 3 Didiášová M, Banning A, Brennenstuhl H. et al. Succinic semialdehyde dehydrogenase deficiency: an update. Cells 2020; 9 (02) 477
    CrossrefPubMedGoogle Scholar
  • 4 Pearson TS, Gilbert L, Opladen T. et al. AADC deficiency from infancy to adulthood: symptoms and developmental outcome in an international cohort of 63 patients. J Inherit Metab Dis 2020; 43 (05) 1121-1130
    CrossrefPubMedGoogle Scholar
  • 5 Himmelreich N, Montioli R, Bertoldi M. et al. Aromatic amino acid decarboxylase deficiency: molecular and metabolic basis and therapeutic outlook. Mol Genet Metab 2019; 127 (01) 12-22
    CrossrefPubMedGoogle Scholar
  • 6 Thöny B, Auerbach G, Blau N. Tetrahydrobiopterin biosynthesis, regeneration and functions. Biochem J 2000; 347 (Pt 1): 1-16
    CrossrefPubMedGoogle Scholar
  • 7 Opladen T, Hoffmann GF, Blau N. An international survey of patients with tetrahydrobiopterin deficiencies presenting with hyperphenylalaninaemia. J Inherit Metab Dis 2012; 35 (06) 963-973
    CrossrefPubMedGoogle Scholar
  • 8 Blau N, Barnes I, Dhondt JL. International database of tetrahydrobiopterin deficiencies. J Inherit Metab Dis 1996; 19 (01) 8-14
    CrossrefPubMedGoogle Scholar
  • 9 Coughlin II CR, van Karnebeek CDM, Al-Hertani W. et al. Triple therapy with pyridoxine, arginine supplementation and dietary lysine restriction in pyridoxine-dependent epilepsy: neurodevelopmental outcome. Mol Genet Metab 2015; 116 (1-2): 35-43
    CrossrefPubMedGoogle Scholar
  • 10 Gannavarapu S, Prasad M, Prasad C. Inborn errors of metabolism in newcomer and refugee populations in Ontario, CA. Univ West Ont Med J 2019; 88 (01) 22-24
    PubMedGoogle Scholar
  • 11 Wang L, Yu WM, 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
  • 12 Jäggi L, Zurflüh MR, Schuler A. et al. Outcome and long-term follow-up of 36 patients with tetrahydrobiopterin deficiency. Mol Genet Metab 2008; 93 (03) 295-305
    CrossrefPubMedGoogle Scholar
  • 13 Pearl PL, Novomy EJ, Acosta MT, Jakobs C, Gibson KM. Succinic semialdehyde dehydrogenase deficiency in children and adults. Ann Neurol 2003; 54 (Suppl. 06) S73-S80
    CrossrefPubMedGoogle Scholar
  • 14 Gibson KM, Gupta M, Pearl PL. et al. Significant behavioral disturbances in succinic semialdehyde dehydrogenase (SSADH) deficiency (gamma-hydroxybutyric aciduria). Biol Psychiatry 2003; 54 (07) 763-768
    CrossrefPubMedGoogle Scholar
  • 15 DiBacco ML, Pop A, Salomons GS. et al. Novel ALDH5A1 variants and genotype: phenotype correlation in SSADH deficiency. Neurology 2020; 95 (19) e2675-e2682
    CrossrefPubMedGoogle Scholar
  • 16 Lee HF, Tsai CR, Chi CS, Chang TM, Lee HJ. Aromatic L-amino acid decarboxylase deficiency in Taiwan. Eur J Paediatr Neurol 2009; 13 (02) 135-140
    CrossrefPubMedGoogle Scholar
  • 17 van Karnebeek CDM, Tiebout SA, Niermeijer J. et al. Pyridoxine-dependent epilepsy: an expanding clinical spectrum. Pediatr Neurol 2016; 59: 6-12
    CrossrefPubMedGoogle Scholar
  • 18 Al Teneiji A, Bruun TUJ, Cordeiro D. et al. Phenotype, biochemical features, genotype and treatment outcome of pyridoxine-dependent epilepsy. Metab Brain Dis 2017; 32 (02) 443-451
    CrossrefPubMedGoogle Scholar
  • 19 Mills PB, Struys E, Jakobs C. et al. Mutations in antiquitin in individuals with pyridoxine-dependent seizures. Nat Med 2006; 12 (03) 307-309
    CrossrefPubMedGoogle Scholar
  • 20 Gallagher RC, Van Hove JLK, Scharer G. et al. Folinic acid-responsive seizures are identical to pyridoxine-dependent epilepsy. Ann Neurol 2009; 65 (05) 550-556
    CrossrefPubMedGoogle Scholar
  • 21 Coughlin II CR, Tseng LA, Bok LA. et al; International PDE Consortium. Association between lysine reduction therapies and cognitive outcomes in patients with pyridoxine-dependent epilepsy. Neurology 2022; 99 (23) e2627-e2636
    PubMedGoogle Scholar
  • 22 Pearl PL, DiBacco ML, Papadelis C. et al. Succinic semialdehyde dehydrogenase deficiency: review of the natural history study. J Child Neurol 2021; 36 (13-14): 1153-1161
    CrossrefPubMedGoogle Scholar
  • 23 Vogel KR, Ainslie GR, McConnell A, Roullet JB, Gibson KM. Toxicologic/transport properties of NCS-382, a γ-hydroxybutyrate (GHB) receptor ligand, in neuronal and epithelial cells: therapeutic implications for SSADH deficiency, a GABA metabolic disorder. Toxicol In Vitro 2018; 46: 203-212
    CrossrefPubMedGoogle Scholar
  • 24 Nylen K, Velazquez JLP, Likhodii SS. et al. A ketogenic diet rescues the murine succinic semialdehyde dehydrogenase deficient phenotype. Exp Neurol 2008; 210 (02) 449-457
    CrossrefPubMedGoogle Scholar
  • 25 Pearl PL, Schreiber J, Theodore WH. et al. Taurine trial in succinic semialdehyde dehydrogenase deficiency and elevated CNS GABA. Neurology 2014; 82 (11) 940-944
    CrossrefPubMedGoogle Scholar
  • 26 Gupta M, Jansen EEW, Senephansiri H. et al. Liver-directed adenoviral gene transfer in murine succinate semialdehyde dehydrogenase deficiency. Mol Ther 2004; 9 (04) 527-539
    CrossrefPubMedGoogle Scholar
  • 27 Hwu WL, Muramatsu S, Tseng SH. et al. Gene therapy for aromatic L-amino acid decarboxylase deficiency. Sci Transl Med 2012; 4 (134) 134ra61
    PubMedGoogle Scholar
  • 28 Opladen T, Brennenstuhl H, Kuseyri Hübschmann O. et al Die intrazerebrale Gentherapie des Aromatischen-L-Aminosäure-Decarboxylase-Mangels mit Eladocagene exuparvovec: Eine Stellungnahme der Gesellschaft für Neuropädiatrie (GNP), der Arbeitsgemeinschaft pädiatrischer Stoffwechselstörungen (APS), der Deutschen Gesellschaft für Neurochirurgie (DGNC) und der Deutschen Gesellschaft für Kinder-und Jugendmedizin (DGKJ). Monatsschrift Kinderheilkunde 2021; 169 (08) 738-747
    CrossrefPubMedGoogle Scholar
  • 29 Roubertie A, Opladen T, Brennenstuhl H. et al Gene therapy for aromatic L-amino acid decarboxylase deficiency: Requirements for safe application and knowledge-generating follow-up. J Inherit Metab Dis 2023; Jul 4. DOI: 10.1002/jimd.12649.
    CrossrefPubMedGoogle Scholar
  • 30 Wassenberg T, Molero-Luis M, Jeltsch K. et al. Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency. Orphanet J Rare Dis 2017; 12 (01) 12
    CrossrefPubMedGoogle Scholar