Index

Monoamines

  • Subgroup of biogenic amines.
  • Contain one amino group connected to an aromatic ring via a two-carbon chain.
  • Divided into:
    • Catecholamines: Dopamine, Norepinephrine, Epinephrine
    • Indoleamines: Serotonin, Melatonin
    • Imidazolamines: Histamine
  • They primarily function as neurotransmitters involved in:
    • Synaptic transmission between neurons
    • Modulation of brain functions such as movement, behavior, excitation, inhibition, memory, temperature regulation, and pain threshold
  • Inherited neurotransmitter disorders may involve:
    • Defects in biosynthesis pathways
    • Defects in catabolism or degradation
    • Deficiencies or dysfunctions in neurotransmitter transporters

Clinical Relevance and Diagnosis

  • Monoamine Neurotransmitter disorders often present in infancy or early childhood
  • Clinical features are diverse and may resemble other neurological conditions
  • Early diagnosis and treatment are critical for optimal motor and cognitive outcomes
  • Diagnosis is based on:
    • Quantitative analysis of neurotransmitters and their metabolites in cerebrospinal fluid (CSF)
    • Analysis of pterin metabolites to differentiate BH4 metabolism disorders
    • Confirmation through molecular genetic testing

Monoamine Neurotransmitter Pathway 

1. Dopamine and Serotonin Synthesis

  • Tyrosine → DOPA via Tyrosine Hydroxylase (TH)
  • DOPA → Dopamine via Aromatic L-Amino Acid Decarboxylase (AADC)
  • Tryptophan → 5-Hydroxytryptophan via Tryptophan Hydroxylase (TPH)
  • 5-Hydroxytryptophan → Serotonin (5-HT) via AADC

2. Synaptic Processing

  • VMAT2 (SLC18A2): Packages dopamine/serotonin into vesicles for release
  • Synaptic Release via exocytosis into the synaptic cleft
  • Receptor Binding: Dopamine binds to D1/D2 receptors; serotonin to 5-HT receptors
  • Reuptake Transporters:
    • SLC6A3 (DAT) for dopamine
    • SLC6A2 (NET) for norepinephrine
    • SLC6A4 (SERT) for serotonin

3. Dopamine to Norepinephrine and Epinephrine

  • Dopamine → Norepinephrine via Dopamine β-Hydroxylase
  • Norepinephrine → Epinephrine via PNMT (Phenylethanolamine N-Methyltransferase)

4. Degradation Pathways

  • Monoamine Oxidase (MAO-A/B) and Catechol-O-Methyl Transferase (COMT) are key enzymes
  • Metabolite Pathways:
    • Dopamine → DOPAC → HVA (Homovanillic Acid)
    • Norepinephrine → Normetanephrine → MHPG
    • Serotonin → 5-HIAA (5-Hydroxyindoleacetic Acid)

Monoamine Neurotransmitter Disorders

Primary Monoamine Neurotransmitter Disorders

  • Disorders of Phenylalanine and Tetrahydrobiopterin (BH4) Metabolism
    • BH4 disorders without HPA
      • Autosomal Dominant GTP cyclohydrolase I deficiency (AD-GTPCHD)
      • Sepiapterin reductase deficiency (SRD)
    • Hyperphenylalaninemia (HPA)
      • Autosomal recessive GTP cyclohydrolase I deficiency (AR-GTPCHD)
      • 6-pyruvoyltetrahydropterin synthase deficiency (PTPSD)
      • Dihydropteridine reductase deficiency (DHPRD)
      • Pterin-4-alpha-carbinolamine dehydratase deficiency (PCDD)
  • Disorders of Folate Metabolism and Transport
    • Inherited Disorders of Folate Metabolism
      • Hereditary folate malabsorption
      • Folate receptor alpha (FRα) deficiency
      • Methylenetetrahydrofolate reductase (MTHFR) deficiency
      • Methenyltetrahydrofolate synthetase deficiency
      • Dihydrofolate reductase deficiency
      • Methylenetetrahydrofolate dehydrogenase deficiency
    • Cerebral Folate Deficiency (CFD) 
  • Glycine disorders
    • Primary (NKH)
    • Secondary
      • Disorders affecting pyridoxal-phosphate (e.g., PNPO deficiency) can cause secondary NKH
      • Disorders in protein lipoylation result in variant forms of NKH
  • Serine disorders
    • 3-Phosphoglycerate Dehydrogenase Deficiency (PHGDH)
    • Phosphoserine Aminotransferase Deficiency (PSAT1)
    • Phosphoserine Phosphatase Deficiency (PSPH)
  • Gamma-Aminobutyric Acid (GABA) Disorders
    • GABA Transaminase deficiency
    • Succinic Semialdehyde Dehydrogenase (SSADH) Deficiency
  • Co-Chaperone Deficiencies
  • Monoamine Cofactor/Enzyme Deficiencies
    • Tyrosine Hydroxylase (TH) Deficiency
    • Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency
    • Dopamine β-Hydroxylase Deficiency
    • Monoamine oxidase A (MAO-A) deficiency
  • Vitamin B6-Dependent Disorders (Essential cofactor for neurotransmitter metabolism)
    • PNPO (Pyridox(am)ine 5'-phosphate oxidase) Deficiency
    • Pyridoxine-Dependent Epilepsy 
  • Defective Transport/Reuptake Disorders
    • Infantile-onset parkinsonism-dystonia-1 (PKDYS1)
    • Infantile-onset-parkinsonism-dystonia-2 (PKDYS2)
    • Brain Dopamine–Serotonin Vesicular Transport Disease (VMAT2 Deficiency)
    • Dopamine Transporter (DAT) Deficiency Syndrome
    • Defective Vesicle Formation/Packaging Disorders

Secondary Monoamine Neurotransmitter Defects in Other Disorders

  • Aicardi-Goutières Syndrome
  • Autistic Spectrum Disorders
  • Cerebral Palsy
  • Dystonic Disorders
  • Epileptic Encephalopathies
  • Folate Metabolism Disorders
  • Leukodystrophies
  • Lesch–Nyhan Syndrome
  • Mitochondrial Disorders
  • Neuropsychiatric Disorders
  • Opsoclonus–Myoclonus Syndrome
  • Pelizaeus–Merzbacher Disease
  • Phenylketonuria (PKU)
  • Pantothenate Kinase-Associated Neurodegeneration (PKAN)
  • Perinatal Asphyxia/Hypoxic Ischaemic Encephalopathy (HIE)
  • Pontocerebellar Hypoplasia
  • Rett Syndrome
  • Spontaneous Periodic Hypothermia and Hyperhydrosis

Disorders of Unknown Origin

  • Idiopathic Focal Dystonia: Unclear pathophysiology; neurotransmitter imbalance suspected
  • Disorders of Selective Serotonin Deficiency: Possible genetic or acquired serotonergic pathway disruption
  • Dopa-Nonresponsive Dystonia: Dystonia not improved by dopamine precursors; unknown cause
  • Paroxysmal Kinesigenic Dyskinesia: Episodic movement disorder with suspected dopamine dysregulation, etiology unknown

Primary Monoamine Neurotransmitter Disorders
Disorders of Phenylalanine and Tetrahydrobiopterin (BH4) Metabolism BH4 Disorders without Hyperphenylalaninemia (HPA) Autosomal Dominant GTP cyclohydrolase I deficiency (AD-GTPCHD); Sepiapterin reductase deficiency (SRD)
BH4 Disorders with HPA Autosomal recessive GTP cyclohydrolase I deficiency (AR-GTPCHD); 6-pyruvoyltetrahydropterin synthase deficiency (PTPSD); Dihydropteridine reductase deficiency (DHPRD); Pterin-4-alpha-carbinolamine dehydratase deficiency (PCDD)
Disorders of Folate Metabolism and Transport Inherited Disorders of Folate Metabolism Hereditary folate malabsorption; Folate receptor alpha deficiency (FRα deficiency); Methylenetetrahydrofolate reductase deficiency; Methenyltetrahydrofolate synthetase deficiency (MTHFR deficiency); Dihydrofolate reductase deficiency; Methylenetetrahydrofolate dehydrogenase deficiency
Cerebral Folate Deficiency (CFD)  
Glycine Disorders Primary Nonketotic Hyperglycinemia (NKH)
Secondary Pyridoxal-phosphate–related disorders e.g., PNPO deficiency; Lipoylation defects
Serine Disorders 3-Phosphoglycerate Dehydrogenase Deficiency (PHGDH); Phosphoserine Aminotransferase Deficiency (PSAT1); Phosphoserine Phosphatase Deficiency (PSPH)
Gamma-Aminobutyric Acid (GABA) Disorders GABA Transaminase deficiency; Succinic Semialdehyde Dehydrogenase Deficiency (SSADH deficiency)
Co-Chaperone Deficiencies  
Monoamine Cofactor/Enzyme Deficiencies Tyrosine Hydroxylase Deficiency (TH deficiency); Aromatic L-Amino Acid Decarboxylase Deficiency (AADC deficiency); Dopamine β-Hydroxylase Deficiency; Monoamine oxidase A deficiency (MAO-A deficiency)
Vitamin B6-Dependent Disorders Pyridox(am)ine 5'-phosphate oxidase deficiency; Pyridoxine-Dependent Epilepsy (PNPO deficiency)
Defective Transport/Reuptake Disorders Infantile-onset parkinsonism-dystonia-1 (PKDYS1); Infantile-onset parkinsonism-dystonia-2 (PKDYS2); Brain Dopamine–Serotonin Vesicular Transport Disease (VMAT2 deficiency)  
Dopamine Transporter Deficiency Syndrome (DAT deficiency)  
Defective Vesicle Formation/Packaging Disorders