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)
- BH4 disorders without HPA
- 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)
- Inherited Disorders of Folate Metabolism
- 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 |