Monoamine Neurotransmitter Disorders

Monoamine neurotransmitters: dopamine, serotonin, norepinephrine, epinephrine.

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)

5. Key Genes and Associated Disorders

6. CSF Monoamine Metabolite Patterns

• ↓ HVA: Suggests reduced dopamine turnover
• ↓ 5-HIAA: Suggests reduced serotonin turnover
• ↑ 3-Methoxytyramine: Indicative of cytosolic dopamine degradation (e.g., VMAT2 defect)
• ↓ HVA + ↓ 5-HIAA: Seen in combined synthesis defects
• Normal Phenylalanine: Indicates selective BH4 pathway defects (e.g., SR deficiency)
• ↑ Phenylalanine: Seen in PTPS or DHPR deficiency

Disorders

• Primary (genetic/metabolic defects affecting neurotransmitter synthesis, metabolism, transport, packaging)
• Secondary (due to other neurological, metabolic, or genetic disorders)
• Disorders of unknown origin

Primary Monoamine Neurotransmitter Disorders

1. Vitamin B6-Dependent Disorders (Essential cofactor for neurotransmitter metabolism)

• PNPO (Pyridox(am)ine 5'-phosphate oxidase) Deficiency: Neonatal seizures, encephalopathy; Responsive to pyridoxal phosphate supplementation
• Pyridoxine-Dependent Epilepsy: Seizures resistant to conventional antiepileptics; Dramatic response to pyridoxine (Vitamin B6)

2. Tetrahydrobiopterin (BH4) Deficiency Disorders

A. Normal Phenylalanine Levels

• Autosomal Dominant GTP Cyclohydrolase I (GTP-CH I) Deficiency: Dopa-responsive dystonia, diurnal fluctuation of dystonia, gait disturbances, normal phenylalanine, reduced CSF biopterin
• Sepiapterin Reductase (SR) Deficiency: Dystonia, hypotonia, motor delay; Normal phenylalanine, impaired serotonin and dopamine synthesis

B. Elevated Phenylalanine Levels

• Autosomal Recessive GTP-CH I Deficiency: Severe neurological impairment, elevated phenylalanine
• 6-Pyruvoyl-Tetrahydropterin Synthase (PTPS) Deficiency: Severe hyperphenylalaninemia, profound neurological dysfunction
• Dihydropteridine Reductase (DHPR) Deficiency: Severe neurological impairment, hyperphenylalaninemia

3. Monoamine Cofactor/Enzyme Deficiencies

• Tyrosine Hydroxylase (TH) Deficiency: Dopamine biosynthesis defect, movement disorders, developmental delay
• Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency: Hypotonia, oculogyric crises, autonomic dysfunction
• Dopamine β-Hydroxylase Deficiency: Severe autonomic dysfunction, orthostatic hypotension
• Monoamine Oxidase Deficiency: Rare, impaired neurotransmitter catabolism

4. Defective Transport/Reuptake Disorders

• Dopamine Transporter (DAT) Deficiency Syndrome: (infantile-onset parkinsonism-dystonia-1 (PKDYS1)
  Infantile parkinsonism-dystonia, progressive motor deterioration, high CSF dopamine metabolites
• Infantile-onset-parkinsonism-dystonia-2 (PKDYS2)

5. Defective Vesicle Formation/Packaging Disorders

• Brain Dopamine–Serotonin Vesicular Transport Disease (VMAT2 Deficiency): Profound developmental delay, hypotonia, dysautonomia, movement disorders; Severe monoamine depletion in CSF

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