Investigations and Management of Rare Treatable Neurological Disorders

1. AR-GCH1 Deficiency Without Hyperphenylalaninaemia

• Presentation: Resembles cerebral palsy, oculogyric crises, tremulousness, bradykinesia.
• Key Investigations:
  • Phenylalanine loading test: Elevated blood spot phenylalanine and phenylalanine/tyrosine ratio.
  • CSF pterins low; monoamine neurotransmitters may be normal.
  • Definitive: Peripheral blood mononuclear or fibroblast GTP cyclohydrolase enzyme assay or mutation analysis.
• Treatment: BH4 (tetrahydrobiopterin), levodopa, 5-hydroxytryptophan, folinic acid.

2. ACTH Unresponsiveness

• Presentation: Recurrent encephalopathy, hypoglycemia, epilepsy, subtle joint hyperpigmentation.
• Key Investigations: ↓ Glucose, ↓ Cortisol, ↑ ACTH.
• Treatment: Cortisol replacement therapy.

3. Biotinidase Deficiency

• Presentation: Epilepsy, developmental delay, neurological deficits, mimics Leigh syndrome ± alopecia, rash.
• Key Investigations:
  • Brain/spinal cord MRI, urine organic acids.
  • Blood lactate, biotinidase activity assay.
• Treatment: Biotin.

4. Biotin-Responsive Basal Ganglia Disease

• Presentation: Rapid motor skill loss, quadriparesis, seizures, akinetic mutism.
• Key Investigations:
  • Brain MRI: Caudate and putamen necrosis.
  • Mutation in SLC19A3 gene.
• Treatment: Biotin (5–10 mg/kg/day).

5. Cerebrotendinous Xanthomatosis

• Presentation: Central and peripheral degeneration, juvenile cataracts.
• Key Investigations: Plasma cholestanol ↑.
• Treatment: Chenodeoxycholic acid.

6. Cobalamin (Vitamin B12) Disorders

• Presentation: Infantile epilepsy, developmental delay, hypotonia, myelopathy, neuropathy.
• Key Investigations:
  • Spinal cord MRI (posterior column changes).
  • Plasma homocysteine, urine methylmalonic acid.
• Treatment: Hydroxycobalamin.

7. DEND Syndrome (Delay, Epilepsy, Neonatal Diabetes)

• Presentation: Neonatal diabetes, developmental delay, epileptic spasms.
• Key Investigations: KCNJ11 mutation analysis.
• Treatment: Sulphonylureas (e.g., tolbutamide).

8. Dopa-Responsive Dystonia (Segawa Disease)

• Presentation: Dystonia in early childhood.
• Key Investigations: Levodopa trial, CSF pterins, and monoamine neurotransmitters.
• Treatment: Levodopa/carbidopa.

9. Folate Deficiency (Cerebral Folate Deficiency)

• Presentation: Developmental delays, autism spectrum features.
• Key Investigations: CSF 5-MTHF low; serum folate normal.
• Treatment: Folinic acid.

10. Glucose Transporter 1 (GLUT1) Deficiency

• Presentation: Epilepsy (absence, myoclonus), ataxia, intermittent dyskinesia.
• Key Investigations:
  • CSF glucose, low CSF/blood glucose ratio (0.19–0.49).
  • Normal/low lactate.
• Treatment: Ketogenic diet.

11. Hashimoto Encephalopathy

• Presentation: Seizures, stroke-like episodes, hallucinations.
• Key Investigations: Anti-thyroperoxidase (anti-TPO) antibodies.
• Treatment: Corticosteroids.

12. Hyperekplexia

• Presentation: Neonatal apnoeas, stiffness, exaggerated startle reflex.
• Key Investigations: Video surface EMG, GLRA1, or SLC6A5 mutations.
• Treatment: Clonazepam.

13. Pyridoxine-Dependent Epilepsy

• Presentation: Neonatal or infantile polymorphous seizures.
• Key Investigations:
  • Pyridoxine trial, urine α-AASA ↑.
  • Antiquitin (ALDH7A1) mutation analysis.
• Treatment: Pyridoxine or pyridoxal phosphate.

14. Pyruvate Dehydrogenase (PDH) Deficiency

• Presentation: Mitochondrial-like symptoms, episodic ataxia, dystonia.
• Key Investigations:
  • MRI: Globus pallidus signal changes.
  • CSF lactate/pyruvate ratio low.
• Treatment: Ketogenic diet.

15. Vitamin E Deficiency

• Presentation: Ataxia, neuropathy, retinopathy, spinocerebellar symptoms.
• Key Investigations: Blood vitamin E levels.
• Treatment: Vitamin E supplementation.

16. Wilson Disease

• Presentation: Behavioral changes, extrapyramidal symptoms, Kayser-Fleischer rings.
• Key Investigations:
  • Serum ceruloplasmin ↓.
  • Urine and plasma copper levels ↑.
  • ATP7B gene mutation analysis.
• Treatment: D-penicillamine, zinc, or trientine.

Conclusion

Early recognition and targeted treatment of these conditions are critical to preventing irreversible damage and ensuring optimal outcomes. This guide emphasizes the importance of clinical suspicion, appropriate investigations, and prompt therapeutic intervention.