What are the aspects of Hartnup disease management and treatment?

Hartnup Disease: Diagnosis, Management, and Treatment

Hartnup disease is a rare autosomal recessive disorder characterized by impaired neutral amino acid transport in the intestines and kidneys that requires treatment with nicotinamide supplementation and a high-protein diet to prevent neurological complications and improve quality of life.

Pathophysiology

Hartnup disease results from mutations in the SLC6A19 gene (located on chromosome 5p15), which encodes the B⁰AT1 transporter responsible for neutral amino acid transport across epithelial cells in the intestines and kidneys 1. This defect leads to:

• Impaired absorption of neutral amino acids in the intestine
• Excessive urinary excretion of neutral amino acids (characteristic aminoaciduria)
• Reduced availability of tryptophan, a precursor for niacin (vitamin B3) synthesis
• Subsequent niacin deficiency that manifests as pellagra-like symptoms

Clinical Presentation

Hartnup disease has variable clinical manifestations that typically appear in childhood but can manifest at any age:

Common Symptoms

• Skin manifestations: Photosensitive pellagra-like rash on sun-exposed areas (face, neck, hands)
• Neurological symptoms:
  • Cerebellar ataxia
  • Tremor
  • Myoclonic jerks
  • Nystagmus
  • Spastic paresis with hyperreflexia and Babinski signs 2
• Psychiatric manifestations:
  • Emotional instability
  • Anxiety
  • Depression
  • Psychosis
  • Cognitive impairment 3

Disease Course

• Symptoms are often intermittent and can be triggered by:
  • Poor nutrition
  • Psychological stress
  • Physical illness
  • Fever
  • Sun exposure
  • Sulfonamide medications

Atypical Presentations

• Some patients may present with primarily neuropsychiatric symptoms without skin manifestations 3
• Adult-onset cases may present with bruxism, ataxia, and psychiatric symptoms 3

Diagnosis

Laboratory Findings

1. Urine amino acid analysis: Characteristic neutral aminoaciduria (increased excretion of alanine, serine, threonine, asparagine, glutamine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, and histidine)
2. Blood tests:
   • Low serum tryptophan levels (<50% of normal values, approximately 20 μM) 4
   • Normal or slightly reduced plasma amino acid levels
3. Cerebrospinal fluid analysis:
   • Reduced tryptophan levels
   • Decreased 5-hydroxyindoleacetic acid (5-HIAA, a serotonin metabolite) 4

Genetic Testing

• Molecular genetic testing for mutations in the SLC6A19 gene confirms the diagnosis
• Most affected individuals are compound heterozygotes with different mutations 1

Treatment

Nutritional Management

1. High-protein diet:

   • Ensure adequate protein intake (1-1.5 g/kg/day)
   • Emphasize complete protein sources (meat, eggs, dairy)
   • Compensates for intestinal amino acid malabsorption 1

2. Nicotinamide supplementation:

   • Dosage: 50-300 mg daily (depending on age and symptom severity)
   • Addresses the niacin deficiency
   • Resolves skin rash and neurological symptoms 2

3. Tryptophan supplementation:

   • For cases with persistent symptoms despite nicotinamide
   • Consider tryptophan ethyl ester (20 mg/kg every 6 hours) which bypasses the defective intestinal transport 4
   • Normalizes serum and CSF tryptophan levels
   • Improves CSF 5-HIAA concentrations
   • May resolve chronic diarrhea and improve weight gain 4

Symptomatic Management

• Avoidance of trigger factors:
  • Sun protection for photosensitive skin
  • Stress reduction
  • Avoidance of sulfonamide medications
  • Prompt treatment of intercurrent infections

Monitoring

• Regular assessment of:
  • Neurological symptoms
  • Skin manifestations
  • Growth parameters in children
  • Serum tryptophan levels (when available)
  • Urine amino acid patterns

Prognosis

• With appropriate treatment, most patients have a good prognosis
• Untreated cases may develop progressive neurological deterioration
• Pathological findings in severe cases include:
  • Diffuse cerebral atrophy
  • Generalized neuronal loss in the cortex
  • Purkinje cell loss in the cerebellum 5

Special Considerations

Genetic Counseling

• Autosomal recessive inheritance pattern
• 25% risk of affected offspring when both parents are carriers
• Genetic testing should be offered to family members of affected individuals

Pregnancy

• Increased protein requirements during pregnancy may exacerbate symptoms
• Close monitoring and potential adjustment of nicotinamide dosage during pregnancy

Clinical Pearls

• Hartnup disease should be considered in patients with intermittent neuropsychiatric symptoms and/or pellagra-like rash
• Not all patients present with the classic triad of dermatitis, cerebellar ataxia, and psychiatric disturbances
• Adult-onset cases may present with primarily neuropsychiatric manifestations
• Symptoms may be precipitated by poor nutrition, stress, or illness
• Treatment with nicotinamide and a high-protein diet is usually effective in controlling symptoms
• Tryptophan ethyl ester is a promising treatment option for refractory cases