Hartnup Disease
Genetics & Metabolism
Illness script · Genetics & Metabolism
Hartnup Disease
Autosomal recessive defect in neutral amino acid transport (SLC6A19) causing tryptophan malabsorption and pellagra-like syndrome.
This illness script for Hartnup Disease covers predisposing factors, classic presentation, mechanism, workup, management, and the clinical pivots that separate it from look-alikes—written for USMLE Step 1 and clerkship reasoning.
01
Predisposing factors
- Autosomal recessive; SLC6A19 gene mutation
- Children and young adults most commonly affected
- Poor nutritional status / low-protein diet unmasks symptoms
- Triggers: sun exposure, febrile illness, stress, sulfonamide use
- Higher prevalence in Northern European populations
02
Presentation
- Classic triad: photosensitive rash, cerebellar ataxia, neuropsychiatric symptoms
- Rash: erythematous, scaly, casal-collar–like distribution in sun-exposed areas
- Cerebellar ataxia: intermittent gait instability, nystagmus, tremor
- Neuropsychiatric: emotional lability, depression, frank psychosis
- Episodes are intermittent; triggered by sun, stress, illness, or low protein intake
- Neutral aminoaciduria with normal plasma amino acid levels (transport, not metabolic defect)
03
Pathophysiology
- SLC6A19 transporter defect impairs neutral amino acid absorption in gut epithelium and renal tubule reabsorption
- Tryptophan, the main precursor to niacin (B3), is severely depleted → functional niacin deficiency
- Unabsorbed tryptophan catabolized by gut bacteria → indole compounds excreted in urine (indicanuria)
- Net result: pellagra-like state despite adequate dietary niacin intake
04
Diagnostics
- Urine amino acid analysis: elevated neutral amino acids (tryptophan, alanine, serine, leucine, phenylalanine, histidine, etc.)
- Key pearl: plasma amino acids are NORMAL — defect is in transport, not catabolism
- Elevated urine indican (indoxyl sulfate) from bacterial tryptophan degradation
- Genetic testing: SLC6A19 pathogenic variants confirm diagnosis
- Pitfall: do not mistake for Fanconi — Hartnup has selective neutral aminoaciduria, not pan-aminoaciduria
05
Management
- Nicotinamide (niacin) supplementation 40–200 mg/day — bypasses tryptophan-dependent niacin synthesis
- High-protein diet to saturate defective transporter and maximize amino acid uptake
- Strict sun protection and avoidance of known triggers
- Avoid low-protein diets, sulfonamides, and prolonged febrile states
- Prognosis is excellent with treatment; episodes remit in adulthood as diet improves
06
Clinical pivots
How to separate this script from the look-alikes that show up on exams and on the wards.
Pellagra (dietary niacin deficiency)
Pellagra has normal urine amino acids and responds to diet/niacin alone; Hartnup shows selective neutral aminoaciduria regardless of diet.
Fanconi Syndrome
Fanconi causes pan-aminoaciduria plus glucosuria and phosphaturia; Hartnup is limited to neutral amino acids with no other tubular dysfunction.
Spinocerebellar ataxia / other cerebellar disorders
Hartnup uniquely pairs episodic cerebellar ataxia with photosensitive rash and neutral aminoaciduria — no other ataxia does this.
Biotinidase deficiency
Biotinidase deficiency causes a similar rash and neurologic features but presents with organic aciduria and responds to biotin, not niacin.
Keep reading
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Educational use only. This illness script is a study framework, not medical advice. Confirm decisions with current guidelines and your clinical supervisors.