Hartnup Disease
Overview
Plain-Language Overview
Hartnup disease is a rare genetic disorder that affects the body's ability to absorb certain amino acids, especially tryptophan, from the intestines and kidneys. This leads to a deficiency of these important building blocks in the body. People with Hartnup disease may experience symptoms like skin rashes, especially after sun exposure, and neurological problems such as difficulty walking or mood changes. The condition is caused by mutations in a gene responsible for transporting amino acids. Although symptoms can vary widely, many individuals live normal lives with proper management.
Clinical Definition
Hartnup disease is an autosomal recessive disorder characterized by defective transport of neutral amino acids, particularly tryptophan, across the epithelial cells of the renal tubules and small intestine. This defect results from mutations in the SLC6A19 gene, which encodes a sodium-dependent neutral amino acid transporter. The impaired absorption and reabsorption lead to increased urinary excretion of neutral amino acids and decreased plasma levels, causing systemic deficiency. Clinically, patients may present with pellagra-like dermatitis, cerebellar ataxia, and psychiatric symptoms due to niacin deficiency secondary to tryptophan loss. Diagnosis is supported by aminoaciduria with elevated neutral amino acids in urine and low plasma levels. The disease manifests typically in childhood or adolescence, with variable expressivity. Treatment focuses on niacin supplementation and sun protection to prevent photosensitive rash. The pathophysiology highlights the importance of amino acid transport in maintaining metabolic homeostasis and neurological function.
Inciting Event
- Symptoms often worsen with sun exposure due to photosensitivity.
- Periods of stress, illness, or poor nutrition can precipitate clinical manifestations.
Latency Period
- none
Diagnostic Delay
- Symptoms can be mistaken for pellagra or other dermatologic conditions, delaying diagnosis.
- Lack of awareness of the rare genetic disorder may contribute to delayed recognition.
Clinical Presentation
Signs & Symptoms
- Photosensitive dermatitis resembling pellagra.
- Cerebellar ataxia and neuropsychiatric symptoms such as anxiety or depression.
- Diarrhea and other gastrointestinal disturbances.
History of Present Illness
- Patient presents with a photosensitive rash on sun-exposed areas, often resembling pellagra.
- Neurologic symptoms such as ataxia, tremor, or psychiatric disturbances may be present.
- Episodes of diarrhea and failure to thrive can also be reported.
Past Medical History
- History of recurrent dermatitis or unexplained neurologic symptoms may be relevant.
- Previous episodes of diarrhea or malabsorption could be noted.
Family History
- Positive family history of similar cutaneous or neurologic symptoms suggests autosomal recessive inheritance.
- Consanguineous parents increase the risk of affected offspring.
Physical Exam Findings
- Presence of a photosensitive rash resembling pellagra, often on sun-exposed areas.
- Ataxia due to cerebellar involvement may be observed.
- Emotional lability or mild neurological deficits can be present.
Diagnostic Workup
Diagnostic Criteria
Diagnosis of Hartnup disease is established by detecting increased urinary excretion of neutral amino acids, especially tryptophan, alongside low plasma levels of these amino acids. Clinical features such as photosensitive dermatitis and neurological symptoms support the diagnosis. Genetic testing confirming mutations in the SLC6A19 gene provides definitive evidence. Laboratory findings exclude other causes of aminoaciduria, and response to niacin supplementation may aid in diagnosis.
Pathophysiology
Key Mechanisms
- Hartnup disease is caused by a defect in the neutral amino acid transporter in the renal and intestinal epithelial cells, leading to impaired absorption of amino acids like tryptophan.
- The decreased absorption of tryptophan results in reduced synthesis of niacin (vitamin B3), causing symptoms similar to pellagra.
- Excess neutral amino acids are excreted in the urine due to defective renal reabsorption.
| Involvement | Details |
|---|---|
| Organs | Small intestine is the primary organ affected by defective amino acid absorption in Hartnup disease. |
| Skin manifests photosensitive dermatitis due to secondary niacin deficiency. | |
| Brain may be affected causing neurological symptoms like ataxia and psychiatric disturbances. | |
| Tissues | Intestinal mucosa is the site of defective neutral amino acid transport in Hartnup disease. |
| Epidermal tissue shows photosensitive rash due to niacin deficiency. | |
| Cells | Enterocytes are intestinal cells responsible for amino acid absorption, defective in Hartnup disease. |
| Keratinocytes in the skin are affected by niacin deficiency leading to photosensitive dermatitis. | |
| Chemical Mediators | Tryptophan is an essential amino acid whose absorption is impaired in Hartnup disease. |
| Niacin (Vitamin B3) deficiency results from impaired tryptophan absorption causing pellagra-like symptoms. |
Treatment
Pharmacological Treatments
Niacin (Vitamin B3)
- Mechanism: Replenishes deficient niacin due to impaired tryptophan absorption
- Side effects: flushing, gastrointestinal upset, hepatotoxicity
Tryptophan supplementation
- Mechanism: Provides precursor to niacin and serotonin to bypass defective absorption
- Side effects: nausea, headache
Non-pharmacological Treatments
- A high-protein diet helps to increase amino acid availability.
- Avoidance of excessive sun exposure to prevent photosensitive skin rash.
- Regular nutritional monitoring to detect and manage deficiencies early.
Prevention
Pharmacological Prevention
- Oral niacin or nicotinamide supplementation to prevent pellagra symptoms.
- High-dose vitamin B6 may be used to support amino acid metabolism.
Non-pharmacological Prevention
- Avoidance of excessive sun exposure to reduce photosensitive rash.
- Diet rich in protein to ensure adequate intake of neutral amino acids.
Outcome & Complications
Complications
- Severe niacin deficiency leading to pellagra with dementia and diarrhea.
- Progressive neurological impairment including ataxia and cognitive decline.
| Short-term Sequelae | Long-term Sequelae |
|---|---|
|
|
Differential Diagnoses
Hartnup Disease versus Cystinuria
| Hartnup Disease | Cystinuria |
|---|---|
| Neutral aminoaciduria including tryptophan, not cystine predominance. | Cystine kidney stones due to impaired renal reabsorption of cystine. |
| Photosensitive dermatitis and neuropsychiatric symptoms due to niacin deficiency. | Positive cyanide-nitroprusside test indicating cystine presence in urine. |
| No cystine stones or positive cyanide-nitroprusside test. | No pellagra-like rash or neurological symptoms. |
Hartnup Disease versus Kwashiorkor
| Hartnup Disease | Kwashiorkor |
|---|---|
| Neutral aminoaciduria with defective amino acid transport in kidneys and intestines. | Edema and hypoalbuminemia due to protein malnutrition. |
| Photosensitive rash and neuropsychiatric symptoms due to niacin deficiency secondary to tryptophan loss. | Fatty liver and growth retardation in malnourished children. |
| Normal serum albumin levels without generalized edema. | No aminoaciduria or specific defects in amino acid transport. |
Hartnup Disease versus Pellagra
| Hartnup Disease | Pellagra |
|---|---|
| Neutral aminoaciduria due to defective intestinal and renal absorption of amino acids. | Dermatitis in sun-exposed areas with a characteristic Casal necklace pattern. |
| Photosensitive rash resembling pellagra but associated with amino acid transport defect. | Diarrhea and dementia as part of the classic triad. |
| Elevated urinary excretion of tryptophan and other neutral amino acids. | Niacin deficiency due to dietary lack or malabsorption. |