Are You Confident of the Diagnosis?
Hartnup disease is an autosomal recessive disorder of amino acid transport manifested with childhood onset of intermittent attacks (usually in the spring/early summer) of photosensitive dermatitis and neurologic symptoms: ataxia, spasticity, photophobia and personality and mood changes.
What you should be alert for in the history
Be alert for episodic deterioration of photosensitive rash and neurologic manifestations of cerebellar ataxia, photophobia, migraine headaches, emotional instability usually precipitated by a low-protein diet or febrile illness; develops after sun exposure, lasts up to 4 weeks and subsides.
Characteristic findings on physical examination
Findings include dry, scaly pellagra-like eruptions resembling eczema or malar rash of lupus erythematosus on light-exposed areas: forehead, cheeks, periorbital area, dorsal aspects of the hands, etc. (Figure 1, Figure 2). The lesions leave long-lasting hypo- and hyperpigmentation that intensifies on sun exposure. Sometimes vesicles and bullae develop. Gingivitis, stomatitis, and glossitis suggest niacin deficiency. Intermittent cerebellar ataxia, wide-based gate, spasticity, and headaches are common as are nystagmus, double vision and photophobia. Personality and mood changes, emotional instability may develop.
Expected results of diagnostic studies
Neutral aminoaciduria on urine chromatography is diagnostic, while excretion of proline, hydroxyproline and arginine remains normal. Urinary indoxyl derivatives (like 5-hydroxy-indol-acetic acid) may be demonstrated following the tryptophan load. Jejunal and skin biopsy is indicated in selected patients. Histopathology of the skin reveals pellagra-like features (hyperkeratosis with parakeratosis, epidermal atrophy, hyperpigmentation of the basal layer, mild superficial dermal infiltrate) and is not diagnostic.
Neutral aminoaciduria on urine chromatography is diagnostic. Ataxia-telangiectasia and other ataxias with biochemical and genetic defects can be a diagnostic difficulty, especially in patients with mild skin involvement. Indicanuria is also present in other inborn errors of metabolism like phenylketonuria. Misdiagnosis of nutritional pellagra is ruled out by performing urine chromatography.
Systemic lupus erythematosus should be ruled out with appropriate testing if clinically suspected. Cockayne syndrome is also manifested with photosensitivity and neurological symptomatology, but without gross aminoaciduria. Infantile atopic and seborrheic eczema are not accompanied with neurological symptomatology.
Who is at Risk for Developing this Disease?
With an overall prevalence of 1/24,000 population, Hartnup disease is among the most common aminoacidurias. There is no sex or racial predilection. Usually it starts between 3-9 years, and most patients remain asymptomatic. Low-protein diet, malnutrition, febrile illness, sulfonamides, possibly emotional stress, and increased physical activity can provoke attacks and increase the number and severity of the attacks. Exacerbations are common in spring or early summer after sun exposure.
What is the Cause of the Disease?
This is a heterogenic autosomal recessive disorder caused by mutations in SLC6A19 gene that encodes the B0AT1 neutral amino acid transporter. Mutation causes failure of the transport of neutral aminoacids (ie, glutamine, valine, phenylalanine, leucine, asparagine, citrulline, isoleucine, threonine, alanine, serine, histidine, tyrosine, tryptophan) in the small intestine and the renal tubules, including tryptophan, which is thought to be one of the key mediators of nonrenal symptoms.
Inefficient transport of tryptophan leads to niacin deficiency, since approximately half of the nicotinamide adenine dinucleotide phosphate (NADPH) synthesis in humans is generated though tryptophan. The photosensitivity which is manifested is likely caused by decrease in NADPH which is necessary for detoxyfication of reactive oxygene species, similarly to pellagra.
Also, neutral amino acids that are not transported are retained within the intestinal lumen where they are converted by bacteria to indolic compounds that can be toxic to the central nervous system. Indole is converted to indican in the liver, where it is conjugated and transported to the kidneys for excretion (i.e. indicanuria).
Systemic Implications and Complications
Neurologic (ataxia, spasticity, nystagmus, photophobia) and psychiatric (anxiety, emotional instability, mood and personality changes) symptoms rarely lead to psychotic episodes, delirium and coma. Consultation with a neurologist and/or psychiatrist for symptomatic therapy is indicated.
In malnourished patients, skin changes can be severe with a vesicullobullous rash on light-exposed areas. A high-protein diet, niacin supplementation and sun protection are essential for the treatment and prevention of attacks, after establishing the diagnosis with urine chromatography.
Urine chormatography is prepared from the first morning clean-catch urine sample for screening and 24-h urine for determining specific amino acids. It is necessary for the child to be at least 6 weeks old and to be protein fed in the 48 h before the test. Also, information about the medicines that has been taken before the test and medicines that have been taken by the mother in breast-fed infants should be obtained and passed to the laboratory. After tryptophan load with 70mg of L-tryptophan per kg of body weight orally, increased excretion of indoxyl deriatives in urine may be demonstrated, but this is seldomly used.
Nicotinic acid or nicotinamide 50-300mg per day
Neurologic and psychiatric symptomatic therapy
Sun protection with avoidance of sun exposure, protective clothing and use of SPF>15 broad-spectrum sunscreen.
Optimal Therapeutic Approach for this Disease
A high-protein diet and nicotinic acid (or nicotinamide) 50-300mg/day provide relief from both the what and neurologic manifestations. Taking aspirin 30-60 minutes before nicotinic acid may alleviate niacin-induced flushing and itching. Neurologic and psychiatric symptomatic therapy is needed based on predominant manifestations.
A high-protein diet and regular intake of proteins (milk, meat, eggs), niacin supplementation, sun protection and avoidance of sulfonamides, other photosensitizing drugs, and exhausting physical activity is necessary for prevention of attacks.
Regular follow-ups are needed to monitor frequency and severity of attacks and relation to food intake, and should be scheduled as needed. Regular intake of proteins (milk, meat, eggs), niacin supplementation and sun protection reduce the number and severity of attacks. Avoidance of excessive exposure to sunlight, protective clothing, hats and eyewear and broad-spectrum SPF>15 sunscreen and avoidance of aggravating factors (photosensitizing drugs, sulfonamides, exhausting physical exercise, emotional stress) is advisable. Prompt treatment of febrile illness, especially if accompanied with diarrhea, is needed.
Unusual Clinical Scenarios to Consider in Patient Management
Rarely the disease can present as early as 10 days after birth. Also one case of Hartnup disease presented for the first time in an adult female after prolonged lactation and increased physical acitivity; another case in an adult Japanese male presented with neurologic symptoms and neutral aminoaciduria without skin changes. One child with a widespread eruption resembling acrodermatitis enteropathica was also described.
Severe exfoliative erythema of malnutrition was described in a patient with coexistent coeliac disease and Hartnup disease. Rarely psychotic episodes with delirium and coma are described, as well as the lethal outcome due to the severe central nervous system involvement. Mental retardation and short stature are not common, but can develop.
What is the Evidence?
Baron, DN, Dent, CE, Harris, H, Hart, EW, Jepson, JB. “Hereditary pellagra-like skin rash with temporary cerebellar ataxia, constant renal amino-aciduria, and other bizzare biochemical features”. Lancet. vol. 271. 1956. pp. 421-8. (Denis N. Baron and coauthors described for the first time the disease with pellagra-like skin rash, cerebellar ataxia and renal aminoaciduria in the Hartnup family of London.)
Kleta Romeo, E, Ristic, Z. “mutations in SLC6A10, encoding B0AT1, cause Hartnup disorder”. Nat Genet. vol. 36. 2004. pp. 999-1002. (Kleta and coworkers were among the first groups of authors to publish results on the identification of the neutral aminoacid transporter B0AT (SLC6A19) and its gene mutation as the cause of Hartnup disorder.)
Seow, HF, Broer, S, Broer, A. “Hartnup disorder is caused by the mutations in the gene encoding the neutral amino acid transporter SLC6A19”. Nat Genet. 2004. pp. 1003-7. (In the same volume of Nature Genetics, Broer and coworkers published the results of the other group that identified B0AT neutral aminoacid transporter and its mutation in Hartnup disorder.)
Azmanov, DN, Kowalczuk, S, Rodgers, H. “Further evidence for allelic heterogeneity in Hartnup disorder”. Hum Mutat. vol. 29. 2008. pp. 1217-21. (In their study on SLC6A19 mutations in seven families with Hartnup disorder, the authors demonstrate the allelic heterogeneity of Hartnup disorder and that two mutated alleles are necessary for characteristic aminoaciduria.)
Milovanovic, DD. “A clinicobiochemical study of tryptophan and other plasma and urinary aminoacids in the family with Hartnup disease”. Adv Exp Med Biol. vol. 527. 2003. pp. 325-35. (Polymorphous clinical manifestations and their relation to plasma and urine aminoacid analysis were described in one family with Hartnup disorder.)
Levy, H, Scriver, CR, Beaudet, AL, Sly, WS, Valle, D. “Hartnup disorder”. The metabolic and molecular bases of inherited diseases. 2001. pp. 4957-69. (The metabolic aspects and clinical manifestations of Hartnup disorder are presented in detail in this chapter.)
Stojanov, Lj, Karadaglic, Dj, Karadaglic, Dj. “Skin changes in children with inborn errors of aminoacid metabolism”. Dermatology. 2000. pp. 1505-12. (In this chapter of a dermatology textbook (in Serbian) Hartnup disorder was described, among other diseases of inborn errors of aminoacid metabolism.)
Oakley, A, Wallace, J. “Hartnup disease presenting in an adult”. Clin Exp Dermatol. vol. 19. 1994. pp. 407-8. (This article reports a female adult patient in whom clinical manifestations of Hartnup disorder manifested for the first time in life after prolonged lactation and increased physical activity. This case highlights the facts that the majority of patients are asymptomatic, and that malnutrition, febrile illness etc are necessary for disease manifestations.)
Seyhan, ME, Selimoglu, MA, Ertekin, V, Fidanoglu, O, Altinkaynak, S. “Acrodermatitis enteropathica-like eruptions in a child with Hartnup disease”. Pediatr Dermatol. vol. 23. 2006. pp. 262-5. (Acrodermatitis enteropathica-like eruption, which is described in other metabolic disorders and not linked to zinc deficiency, is described in a patient with Hartnup disorder, which is known for its variable presentation.)
Sander, CS, Hertecant, J, Abdulrazzaq, YM, Berger, TG. “Severe exfoliative erythema of malnutrition in a child with coexisting coeliac and Hartnup’s disease”. Clin Exp Dermatol. vol. 34. 2009. pp. 178-82. (Severe exfoliative erythema of malnutrition developed in a child with coexistent coeliac and Hartnup disease. A high-protein gluten-free diet was sufficient for rapid improvement of the skin condition.)
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