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Dermatology > PEDIATRIC DISEASES
Hartnup Disease
Article Last Updated: Sep 20, 2006
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Lidija Kandolf Sekulovic, MD, PhD, Consulting Staff, Department of Dermatology and Venereology, Military Medical Academy, Belgrade
Coauthor(s):
Djordjije Karadaglic, MD, DSc, Professor, School of Medicine, University of Podgorica, Podgorica, Montenegro;
Ljubomir Stojanov, MD, PhD, Mother and Child Health Care Institute, Professor, Department of Metabolic and Genetic, University of Belgrade School of Medicine, Serbia
Editors: Mark A Crowe, MD, Assistant Clinical Instructor, Department of Medicine, Division of Dermatology, University of Washington School of Medicine; David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Director, Division of Dermatology, Scott and White Clinic; Director Dermatology Residency Training Program, Scott and White Clinic; Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School; Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University; William D James, MD, Paul R Gross Professor of Dermatology, University of Pennsylvania School of Medicine; Vice-Chair, Program Director, Department of Dermatology, University of Pennsylvania Health System
Author and Editor Disclosure
Synonyms and related keywords:
Hartnup disorder, Hartnup aminoaciduria, Hartnup syndrome, MIM #234500, Mendelian Inheritance in Man #234500
Background
Hartnup disease is an autosomal recessive disorder caused by defective transport of neutral (ie, monoaminomonocarboxylic) amino acids in the small intestine and the kidneys. Patients present with a pellagralike skin eruptions, cerebellar ataxia, and gross aminoaciduria.
In 1956, Baron et al described the disorder in the Hartnup family of London; 4 of the 8 family members presented with aminoaciduria, a skin rash resembling pellagra, and cerebellar ataxia.
Hartnup disease is inherited as an autosomal recessive trait. Heterozygotes are normal. Consanguinity is common. In 2004, a causative gene, SLC6A19, was located on band 5p15.33. SLC6A19 is a sodium-dependent and chloride-independent neutral amino acid transporter, expressed predominately in the kidneys and intestine.
Pathophysiology
In 2001, homozygosity mapping by Nozaki et al in consanguineous Japanese pedigrees demonstrated linkage of Hartnup disorder to band 5p15. A gene survey of 5p15 revealed several members of the SLC6 family comprising transporters for neurotransmitters, osmolytes, and amino acids, and linkage analysis in 7 Australian families narrowed the region to 7cM on 5p15.33 containing SLC6A18 and SLC6A19. Cloning and expression of the mouse SLC6A19 gene demonstrated that this transporter has all the properties of the amino-acid transport system B0AT1.
The human SLC6A19 gene was cloned independently by 3 groups of researchers in 2004 (Kleta et al and aSeow et al). It has the same transporter properties and expression pattern as the mouse transporter. Both studies demonstrated that mutations in SLC6A19 are associated with Hartnup disorder. The requirement for 2 transport-impairing mutations for disease expression confirmed a recessive mode of inheritance.
Mutations in SLC6A19 gene, which encodes the B0AT1 neutral amino-acid transporter, causes a failure of the transport of neutral (ie, monoaminomonocarboxylic) amino acids in the small intestine and the renal tubules. The B0AT1 transporter is a Na+-dependent, Cl--independent system and transports all neutral amino acids in the following order: Leu=Val=Ile=Met –> Gln=Phe=Ala=Ser=Cys=Thr –> His=Trp=Tyr=Pro=Gly.
Although tryptophan is transported by this transporter rather inefficiently, it is thought to be one of the key substrates in the development of the nonrenal symptoms of Hartnup disorder. Tryptophan is converted in the liver to niacin, and approximately half of the nicotinamide adenine dinucleotide phosphate (NADPH) synthesis in humans is generated through tryptophan. As a result, tryptophan and niacin deficiencies generate similar symptoms. In addition, symptoms in persons with Hartnup disorder quickly respond to nicotinic acid supplementation.
Amino acids are retained within the intestinal lumen, where they are converted by bacteria to indolic compounds that can be toxic to the CNS. Tryptophan is converted to indole in the intestine. Following absorption, indole is converted to 3-hydroxyindole (ie, indoxyl, indican) in the liver, where it is conjugated with potassium sulfate or glucuronic acid. Subsequently, it is transported to the kidneys for excretion (ie, indicanuria). Other tryptophan degradation products, including kynurenine and serotonin, are also excreted in the urine. Tubular renal transport is also defective, contributing to gross aminoaciduria. Neutral amino acids are also found in the feces.
Resorption of the peptides may partially compensate for the lack of amino acid transport in persons with Hartnup disorder, and thus phenotypic variability is wide, which may result from a number of factors: differential resorption, allelic and genetic heterogeneity, modifier genes, and dietary intake. Most of the patients remain asymptomatic, and it has been suggested that Hartnup phenotype becomes apparent when environmental or genetic factors predispose individuals to a lack of amino acid uptake. Oakley and Wallace reported a case of Hartnup disease in an adult, with the first appearance of symptoms after prolonged lactation and increased physical activity.
Frequency
United States
Levy et al found that the incidence of Hartnup disease in Massachusetts is 1 case per 14,219 births, approximately the same incidence as that of phenylketonuria.
International
Hartnup defect, with an overall prevalence of 1 case per 24,000 population (range, 1 case per 18,000-42,000 population), ranks among the most common amino acid disorders in humans.
Mortality/Morbidity
Hartnup disease is manifested by a wide clinical spectrum. Most patients remain asymptomatic, but, in a minority of patients, skin photosensitivity and neurologic and psychiatric symptoms may have a considerable influence on their quality of life. Rarely, severe CNS involvement may lead to death. Mental retardation and short stature have been described in few patients. Malnutrition and a low-protein diet are the primary factors that contribute to morbidity.
Race
No racial predilection is recognized for Hartnup disease.
Sex
No sexual predilection has been reported for Hartnup disease.
Age
The onset of Hartnup disease is in childhood, usually in children aged 3-9 years, but it may present as early as 10 days after birth. In addition, a case of Hartnup disease presenting for the first time in an adult female, after prolonged lactation and increased physical activity, is described.
History
Hartnup disease is manifested by a wide clinical spectrum (see Physical for a complete discussion of the clinical signs).
- Most children with the Hartnup defect remain asymptomatic.
- In Australia, an 8-year follow-up study of 12 patients found only 2 clinical episodes that may be ascribed to Hartnup disease; mental development of all of the children was normal. In the United States, a full-blown picture of the disorder is rarely seen, probably because the diet of US residents is adequate.
- Patients who are symptomatic present with episodic deterioration of neurologic and dermatologic manifestations. Symptoms progress over several days and last for 1-4 weeks before spontaneous remission occurs.
- Cutaneous signs usually precede the neurologic manifestations.
- Psychiatric symptoms (eg, anxiety, emotional instability, mood changes) are common in patients who are symptomatic. Psychotic episodes and delirium are rarely seen.
Physical
- Skin
- Photosensitivity occurs (see Image 1). The skin reddens after exposure to sunlight (see Image 2). Further exposures lead to the development of dry, scaly, well-marginated eruptions, sometimes resembling chronic eczema. This eruption preferentially affects the forehead, the cheeks, the periorbital regions, the dorsal surfaces of the hands, and other light-exposed areas.
- Lesions on the face may resemble the malar rash of lupus erythematosus.
- A vesiculobullous eruption with exudation may occur.
- Skin changes leave long-lasting hypopigmentation and/or hyperpigmentation, which are intensified with further sunlight exposure.
- Central nervous system
- Mental development is normal in most patients, but mental retardation (intelligence quotient of 50-70) is described in a few patients. Of 1087 patients screened for the detection of inherited metabolic diseases from the Alexandra Institute for persons with mental retardation in Cape Town, Hartnup disease was found in only 1 patient.
- Neurologic symptoms may vary and are fully reversible. Intermittent cerebellar ataxia, a wide-based gait, spasticity, delayed motor development, and tremulousness are the most frequent findings. Headaches and hypotonia may also occur.
- Ocular manifestations include double vision, nystagmus, photophobia, and strabismus.
- Gingivitis, stomatitis, and glossitis suggest niacin deficiency.
- Diarrhea occasionally precedes or follows attacks of the disease.
- Short stature has been described. Wilcken et al found that of 14 patients with Hartnup disorder who were observed for 8 years, 10 had height percentiles less than the midparent height percentiles, while 4 had percentiles equal to or above the midparent percentiles.
Causes
Exacerbations are seen most frequently in the spring or early summer after exposure to sunlight. The attacks may be provoked by a febrile illness, poor nutrition, sulfonamides, and possibly emotional stress and increased physical activity.
Ataxia-Telangiectasia
Hydroa Vacciniforme
Pityriasis Alba
Xeroderma Pigmentosum
Other Problems to be Considered
Skin rash
Infantile atopic eczema
Seborrheic eczema
Nutritional pellagra (Misdiagnosis can be prevented by performing urine chromatography.)
Congenital poikilodermas with photosensitivity (eg, Cockayne syndrome)
Malar rash of lupus erythematosus
Carcinoid syndrome (may lead to disturbance of tryptophan metabolism and pellagralike skin rash)
Indicanuria in inborn errors of amino acid metabolism (eg, phenylketonuria, blue diaper syndrome)
Central nervous system
Ataxia-telangiectasia (can cause diagnostic difficulties, especially in patients with mild skin involvement)
Systemic lupus erythematosus (can be confused if photosensitivity with neuropsychiatric symptoms is present)
Other ataxias with biochemical and genetic defects
Lab Studies
- Urine chromatography
- Increased levels of neutral amino acids (eg, glutamine, valine, phenylalanine, leucine, asparagine, citrulline, isoleucine, threonine, alanine, serine, histidine, tyrosine, tryptophan) and indican are found in the urine.
- Urinary indoxyl derivatives (ie, 5-hydroxyindoleacetic acid) may be demonstrated following an oral tryptophan load.
- Urine excretion of proline, hydroxyproline, and arginine remains normal, which differentiates Hartnup disease from other causes of gross aminoaciduria.
- Perform urine chromatography to exclude nutritional pellagra.
- Plasma concentrations of amino acids are usually normal.
Procedures
- Jejunal biopsy may be required in selected patients (transport defect may be identified in vitro).
- Skin biopsy may be required in selected patients.
Histologic Findings
Changes in the skin are similar to those seen in pellagra. Findings are not diagnostic and include hyperkeratosis, parakeratosis, epidermal atrophy, hyperpigmentation of the basal layer, and a mild superficial dermal lymphocytic infiltrate. Bullae may be either intraepidermal or subepidermal. Hyperplasia of the sebaceous glands with follicular dilatation and plugging may occur.
Medical Care
- A high-protein diet can overcome the deficient transport of neutral amino acids in most patients. Poor nutrition leads to more frequent and more severe attacks of the disease, which is otherwise asymptomatic.
- Advise all patients who are symptomatic to use physical and chemical protection from sunlight. Avoiding excessive exposure to sunlight, wearing protective clothing, and using physical and chemical sunscreens are mandatory. Recommend sunscreens with a skin protection factor of 15 or greater.
- Advise patients to avoid other aggravating factors, such as photosensitizing drugs, as much as possible.
- In patients with niacin deficiency and symptomatic disease, daily supplementation with nicotinic acid or nicotinamide reduces the number and the severity of attacks.
- Neurologic and psychiatric treatment is needed in patients with severe CNS involvement.
Consultations
- Consult a dermatologist for diagnosis and treatment of photosensitivity and pellagralike skin rash.
- Consult an experienced neurologist for thorough follow-up monitoring and treatment of CNS involvement.
- Consult a psychiatrist to diagnose and treat psychiatric symptoms, which may vary considerably.
- Consult an ophthalmologist if ocular manifestations, which are rare, occur.
Diet
Advise patients who are symptomatic to consume a high-protein diet because it decreases the number of attacks.
Activity
Advise patients to protect themselves from sunlight. Protective clothing, hats and eyewear, and physical and chemical sunscreens provide photoprotection.
Nicotinic acid or nicotinamide (50-300 mg/d) provides relief from both the skin manifestations and the neurologic manifestations.
Administration of tryptophan ethyl ester (a lipid-soluble tryptophan metabolite) in a child with Hartnup disease at a dose of 20 mg/kg every 6 hours resulted in normalization of serum and cerebrospinal fluid tryptophan levels.
Drug Category: Vitamins
Vitamins are necessary for normal growth and development. These agents are used to replace essential vitamins not obtained in sufficient quantities in the diet or to further supplement levels.
| Drug Name | Vitamin B-3 (Niacin, Nicotinic acid, Nicotinamide) |
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| Description | Nicotinamide is more commonly recommended.
Source of niacin used in tissue respiration, lipid metabolism, and glycogenolysis. Provides relief from skin and neurologic manifestations. |
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| Adult Dose | 50-100 mg PO tid/qid; not to exceed 500 mg/d |
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| Pediatric Dose | 50-100 mg/dose PO tid |
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| Contraindications | Documented hypersensitivity; active liver disease or unexplained significant increases in AST and ALT levels; large doses of niacin, especially when administered in SR form (associated with severe hepatotoxicity, peptic ulcer, severe hypotension, arterial hemorrhaging) |
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| Interactions | Cutaneous vasodilation may be problematic if high dose is used with peripheral dilators, such as nitroglycerin; decreased effect of oral hypoglycemics; may inhibit uricosuric effects of sulfinpyrazone and probenecid; decreased toxicity (flush) with aspirin; increased toxicity with lovastatin (myopathy) and possibly with other HMG-CoA reductase inhibitors; adrenergic blocking agents can have additive vasodilating effect and postural hypotension |
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| Pregnancy | A - Safe in pregnancy
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| Precautions | Caution in gallbladder disease, diabetes, and in patients predisposed to gout; monitor blood glucose levels and liver function test results; may elevate uric acid levels; pregnancy category C when used at doses greater than RDA; taking aspirin 30-60 min before first daily dose may help alleviate prostaglandin-mediated adverse effects of niacin (eg, flushing, itching); clonidine may inhibit niacin-induced flushing; some products may contain tartrazine |
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Further Outpatient Care
- Advise patients to use protection from sunlight, to avoid other aggravating factors, to consume a high-protein diet, and to take daily supplements of nicotinic acid.
- In patients who are symptomatic, recommend regular follow-up examinations, depending on the severity of symptoms and the organ systems involved.
In/Out Patient Meds
- Patients should continue taking daily supplements of nicotinic acid.
Deterrence/Prevention
- Because sun exposure can exacerbate Hartnup disease, advise patients to protect themselves from sunlight.
- Because aggravating factors, such as sulfonamides and possibly emotional stress, can exacerbate Hartnup disease, advise patients to avoid these factors.
Complications
- Severe CNS involvement may rarely lead to death in the first years of life.
- Psychotic episodes and delirium are described in a minority of patients.
- Mild mental retardation is described in only a few patients.
- Long-lasting hypopigmentation and/or hyperpigmentation of the skin are seen with repeated exposures to sunlight, which should be avoided by using proper photoprotection.
Prognosis
- Attacks become less frequent with increasing age.
Patient Education
- Educate patients to protect themselves from sunlight, to avoid other aggravating factors, and to consume a high-protein diet.
Medical/Legal Pitfalls
- Failure to diagnose and to treat Hartnup disease because of the wide clinical spectrum of the disease, especially in patients with mild skin involvement, is a pitfall.
- Failure to advise patients regarding adequate protein intake and niacin supplementation, without which remission cannot be achieved, is a pitfall.
Special Concerns
- Maternal Hartnup disease does not influence the outcome of pregnancy. Placental transport of free amino acids may not be reduced in maternal Hartnup disorder.
| Media file 1:
Photosensitivity with erythema, desquamation, and hypopigmentation and hyperpigmentation on the face. |
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Media type: Photo
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| Media file 2:
Erythema and desquamation on the sun-exposed area of the right arm. |
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Media type: Photo
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Hartnup Disease excerpt Article Last Updated: Sep 20, 2006
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